6,7-dihydro-5h-pyrazolo[1,2-a]pyrazole-1-ones (variants) inhibiting release of inflammatory cytokines, pharmaceutical composition and inhibition method

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): possessing properties of inhibitor of inflammatory cytokines release from cells. In compound of the formula (I) R is chosen from: (a) fragment of the formula -OR3 wherein R3 is chosen from group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-N-acetylaminophenyl, 2-methoxyphenyl, 4-methoxyphenyl and 3-benzo[1,3]dioxol-5-yl; (b) fragment of the formula: wherein R6 is chosen from group consisting of hydrogen atom, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy-group, 4-fluorophenyl, 2-aminophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridine-2-yl, pyridine-3-yl, or (c) fragment of the formula: wherein R6 is chosen from group consisting of hydrogen atom, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy-group, phenyl, 4-fluorophenyl, 2-aminophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridine-2-yl, pyridine-3-yl; each radical R2 is chosen independently from group consisting of (a) hydrogen atom; (b) -(CH2)jO(CH2)nR8; (c) -(CH2)jNR9aR9b; (e) -(CH2)OCO2R10; (g) -(CH2)jOCON(R10)2 wherein each radical R8, R9a, R9b and R10 represents independently hydrogen atom, (C1-C4)-alkyl; or R9a and R9b can form in common 5-6-membered heterocyclic ring comprising 1-2 heteroatoms chosen from nitrogen and/or oxygen atoms; or two radicals R10 can form in common 5-6-membered heterocyclic ring comprising 1-2 heteroatoms chosen from nitrogen and/or oxygen atoms; j represents index 0; n represents index 0. Also, invention relates to a pharmaceutical composition and a method for inhibition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 2 sch, 8 tbl, 13 ex

 

DESCRIPTION

The present invention relates to 6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-Onam, which inhibit the release of unclear inflammatory cytokines, and these cytokines are responsible for one or more of painful conditions of humans or higher mammals. The present invention also relates to compositions containing the specified 6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-ones, and to a method of prevention, elimination or control of enzymes, which are believed to represent the active components responsible for described here painful condition.

Interleukin-1 (IL-1) and factor-α tumor necrosis (TNF-α) are among the important biological substances, known together as "cytokines." These molecules are considered to mediate the inflammatory response associated with immunological detection of infectious agents.

These Pro-inflammatory cytokines are considered to be involved as important mediators in many disease States or syndromes, among other things, in rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and for this reason, responsible for the development and manifestation of painful conditions of the person.

For this reason, there is tsya felt in a long time need to compounds and pharmaceutical compositions containing compound capable to inhibit, eliminate, manage, mitigate or prevent the release of cytokines from cells that they produce.

The present invention meets the aforementioned needs in that, as unexpectedly discovered that certain bicyclic pyrazolones and their derivatives are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF)from cells and thereby prevent, control, or otherwise, of the enzymes that are supposed to be the active components responsible for described here painful condition.

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

where R represents:

a) -O (CH2]kR3; or

b) -NR4aR4b;

R3represents a substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or alkylaryl, substituted or unsubstituted heteroaryl or acceleratorkey; the index k is from 0 to 5;

R 4aand R4bare each, independently:

a) hydrogen; or

b) -[C(R5aR5b)]mR6;

each of R5aand R5brepresents, independently, hydrogen, -OR7, -N(R7)2, -CO2R7, -CON(R7)2; C1-C4linear, branched or cyclic alkyl, and mixtures thereof; R6represents hydrogen, -OR7, -N(R7)2-CO2R7, -CON(R7)2; substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted aryl heterocycle, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7represents hydrogen, a water-soluble cation, C1-C4alkyl or substituted or unsubstituted aryl; the index m is from 0 to 5;

R1represents:

a) substituted or unsubstituted aryl; or

b) substituted or unsubstituted, heteroaryl;

each radical R2independently selected from the group consisting of:

a) hydrogen;

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

c) -(CH2)jNR9aR9b;

d) -(CH2)jCO2R10;

(e) -(CH2)jOCO2R10;

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

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

h) two of the radicals R2that can be taken in the natural, forming a carbonyl group;

i) and their mixtures;

R8, R9a, R9band R10are each, independently, hydrogen, C1-C4alkyl and mixtures thereof; R9band R9bmay together form a carbocyclic or heterocyclic ring containing from 3 to 7 atoms; two of the radicals R10may together form a carbocyclic or heterocyclic ring containing from 3 to 7 atoms; j is an index from 0 to 5, n is an index from 0 to 5;

Z represents O, S, NR11or NOR11; R11represents hydrogen or C1-C4alkyl.

Another aspect of the present invention relates to pharmaceutical compositions that can deliver the compounds of the present invention to humans or higher mammals, these compositions contain:

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 a method of controlling one or more diseases or conditions mammals mediated by inflammatory cytokines or modulated by inflammatory cytokines, and this method includes a stage of introduction of the human or higher mammal efficiency the effective amount of the composition, containing one or more compounds of the present invention.

Another aspect of the present invention relates to a preparative forms of the compounds of the present invention, which, under normal physiological conditions, will release the connection, as described here.

Data and other objectives, features and advantages will become apparent to experts in this field from the following further detailed description and the accompanying claims. All percentages, ratios, and proportions given here are by weight, unless otherwise stated. All temperatures are given in degrees Celsius (° (C)if not stated otherwise. All documents cited in relevant part, incorporated here by reference; the citation of any document should not be construed as a recognition of the fact that he belongs to the modern level of technology, in relation to the present invention.

The present invention relates to compounds that are able to mediate, manage, or inhibit, otherwise, the release from cells of certain cytokines, in particular of inflammatory cytokines, and these cytokines play a role in stimulation, the appearance or manifestation of a wide variety of diseases, morbid conditions or syndromes.

In the present invention, the term "ug is avodart" is defined here as any organic fragment or residue, which consists of carbon atoms and hydrogen atoms. The term "hydrocarbon" includes heterocycles, which are described below. Examples of various unsubstituted nheterocyclic hydrocarbon radicals include pentyl, 3-atelectasis, 1,3-dimetilfenil, cyclohexyl, CIS-3-hexyl, 7,7-dimethylbicyclo[2,2,1]heptane-1-yl and naphthas-2-yl.

Included in the definition of "hydrocarbon" are 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]heptanes (norbornyl), bicyclo[0,2,4]octanol (caryophyllene), spiropentane, dicyclopentadienyl, decaline, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulene, tenantry, antril, fluorenyl, acenaphthylene, 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, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-Piran-2-IMT, Piri is inil, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinil, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepine, oxepin, 4H-1,2-diazepine, indenyl-2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, chinoline, ethenolysis, hintline, 2H-1,4-benzoxazine, pyrrolidinyl, pyrrolyl, honokalani, furanyl, thiophenyl, benzimidazolyl and the like, each of which can be substituted or unsubstituted.

An example of a radical defined as "alkylene"represents a benzyl radical, having the formula:

while the example of the radical, defined as "acceleratorkey", is a 2-picalilly radical having the formula:

The term "substituted" is used throughout the description. The term "substituted" is defined here as encompassing residues or radicals, which may substitute the hydrogen atom, two hydrogen atoms or three hydrogen atoms of the hydrocarbon residue. Also "substituted" may include the substitution of hydrogen atoms on two adjacent carbon atoms, forming a new residue or radical. For example, a substituted radical, the replacement of one hydrogen atom, and includes halogen, hydroxyl and the like. The substitution of two hydrogen atoms VK is uchet the carbonyl, oximino and the like. The substitution of two hydrogen atoms on adjacent carbon atoms includes epoxy and the like. Replacement of three hydrogen atoms include cyano and the like. Epoxy radical is an example of a substituted radical, which requires replacement of a hydrogen atom on adjacent carbon atoms. The term "substituted" is used throughout this description to indicate that hydrocarbon residue, among other things, an aromatic ring, the alkyl chain may have one or more hydrogen atoms replaced by a substituent. When the balance 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 radical"3-guanidinopropionic represents a substituted C3alkyl radical, and 2-carboxyphenyl represents a substituted heteroaryl radical". Continue following non-limiting examples of radicals, which can serve as a substitution for hydrogen atoms, when the hydrocarbon radical is described as "substituted".

i) -[C(R12)2]p(CH=CH)qR12; where p 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 C1-C20linear, branched or cyclic alkyl, C6-C20aryl, C7-C20alkylaryl and mixtures thereof; M is hydrogen or a cation forming a salt; Z represents =O, =S, =NR11and mixtures thereof. The corresponding cations, forming salts include sodium, lithium, potassium, calcium, magnesium, ammonium and the like.

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

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

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

which are 2-R1substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-thiones.

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

which are 2-R1substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-ylideneamino and their derivatives.

R represents a Deputy at the 2-position of the pyrimidine-4-ilen part of the overall structure, and specified the radical R represents:

a) simple ether having the formula-O[CH2]kR3; or

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

where R3represents a substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted cyclic hydrocarbons, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or alkylaryl, substituted or unsubstituted heteroaryl or acceleratorkey; the index k is from 0 to 5.

This is followed by various radicals R of the present invention, where R is a simple ether having the formula-O[CH2]kR3. However, the manufacturer of the drug limit the n approximations and examples presented here as illustrations.

A) the Radicals R include ethers having the formula-OR3(the index k is equal to 0), and R3represents a substituted or unsubstituted aryl.

i) In one aspect, R comprises ethers having the formula-OR3where R3represents a substituted or unsubstituted aryl and includes the following non-limiting examples of R: phenoxy, 2-fervency, 3 fervency, 4-fervency, 2,4-divergence, 3 triptoreline, 4-triptoreline, 2,4-triptoreline and the like.

ii) In another aspect, R comprises ethers having the formula-OR3where R3represents a substituted or unsubstituted aryl and 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) R includes ethers having the formula-OR3and R3represents a substituted or unsubstituted aryl, including 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 Radicals R, which includes ethers of the formula OR3(the index k is equal to 0), where R3represents for ewenny or an unsubstituted heteroaryl.

i) In the first aspect, R comprises ethers having the formula-OR3where R3represents an unsubstituted heteroaryl and 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) In the second aspect, R comprises ethers having the formula-OR3where R3represents a substituted heteroaryl and includes the following non-limiting examples: 2-aminopyrimidine-4-yl and the like.

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

i) In the first aspect, R comprises ethers having the formula-OCH2R3where R3represents a substituted or unsubstituted heteroaryl and 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) In the second aspect, R is a simple ester of the formula-OCH2R3where R3represents a substituted or unsubstituted acceleratorkey-aryl and includes the following non-limiting examples: pyridine-3-retil, (2-methyl-2-pyridin-3-yl)ethyl and the like.

D) the Radicals R, Katya is the following ethers, having the formula-OR3(the index k is equal to 1), where R3represents a substituted or unsubstituted C1-C4alkyl.

i) In the first aspect, R is a simple ether having the formula-OR3where R3represents unsubstituted C1-C4linear, branched or cyclic alkyl and includes the following non-limiting examples: methyl, ethyl, isopropyl, (S)-1-methylpropyl and the like.

ii) In the second aspect, R is a simple ether having the formula-OR3where R3represents a substituted C1-C4linear, branched or cyclic alkyl and includes the following non-limiting examples: 2-methoxyethyl, (S)-1-methyl-3-methoxypropyl and the like.

Further, other values of the radicals R in accordance with the present invention include amine having the formula-NR4aR4b, R4aand R4bare each, independently:

a) hydrogen; or

b) -[C(R5aR5b)]mR6;

each of R5aand R5brepresents, independently, hydrogen or C1-C4linear, branched, cyclic alkyl, -OR7, -N(R7)2, -CO2R7, -CON(R7)2; and mixtures thereof; R6represents hydrogen, substituted or unsubstituted C1-C4alkyl, substituted is whether the unsubstituted heterocycle, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; -OR7, -N(R7)2, -CO2R7, -CON(R7)2, R7represents hydrogen, a water-soluble cation, C1-C4alkyl or substituted or unsubstituted aryl; the index m is 0-5. However, the manufacturer of the drug is not limited by the approximations and the examples here as illustrations.

A) the Radicals R, covering the chiral amino groups, where R4arepresents hydrogen, R5arepresents hydrogen, and R5brepresents methyl, and these radicals have the formula:

and the indicated stereochemistry.

i) In the first aspect, R is an amine comprising R6that represents a substituted or unsubstituted phenyl and 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) In the second aspect, R is an amine, including R6that represents a substituted or unsubstituted heteroaryl and includes the following non-limiting examples: (S)-1-METI is-1-(pyridine-2-yl)methylamino, (S)-1-methyl-1-(pyridine-3-yl)methylamino, (S)-1-methyl-1-(pyridine-4-yl)methylamino, (S)-1-methyl-1-(furan-2-yl)methylamino, (S)-1-methyl-1-(3-benzo[1,3]dioxol-5-yl)methylamino and the like.

iii) In the third aspect, R is an amine comprising R6that represents a C1-C4substituted or unsubstituted alkyl and includes the following non-limiting examples: (S)-1-methylpropylamine, (S)-1-methyl-2-(methoxy)ethylamino.

B) the Radicals R, covering the chiral amino groups, where R4arepresents hydrogen, R5aand R5brepresent, each, C1-C4alkyl, and these radicals have the formula:

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

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

ii) In the second aspect, R is an amine comprising R6that represents a substituted or unsubstituted C1-C4alkyl and 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 Radicals R, covering alkylenediamine, the de R 4arepresents hydrogen as R5aand R5bfromR4brepresent hydrogen, R6represents a substituted or unsubstituted aryl, these radicals have the formula:

where R11represents hydrogen or substituted radical, as defined above.

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

ii) the Second aspect includes the following non-limiting examples of radicals R: (2-were)methylamino; (3-were)methylamino; (4-were)methylamino and the like.

D) the Radicals R, covering amines where R4arepresents hydrogen, R4bincludes R5aequal to hydrogen, and R5bequal-CO2R7or-CON(R7)2; moreover, these radicals have the formula:

i) In the first aspect, R is an amine comprising R6that represents a substituted or unsubstituted phenyl and includes the following non-limiting examples:

where R11represents hydrogen or "Deputy"as defined in the above.

ii) In the second aspect, R is an amine comprising R6that represents a substituted or unsubstituted alkyl and includes the following non-limiting examples:

the radicals R1selected from

a) substituted or unsubstituted aryl; or

b) substituted or unsubstituted heteroaryl.

The first aspect of the radicals R1covers halogen-substituted phenyl radicals, non-limiting examples of which include 4-forfinal, 2,4-differenl, 4-chlorophenyl, and the like.

Each radical R2, independently, is selected from the group consisting of

a) hydrogen;

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

c) -(CH2)jNR9aR9b;

d) -(CH2)jCO2R10;

(e) -(CH2)jOCO2R10;

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

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

h) two of the radicals R2that form together a carbonyl group;

i) and their mixtures;

R8, R9a, R9band R10are each, independently, hydrogen, C1-C4alkyl and mixtures thereof; R9aand R9bmay together form a carbocyclic or heterocyclic ring containing from 3 to 7 atoms; two of the radicals R10may together form a Carbo is clichesque or heterocyclic ring, containing from 3 to 7 atoms; j is an index from 0 to 5, n is an index from 0 to 5.

