Pyridin-3-yl derivatives as immunomodulatory agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

 

The scope of the invention

The invention relates to agonists of S1P1/EDG1 receptor (libedataserverui associated with G-protein, specific sphingosine-1-phosphate receptor) of the formula (I) and their use as active ingredients in obtaining pharmaceutical compositions. The invention also concerns related aspects including methods of making the compounds, pharmaceutical compositions containing the compound of formula (I)and their use as compounds, improves vascular function, and as immunomodulatory agents, either alone or in combination with other active compounds or treatments. In addition, the invention includes the new compounds of formula (II), which are intermediate compounds for preparing compounds of formula (I).

Background of invention

The human immune system is designed to protect the body from foreign organisms and substances that cause infection or disease. Complex regulatory mechanisms provide the orientation of the immune response against the introduced substance or organism, but not against the owner. In some cases, such control mechanisms violated the regulation, which can lead to autoimmune responses. The consequence of uncontrolled response to opalanie is a serious danger to the body, cells, tissue or joint. With modern methods of treatment of the immune system in such cases normally suppressed, and the body's ability to respond to infection is also exposed to serious risk. Typical medications used in this case include azathioprine, chlorambucil, cyclophosphamide, cyclosporine or methotrexate. Corticosteroids that reduce inflammation and suppress the immune response can cause side effects in long-term care. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce pain and inflammation, but they also have unwanted side effects. Alternative treatments include the use of agents, activating or blocking cytokine signaling.

Orally active compounds with immunomodulatory properties, without dangerous immune responses and with reduced side effects significantly improve current methods of treatment of inflammatory diseases.

In the field of organ transplantation, the immune response of the host must be supressive to prevent organ rejection. The transplant organ recipient may be exposed to partial exclusion even when using immunosuppressive drugs. Rejection often occurs in the first few weeks after transplantation, but SL is teas rejection can occur after several months or even years after transplantation. A combination of up to three or four drugs are used together, the most protected from rejection and minimize side effects. Modern standard medications used to treat rejection of transplanted organs, enter into interaction with discrete metabolism in the activation of T-type or b-type lymphocytes. Examples of such drugs are cyclosporine, daclizumab, basiliximab, everolimus or FK506, which interact with the processes of cytokine secretion or signal transmission; azathioprine or Leflunomide, which inhibits the synthesis of nucleotides; or 15-doxicillin, which is the inhibitor of differentiation of cells.

The best results are obtained when immunosuppressive therapy blood, relate to the effects of these drugs; however, generalized immunosuppression, which is achieved with the help of these drugs, weakens the body's immune defenses against infections and malignancies. In addition, standard immunosuppressive drugs are often used in large doses and can cause or accelerate the damage to the body.

Description of the invention

The present invention provides new compounds of formula (I), which are agonists for G protein-conjugated receptor S1P1/EDG and have potent and long-lasting immunomodulatory effect, which is achieved by reducing the number of circulating and infiltracinei T - and b-lymphocytes, without the provision of this damaging impact on their maturation, memory or expansion. Reduction of circulating T - and b-lymphocytes in the S1P1/EDG1 agonism possibly in combination with the observed improvement of function of the endothelial cell layer associated with the S1P1/EDG1 activation, makes possible the use of such compounds for the treatment of uncontrolled inflammatory disease and improve vascular function.

Compounds of the present invention can be used alone or in combination with standard drugs, any abscopal T-cell activation, providing a new together with immunomodulating therapy with reduced susceptibility to infection compared to standard immunosuppressive therapy. In addition, the compounds of the present invention can be used in combination with lower doses of drugs used in immunosuppressive therapy to provide immunomodulatory activity, which is very important taking into account, on the other hand, the reduction of damage to the transplanted organ is associated with the use of higher doses of immunosuppressive drugs. The results of monitoring to improve endothelial function cleocin the layer, associated with the S1P1/EDG1 activation, additional evidence in favor of the considered compounds due to the resulting improvement in vascular function.