The first aspect of the present invention related to R2covers structure having the formula:

where each radical R2represents hydrogen.

The second aspect refers to structures having the formula:

where R8represents hydrogen or C1-C4alkyl.

The third aspect refers to structures having the formula:

where R9aand R9bare each, independently, hydrogen, methyl, or R9aand R9bmay together form piperidino or morpholino ring.

A fourth aspect relates to structures having the formula:

where one of R2represents-CO2R10and the other radicals R2represent hydrogen; one of R10represents hydrogen or methyl.

Z represents O, S, NR11or NOR11; R11represents hydrogen or C1-C4alkyl. The first aspect of the present invention, as it applies for the radical Z, includes oxygen atoms, which create 2-R1substituted-3-(2-substituted-pyrimidine-4-yl)-6,7-dihydro-spinazola[1,2-a]pyrazole-1-ones, the second aspect refers to the radical Z, containing sulfur atoms, which create 2-R1substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-thiones, and the third aspect of the present invention, as it relates to the radicals Z, includes radicals NR11thereby creating a 2-R1substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-ylideneamino and their derivatives.

The first category of compounds, inhibiting the release of inflammatory cytokines, in accordance with the present invention has a General structure having the formula:

where the radicals R are ethers having the formula-OR3where R1and R3described below in table I.

Table I
No.R1R
14-forfinalphenoxy
24-forfinal2 fervency
34-forfinal3 fervency
44-forfinal4 fervency
54-forfinal2,6-divergence
64-forfinal 2 cianfrocca
74-forfinal3 cianfrocca
84-forfinal2 triptoreline
94-forfinal4 triptoreline
104-forfinalN-methylpiperidin-4-yl
114-forfinal4 methylphenoxy
124-forfinal2,4-dimethylphenoxy
134-forfinal3-N-acetylaminophenol
144-forfinalPiran-4-yloxy
154-forfinal4 methoxyphenoxy
164-forfinal3-benzo[1,3]dioxol-5-yl
172,4-differenlphenoxy
182,4-differenl2 fervency
192,4-differenl3 fervency
202,4-differenl4 fervency
212,4-differenl2,6-divergence
222,4-differenl2 cianfrocca
232,4-differeni the 3 cianfrocca
242,4-differenl2 triptoreline
252,4-differenl4 triptoreline
262,4-differenlN-methylpiperidin-4-yl
272,4-differenl4 methylphenoxy
282,4-differenl2,4-dimethylphenoxy
292,4-differenl3-N-acetylaminophenol
302,4-differenlPiran-4-yloxy
312,4-differenl4 methoxyphenoxy
322,4-differenl3-benzo[1,3]dioxol-5-yl
333-triptorelinephenoxy
343-triptoreline2 fervency
353-triptoreline3 fervency
363-triptoreline4 fervency
373-triptoreline2,6-divergence
383-triptoreline2 cianfrocca
393-triptime lpanel 3 cianfrocca
403-triptoreline2 triptoreline
413-triptoreline4 triptoreline
423-triptorelineN-methylpiperidin-4-yl
433-triptoreline4 methylphenoxy
443-triptoreline2,4-dimethylphenoxy
453-triptoreline3-N-acetylaminophenol
463-triptorelinePiran-4-yloxy
473-triptoreline4 methoxyphenoxy
483-triptoreline3-benzo[1,3]dioxol-5-yl

Connection 1-48 and others like them, can be prepared accordingly, using the techniques described below. In the following example, R1is a 4-forfinal, but can be used any source material that is compatible with this procedure, among other things, methylphenylacetic, methyl 4-chlorophenylacetic and methyl 3- (trifluoromethyl)phenyl acetate.

The General scheme of obtaining intermediate compounds of type I

Real the options and conditions: (a) LDA, THF; -78°C, 1 o'clock

Reagents and conditions: (b) CrO3CH2Cl2; room temperature, 16 hours

EXAMPLE 1

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

Followed the procedure for preparation of 2-methylsulfonylamino-4-carbaldehyde,1corresponding to the procedure disclosed in H. Bredereck et al., Chem. Ber., 97, pp. 3407-3417 (1964), included here as a reference.

In a 12 l 3-necked flask, under inert atmosphere, load N,N-dimethylformamidine (801 g) and pyruvic aldehyde, dimethylacetal (779 g). The mixture is heated 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. Then the solution is cooled to 20°C and add thiourea (892 g, 11.7 mol). After the mixture allow to mix for about 15 minutes, add sodium methoxide (741 g, 13.7 mol), 4 equal parts, within 1 hour, while the temperature of the solution is maintained within 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), while the reaction temperature is maintained within 17-9° C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyliodide removed by heating the solution at 35°C and 40 Torr to obtain approximately of 4.46 kg dark residue, which was partitioned between 14 l of water and 5 l of ethyl acetate. The aqueous fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo, also getting 685 g of oil, which is purified on silica to obtain 522 g of 4-dimethoxymethyl-2-methylsulfonylamino.

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

The complex preparation of methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-(hydroxypropionic acid (2)

To a cooled (-78° (C) the solution sitedisability (21,4 ml of 2 M solution in THF, 42.8 mmol) in THF (70 ml) is added dropwise a solution of methyl ester 4-florfenicol acid (6.0 g, to 35.7 mmol) in THF (30 ml). The solution is stirred for 1 h at -78°C, after which the reaction mixture is added dropwise a solution of 2-methylsulfinylphenyl is n-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 is quenched by pouring the reaction solution into aqueous saturated solution of NH4Cl. The aqueous phase is extracted with ethyl acetate. The combined organic phases, dried (MgSO4), filtered and concentrated in vacuo. The crude residue purified on silica (33% EtOAc/hexane) to obtain 8.7 g (76%) of the desired product as a mixture (1:1) of diastereomers.

The complex preparation of 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 h at room temperature. A solution of crude complex methyl ester of 2-(4-(forfinal)-3-(2-methylsulfonylamino-4-yl)-3-hydroxypropionic acid,2prepared above in CH2Cl2(50 ml) is added dropwise to a suspension ofchromium. The reaction mixture was stirred at room temperature for 16 hours, diluted with simple 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 obtain 3.7 g (yield 43%) of the desired product as a yellow solid product.

The following example relates to the preparation of 6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-nowych ring systems, using pyrazolidine, however, the manufacturer of the drug can use the reagents on the basis of substituted cyclic hydrazine to obtain other structures having a ring radicals R2who are not hydrogen, inter alia 3-methylpyrazole.

The General scheme for intermediate compounds of type II

Reagents and conditions: (c) pyridine; 90°C, 16 o'clock

Reagents and conditions: (d) Oxone®, MeOH/THF/H2O; room temperature, 1 h

EXAMPLE 2

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

Preparation of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-she (4)

To a solution of pyrazolidine (7,8 g, 54.16 per mmol) in pyridine (100 ml) is added methyl ester 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-oxopropanoic acid3(11.5g, 36,1 mmol). The reaction mixture is heated to 90°C for 16 hours. The solvent is removed in vacuo and the resulting residue purified on silica (100% EtOAc, then 10% MeOH/EtOAc) to obtain 3.9 g (yield 37%) of the desired product as a yellow solid product.

Preparation of 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-she (5)

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

Then a process where the intermediate compounds of type II can be used for the preparation of inhibitors of the release of inflammatory cytokines category 1.

EXAMPLE 3

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

Reagents and conditions: (e) phenol, NaH, THF, 1.5 h, room temperature.

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

To a solution of phenol (0.66 g, was 7.08 mmol) in THF (5 ml) is added NaH (0.24 g, 5,91 mmol), and then a solution of crude 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it,5prepared above (0.25 g, 0.67 mmol)in THF (2 ml). The reaction mixture was stirred for 1.5 hours at room temperature, diluted with aqueous solution of NaHCO3and extracted twice with ethyl acetate. About the organic layers are combined dried over MgSO4and concentrated in vacuo to obtain the crude product, which was purified on silica (100% EtOAc, then 10% MeOH/EtOAc) to give 0.35 g (38% yield) of the desired product as a yellow solid product.1H NMR (300 MHz, CDCl3) δ of 8.47 (d, J=5,1 Hz, 1H), 7,49 (DD, J=7,8, and 7.8 Hz, 2H), 7,40 (DDD, J=5,4, a 5.4 Hz, 2H), 7,35-7,22 (m, 3H), 7,10 (DD, J=8,4, and 8.4 Hz, 2H), make 6.90 (d, J=6,8 Hz, 1H), of 4.05 (t, J=7.2 Hz, 2H), 3,86 (t, J=7.2 Hz, 2H), 2,59 (dt, J=7,2, 7.2 Hz, 2H); HRMS calculated for C22H18FN4O2(M + H)+389,1414; found 389,1407.

This connection corresponds to the analog 1 from table I.

The following compounds of the first aspect of category I can be prepared using procedures described above.

N-(3-{4-[2-(4-Forfinal)-3-oxo-6,7-dihydro-3H,5H-pyrazolo[1,2-a]pyrazole-1-yl]pyrimidine-2-yloxy}phenyl)ndimethylacetamide;1H NMR (300 MHz, d6-DMSO) δ 10,11 (s, 1H), 8,66 (d, J=5,1 Hz, 1H), to 7.64 (m, 1H), 7,41-7,34 (m, 4H), 7,17 (t, J=9.0 Hz, 2H), 7,02 (d, J=5,1 Hz), 6,92-to 6.80 (m, 1H), 3,84 (t, J=6.9 Hz, 2H), 3,81 (t, J=6.9 Hz, 2H), 2,46 (m, 2H), 2.06 to (s, 3H); HRMS calculated for C24H20FN5O3(M + H)+446,1628; found 446,1606.

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

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

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

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

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

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

The second aspect of the compounds, and gibiruei the release of inflammatory cytokines, category I, in accordance with the present invention, which have a common structure, with the formula:

where the radicals R are amines having the formula-NR4a[CHR5b]R6and R1, R4a, R5band R6below, in table II. The stereochemistry of R5brepresents the configuration when R5bor R6are not hydrogen.

Table II
No.R1R4aR5bR6
494-forfinalHHphenyl
504-forfinalHH4-forfinal
514-forfinalHH2-AMINOPHENYL
524-forfinalHH2-were
534-forfinalHH4-were
544-forfinalHH4-methoxyphenyl
554-forfinalHH4-(propane is sulfonyl)phenyl
564-forfinalHH3-benzo[1,3]dioxol-5-yl
574-forfinalHHpyridine-2-yl
584-forfinalHHpyridine-3-yl
594-forfinalHmethylphenyl
604-forfinalHmethyl4-forfinal
614-forfinalHmethyl2-AMINOPHENYL
624-forfinalHmethyl2-were
634-forfinalHmethyl4-were
644-forfinalHmethyl4-methoxyphenyl
654-forfinalHmethyl4-(propanesulfonyl)phenyl
664-forfinalHmethyl3-benzo[1,3]dioxol-5-yl
674-forfinalHmethylpyridine-2-yl
68/td> 4-forfinalHmethylpyridine-3-yl
694-forfinalHHH
704-forfinalHHmethyl
714-forfinalHHethyl
724-forfinalHHvinyl
734-forfinalHHcyclopropyl
744-forfinalHHcyclohexyl
754-forfinalHHmethoxymethyl
764-forfinalHHmethoxyethyl
774-forfinalHH1-hydroxy-1-methylethyl
784-forfinalHH-CO2H
794-forfinalHmethylH
804-forfinalHmethylmethyl
81-forfinal Hmethylethyl
824-forfinalHmethylvinyl
834-forfinalHmethylcyclopropyl
844-forfinalHmethylcyclohexyl
854-forfinalHmethylmethoxymethyl
864-forfinalHmethylmethoxyethyl
874-forfinalHmethyl1-hydroxy-1-methylethyl
884-forfinalHmethyl-CO2H
893-triptorelineHmethylphenyl
903-triptorelineHmethyl4-forfinal
913-triptorelineHmethyl2-AMINOPHENYL
923-triptorelineHmethyl2-were
933-triptoreline the Hmethyl4-were
943-triptorelineHmethyl4-methoxyphenyl
953-triptorelineHmethyl4-(propanesulfonyl)phenyl
963-triptorelineHmethyl3-benzo[1,3]dioxol-5-yl
973-triptorelineHmethylpyridine-2-yl
983-triptorelineHmethylpyridine-3-yl
993-triptorelineHmethylH
1003-triptorelineHmethylmethyl
1013-triptorelineHmethylethyl
1023-triptorelineHmethylvinyl
1033-triptorelineHmethylcyclopropyl
1043-triptorelineHmethyl
1053-triptorelineHmethylmethoxymethyl
1063-triptorelineHmethylmethoxyethyl
1073-triptorelineHmethyl1-hydroxy-1-methylethyl
1083-triptorelineHmethyl-CO2H

Using such intermediate compounds as compound 5, as the original product, connection 49-108 and other similar compounds may be prepared accordingly using the procedure described below. In the following example, R1is a 4-forfinal, but you can use source material that is compatible with this technique, among other things, methylphenylacetic, methyl 4-chlorophenylacetic and methyl 3-(trifluoromethyl)phenyl acetate.

Reagents and conditions: (a)(S)-(α)-methylbenzylamine, toluene, 140°C, 12 o'clock

EXAMPLE 4

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

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

A solution of crude 2-(4-fluoro who enyl)-3-(2-(methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it, 5prepared above (0,86 g, 2.3 mmol)and (S)-(-)-α-methylbenzylamine (10,5 ml of 81.6 mmol) dissolved in toluene (18 ml). The resulting mixture was heated to 140°C for 12 hours, cooled to room temperature and the solvent is removed in vacuum. The obtained residue is purified on silica (1:1 EtOAc/hexane) to give the desired product, which is a similar 59 from table II.1H NMR (300 MHz, CDCl3) δ 8,18 (d, J=5,1 Hz,1H), 7,42-7,34 (m, 7H),? 7.04 baby mortality (DDD, J=9,0, to 6.9, 2.1 Hz, 2H), to 6.39 (d, J=5,1 Hz, 1H), 5,68 (sirens, 1H), 5,10 (m, 1H), 3,97 (dt, J=7,5, to 7.5, 7.5 Hz, 2H), 2,45 (sirens, 2H), 1,67 (m, 2H), 1,60 (d, J=7.5 Hz, 3H); HRMS calculated for C24H22FN5O (M + H)+416,1887; found 416,1897.

The following compounds can be prepared using the procedure described above.