Nucleotide and amino acid sequences for human S1P1/EDG1 receptor known from the field of engineering and publications, for example, in: Hla, T., and Maciag, T. J. Biol. Chem., 265 (1990). 9308-9313; WO 91/15583 (published October 17, 1991); WO 99/46277 (published 16 September 1999). The potential and effectiveness of the compounds of formula (I) was studied by using GTPγS analysis to determine EU50values and by measuring circulating lymphocytes in rats after oral administration, respectively (see examples).

General terms used above and hereinafter, have the following meanings, unless otherwise indicated.

When using multiple forms of the compounds, salts, pharmaceutical compositions, disease, and similar terms refers to one form of the compound, salt or the like.

Any reference used above and hereinafter, the compound of formula (I) also implies a reference to salts, in particular pharmaceutically acceptable salts of the compounds of formula (I), as appropriate and expedient.

The term1-5alkyl, alone or in combination with other groups, means saturated, branched or linear g is uppy with the number of carbon atoms from one to five. Examples1-5alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopentyl.

Similarly, the term1-4alkyl, alone or in combination with other groups, means saturated, branched or linear group with the number of carbon atoms one to four. Examples1-4alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

Similarly, the term C1-3alkyl, alone or in combination with other groups, means saturated, branched or linear group with the number of carbon atoms of from one to three or represents methyl, ethyl, n-propyl or isopropyl; preferably, methyl and ethyl.

Similarly, the term2-5alkyl, alone or in combination with other groups, means saturated, branched or linear group with the number of carbon atoms from two to five.

Similarly, the term2-4alkyl, alone or in combination with other groups, means saturated, branched or linear group with the number of carbon atoms from two to four. Examples2-4the alkyl represents ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

The term1-4alkoxygroup, alone or in combination with other groups, means R-O-group,where R denotes 1-4alkyl. Examples1-4alkoxygroup represent a methoxy group, ethoxypropan, propoxylate and isopropoxy.

The term2-5alkoxygroup, alone or in combination with other groups, means R-O-group, where R denotes2-5alkyl. Examples2-5alkoxygroup represent ethoxypropan, propoxylate, isopropoxy, isobutoxy and isobutoxy.

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

Salts are preferably pharmaceutically acceptable salts of compounds of formula (I).

The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or basic additive salts, see, for example: "Salt selection for basic drugs", Int. J. Pharm., (1986), 33, 201-217.

The compounds of formula (I) can contain one or more stereo or asymmetric centers, such as one or more asymmetric carbon atoms. The substituents at the double bond or a ring may be present in CIS-(Z-) or TRANS-(=E-) form, unless otherwise specified. The compounds of formula (I) may thus be present as mixtures of stereoisomers or, preferably, in the form of pure stereoisomers. Mixture of stereoisomers can be separated using the method is in, well-known specialists in the field of technology.

i) the Invention relates to pyridin-3-yl derivatives of formula (I),

,

where

But a *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-,

,,,

,,,

or

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I);

R1represents hydrogen, C1-4alkyl or chlorine;

R2represents a C1-5alkyl or C1-4alkoxygroup;

R3represents hydrogen, C1-4alkyl, C1-4alkoxygroup or halogen;

R4represents hydrogen, C1-4alkyl, C1-4alkoxygroup, halogen, trifluoromethyl or cryptometer;

R5represents a 2,3-dihydroxypropyl, di-(hydraxis1-4alkyl)1-4alkyl, -CH2-(CH2)k-NHSO2R53, -(CH2)nCH(OH)-CH2-NHSO2R53, -CH2-(CH2)k-NHCOR54, -(CH2)nCH(OH)-CH2-NHCOR54, -CH2-(CH2)n-CONR51R52, -CO-other51, 1-(3-carboxyethylidene)-acetyl, 1-(2-carboxypropyl)-2-acetyl, 1-(3-carboxypropyl)-2-acetyl, 1-(3-carboxyethylidene)-3-propionyl, 1-(2-carboxypropyl)-3-propionyl, 1-(3-carboxypropyl)-3-propionyl, -(CH2)nCH(OH)-CH2-NR51R52the hydroxy-group, hydroxys2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropane, -OCH2-(CH2)m-NR51R52, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(C1-5alkilany broadcast azetidin-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(pyrrolidine-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(C1-5alkilany ether pyrrolidin-3-carboxylic acid)-1-yl]ethoxypropan, -OCH2-CH(OH)-CH2-NR51R52, 3-[(azetidin-3-carbolic acid)-1-yl]-2-hydroxypropoxy, 3-[(C1-5alkilany broadcast azetidin-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-3-carboxylic acid)-1-yl] propoxylate, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-2-carboxylic acid)-1-yl]propoxylate, -OCH2-(CH2)m-NHSO2R53, -OCH2-CH(OH)-CH2-NHSO2R53, -OCH2 2)m-NHCOR54, -OCH2-CH(OH)-CH2-NHCOR54;

R51represents hydrogen, C1-3alkyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydrodiol, carboxymethyl, 1-(C1-5alkylcarboxylic)methyl, 2-carboxyethyl or 2-(C1-5alkylcarboxylic)ethyl;

R52represents hydrogen, methyl or ethyl;

R53represents a C1-3alkyl, methylaminopropyl, ethylamino or dimethylaminopropyl;

R54represents hydroxymethyl, hydroxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, aminoethyl, 2-methylaminomethyl, or 2-dimethylaminoethyl;

k represents the integer 1, 2 or 3;

m represents the integer 1 or 2;

n represents 0, 1 or 2; and

R6represents hydrogen, C1-4alkyl or halogen.

ii) Another variant of the invention relates to pyridin-3-yl derivatives according to option (i), where a is a

,,,

,,,

or,

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I).

iii) Another option on the image the structure relates to pyridin-3-yl derivatives according to option (i), where a represents a

,,,

or,

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I).

iv) Another variant of the invention relates to pyridin-3-yl derivatives according to option (i), where a is a

,,or

,

in particular, As it represents

,or,

,

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I).

v) Another variant of the invention relates to pyridin-3-yl derivatives according to option (i), where a is a

or,

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I).

vi) Another variant of the invention relates to pyridin-3-yl derivatives according to option (i), where a is a

,

where the asterisk indicates the bond through which soedinenie the pyridine group of formula (I).

vii) Another variant of the invention relates to pyridin-3-yl derivatives according to option (i), where a is a

viii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(vii), where R1represents a C1-4alkyl or chlorine.

ix) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(vii), where R1represents a C1-4alkyl.

x) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(vi), where R1represents methyl or ethyl.

xi) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(vi), where R1represents methyl.

xii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-xi), where R1represents a C1-5alkyl.

xiii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-xi), where R2represents a C2-4alkyl.

xiv) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-xi), where R2represents ethyl, n-propyl, isopropyl or isobutyl.

xv) Another variant according to the invention relative is seeking to pyridine-3-yl derivatives according to one of the options (i)-(xi) where R2represents n-propyl or isobutyl.

xvi) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-xi), where R2represents a C1-4alkoxygroup.

xvii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where at least one of R3, R4and R6represents a non-hydrogen group.

xviii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents a methyl or methoxy group (in particular, methoxy group), and R4and R6represent hydrogen.

xix) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents hydrogen.

xx) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents hydrogen; and R4represents a C1-4alkyl or C1-4alkoxygroup, and R6represents a C1-4alkyl or halogen.

xxi) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents hydrogen, R4represents a C1-3alkyl or meth is xygraph (in particular, methyl, ethyl or methoxy group), and R6represents methyl, ethyl, or halogen (in particular chlorine).

xxii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents hydrogen, and R4and R6represent a methyl group.

xxiii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents hydrogen, R4represents a methyl group and R6represents an ethyl group.

xxiv) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents hydrogen, R4represents a methoxy group, and R6represents chlorine.

xxv) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xvi), where R3represents hydrogen, R4represents a methyl group and R6represents chlorine.