2-(4-Forfinal)-3-[2-(N'-methyl-N'-phenylhydrazine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,29 (d, J=5,1 Hz, 1H), 7,40 (DD, J=8,4, a 5.4 Hz, 2H), 7,29-7,25 (m, 2H), 7,06 (DD, J=8,4, and 8.4 Hz, 2H), 6,91 (d, J=9.0 Hz, 2H), 6,85 (t, J=7.8 Hz, 1H), to 6.57 (d, J=5,1 Hz, 1H), 4.00 points (t, J=6,9 Hz, 4H), 3,39 (s, 3H), 2,48 is 2.33 (m, 2H); MS (M + H)+417,2.

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

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

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

2-(4-Forfinal)-3-[2-(allylamino)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ to 8.20 (d, J=5,1 Hz, 1H), 7,43 (DD, J=9,0, a 5.4 Hz, 2H), 7,05 (t, J=8.7 Hz, 2H), to 6.43 (d, J=5,1 Hz, 1H), 6,00 (dddd, J=7.2V 7.2V 7.2V, 5,1 Hz, 1H), 5,45 (sirens, 1H), 5,28 (DD, J=17,1, 1.5 Hz, 1H), 5,20 (DD, J=to 10.2, 1.5 Hz, 1H), 4,13-Android 4.04 (m, 6H), 2,71 (dt, J=7,2, 7.2 Hz, 2H); HRMS calculated for C19H18FN5O (M + H)+352,1573; found 352,1582.

2-(4-Forfinal)-3-{2-[1-(S)-(4-were)ethylamino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,15 (d, J=5.4 Hz, 1H), 7,40 (DD, J=8,7, 5.7 Hz, 2H), 7,28-7,27 (m, 2H), 7,17 (d, J=7.8 Hz, 2H),? 7.04 baby mortality (t, J=9.0 Hz, 2H), 6,41 (d, J=5.4 Hz, 1H), 5,20 (m, 1H), was 4.02-of 3.96 (m, 4H), 2,52 at 2.45 (m, 2H), a 2.36 (s, 3H), 1,60 (d, J=6.9 Hz, 3H); HRMS calculated for C25H24FN5O (M + H)+430,2043; found 4302057.

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

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

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

2-(4-Forfinal)-3-[2-(2-hydroxy-1,2-dimethylpropylene)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 7,99 (m, 1H), 7,40 (DD, J=9,0, 5.7 Hz, 2H), 7,10 (t, J=8.7 Hz, 2H), 6,55 (d, J=5.4 Hz, 1H), 4,24-4,10 (m, 5H), and 2.83 (dt, J=8,4, and 8.4 Hz, 2H), 1,51-of 1.36 (m, 9H); MS (M + H)+398,1.

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

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

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

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

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

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

The second type of compounds inhibiting the release of inflammatory cytokines in accordance with the present invention has a General structure having the formula:

where the radicals R are ethers having the formula-OR3and R9aand R9btogether form a ring as described below in table III.

td align="center"> pyrrolidin-1-yl
Table III
No.R1R3The ring R9a/R9b
1094-forfinalPhenoxymorpholinyl
1104-forfinal2 fervencymorpholinyl
1114-forfinal3 fervencymorpholinyl
1124-forfinal4 fervencymorpholinyl
1134-forfinal2,6-divergencemorpholinyl
1144-forfinal/td> 2 cianfroccamorpholinyl
1154-forfinal3 cianfroccamorpholinyl
1164-forfinal2 triptorelinemorpholinyl
1174-forfinal4 triptorelinemorpholinyl
1184-forfinal2 methylphenoxymorpholinyl
1194-forfinal4 methylphenoxymorpholinyl
1204-forfinal2,4-dimethylphenoxymorpholinyl
1214-forfinal3-N-acetylaminophenolmorpholinyl
1224-forfinal2 methoxyphenoxymorpholinyl
1234-forfinal4 methoxyphenoxymorpholinyl
1244-forfinal3-benzo[1,3]dioxol-5-ylmorpholinyl
1254-forfinalPhenoxypiperidine-1-yl
1264-forfinal2 fervencypiperidine-1-yl
127 4-forfinal3 fervencypiperidine-1-yl
1284-forfinal4 fervencypiperidine-1-yl
1294-forfinal2,6-divergencepiperidine-1-yl
1304-forfinal2 cianfroccapiperidine-1-yl
1314-forfinal3 cianfroccapiperidine-1-yl
1324-forfinal2 triptorelinepiperidine-1-yl
1334-forfinal4 triptorelinepiperidine-1-yl
1344-forfinal2 methylphenoxypiperidine-1-yl
1354-forfinal4 methylphenoxypiperidine-1-yl
1364-forfinal2,4-dimethylphenoxypiperidine-1-yl
1374-forfinal3-N-acetylaminophenolpiperidine-1-yl
1384-forfinal2 methoxyphenoxypiperidine-1-yl
1394-forfinal4-label is iproxy piperidine-1-yl
1404-forfinal3-benzo[1,3]dioxol-5-ylpiperidine-1-yl
1414-forfinalPhenoxypiperidine-1-yl
1424-forfinal2 fervencypiperazine-1-Il
1434-forfinal3 fervencypiperazine-1-Il
1444-forfinal4 fervencypiperazine-1-Il
1454-forfinal2,6-divergencepiperazine-1-Il
1464-forfinal2 cianfroccapiperazine-1-Il
1474-forfinal3 cianfroccapiperazine-1-Il
1484-forfinal2 triptorelinepiperazine-1-Il
1494-forfinal4 triptorelinepiperazine-1-Il
1504-forfinal2 methylphenoxypiperazine-1-Il
1514-forfinal4 methylphenoxypiperazine-1-Il
152 4-forfinal2,4-dimethylphenoxypiperazine-1-Il
1534-forfinal3-N-acetylaminophenolpiperazine-1-Il
1544-forfinal2 methoxyphenoxypiperazine-1-Il
1554-forfinal4 methoxyphenoxypiperazine-1-Il
1564-forfinal3-benzo[1,3]dioxol-5-ylpiperazine-1-Il
1574-forfinalPhenoxypyrrolidin-1-yl
1584-forfinal2 fervencypyrrolidin-1-yl
1594-forfinal3 fervencypyrrolidin-1-yl
1604-forfinal4 fervencypyrrolidin-1-yl
1614-forfinal2,6-divergencepyrrolidin-1-yl
1624-forfinal2 cianfroccapyrrolidin-1-yl
1634-forfinal3 cianfroccapyrrolidin-1-yl
1644-forfinal2 triptoreline
1654-forfinal4 triptorelinepyrrolidin-1-yl
1664-forfinal2 methylphenoxypyrrolidin-1-yl
1674-forfinal4 methylphenoxypyrrolidin-1-yl
1684-forfinal2,4-dimethylphenoxypyrrolidin-1-yl
1694-forfinal3-N-acetylaminophenolpyrrolidin-1-yl
1704-forfinal2 methoxyphenoxypyrrolidin-1-yl
1714-forfinal4 methoxyphenoxypyrrolidin-1-yl
1724-forfinal3-benzo[1,3]dioxol-5-ylpyrrolidin-1-yl

There follows a scheme for the preparation of compounds belonging to the first aspect of the second type in accordance with the present invention. The first stage involves the use of intermediate compounds of type III for the introduction of the radicals R1(4-ftoheia, in this example) in the molecule. Intermediate ketones, such as connection11can be used in the following stages for the introduction of selected aminogroup the dust in the 6-position of the pyrazolo[1,2-a]pyrazole-1-about the ring system.

The General scheme for intermediate compounds of type III

Reagents and conditions: (a) NaH, DMF, room temperature, 12 hours

Reagents and conditions: (b) SOCl2MeOH, 0°C to room temperature, 18 hours

Reagents and conditions: (c) NaOH, CH2Cl2/water, room temperature, 18 hours

Reagents and conditions: (d) O3CH2Cl2, VHI; from -78°C to room temperature, 18 hours

EXAMPLE 5

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-oxopyrrolidin-1-carboxylic acid (11)

The preparation of complex 1-benzyl ether complex 2-butyl methyl ether 4-metrobidazole-1,2-dicarboxylic acid (8)

To a suspension of NaH (3,81 g of 95.4 mmol) in DMF (80 ml) is added dropwise a solution of N-Cbz-N'-Boc-hydrazine (12.1 g, to 45.4 mmol) in DMF (20 ml). The reaction mixture is stirred for about 20 minutes, added dropwise 3-chloro-2-chloromethylated (5.8 ml, 50 mmol) and the reaction mixture is allowed the opportunity to mix at room temperature for approximately 12 hours until, according to TLC until the reaction is complete. The reaction solution was distributed between ethyl acetate and water, the aqueous layer was extracted with solvent several times. The combined organic layers dried, filtered and concentrated to give the desired product as a clear oil which is used without further purification.

The preparation of complex 1-benzyl ester 4-metrobidazole-1-carboxylic acid (9)

To the crude solution of complex 1-benzyl ether complex 2-butyl methyl ether 4-metrobidazole-1,2-dicarboxylic acid8(30 g) in methanol (300 ml) was added dropwise thionyl chloride at 0°C. the Reaction mixture is heated to room temperature and stirred an additional 18 hours. Concentration of the reaction mixture in vacuo giving a yellow oil, which crystallized upon standing to obtain 23 g (yield 97%) of the desired product as HCl salt.

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-metrobidazole-1-carboxylic acid (10)

Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a solution of 1:2 water/methylene chloride (30 ml) with rapid stirring, followed by the addition of complex 1-benzyl ester 4-metrobidazole-1-carboxylic acid9(of 0.62 g, 2.8 mmol) at room temperature. Add (4-forfinal)acetylchloride (of 0.39 ml, 4.2 mmol) and the reaction mixture allow to mix for 18 hours, after this time the reaction mixture was diluted with water (10 ml) and the layers give the opportunity for separation. The aqueous layer was extracted with methylene chloride, the organic layers combined, dried and filtered. Kontsentrirovanie the in vacuo gives the crude product, which is purified on silica (1:3 ethyl acetate/hexane) to give 0.54 g (yield 62%) of the desired product.

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-oxopyrrolidin-1-carboxylic acid (11)

Gaseous ozone is bubbled in the solution of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-metrobidazole-1-carboxylic acid10(0.28 g, 0.8 mmol) in methylene chloride (15 ml) at -78°C to until the solution retains the blue color. The source of ozone is removed and added dimethyl sulfoxide (0,23 ml), the reaction solution was allow to warm to room temperature and stirred for 18 hours. The solvent is removed in vacuo and the resulting oil purified on silica (1:3 ethyl acetate/hexane) to give 0.15 g (yield 53%) of the desired product as a clear oil.

Synthetic intermediate compounds of type III, for example the connection11can be used as a template for introducing the desired aminoacetate in the 6-position, as described below in the example.

The General scheme of the intermediate compounds of type IV

The introduction of 6-amino radical in the structure of the compounds, covering the first aspect analogues category II.

Reagents and conditions: (e) Na(OAc)3BH, HOAc, THF, room temperature, 12 hours

eagency and conditions: (f) H 2; Pd/C, MeOH.

EXAMPLE 6

2-(4-Forfinal)-1-(4-(morpholine-4-imperatorin-1-yl)alanon (13)

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-morpholine-4-imperatorin-1-carboxylic acid (12)

To a solution of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-oxopyrrolidin-1-carboxylic acid11(0.14 g, 0.4 mmol) and research (0,038 ml, 0.43 mmol) in THF at room temperature is added Na(OAc)3BH (0.125 g, 0.6 mmol) and HOAc (of 0.022 ml, 0.4 mmol). The solution was stirred for 12 hours, then partitioned between simple diethyl ether and NaHCO3. The aqueous layer was extracted several times with simple ether and the organic layers combined, dried and concentrated in vacuo to a clear oil, which was re-dissolved in simple ether, and add to it one equivalent of ethereal HCl solution and a white solid product. The solid product is collected by filtration and 100 mg (yield 60%) of the desired product is isolated in the form of HCl salt.

Preparation of 2-(4-forfinal)-1-(4-(morpholine-4-imperatorin-1-yl)ethanone (13)

Salt HCl and complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-morpholine-4-imperatorin-1-carboxylic acid12(100 mg, 0.2 mmol) is dissolved in methanol and added Pd/C (5 mg). The solution is then hydronaut using Parr apparatus for 3 days, after which the catalyst was removed by filtration and f is ltrate concentrated in vacuo to obtain 55 mg (yield 81%) of the desired product as a yellowish-brown solid product.

When selected 6-amino radical is in its position in the structure of 2-R1-substituted-pyrazolo[1,2-a]pyrazole-1-it, the end segments analogues that contain the selected radicals R can be assembled together with the use phase of the synthesis of information. This stage uses the intermediate compounds of type V, having the General formula:

thereby introducing the desired radical OR3in structure, these intermediate compounds of type V can be prepared according to the procedure described in the diagram below.

The General scheme for intermediate compounds of type V

Reagents and conditions: (a) SOCl2, MeOH, room temperature, 12 hours

Reagents and conditions: (b) Oxone®, MeOH/THF/H2O; room temperature, 12 hours

Reagents and conditions: (c) phenol, NaH, THF, room temperature, 12 hours

Reagents and conditions: (d) NaOH MeOH/H2O; room temperature, 1,5 hours

Reagents and conditions: (e) oxalicacid, CH2Cl2/DMF; room temperature, 2 hours

EXAMPLE 7

2-Phenoxypyridine-4-carbonylchloride (18)

The preparation of complex methyl ester 2-methylsulfonylamino-4-carboxylic KIS is the notes (14)

To a suspension of 2-methylsulfonylamino-4-carboxylic acid (15 g, 88 mmol) in methanol (200 ml) was added dropwise thionyl chloride (25 ml). Solution allow to warm to room temperature and stirred for 12 hours. The solution is then concentrated in vacuo and the yellow solid product which remains can be extracted in methylene chloride and re-concentrated to obtain 19 g (yield 97%) of saltHCl desired product as a white solid product.

The preparation of complex methyl ester 2-methanesulfonamido-4-carboxylic acid (15)

An aqueous solution (1 l) Oxone® (211,7 g, 344 mmol) added dropwise at 0°C to a solution of complex methyl ester 2-methylsulfonylamino-4-carboxylic acid14(19 grams of 86.1 mmol) in a mixture of 1:1 methanol/THF (1 l). The reaction solution was allow to warm to room temperature and stirred it for1,5 hours, the resulting suspension is distributed between methylene chloride and water. The aqueous phase make alkaline by adding NaOH and re-extracted with a solvent. The combined organic layers dried, filtered and concentrated in vacuo to obtain an 18.4 g of the desired product as a yellow oil.

The preparation of complex methyl ester 2-phenoxypyridine-4-carboxylic acid (16)

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

Preparation of 2-phenoxypyridine-4-carboxylic acid (17)

To a solution of complex methyl ester 2-phenoxypyridine-4-carboxylic acid16(1,72 g, 74,8 mmol) in methanol (50 ml), at room temperature, add 50% NaOH solution (10 ml). After stirring for 1.5 hours the solvent is removed in vacuum and the remaining aqueous phase is extracted with ethyl acetate. Then the aqueous phase can be carefully acidified with concentrated HCl and the white solid product which is formed, extracted twice with ethyl acetate. The organic layers are combined, dried and concentrated in vacuo to obtain 0.95 g (yield 60%) of the desired product as a white solid product.

Preparation of 2-phenoxy rimidine-4-carbonylchloride (18)

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

The final sequence of stages for the preparation of compounds which comprise the first aspect of the analogues of the category II, in accordance with the present invention, can be carried out using the procedure described below. This procedure includes phase information, where the first half includes the selected radical R1and the amino group in 6-position, for example, as an intermediate connection13, while the second half includes the final radical R, is already entered in the pyrimidine ring, for example, as in the intermediate connection18.

Reagents and conditions: (g) NaOH: CH2Cl2/water, room temperature, 12 hours

Reagents and conditions: (h) NaH, DMF; 0°C, 2 hours

EXAMPLE 8

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

Preparation of 2-(4-forfinal)-1-[4-morpholine-4-yl-2-(2-phenoxypyridine-4-carbonyl)pyrazolo the Jn-1-yl]ethanone (19)

2-phenoxypyridine-4-carbonylchloride18(0.07 g, 0.28 mmol) in methylene chloride (1.5 ml) is added dropwise to a suspension of 2-(4-forfinal)-1-(4-(morpholine-4-imperatorin-1-yl)ethanone13(0.06 g, 0.18 mmol) in a solution of 2:5 water/CH2Cl2(7 ml)containing NaOH (0,0112 g, 0.28 mmol) at room temperature. The solution is stirred for 18 hours and diluted with an additional mixture of 2:5 water/CH2Cl2. Layers give you the ability to separate and the aqueous phase is extracted with additional methylene chloride. The organic layers are combined, dried, filtered and concentrated in vacuo to obtain a yellowish-brown solid product, which was purified using preparative HPLC to obtain 0,021 g (yield 23%) of the desired product as an oily solid product.

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

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

Following connection of the first speaker is EKTA category II can be prepared using procedures above.

2-(4-Forfinal)-6-morpholine-4-yl-3-[2-(4-pertenece)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he:1H NMR (CDCl3, 300 MHz) δ to 1.61 (s, 4H), 2,58 (s, 4H), 3,70-3,99 (m, 4H), 4,23-of 4.25 (m, 1H), 6,94 (d, 1H, J=5,1 Hz), 7,10 (t, 2H, J=8.7 Hz), 7,26-7,41 (m, 6H), and 8.50 (d, 1H, J=5,1 Hz). ESI+MS: m/z (relative intensity) 491,9 (100, M++ H). Anal. calculated for C26H23F2N5O30,5H2O: C, 62,39; H, a 4.83; N, 13,99; found: C, 62,02; H, to 4.38; N, 13,62.

The second aspect of the compounds of type II refers to compounds having the formula:

where R represents an amino group, as indicated in the formula. The compounds of table IV contain the radicals R having the formula-NHC(HR5bR6where R4arepresents hydrogen, and R1, R5a, R6, R9aand R9bare described here.

H
Table IV
No.R1R5bR6R9aR9b
1734-forfinalHphenylHH
1744-forfinalH4-forfinalHH
1754-forfinalH 2-AMINOPHENYLHH
1764-forfinalH2-wereHH
1774-forfinalH4-wereHH
1784-forfinalH4-methoxyphenylHH
1794-forfinalH4-(propanesulfonyl)phenylHH
1804-forfinalH3-benzo[1,3]dioxol-5-ylHH
1814-forfinalHpyridine-2-ylHH
1824-forfinalHpyridine-3-ylHH
1834-forfinalmethylphenylHH
1844-forfinalmethyl4-forfinalHH
1854-forfinalmethyl2-AMINOPHENYLHH
1864-forfinalmate the 2-wereHH
1874-forfinalmethyl4-wereHH
1884-forfinalmethyl4-methoxyphenylHH
1894-forfinalmethyl4-(propanesulfonyl)phenyl)HH
1904-forfinalmethyl3-benzo[1,3]dioxol-5-ylHH
1914-forfinalmethylpyridine-2-ylHH
1924-forfinalmethylpyridine-3-ylHH
1934-forfinalHphenylmethylmethyl
1944-forfinalH4-forfinalmethylmethyl
1954-forfinalH2-AMINOPHENYLmethylmethyl
1964-forfinalH2-weremethylmethyl/td>
1974-forfinalH4-weremethylmethyl
1984-forfinalH4-methoxyphenylmethylmethyl
1994-forfinalH4-(propanesulfonyl)phenyl)methylmethyl
2004-forfinalH3-benzo[1,3]dioxol-5-ylmethylmethyl
2014-forfinalHpyridine-2-ylmethylmethyl
2024-forfinalHpyridine-3-ylmethylmethyl
2034-forfinalmethylphenylmethylmethyl
2044-forfinalmethyl4-forfinalmethylmethyl
2054-forfinalmethyl2-AMINOPHENYLmethylmethyl
2064-forfinalmethyl2-weremethylmethyl
2074-forfinalmethyl4-weremethylmethyl
2084-forfinalmethyl4-methoxyphenylmethylmethyl
2094-forfinalmethyl4-(propanesulfonyl)phenyl)methylmethyl
2104-forfinalmethyl3-benzo[1,3]dioxol-5-ylmethylmethyl
2114-forfinalmethylpyridine-2-ylmethylmethyl
2124-forfinalmethylpyridine-3-ylmethylmethyl
2134-forfinal-CO2CH3phenylHH
2144-forfinal-CO2CH34-forfinalHH
2154-forfinal-CO2CH32-AMINOPHENYLHH
2164-forfinal-CO2CH32-wereH
2174-forfinal-CO2CH34-wereHH
2184-forfinal-CO2CH34-methoxyphenylHH
2194-forfinal-CO2CH34-(propanesulfonyl)phenyl)HH
2204-forfinal-CO2CH33-benzo[1,3]dioxol-5-ylHH
2214-forfinal-CO2CH3pyridine-2-ylHH
2224-forfinal-CO2CH3pyridine-3-ylHH
2234-forfinal-CO2CH3phenylmethylmethyl
2244-forfinal-CO2CH34-forfinalmethylmethyl
2254-forfinal-CO2CH32-AMINOPHENYLmethylmethyl
2264-terphenyl -CO2CH32-weremethylmethyl
2274-forfinal-CO2CH34-weremethylmethyl
2284-forfinal-CO2CH34-methoxyphenylmethylmethyl
2294-forfinal-CO2CH34-(propanesulfonyl)phenyl)methylmethyl
2304-forfinal-CO2CH33-benzo[1,3]dioxol-5-ylmethylmethyl
2314-forfinal-CO2CH3pyridine-2-ylmethylmethyl
2324-forfinal-CO2CH3pyridine-3-ylmethylmethyl

Compounds which comprise the second aspect of the compounds of type II, where R represents an amino group, can be prepared according to the scheme described below, based on the total intermediate11. For the next next example, R9band R9bare each methyl, and R submitted the a (S)-(1-phenyl)ethylamine.

Reagents and conditions: (a) Na(OAc)3BH, HOAc, THF, room temperature, 12 hours

Reagents and conditions: (b) H2; Pd/C, MeOH.

Reagents and conditions: (c) NaOH: CH2Cl2/water, room temperature, 12 hours

Reagents and conditions: (d) NaH, DMF; 0°C to room temperature, 2 hours

Reagents and conditions: (e) Oxone®, MeOH/THF/H2O; room temperature, 12 hours

Reagents and conditions: (f) toluene, 140°C, 12 o'clock

EXAMPLE 9

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

The preparation of complex benzyl ester 4-dimethylamino-2-[2-(4-forfinal)acetyl]pyrazolidine-1-carboxylic acid (21)

To a solution of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-oxopyrrolidin-1-carboxylic acid11(3.6 g, 10 mmol) and dimethylamine (10 ml of 2M solution, 20 mmol) in THF at room temperature is added Na(OAc)3BH (3.1 g, 15 mmol) and HOAc (0.6 g, 10 mmol). The solution was stirred for 12 hours, then partitioned between simple diethyl ether and NaHCO3. The aqueous layers extracted several times with simple ether and the organic layers combined and dried to concentrate the t in vacuo to a clear oil, which re-dissolve in a simple ether, and adding one equivalent of ethereal HCl solution and a white solid product. The solid product is collected by filtration to give the desired product as HCl salt.

Preparation of 1-(4-dimethylaminopyridine-1-yl)-2-(4-forfinal)ethanone (22)

Salt HCl and complex benzyl ester 4-dimethylamino-2-[2-(4-forfinal)acetyl]pyrazolidine-1-carboxylic acid21(4,22 g, 10 mmol) is dissolved in methanol and added Pd/C (100 mg). Then the solution hydronaut 18 hours using the apparatus Parra, after this time the catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the desired product.

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

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

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

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

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

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

Preparation of 6-dimethylamino-2-(4-forfinal)-3-[2-(1-(S)-phenylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it (26)

A solution of crude dimethylamino-2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-(pyrazolo[1,2-a]pyrazole-1-it,25prepared as described above (4,2 g, 10 mmol)and (S)-(-)-α-methylbenzyl amine (45,2 ml, 351 mmol) dissolved in toluene (100 ml). The resulting mixture was heated to 140°C for 12 hours, cooled to room temperature and the solvent is removed in vacuum. The obtained residue is purified on silica (1:1 EtOAc/hexane) to give the desired product.

Type III compounds, inhibiting the release of inflammatory cytokines, in accordance with the present invention has a General structure having the formula:

the first aspect relates to an ether analogs having the formula:

where the radicals R and R1defined below, in table the E. V.

Table V
No.R1R
2334-forfinalphenoxy
2344-forfinal2 fervency
2354-forfinal3 fervency
2364-forfinal4 fervency
2374-forfinal2,6-divergence
2384-forfinal2 cianfrocca
2394-forfinal3 cianfrocca
2404-forfinal2 triptoreline
2414-forfinal4 triptoreline
2424-forfinal2 methylphenoxy
2434-forfinal4 methylphenoxy
2444-forfinal2,4-dimethylphenoxy
2454-forfinal3-N-acetylaminophenol
2464-forfinal2 methoxyphenoxy
2474-forfinal4 methoxyphenoxy
2484-forfinal3-benzo[1,3]dioxol-5-yl
2493-forfinalphenoxy
2503-forfinal2 fervency
2513-forfinal3 fervency
2523-forfinal4 fervency
2533-forfinal2,6-divergence
2543-forfinal2 cianfrocca
2553-forfinal3 cianfrocca
2563-forfinal2 triptoreline
2573-forfinal4 triptoreline
2583-forfinal2 methylphenoxy
2593-forfinal4 methylphenoxy
2603-forfinal2,4-dimethylphenoxy
2613-forfinal3-N-acetylaminophenol
2623-forfinal2 methoxyphenoxy
2633-forfinal4 methoxyphenoxy
2643-forfinal3-benzo[1,3]dioxol-5-yl
2653-triptorelinephenoxy
2663-triptoreline2 fervency
2673-triptoreline3 fervency
2683-triptoreline4 fervency
2693-triptoreline2,6-divergence
2703-triptoreline2 cianfrocca
2713-triptoreline3 cianfrocca
2723-triptoreline2 triptoreline
2733-triptoreline4 triptoreline
2743-triptoreline2 methylphenoxy
2753-triptoreline4 methylphenoxy
2763-triptoreline2,4-dimethylphenoxy
2773-triptoreline3-N-acetylaminophenol
2783-triptoreline2 methoxyphenoxy
2793-triptoreline4 methoxyphenoxy
2803-triform terphenyl 3-benzo[1,3]dioxol-5-yl

Compounds which comprise the first aspect of the compounds of type III, can be prepared in accordance with the scheme described below, using the intermediate compound 8 as a suitable starting material.

Reagents and conditions: (a) O3CH2Cl2, THF; -78°C, 20 min, room temperature, 12 hours

Reagents and conditions: (b) BH3: DMS, THF; -78°C, 40 minutes

Reagents and conditions: (c)(CH3)3CCOCl, pyridine, DMAP; room temperature, 12 hours

Reagents and conditions: (d) SOCl2, MeOH; 0°C to room temperature, 12 hours

Reagents and conditions: (e) Et3N 0°C; RCO2H at room temperature; EDCl, CH2Cl2; 0°C to room temperature, 12 hours

Reagents and conditions: (f) H2: Pd/C, MeOH, room temperature, 6 hours

Reagents and conditions: (g) NaOH: CH2Cl2/water, room temperature, 12 hours

Reagents and conditions: (h) NaH, DMF; 0°C to room temperature, 3 hours

Reagents and conditions: (i) Oxone® , MeOH/THF/H2O; room temperature, 12 hours

Reagents and conditions: (j) phenol, base, 0°C to room temperature, 1 h

EXAMPLE 10

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

The preparation of complex 1-benzyl ether complex 2-butyl methyl ether4-oxopyrrolidin-1,2-dicarboxylic acid (27)

Complex 1-benzyl ether complex 2-tributyl ether 4-metrobidazole-1,2-dicarboxylic acid8(23.9 g, a 75.1 mmol) dissolved in dichloromethane (200 ml). The solution is cooled to -78°C and rinsed with oxygen for 5 minutes. Gaseous ozone is bubbled through the solution until until the solution remains a deep blue color (about 20 minutes). The solution is rinsed with oxygen and argon, and then it loads 40 ml of dimethyl sulfide. The cooling bath removed and the solution stirred at ambient temperature for 12 hours. The reaction solution was concentrated in vacuo and the resulting oil purified on silica (hexane/ethyl acetate 3:1 to 2:1) to obtain 13.5 g (yield 56%) of the desired product as a viscous clear oil.

The preparation of complex 1-benzyl ether complex 2-butyl methyl ether 4-hydroxypyrrolidine-1,2-dicarboxylic acid (28)

Complex 1-benzo is lovy ether complex 2-tributyl ether 4-oxopyrrolidin-1,2-dicarboxylic acid 27(5.0 g, 15.6 mmol) dissolved in tetrahydrofuran (150 ml) and the solution cooled to -78°C. Add dropwise, a 5.0 M solution of the complex brandibelle simple ether (6,24 ml, and 31.2 mmol) via syringe. After 40 minutes at -78°C the reaction is quenched by slowly adding saturated aqueous solution of ammonium chloride (20 ml). The cooling bath removed and the mixture allow to warm to ambient temperature, with vigorous stirring. The solvent is removed in vacuo and the residue diluted with dichloromethane (200 ml). The mixture was washed with water (150 ml) and saturated aqueous sodium bicarbonate (150 ml), water and saturated salt solution. The combined aqueous layers extracted with dichloromethane (200 ml), water (150 ml), NaCl (saturated) (200 ml), dried over sodium sulfate, filtered and concentrated in vacuo obtaining of 4.66 g (yield 93%) of the desired product as a clear viscous oil.

The preparation of complex 1-benzyl ether complex 2-butyl ester of 4-(2,2-dimethylpropionic)pyrazolidine-1,2-dicarboxylic acid (29)

Complex 1-benzyl ether complex 2-tributyl ether 4-hydroxypyrrolidine-1,2-dicarboxylic acid28(1,42 mg, 4.40 mmol) dissolved in pyridine (22 ml). Add 4-dimethylaminopyridine (10 mg), and then trimethylacetylchloride (1,63 ml, 13,2 mmol). The reaction mixture was stirred at which the temperature of the environment within 12 hours. Then turbid reaction mixture was concentrated in vacuo to obtain a white residue. To the residue is added dichloromethane (75 ml) and the mixture is washed with 1.0 N. aqueous solution of hydrochloric acid (75 ml). The aqueous layer was extracted with dichloromethane (75 ml), the combined organic layers washed with saturated aqueous NaHCO3(75 ml), water (75 ml), saturated brine (75 ml), then dried, filtered and concentrated in vacuo to obtain the crude product. The crude product is purified on silica (hexane/ethyl acetate, 4:1 to 1:1) obtaining of 1.76 g (yield 98%) of the desired product as a clear viscous oil.

The preparation of complex 1-benzyl ester 4-(2,2-dimethylpropionic)pyrazolidine-1-carboxylic acid (30)

Complex 1-benzyl ether complex 2-tributyl ester of 4-(2,2-dimethylpropionic)pyrazolidine-1,2-dicarboxylic acid29(1,76 g, 4,33 mmol) dissolved in methanol (40 ml) and the solution cooled to 0°C. are added dropwise thionyl chloride (3,16 ml of 43.3 mmol), the reaction mixture was allow to warm to room temperature and stirring is continued for 12 hours. The reaction solution was concentrated in vacuo to obtain 1.45 g (yield 98%) of the desired product as HCl salt, in the form of a whitish solid product.

The preparation of complex 1-benzyl ester 2-[2-(4-forfinal)acetyl]-4-(2,2-DIMET is propionyloxy)pyrazolidine-1-carboxylic acid (31)

Complex 1-benzyl ester 4-(2,2-dimethylpropionic)pyrazolidine-1-carboxylic acid30(1.45 g, to 4.23 mmol) dissolved in dichloromethane (21 ml). The solution is cooled to 0°C and via syringe is added dropwise a triethylamine (1,30 ml, 9,31 mmol). The cooling bath is removed, the reaction mixture was allow to warm to room temperature and stirring is continued for 20 minutes. Add 4-florfenicol acid (848 mg, of 5.50 mmol). After stirring for 5 minutes the reaction mixture was transferred via cannula into a solution of 1-ethyl-3-(3-(dimethylaminopropyl)carbodiimide hydrochloride in dichloromethane (21 ml)maintained at 0°C. the Reaction mixture is allowed the opportunity to mix and gradually warm to room temperature for 12 hours. The reaction mixture is washed with 5% aqueous solution of Na2CO3(2 · 50 ml). The combined aqueous layers extracted several times with dichloromethane (50 ml) and the combined organic layers washed with saturated saline solution, dried, filtered and concentrated in vacuo. The crude product is purified on silica (hexane/ethyl acetate, 2:1 to 1:1) to obtain the 1,71 g (yield 91%) of the desired product as a white solid product.

The preparation of complex 1-[2-(4-forfinal)acetyl]pyrazolidine-4-silt ether of 2,2-dimethylpropionic acid (32)

Complex 1-benzyl ether -[2-(4-forfinal)acetyl]-4-(2,2-dimethylpropionic)pyrazolidine-1-carboxylic acid 31(1,71 g, 3,86 mmol) dissolved in methanol (40 ml). The flask is rinsed with nitrogen and download it 10% palladium-on-coal (300 mg). The reaction mixture in the flask was vigorously stirred at room temperature under 1 atmosphere of hydrogen gas for 6 hours. The flask is rinsed with nitrogen and the reaction mixture is filtered through a layer of celite, rinsing with ethyl acetate (100 ml). The filtrate was concentrated in vacuo to obtain 1.18 g (yield 98%) of the desired product as a yellowish-brown solid product.

The preparation of complex 1-[2-(4-forfinal)acetyl]-2-(methylsulfonylamino-4-carbonyl)pyrazolidine-4-silt ether of 2,2-dimethylpropionic acid (33)

To a solution of complex 1-[2-(4-forfinal)acetyl]pyrazolidine-4-silt ether of 2,2-dimethylpropionic acid32(427 mg, to 1.79 mmol) in dichloromethane (3 ml) is added 2-methylsulfonylamino-4-carbonylchloride (676 mg, 3.58 mmol)and then added dropwise to 1.0 N. aqueous sodium hydroxide solution (6 ml). The mixture is vigorously stirred at room temperature for 12 hours. The reaction mixture was diluted with dichloromethane (25 ml) and washed with water (25 ml). The aqueous layer was back extracted with dichloromethane (25 ml). The combined organic layers washed with saturated aqueous sodium bicarbonate (25 ml) and saturated brine (25 ml), dried, filtered and concentrated in vacuo. Floor the obtained crude material is purified on silica (1:1 hexane/ethyl acetate to 100% ethyl acetate) to give 464 mg (yield 96,6%) of the desired product as a brown, viscous oil.

Preparation of complex of 6-(4-forfinal)-7-(2-methylsulfonylamino-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether of 2,2-dimethylpropionic acid (34)

Complex 1-[2-(4-forfinal)acetyl]-2-(methylsulfonylamino-4-carbonyl)pyrazolidine-4-silt ether of 2,2-dimethylpropionic acid33(300 mg, 0,651 mmol) dissolved in THF (6 ml). Then this solution was added dropwise via cannula to a suspension of NaH (29 mg, 60% dispersion in mineral oil, 0,716 mmol) at -30°C. the Reaction mixture is allowed gradually to warm to 0°C, for 3 hours. The reaction is quenched with NH4Cl (saturated aqueous solution) (1 ml). The mixture is stirred at room temperature, then concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 ml) and the mixture filtered through celite. The filtrate was concentrated in vacuo to obtain an orange oil. The crude product is purified on silica (100% ethyl acetate to 5% - 10% - 20% methyl alcohol/ethyl acetate) to give 87 mg (30%yield) of the desired product as a yellow solid product.

Preparation of complex of 6-(4-forfinal)-7-(2-methanesulfonamido-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether of 2,2-dimethylpropionic acid (35)

Complex 6-(4-forfinal)-7-(2-methylsulfonylamino-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether 2,-dimethylpropionic acid 34(96 mg, 0,217 mmol) dissolved in chloroform (2 ml). The solution is cooled to 0°C and a solution of 3-chloroperbenzoic acid (117 mg ˜77% purity, 0,521 mmol) in chloroform (3 ml) is added dropwise to the yellow suspension. The reaction mixture was stirred at 0°C for 3 hours and then at room temperature for 12 hours. The reaction solution yellow washed NaHSO3(saturated aqueous) (2 × 15 ml). The layers are separated and the aqueous layer was extracted with chloroform (2 × 15 ml). The combined organic layers washed with NaHCO3(saturated aqueous solution) (20 ml), dried, filtered and concentrated in vacuo to obtain 50 mg (yield 48%) of the desired product as a yellow oil.

Preparation of 2-(4-forfinal)-6-hydroxy-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it (36)

The solution of complex 6-(4-(forfinal)-7-(2-methanesulfonamido-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether of 2,2-dimethylpropionic acid35(50 mg, 0,105 mmol) in THF (1 ml) slowly candleroom in a solution of sodium phenolate in THF (1 ml) at 0°C. the Cooling bath removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction is quenched with NH4Cl (saturated aqueous) (500 μl). The reaction mixture was concentrated in vacuo and dilute the residue is extracted with ethyl acetate (15ml). The solution was washed with water (20 ml) and 5% aqueous solution of Na2CO3(20 ml). The combined aqueous layers are extracted with ethyl acetate (25 ml) and saturated saline (20 ml), dried, filtered and concentrated in vacuo. The crude material is purified on silica (100% ethyl acetate to 5% - 10% - 20% methyl alcohol/ethyl acetate) to obtain 9 mg (yield 21%) of the desired product as a yellow solid product.1H NMR (300 MHz, CDCl3) δ 8,43 (d, J=5,2 Hz, 1H), 7,46 (t, J=7.8 Hz, 2H), 7,31-7,27 (m, 3H), 7,19 (d, J=8,2 Hz, 2H), 7,03 (t, J=8.6 Hz, 2H), 6,80 (d, J=5,2 Hz, 1H), 5,41 (sirens, 1H), 4,82 (m, 1H), 4,23 (d, J=12,4 Hz, 1H), 3,95-of 3.85 (m, 2H), 3,76 (DD, J=12,4, 4,4 Hz, 1H); HRMS m/z calculated for C22H18FN4O3(MH+) 405,1363; found 405,1365.

This procedure may be used to prepare compounds of the type III of the first aspect, where R8represents a C1-C4alkyl. The conversion of intermediate compounds28in the intermediate connection type IV, such as methoxycoumarin37using the following procedure enables the manufacturer of the drug to collect 6-alkoxysilane connection type III.

Reagents and conditions: CH3I, Ag2O; DMF; in the dark, room temperature, 12 hours

EXAMPLE 11

The preparation of complex 1-benzyl ether complex 2-butyl methyl ether 4-methoxypiperidine-1,2-dicarbon the Oh of the acid (37)

Complex 1-benzyl ether complex 2-tributyl ether 4-methoxypiperidine-1,2-dicarboxylic acid28(2.55 g, to $ 7.91 mmol) dissolved in dimethylformamide (40 ml). Add methyliodide (1.97 ml of 31.6 mmol), and then the silver oxide (3,67 g, 15.8 mmol). The flask was covered with foil and the contents stirred for 12 hours, in the absence of light. The reaction mixture is poured into a simple ether (150 ml). The mixture is vigorously stirred at room temperature and filtered through a layer of celite. The filtrate is washed with water (2 × 150 ml) and saturated brine (150 ml), dried, filtered and concentrated in vacuo to obtain 2.58 g (yield 97%) of the desired product as a yellow transparent oil.

The second aspect of compounds of the type III refers to structures having a substituent R2in the 6-position of the pyrazolo[1,2-a]pyrazole-1-about ring system, which includes a carbonyl group selected from -(CH2)jCO2R10; -(CH2)jOCO2R10; -(CH2)jCON(R10)2; and -(CH2)jOCON(R10)2where R10is the same as defined above. A non-limiting example of compounds in accordance with the second aspect of the type III has the formula:

Table VI illustrates examples of this aspect of the present invention, where two radicals R10 together form a ring.

Table VI
No.R1R3Ring with R10
2814-forfinalphenylmorpholine-1-yl
2824-forfinal4-forfinalmorpholine-1-yl
2834-forfinal2-AMINOPHENYLmorpholine-1-yl
2844-forfinal2-weremorpholine-1-yl
2854-forfinal4-weremorpholine-1-yl
2864-forfinal4-methoxyphenylmorpholine-1-yl
2874-forfinal4-(propanesulfonyl)phenylmorpholine-1-yl
2884-forfinal3-benzo[1,3]dioxol-5-ylmorpholine-1-yl
2894-forfinalpyridine-2-ylmorpholine-1-yl
2904-forfinalpyridine-3-ylmorpholine-1-yl
2914-forfinalphenylPiperi is Jn-1-yl
2924-forfinal4-forfinalpiperidine-1-yl
2934-forfinal2-AMINOPHENYLpiperidine-1-yl
2944-forfinal2-werepiperidine-1-yl
2954-forfinal4-werepiperidine-1-yl
2964-forfinal4-methoxyphenylpiperidine-1-yl
2974-forfinal4-(propanesulfonyl)phenylpiperidine-1-yl
2984-forfinal3-benzo[1,3]dioxol-5-ylpiperidine-1-yl
2994-forfinalpyridine-2-ylpiperidine-1-yl
3004-forfinalpyridine-3-ylpiperidine-1-yl
3014-forfinalphenylpiperazine-1-Il
3024-forfinal4-forfinalpiperazine-1-Il
3034-forfinal2-AMINOPHENYLpiperazine-1-Il
3044-forfinal2-werepiperazin-1-yl
3054-forfinal4-werepiperazine-1-Il
3064-forfinal4-methoxyphenylpiperazine-1-Il
3074-forfinal4-(propanesulfonyl)phenylpiperazine-1-Il
3084-forfinal3-benzo[1,3]dioxol-5-ylpiperazine-1-Il
3094-forfinalpyridine-2-ylpiperazine-1-Il
3104-forfinalpyridine-3-ylpiperazine-1-Il

As described above, the procedure for obtaining compounds included in the first aspect of type III, addresses the final stage, where the O-protective group, among other things,- C(O)C(CH3)3is removed at the same stage, where the radical OR3included in the structure, for example, by converting35in36. For compounds of the second aspect, the following procedure, as described below, is used to prepare compounds where the radical R2in the 6-position represents a carbonyl group, as described herein, relative to a second aspect of type III.

The following diagram begins with the intermediate connection11prepared as op is described above.

Reagents and conditions: (a) BH3:DMS, THF; -78°C, 1 o'clock

Reagents and conditions: (b) p-nitrophenyl chloroformiate, CH2Cl2, pyridine, 0°C, 1 h, room temperature, 12 hours

Reagents and conditions: (c) morpholine, CH2Cl2at room temperature for 1.5 hours

Reagents and conditions: (d) H2Pd/C, MeOH, room temperature, 2,5 hours

Reagents and conditions: (e) 1 n NaOH, CH2Cl2.

Reagents and conditions: (b) NaH, THF, DMF: -10°C, 1 h, 0°C, 2 hours

EXAMPLE 12

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

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-hydroxypyrrolidine-1-carboxylic acid (38)

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid11(1.0 g, of 2.81 mmol) dissolved in THF (30 ml) and the solution cooled to -78°C. are added dropwise 5.0 M solution of the complex brandibelle simple ether (1.2 ml, 5,61 mmol). After 1 hour at -78°C the reaction is quenched by slow addition of NH4Cl (saturated aqueous solution) (10 ml). Then ohla is giving bath removed and the mixture allow to warm to room temperature with vigorous stirring. THF is removed in vacuo and the residue diluted with water (50 ml). The mixture is extracted with ethyl acetate (2 × 100 ml), dried, filtered and concentrated in vacuo to obtain a yellow oil, which was purified on silica (hexane/ethyl acetate, from 1:1 to 1:2, to 100% ethyl acetate) to obtain 731 mg (yield 73%) of the desired product as a clear viscous oil.

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-(4-nitrobenzeneboronic)pyrazolidine-1-carboxylic acid (39)

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-hydroxypyrrolidine-1-carboxylic acid38(366 mg, of 1.02 mmol) dissolved in dichloromethane (10 ml). The solution is cooled to 0°C and at once add p-nitrophenylphosphate (411 mg, 2.04 mmol). The solution was stirred at 0°C and add pyridine (198 μl, 2.45 mmol). Stirring is continued at 0°C for 1 hour, followed by stirring at room temperature for 12 hours. The reaction mixture was diluted with water (40 ml) and extracted with dichloromethane (40 ml). The organic layer is washed with 0.5 N. NaOH (2 × 40 ml). The combined aqueous layers are back extracted with dichloromethane (30 ml). The combined organic layers washed with saturated saline solution (30 ml), dried, filtered and concentrated in vacuo. The crude material is purified on silica (hexane/ethyl acetate, 3:1 to 2:1 to 1:1) with the floor is rising 462 mg (yield 86%) of the desired product as a white foam.

The preparation of complex 1-benzyloxycarbonyl-2-[2-(4-(forfinal)acetyl]pyrazolidine-4-silt ether morpholine-4-carboxylic acid (40)

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-(4-nitrobenzeneboronic)pyrazolidine-1-carboxylic acid39(462 mg, 0,882 mmol) dissolved in dichloromethane (9 ml). Add morpholine (770 μl, 8,82 mmol)and the reaction mixture immediately becomes bright yellow color. After stirring for approximately 1.5 hours at room temperature, the reaction mixture was diluted with dichloromethane (20 ml) and washed with 5% solution of Na2CO3(2 × 20 ml). The combined aqueous layers extracted with dichloromethane (20 ml), organic layers combined, washed with water, saturated salt solution and dried. The solvent is removed in vacuum to obtain 414 mg of the desired product as a clear oil.

The preparation of complex 1-[2-(4-forfinal)acetyl]pyrazolidine-4-silt ether morpholine-4-carboxylic acid (41)

Complex 1-benzyloxycarbonyl-2-[2-(4-(forfinal)acetyl]pyrazolidine-4-silt ether morpholine-4-carboxylic acid40(512 mg, of 1.09 mmol) was dissolved in methanol (10 ml) and the flask is rinsednitrogen, then it loads 10% palladium-on-coal (103 mg). The reaction mixture is vigorously stirred and hydronaut at 1 atmosphere for 2.5 h at room temperature. The reaction mixture was fil who demonstrate through a layer of celite, washed with ethyl acetate (100 ml) and concentrated in vacuo to obtain 354 mg of the desired product as a white powder.

The preparation of complex 1-[2-(4-forfinal)acetyl]-2-(2-phenoxypyridine-4-carbonyl)pyrazolidine-4-silt ether morpholine-4-carboxylic acid (42)

Complex 1-[2-(4-forfinal)acetyl]pyrazolidine-4-silt ether morpholine-4-carboxylic acid41(354 mg, 1.05 mmol) and 2-phenoxypyridine-4-carbonylchloride18(345 mg, about 1.47 mmol) dissolved in dichloromethane (2 ml). Added dropwise to 1.0 N. NaOH (3 ml) at room temperature while vigorously stirred. Reactions allow to occur within 12 hours, then add additional acid chloride,18and stirring is continued for 3 hours. Add additional acid chloride18(83 mg), and stirring is continued for an additional 12 hours. After this time the reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The combined organic layers washed with NaHCO3(saturated solution) (50 ml) and saturated saline (50 ml), dried, filtered and concentrated to obtain a brown oil. The crude material is purified on silica (100% ethyl acetate to 5% methyl alcohol/ethyl acetate)to give 348 mg (yield 61%) of the desired product as a viscous oil.

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

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

The third aspect of compounds of the type III refers to amino groups having the formula:

where the radicals R are amines having the formula-NH[CHR5b] 6and R1, R5b, R6and R8described below in table VII.

Table VII
No.R1R5bR6R8
3114-forfinalHPhenylmethyl
3124-forfinalH4-forfinalmethyl
3134-forfinalH2-AMINOPHENYLmethyl
3144-forfinalH2-weremethyl
3154-forfinalH4-weremethyl
3164-forfinalH4-methoxyphenylmethyl
3174-forfinalH4-(propanesulfonyl)phenylmethyl
3184-forfinalH3-benzo[1,3]dioxol-5-ylmethyl
3194-forfinalHpyridine-2-ylmethyl
3204-forfinal Hpyridine-3-ylmethyl
3214-forfinalHHmethyl
3224-forfinalHMethylmethyl
3234-forfinalHEthylmethyl
3244-forfinalHVinylmethyl
3254-forfinalHCyclopropylmethyl
3264-forfinalHCyclohexylmethyl
3274-forfinalHMethoxymethylmethyl
3284-forfinalHMethoxyethylmethyl
3294-forfinalH1-hydroxy-1-methylethylmethyl
3304-forfinalH-CO2Hmethyl
3314-forfinalmethylPhenylmethyl
3324-forfinalmethyl4-forfinalm is Teal
3334-forfinalmethyl2-AMINOPHENYLmethyl
3344-forfinalmethyl2-weremethyl
3354-forfinalmethyl4-weremethyl
3364-forfinalmethyl4-methoxyphenylmethyl
3374-forfinalmethyl4-(propanesulfonyl)phenylmethyl
3384-forfinalmethyl3-benzo[1,3]dioxol-5-ylmethyl
3394-forfinalmethylpyridine-2-ylmethyl
3404-forfinalmethylpyridine-3-ylmethyl
3414-forfinalmethylHmethyl
3424-forfinalmethylMethylmethyl
3434-forfinalmethylEthylmethyl
3444-forfinalmethyl methyl
3454-forfinalmethylCyclopropylmethyl
3464-forfinalmethylCyclohexylmethyl
3474-forfinalmethylMethoxymethylmethyl
3484-forfinalmethylMethoxyethylmethyl
3494-forfinalmethyl1-hydroxy-1-methylethylmethyl
3504-forfinalmethyl-CO2Hmethyl

Compounds which comprise the third aspect of type III of the present invention can be prepared using the procedures described below on the basis of the intermediate28.

Reagents and conditions: (a) CH3I, Ag2O, DMF, in the dark, room temperature, 12 hours

Reagents and conditions: (b) SOCl2, MeOH; 0°C to room temperature, 12 hours

Reagents and conditions: (c) RCOCl, NaOH, room temperature, 6 hours

Reagents and conditions: (6) H2 : Pd/C, MeOH, room temperature, 3 hours

Reagents and conditions: (e) NaOH: CH2Cl2/water, room temperature, 4 hours

Reagents and conditions: (h) NaH, DMF; 0°C to room temperature for 2 hours.

Reagents and conditions: (g) m-chloroperbenzoic acid; CH2Cl2; room temperature, 30 minutes

Reagents and conditions: (h) toluene; 120°C, 2 hours.

EXAMPLE 13

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

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylic acid (44)

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-hydroxypyrrolidine-1-carboxylic acid28(2.55 g, to $ 7.91 mmol) dissolved in dimethylformamide (40 ml). Add methyliodide (1.97 ml of 31.6 mmol), and then the silver oxide (3,67 g, 15.8 mmol). The flask was covered with foil and the contents stirred overnight in the absence of light. The reaction mixture is poured into a simple ether (150 ml). The mixture is vigorously stirred at room temperature and filtered through a layer of celite. The filtrate is washed with water (2 × 150 ml) and saturated brine (150 ml), dried over sodium sulfate, filtered and conc is the shape in vacuum to obtain 2.58 g (yield 97%) of the desired product as a yellow transparent oil.

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-(4-methoxy)pyrazolidine-1-carboxylic acid (45)

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylic acid44(to 2.57 g of 7.64 mmol) is dissolved in methyl alcohol (75 ml) and the solution cooled to 0°C. are added dropwise thionyl chloride (5,58 ml, to 76.4 mmol) and the reaction mixture was allow to warm to room temperature over night. The reaction solution was concentrated in vacuo to obtain 2,07 g (yield 99%) of the desired product as HCl salt, in the form of a whitish solid product.

The preparation of complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylic acid (46)

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-(4-methoxy)pyrazolidine-1-carboxylic acid45(8,81 g, and 32.3 mmol) dissolved in dichloromethane (150 ml). Add 4-pertenecer chloride (5.31g, to 38.8 mmol), and then to 0.5 N. aqueous sodium hydroxide solution (150 ml). The mixture is vigorously stirred at room temperature for 6 hours. The reaction mixture was diluted with dichloromethane (200 ml) and washed with water (200 ml). The aqueous layer was extracted with dichloromethane (2 × 200 ml). The combined organic layers washed with 5% aqueous sodium carbonate solution (250 ml) and saturated brine (250 ml), dried over sodium sulfate, introit and concentrated in vacuo to obtain 12.0 g of the desired product as a viscous yellow-brown oil.

Preparation of 2-(4-forfinal)-1-(4-methoxypiperidine-1-yl)ethanone (47)

Complex benzyl ester 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylic acid46(12.0 g, to 32.2 mmol) is dissolved in methyl alcohol (300 ml). The flask is rinsed with nitrogen and download it 10% palladium-on-coal (1.2 g). The reaction mixture was vigorously stirred at room temperature under 1 atmosphere of gaseoushydrogen for 3 hours. The flask is rinsed with nitrogen and the reaction mixture is filtered through a layer of celite, rinsing with ethyl acetate (100 ml). The filtrate was concentrated in vacuo to obtain to 7.67 g of the desired product as a viscous clear oil.

Preparation of 2-(4-forfinal)-1-[4-methoxy-2-(2-methylsulfonylamino-4-carbonyl)pyrazolidine-1-yl]ethanone (48)

2-(4-Forfinal)-1-(4-methoxypiperidine-1-yl)alanon47(to 7.67 g is 32.2 mmol) and 2-methylsulfonylamino-4-carbonylchloride (9,11 g, to 48.3 mmol) dissolved in dichloromethane (150 ml). 0,5 N. aqueous sodium hydroxide solution (150 ml) was carefully added via addition funnel and the mixture is vigorously stirred at room temperature for 4 hours. The reaction mixture was diluted with 5% aqueous sodium carbonate solution (1 l). The mixture is extracted with dichloromethane (6 × 200 ml). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to obtain a red oil. When Roy material is purified on silica (hexane/ethyl acetate, from 1:1 to 1:3, to 100% ethyl acetate) to obtain 10.3 g of the desired product as a brown viscous oil.

Preparation of 2-(4-forfinal)-6-methoxy-3-(2-methylsulfonylamino-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-she (49)

A solution of 2-(4-forfinal)-1-[4-methoxy-2-(2-methylsulfonylamino-4-carbonyl)pyrazolidine-1-yl]ethanone48(2,04 g, with 5.22 mmol) in a mixture of 1:1 dimethylformamide/tetrahydrofuran (30 ml) was added dropwise to a suspension of sodium hydride (230 mg, 60% dispersion in mineral oil, of 5.75 mmol), at 0°C in dimethylformamide (60 ml). After 2 hours at 0°C bright redthe solution is quenched by slowly adding saturated aqueous solution of ammonium chloride (5 ml). The cooling bath removed and the solution allow to warm to room temperature. The reaction mixture was concentrated in vacuo and the resulting residue diluted with ethyl acetate (175 ml). The mixture was washed with saturated aqueous ammonium chloride (150 ml). The aqueous layer was extracted with ethyl acetate (4 × 75 ml). The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified on silica gel (100% ethyl acetate to 5% - 10% - 20% methyl alcohol/ethyl acetate) to obtain 1.1 g (yield 57%) of the desired product as an orange oil.

Preparation of 2-(4-forfinal)-6-methoxy-3-(2-methanesulfonamido-4-yl)-(6,-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it (50)

2-(4-Forfinal)-6-methoxy-3-(2-methylsulfonylamino-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he49(1.10 g, 2,95 mmol) diluted with dichloromethane (60 ml). To the yellow suspension at one time add 3-chloroperbenzoic acid (662 mg ˜77% purity, 2,95 mmol). After 20 minutes add additional 3-chloroperbenzoic acid (240 mg, 1.07 mmol). After 10 minutes, clear yellow reaction solution was poured into 10% aqueous solution of sodium bisulfite (60 ml). The layers are separated and the aqueous layer was extracted with dichloromethane (2 × 50 ml). The combined organic layers washed with saturated aqueous sodium bicarbonate (2 × 50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 948 mg of a mixture of the corresponding sulfoxide and sulfone in the form of a yellow solid product. Use as is for the next stage.

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

A mixture of 2-(4-(forfinal)-6-methoxy-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it50(948 mg, 2,44 mmol) and (S)-2-amino-1-methoxypropane (652 mg, to 7.32 mmol) diluted with toluene (16 ml). The mixture is heated to 120°C for 2 hours. The orange solution allow to cool to room temperature before concentration in vacuo from gaining the m orange residue. The crude product is purified on silica (methyl alcohol/dichloromethane, 5% to 10%) to obtain 550 mg of the desired product in the form of fluorescing yellow solid product.1H NMR (300 MHz, CDCl3) δ is 8.16 (d, J=5,1 Hz, 1H), 7,40 (DD, J=8,8, 5.5 Hz, 2H), 7,03 (t, J=8,8 Hz, 2H), to 6.39 (d, J=5,1 Hz, 1H), 5,39 (userend, J=8.0 Hz, 1H), 4,57 (m, 1H), 4,30-was 4.02 (m, 5H), of 3.45 (d, J=4,6 Hz, 2H), 3,42 (s, 3H), 3,39 (s, 3H), of 1.28 (d, J=6.6 Hz, 3H); HRMS m/z calculated for C21H25FN5O3(MH+) 414,1941 found 414,1945.

Using an intermediate connection10that includes the 6-methylene group, the following compound can be prepared using similar procedures as described above:

2-(4-forfinal)-6-methylene-3-[2-(2-(S)-phenyl-1-methylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it,52;1H NMR (CDCl3, 300 MHz) δ and 1.60 (d, 3H, J=6.9 Hz), to 4.52 (DD, 2H, J=15,9, 24 Hz), 5.08 to further 5.15 (m, 2H), 5,26 (s, 1H), 6,03 (s, 1H), 6,38 (d, 1H, J=5,1 Hz), 7,00-7,05 (m, 2H), 7,22-7,42 (m, 8H), 8,16 (d, 1H, J=5,1 Hz). HRMS: exact mass of C25H22FN5O 428,1887 (M++H), found 428,1871.

The intermediate connection10can also be oxidized under standard conditions, in accordance with the scheme below using OsO4with the intermediate connection53:

which can be used to prepare the following:

2-(4-forfinal)-6-hydroxy-6-guide is oxymethyl-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it, 54;1H NMR (DMSO-d6, 300 MHz) δ 3,41-to 3.52 (m, 2H), 3.72 points-3,86 (m, 3H), of 3.94 (d, 1H, J=11,1 Hz), 5,23 (t, 1H, J=5.7 Hz), 5,71 (s, 1H), 7,06 (d, 1H, J=4,8 Hz), 7.18 in-7,34 (m, 5H), 7,40-to 7.50 (m, 4H), 8,69 (d, 1H, J=4,8 Hz). ESI MS: m/z (relative intensity) 435,32 (100, M++H). Anal. calculated for C23H19FN4O40,5H2O: C, 62,30; H, 4,55; N, 12,63. Found: C, 62,33; H, 4,13; N, 12,41.

Other compounds of the present invention, which can be prepared using procedures or their modifications described above, include the following:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Compounds of the present invention is distributed to multiple types in order to help the manufacturer of the drug to use rational strategy synthesis for the preparation of compounds. The distribution of types does not increase or decrease the effectiveness of any of the compositions described herein.

Compounds listed and described above, as found, in many cases active (value IC50in the analysis using cells, described below, or in those which are mentioned here) at a level lower than 1 micromoles (μm).

Compounds of the present invention is the contrasted effectively block the production of inflammatory cytokines from cells thus giving the opportunity to mitigate, alleviate, control, elimination, slowing or preventing one or more medical conditions or syndromes that are associated with the release from cells of one or more cytokines. Inflammatory painful conditions include those that are associated with the following non-limiting examples:

i) interleukin-1 (IL-1): is measured as the molecule responsible for a large number of painful conditions, among other things, for rheumatoid arthritis, osteoarthritis, and other painful conditions that are associated with the degradation of connective tissue;

ii) the cyclooxygenase-2 (COX-2)inhibitors of the release of cytokines, as expected, participate as inhibitors induced the expression of COX-2, which, as shown, increases under the action of cytokines. M.K. O Banion et al., Proc. Natl. Acad. Sci. USA, 89, 4888 (1998);

iii) tumor necrosis factor-α (TNF-α): this Pro-inflammatory cytokine, assumed to be involved as an important mediator in many disease States or syndromes, among other things, in rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease and cachexia.

Each of painful conditions or statuses to the E. the manufacturer of the drug wants to heal, may require different levels or amounts of compounds described herein, to obtain a therapeutic level. The manufacturer of the drug can determine this amount by using any of the known procedures of research that well-known experts in this field.

In addition, the present invention relates to compounds represented that, under normal physiological conditions of the human or higher mammal, release the compounds described herein. One aspect of the present invention includes pharmaceutically acceptable salts of the compounds described herein. Depending on destination, shipping method, compatibility with fillers and the like can prefer one salt form of the compounds represented another, because the connections themselves are active particles, which mitigate the painful processes described here.

Associated with this aspect are various forms predecessors "Pro-drug" of the present invention. It may be desirable to prepare compounds of the present invention in the form of chemical particles, which are, by themselves, do not show activity against the activity of the cytokines described here, but, instead, represent the form of the presented compounds, the cat is who, when they are delivered into the body of a human or higher mammal, undergo chemical interaction catalyzed normal functioning of the body, among other enzymes present in the stomach, blood serum, and the specified chemical interaction releases the original connection. The term "Pro-drug" refers to those particles, which are converted in vivo to the active drug.

DRUGS

The present invention also relates to compositions or preparations which contain compounds that inhibit the release of inflammatory cytokines, according to the present invention. In General, the compositions of the present invention contain:

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

b) one or more pharmaceutically acceptable excipients.

In the present invention, the terms "filler" and "carrier" are used interchangeably throughout the description of the present invention, and these terms are defined here as "the ingredients that are used in the practice of making safe and effective pharmaceutical compositions.

It is clear that the fillers used which are, first of all, in order to serve in the delivery of safe, stable and functional pharmaceuticals, serving not only as part of a common carrier for delivery, but also as a means to achieve effective absorption by the patient of the active ingredient. The filler can play the role as a simple and direct filler, such as an inert filler, or filler, as it is used here, can be a part of the stabilization system pH or coating to ensure the safe delivery of the ingredients in the stomach. You can also use the fact that the compounds of the present invention have an improved effect on the cells, pharmacokinetic properties, and improved bioavailability when administered orally.

The present invention also relates to compositions or preparations that contain the form of a precursor or Pro-drugs of compounds inhibiting the release of inflammatory cytokines of the present invention. In General, these compositions containing the predecessors of the present invention, include:

a) an effective amount of one or more derivatives of bicyclic pyrazolones of the present invention, which act to release in vivo of the corresponding connection is to be placed, which are effective for inhibiting release of inflammatory cytokines; and

b) one or more pharmaceutically acceptable excipients.

METHOD of USE

The present invention also relates to a method for control of the level of one or more cytokines that induce inflammation, inter alia, interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8), and, thereby, driving, Poreba or eliminating painful conditions, which affect the extracellular levels of inflammatory cytokines. The present method includes a stage of introduction of the human or higher mammal an effective amount of a composition containing one or more inhibitors of inflammatory cytokines of the present invention.

As inhibitors of inflammatory cytokines of the present invention can be delivered in such a way that can be achieved with more than one active control center, at the same time can be modulated more than one painful condition. Non-limiting examples of diseases that are subject to the control or inhibition by inhibitors of inflammatory cytokines, and thus modulating the excessive activity of cytokines include osteoarthritis, rheumatoid arthritis, di is Beth, infection of human immunodeficiency virus (HIV).

PROCEDURES

Compounds of the present invention can be assessed for effectiveness, for example, measuring the constants of inhibition of cytokines, values of KIand IC50can be done using any method chosen by the manufacturer of the drug.

Non-limiting examples of appropriate tests include:

i) analysis of the substrate-enzyme complexes in the UV and visible light, as described L. Al Reiter, Int. J. Peptide Protein Res., 43,87-96 (1994);

ii) fluorescent analysis of substrate-enzyme complexes, as described Thornberry et al., Nature, 356, 768-774 (1992);

iii) analysis using PBMC cells (mononuclear peripheral blood cells), as described in U.S. patent No. 6204261 B1, Bachelor et al., issued March 20, 2001.

Each of the above sources is included here as a reference.

In addition, inhibition of tumor necrosis factor, TNF-αcan be measured by using human monocytes (THP-1)stimulated by lipopolysaccharide (LPS), as described in the

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

ii) in U.S. patent No. 6297381 B1, Cirillo et al., issued October 2, 2001, included here as a reference and reproduced below, in that part of it which is relevant to the present description.

<> Inhibition of the production of cytokines can be observed by measuring the inhibition of TNF-α in cells THP stimulated by lipopolysaccharides. All cells and reagents were diluted in RPMI 1640 with phenol red and L-glutamine, to which is added an extra L-glutamine (General: 4 mm), penicillin and streptomycin (50 units/ml each) and fetal bovine serum (FBS 3%) (GIBCO, all concentrations are final).

The analysis is carried out in sterile conditions, only the study drug compound is non-sterile. Source uterine solutions prepared in DMSO, followed by dilution in RPMI 1640, higher, 2 times the desired final concentration in the analysis. Confluent cells THP-1 (2 × 106cells/ml, final concentration; American Type Culture Company, Rockville, Md.) add in 96-well polypropylene round-bottom plates to crops (Costar 3790; sterile)containing 125 μl of the compounds (2-fold concentration) or the carrier DMSO (control, empty). The final concentration of DMSO should not, ultimately, to exceed 0.2%. Cell culture provide an opportunity for pre-incubation for 30 minutes at 37°C, 5% CO2before stimulation lipolysaccharide (LPS, 1 μg/ml final; Sigma L-2630 from E. coli, serotype 0111.B4; store in the form of a stock solution of 1 mg/ml, tested for endotoxins is assaultmom H 2O the media at -80°C). Empty (estimulando) cells takes H2O media; the final volume of the incubation of 250 μl. Incubation (4 hours) is carried out as described above. The analysis should be completed by centrifugation tablets for 5 minutes at room temperature, 1600 rpm (4033×g); then supernatant transferred to clean 96 well plates and stored at -80°C until their analysis on TNF-α man using a commercially available ELISA kit (Biosource #KHC3015, Camarillo, Ca.). The calculated value of the IC50represents the concentration of the tested compound that causes 50% reduction in the maximum production of TNF-α.

Although illustrated and described a specific embodiment of the present invention, the person skilled in the art would be obvious that numerous other changes and modifications can be made without changing the scope of the present invention.

1. The compound having the formula

where R is selected from the

a) a fragment having the formula-OR3where R3is selected from the group consisting of phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,6-dipthera, 2-cyanophenyl, 3-cyanophenyl, 2-triptoreline, 4-trifloromethyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimetilfenil, 3-N-acetylamino the sludge, 2-methoxyphenyl, 4-methoxyphenyl and 3-benzo[1,3]dioxol-5-yl;

b) a fragment having the formula

where R6is selected from the group consisting of hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy, phenyl, 4-ftoheia, 2-AMINOPHENYL, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridin-2-yl, pyridin-3-yl; or

C) a fragment having the formula

where R6is selected from the group consisting of hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy, phenyl, 4-ftoheia, 2-AMINOPHENYL, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridin-2-yl,pyridin-3-yl,

each radical R2independently selected from the group consisting of

a)hydrogen;

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

(C) -(CH2)jNR9aR9b;

(e) -(CH2)jOCO2R10;

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

R8, R9aR9band R10are each, independently, hydrogen, C1- 4alkyl; or

R9aand R9bmay together form a 5-6-membered heterocyclic ring containing 1-2 heteroatom selected from nitrogen and/or oxygen; or

two radicals R10may together form a 5-6-membered heterocyclic ring containing 1-2 heteroatom selected from nitrogen and/or oxygen;

j represents 0, n represents an index of 0.

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

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

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

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

where R is selected from the

a) a fragment having the formula-OR3where R3is selected from the group consisting of phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,6-dipthera, 2-cyanophenyl, 3-cyanophenyl, 2-triptoreline, 4-trifloromethyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimetilfenil, 3-N-acetylaminophenol, 2-methoxyphenyl, 4-methoxyphenyl and 3-benzo[1,3]dioxol-5-yl;

b) a fragment having the formula

where R6is selected from the group consisting of hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, m is toximeter, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy, phenyl, 4-ftoheia, 2-AMINOPHENYL, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridin-2-yl, pyridin-3-yl; or

C) a fragment having the formula

where R6is selected from the group consisting of hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy, phenyl, 4-ftoheia, 2-AMINOPHENYL, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3] dioxol-5-yl, pyridin-2-yl, pyridin-3-yl;

R8represents hydrogen, C1-4alkyl;

the index j is 0 and n is 0.

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

where R is selected from the

a) a fragment having the formula-OR3where R3is selected from the group consisting of phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,6-dipthera, 2-cyanophenyl, 3-cyanophenyl, 2-triptoreline, 4-trifloromethyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimetilfenil 3-N-acetylaminophenol, 2-methoxyphenyl, 4-methoxyphenyl and 3-benzo[1,3]dioxol-5-yl;

b) a fragment having the formula

where R6is selected from the GRU is dust, consisting of hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy, phenyl, 4-ftoheia, 2-AMINOPHENYL, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridin-2-yl, pyridin-3-yl; or

C) a fragment having the formula

where R6is selected from the group consisting of hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy, phenyl, 4-ftoheia, 2-AMINOPHENYL, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridin-2-yl, pyridin-3-yl;

R9aand R9bare each, independently, hydrogen or C1-C4alkyl;

R9aand R9btogether can form a carbocyclic or heterocyclic ring containing 5 to 6 atoms in the cycle and 1-2 heteroatoms selected from nitrogen or oxygen; the index j is equal to 0.

7. The compound having the formula

where the radical R2is selected from the group consisting of

a) hydrogen;

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

(C) -(CH2)jNR9aR9b;

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

R8, R9aR9band R10are each, independently, hydrogen, C1-C4alkyl; or

R9band R9bmay together form a 5-6-membered heterocyclic ring containing 1-2 heteroatom selected from nitrogen and/or oxygen; or

two radicals R10may together form a 5-6-membered heterocyclic ring containing 1-2 heteroatom selected from nitrogen and/or oxygen;

j represents 0, n represents an index of 0;

R3represents aryl represents unsubstituted phenyl or phenyl substituted by halogen, C1-4-alkyl, Halogens1-4-alkyl, C1-4-acylamino, C1-4-alkoxy, amino, cyano, C1-4-alkylsulfonyl, methylendioxyphenyl, 6-membered nitrogen containing heteroaryl; the index k is equal to 0.

8. The compound having the formula

where the radical R2is selected from the group consisting of

a) hydrogen;

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

c) - (CH2)jNR9aR9b;

R8, R9a, R9bare each, independently, hydrogen, C1-C4alkyl; or

R9band R9bmay together form a 5-6-member of the second heterocyclic ring, containing 1-2 heteroatoms selected from nitrogen and/or oxygen; or

j is an index 0; n represents an index of 0;

R4arepresents hydrogen;

one of R5aand R5brepresents, independently, hydrogen, and the other is hydrogen, -CO2R7linear C1-C4alkyl;

R6represents hydrogen, -OR7, -CO2R7; substituted or unsubstituted With1-C4alkyl, where the substituents are selected from hydroxy, C1-C4-alkoxy; substituted or unsubstituted phenyl, where the substituents are selected from C1-C4-alkyl, halogen-C1-C4-alkyl With1-C4-alkoxy, halogen, amino, cyano, C1-C4-alkylsulfonyl or methylenedioxy; or an unsubstituted 5-6-membered heteroaryl, which heteroatom is selected from nitrogen;

R7represents hydrogen, a water-soluble cation or1-C4-alkyl, index m equal to the number 1.

9. The compound having the formula

where R5brepresents methyl; R6is selected from the group consisting of-OH, -CO2H and CO2CH3.

10. The compound according to claim 1, selected from the group consisting of

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

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

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

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

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

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

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

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

11. The compound according to claim 1, selected from the group consisting of

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

12. The compound according to claim 1, selected from the group consisting of

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

13. Pharmaceutical composition having the properties of an inhibitor of the release of inflammatory cytokines from cells containing

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

b) one or more pharmaceutically acceptable excipients.

14. Method of inhibiting the release of CL is current inflammatory cytokines in humans and higher mammals, includes introduction to the specified people or higher mammal a pharmaceutical composition containing

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, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of sulfamide-substituted imidazotriazinones represented by the general formula (I): Method involves interaction of compound of the formula (II): with sulfuric acid followed by treatment of synthesized substances with thionyl chloride and interaction with amine without their isolation to yield the end compound that is converted if necessary to the corresponding salts or hydrates. Method provides the development of a simple realization of synthesis of sulfamide-substituted imidazotriazinones in large-scale and high yield being without isolation of hydrolysis-sensitive imidazotriazinone sulfonyl chloride in intermediate step with exception of variations in yield at intermediate step of synthesis.

EFFECT: improved method of synthesis.

5 cl, 2 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel condensed derivatives of imidazole that are inhibitors of dipeptidyl peptidase IV. Invention describes compound represented by the following formula (I): or its salt or hydrate wherein T1 represents monocyclic 5-6-membered heterocyclic group comprising one or two nitrogen atoms in ring that can comprise one or more amino-groups as substitutes; X represents (C2-C6)-alkenyl group that can comprise one or more substitutes, (C2-C6)-alkynyl group, phenyl group that can comprise one or some substitutes chosen from alkyl group or halogen atom or phenyl-(C1-C6)-alkyl group; each Z1 and Z2 represents independently nitrogen atom or group of the formula -CR2=; each R1 and R2 represents independently group of the formula -A0-A1-A2 wherein A0 represents a single bond or (C1-C6)-alkylene group that can comprise 1-3 substitutes chosen from group B consisting of given below substitutes; A1 represents a single bond, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, carbonyl group, group represented by formula -O-CO-, group represented by formula -CO-O-, group represented by formula -NRA-, group represented by formula -CO-NRA-, group represented by formula -NRA-CO-, group represented by formula -SO2-NRA-, or group represented by formula -NRA-SO2-; each A2 and RA represents independently hydrogen atom, halogen atom, cyano-group, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, 5-10-membered heteroaryl-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or (C2-C7)-alkylcarbonyl group wherein each A2 and RA can comprise independently 1-3 substitutes chosen from the given below group of substitutes D: when Z2 represents group of the formula -CR2= then R1 and R2 can form in common 5-7-membered ring with exception cases when: [1] R1 represents hydrogen atom; Z1 represents nitrogen atom, and Z2 represents group -CH=; and [2] Z1 represents nitrogen atom and Z2 represents group -C(OH)=; <group of substitutes B>. Group of substitutes B represents group comprising: hydroxyl group, mercapto-group, cyano-group, nitro-group, halogen atom, trifluoromethyl group, (C1-C6)-alkyl group that can comprise one or some substitutes, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, (C1-C)-alkoxy-group, (C1-C6)-alkylthio-group, group represented by formula -SO2-NRB1-RB2, group represented by formula -NRB1-CO-RB2, group represented by formula -NRB1-RB2 (wherein each RB1 and RB2 represents independently hydrogen atom or (C1-C6)-alkyl group), group represented by formula -CO-RB3 (wherein RB3 represents 4-8-membered heterocyclic group), group represented by formula -CO-RB4-RB5, and group represented by formula -CH2-CO-RB4-RB5 wherein RB4 represents a single bond, oxygen atom or group represented by formula -NRB6- wherein each RB5 and RB6 represents independently hydrogen atom, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocycle-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or 5-10-membered heteroaryl-(C1-C6)-alkyl group. Also, invention describes inhibitor, pharmaceutical composition, method of treatment and using based on thereof. Invention describes novel compounds possessing useful biological properties.

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

33 cl, 3 tbl, 352 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to dihydropyrimidine compounds of the formula (I*): their enantiomers, diastereoisomers and pharmaceutically acceptable salts wherein X1, X2 and X3 in common with atoms to which they are added form ring of the formula: or ; R1 represents hydrogen atom; R2, R3*, R4, R5, R6 and R7 have values given in cl. 1 of the invention claim. Also, invention relates to separate dihydropyrimidine compounds. Proposed compounds are inhibitors of calcium channel function being especially inhibitors of Kv1 subfamily of potential-overlapping K+-channels and especially inhibitors of Kv 1.5 that associated with super-rapid activating delayed cleaning K+-flow of Ikur and can be used in treatment of arrhythmia and Ikur-associated diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 589 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

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

12 cl, 4 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to biologically active compounds and concerns the development of a novel substance - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7-(4H)-one sodium salt dihydrate of the formula: . This compound is designated for treatment and prophylaxis of diseases caused by viruses that are pathogenic form humans and animals. Proposed compound protects against infections caused by Rift Valley fever virus. Also, it shows activity against viruses of WEE(West Equine Encephalomyelitis), parainfluenza, respiratory-syncytium, Aujeszky's disease virus, avian infectious laryngotracheitis virus, avian influenza virus - totally against above 10 RNA- and DNA-containing viruses. The proposed compound is active in curative schedule of its using that is especially valuable.

EFFECT: valuable medicinal properties of compound.

1 cl, 6 tbl, 2 dwg, 7 ex

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to novel 3,7-diazabicyclo[3.3.0]octanes of the formula (I): wherein wavy lines mean the possible relative cis- or trans-stereochemistry; R means (C1-C12)-alkyl (possibly substituted and/or terminating by one or more groups chosen from aryl, Het1, -C(O)R5a, -OR5b, -N(R6)R5c, -C(O)XR7, -C(O)N(R8)R5d and -S(O)2R9), Het2, -C(O)R5a, -C(O)XR7 or -S(O)2R9 wherein R5a - R5d in each case mean independently hydrogen atom (H), (C1-C6)-alkyl (possibly substituted and/or terminating by one or more substitute chosen from -OH, (C1-C6)-alkoxy-group, cyano-group, aryl, Het3 and -NHC(O)R10), aryl or Het4; R10means H, (C1-C4)-alkyl; R6 means H, aryl; X means oxygen atom (O); R7 means in each case (C1-C12)-alkyl (wherein alkyl group can be substituted and/or terminating by one substitute chosen from -OH, cyano-group, (C1-C6)-alkoxy-group, -SO2R13a, -C(O)R13b and Het5) wherein R13a and R13b mean independently (C1-C6)-alkyl; R8 means in each case H, (C1-C12)-alkyl, (C1-C6)-alkoxy-group (wherein two latter groups are substituted possibly and/or terminating by one substitute chosen from -OH, (C1-C4)-alkyl and (C1-C4)-alkoxy-group), -D-aryl, -D-Het6, -D-S(O)2R15a wherein R15a means independently aryl; D means a direct bond or (C1-C6)-alkylene; R9 means in each case (C1-C6)-alkyl (possibly substituted and/or terminating by one substitute chosen from aryl) or aryl; R2 means H, -E-OR16, -E-N(R17)R18 or in common with R3 represent =O; R3 means H or in common with R2 represent =O; R16 means H, (C1-C6)-alkyl or -E-aryl; R17 means H; R18 means H; E means in each case a direct bond or (C1-C4)-alkylene; A means -G-; B means -Z-, -Z-N(R22)-Z-, -Z-S(O)n-. -Z-O- (wherein in two latter groups Z is bound to carbon atom carrying R2 and R3); G means a direct bond or (C1-C6)-alkylene; Z means a direct bond or (C1-C4)-alkylene; R22 means independently H; R4 means aryl or het13 wherein both these groups are substituted possibly with one or more substitute chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; Het13 means 5-6-membered heterocyclic group comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur; Het1 - Het6 in each case mean independently 5-6-membered heterocyclic groups comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur wherein these heterocyclic groups are substituted possibly with one or more substitutes comprising (C1-C6)-alkyl or -C(O)R24c wherein R23c means in each case independently (C1-C6)-alkyl; R24c means in each case H or (C1-C6)-alkyl; n means 0, 1 or 2 in each case; Ra - R1 mean independently H or (C1-C4)-alkyl wherein each aryl or aryloxy-group (if not indicated otherwise) is substituted possibly with one or more substitutes chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; or it pharmaceutically acceptable derivative under condition that: (a) when R2 means -E-OR16 or -E-N(R17)R18 wherein E means a direct bond then: (1) A can't mean a direct bond; and (2) B doesn't mean -N(R22)-, -S(O)n-. -O- or -N(R22)-Z- (wherein in the latter group -N(R22) is bound to carbon atom carrying R2 and R3; (b) this compound is not 3,7-bis-(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane, 3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0], 3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane; (c) when R in common with R3 represent =O, and B means -Z-N(R22)- or -N(R22)-Z- then G is not a direct bond. Compounds of the formula (I) can be used as components of a pharmaceutical composition in treatment or prophylaxis of arrhythmia. Also, invention describes methods for its synthesis and intermediate compounds used in these methods.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

38 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to anthranylamidepyridine amides of selective effect as inhibitors of VEGFR-2 and VEGFR-3. Invention describes compounds of the general formula (I): wherein A, B and D represent independently of one another nitrogen atom or carbon atom wherein at least one nitrogen atom is in a ring; E represents aryl comprising 6-12 ring carbon atoms or heteroaryl comprising 5 or 6 ring atoms and comprising in ring instead carbon atom similar or different heteroatoms chosen from nitrogen or sulfur atoms, or represents group -COOR8, -CONR2R3 or -C≡C-R9; G represents nitrogen atom or group -C-X; L represents nitrogen atom or group -C-X; M represents nitrogen atom or group -C-X; Q represents nitrogen atom or group -C-X and wherein a ring comprises maximally one nitrogen atom; X represents hydrogen atom; W represents hydrogen or halogen atom; R1 represents aryl similarly or differently optionally mono- or multi-substituted with halogen atom, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl or group =O and wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 16 ring atoms and comprising in ring instead carbon one or more similar or different heteroatoms, such as oxygen, nitrogen or sulfur and it can be mono-, bi- or tricyclic and condensed additionally condensed with benzene ring; R2 and R3 represent independently of one another hydrogen atom or aryl similarly or differently mono- or multi-substituted with halogen atom, cyano-group, (C1-C6)-alkyl, phenyl, hydroxy-(C1-C6)-alkyl, halogen-(C1-C6)-alkyl or group -NR6R7, -OR5, (C1-C6)-alkyl-OR5-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkenyl wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms and comprising in ring instead carbon one or more heteroatoms, such as nitrogen or sulfur; or R2 and R3 in common with nitrogen atom form (C3-C8)-ring that can comprise optionally one more nitrogen or oxygen atom or it can comprise group -N(R10); R5 represents hydrogen atom; R6 and R7 represent independently of one another hydrogen atom or (C1-C6)-alkyl; R8 represents (C1-C6)-alkyl mono- or multi-substituted optionally with halogen atom or benzyl; R9 represents hydrogen atom or tri-(C1-C6)-alkylsilyl; R10 represents hydrogen atom or (C1-C6)-alkyl, and their isomers, enantiomers and salts also. Also, invention describes a medicinal agent based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 162 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1): , their pharmaceutically acceptable salts or hydrates wherein each among R1, R2 and R3 represents independently hydrogen atom, halogen atom, hydroxy-group, (C1-C8)-alkoxy-group; each among W1 and W2 represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR4, -COONR4 or -NR4CO; R4 represents hydrogen atom, (C1-C8)-alkyl, (C3-C6)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkoxy-group substituted with 1-3 halogen atoms, (C1-C8)-alkylthio-group, (C1-C8)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C1-C3)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

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

6 cl, 1 tbl, 439 ex

FIELD: medicine.

SUBSTANCE: invention relates to perorally delivered pharmaceutical composition including low water-soluble preparation and liquid solvent containing at least one pharmaceutically acceptable solvent, at least one pharmaceutically acceptable fatty acid, and at least one pharmaceutically acceptable organic amine, wherein (a) sufficient part, for example at least 15 mass % of preparation being in dissolved or solubilized form in solvent liquid, and (b) fatty acid and organic amine represent in such total and relative amounts that composition self finely emulsifies in simulated gastric juice. Also disclosed is method for production of said composition.

EFFECT: composition containing preparations with law water-solubility in appropriate concentrations without delay of resorption thereof in body.

24 cl, 10 tbl, 7 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts or solvates wherein m represents 0, 1, 2 or 3; each R1 represents halogen atom or (C1-C6)-alkylcarbonyl; Z1 represents a bond or group -(CH2)q wherein q represents 1 or 2; Z2 represents a bond or group -CH2 under condition that both Z1 and Z2 don't represent a bond simultaneously; Q represents oxygen or sulfur atom or group -CH2 or -NH; R2 represents group of the formula: ; n = 0; each R4, R5, R6 and R7 represents hydrogen atom; R8 represents hydrogen atom or (C1-C6)-alkyl group; R15 represents -C(O)NR17R18 or -NHC(O)R20; t represents 0, 1, 2 or 3; each R16 represents halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, phenyl or (C1-C6)-alkyl; each R17 and R18 represents hydrogen atom or (C1-C6)-alkyl; R20 represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heterocyclic system that can be substituted with (C1-C6)-alkyl. Compounds of the formula (I), their salts and solvates possess a modulating activity with respect to chemokine MIP-1α receptors and can be used in medicine.

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

19 cl, 64 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a preparation containing granulates and extra-granulated compositions. Granulated composition comprises numbers of hardened granules form a melt and containing the constant phase of non-steroid anti-inflammatory drug (NSAID). NSAID is chosen from racemic naproxen, racemic flurbiprofen, racemic ibuprofen and racemic ketoprofen. Granules are prepared by the complete melting of NSAID. Extra-granulated composition comprises a water-insoluble absorbing agent. Absorbing agent represents at least one inorganic substance, stearic acid or its insoluble salt, starch substance, cellulose substance or their mixture, polytetrafluoroethylene powder. The preparation doesn't comprise silicon dioxide. The proposed preparation is used in pain treatment and/or inflammation, and/or fever. The preparation shows improved properties for tabletting, in particular, good fluidity and provides preparing small tablets. The preparation as a single dosed formulation releases high percent of NSAID for relatively short period.

EFFECT: improved and valuable pharmaceutical properties of preparation.

37 cl, 53 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

8 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel using to compounds of the general formula (I): . Also, invention relates to preparing a medicinal agent used for modulating sodium channels and, in particular, in treatment of pain (for example, neuropathic pain), epilepsy, neurodegenerative states and bipolar states.

EFFECT: valuable medicinal properties of compounds.

10 cl, 18 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

Sedative agent // 2295955

FIELD: medicine, chemical-pharmaceutical industry, phytotherapy, pharmacy.

SUBSTANCE: invention relates to designing agents of vegetable origin with sedative effect. Sedative agent is made as a tablet, its core is covered by envelope and tablet contains deviating peony dry extract, lactose, starch, magnesium basic carbonate, polyvinulpyrrolidone and calcium stearate. Envelope contains sugar, magnesium basic carbonate, polyvinylpyrrolidone, titanium dioxide, aerosil, bee wax and vaseline oil taken in the definite ratio. Deviating peony dry extract is prepared from deviating peony rhizomes, roots and herb 40% alcoholic tincture. Invention provides development of agent designated for using in neurotic and neurosis-like states of different genesis that has no toxic effect on morphofunctional state of vital organs and systems of body and doesn't cause impairment of metabolic processes.

EFFECT: valuable medicinal properties of agent.

3 cl

FIELD: medicine, anesthesiology-resuscitation, neuropathology.

SUBSTANCE: it is necessary to carry out oxygenotherapy, intravenous injection of physiological solution and those of hydroxyethyl starch. Also, it is important to inject beta-blocators, heparin, opioids, alpha2-adrenoagonists, antagonists of NMDA-receptors, glucocorticoids, nimotope, actovegin. One should prescribe early enteral nutrition. On stabilizing the parameters of cardio-vascular and respiratory systems it is necessary to inject intravenously the solution of mildronate 10% - 10 ml for 10-14 d once daily and the intake of rheaferon-EC-lipint at the dosage of 10000-15000 U/kg or through a gastric probe for 5 d. The innovation enables to efficiently prevent pneumonia due to adequate immunotherapy of the above-mentioned pathology.

EFFECT: higher efficiency of prophylaxis.

3 ex, 1 tbl

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