xxvi) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xxv), where R5represents a 2,3-dihydrodiol, di-(hydraxis1-4alkyl)1-4alkyl, -CH2-(CH2)k-NHSO2R53, -(CH2)nCH(OH)-CH2-NHSO2R , -CH2-(CH2)k-NHCOR54, -(CH2)nCH(OH)-CH2-NHCOR54, -CH2-(CH2)n-CONR51R52, -CO-other51, -(CH2)nCH(OH)-CH2-NR51R52the hydroxy-group, hydroxys2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropane, -och2-(CH2)m-NR51R52, -OCH2-CH(OH)-CH2-NR51R52, -OCH2-(CH2)m-NHSO2R53, -OCH2-CH(OH)-CH2-NHSO2R53, -OCH2-(CH2)m-NHCOR54or-och2-CH(OH)-CH2-NHCOR54.

xxvii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xxv), where R represents a 2,3-dihydrodiol, -CH2-(CH2)k-NR51R52, -CH2-(CH2)k-NHCOR54, -(CH2)nCH(OH)-CH2-NHCOR54, -CH2-(CH2)n-CONR51R52, -CO-other51, -(CH2)nCH(OH)-CH2-NR51R52hydraxis2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropane, -och2-(CH2)m-NR51R52, -OCH2-CH(OH)-CH2-NR51R52, -OCH2-(CH2)m-NHCOR54or-CH 2-CH(OH)-CH2-NHCOR54(in particular, R5represents a 2,3-dihydrodiol, -CH2-(CH2)k-NR51R52, -CH2-(CH2)k-NHCOR54, -(CH2)nCH(OH)-CH2-NHCOR54, -CH2-(CH2)n-CONR51R52, -(CH2)nCH(OH)-CH2-NR51R52hydraxis2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropane, -OCH2-(CH2)m-NR51R52, -Och2-CH(OH)-CH2-NR51R52, -OCH2-(CH2)m-NHCOR54or-OCH2-CH(OH)-CH2-NHCOR54).

xxviii) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xxv), where R5is hydraxis2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, -OCH2-(CH2)m-NR51R52, -Och2-CH(OH)-CH2-NR51R52, -OCH2-(CH2)m-NHCOR54or-OCH2-CH(OH)-CH2-NHCOR54.

xxix) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xxv), where R5is a 3-hydroxy-2-hydroxymethylpropane, 2,3-dihydroxypropyl or-OCH2-CH(OH)-CH2/sub> -NHCOR54(in particular, R5represents a 2,3-dihydroxypropane or-OCH2-CH(OH)-CH2-NHCOR54where R54represents hydroxymethyl).

xxx) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xxv), where R5represents-OCH2-CH(OH)-CH2-NHCOR54where R54represents hydroxymethyl.

xxxi) Another variant of the invention relates to pyridin-3-yl derivatives according to one of the options (i)-(xxv), where R5represents a 2,3-dihydroxypropane.

xxxii) Another variant of the invention relates to pyridin-3-yl derivatives according to option (i), where

But a

,,or,

in particular, As it represents

,or,

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I);

R1represents methyl, ethyl or chlorine (in particular, methyl or ethyl);

R2represents n-propyl, isobutyl or isopropoxide (in particular, n-propyl or isobutyl);

R3represents hydrogen, methyl or methoxypropyl is (in particular, hydrogen or a methoxy group);

R4represents hydrogen, methyl, ethyl or methoxy group;

R5is hydraxis2-5alkoxygroup, di-(hydraxis1-4alkyl)-C1-4alkoxygroup, 2,3-dihydroxypropyl, -och2-CH(OH)-CH2-NR51R52or-OCH2-CH(OH)-CH2-NHCOR54(in particular, R5represents a 2,3-dihydroxypropane or-OCH2-CH(OH)-CH2-NHCOR54);

R54represents hydroxymethyl, methylaminomethyl or 2-methylaminomethyl; and

R6represents hydrogen, methyl, ethyl or chlorine;

with this option, the value of one or more of the substituents or groups can be replaced with the value(s)given for the named substituent(s) or group(s) in one embodiment, v)-(vii), (x), xi), (xv), (xvii)-(xix), xxii-xxv) and xxix-xxxi).

xxxiii) Another variant of the invention relates to pyridin-3-yl derivatives according to option (i), where a is a

,or,

in particular, As it represents

or,

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I);

R1represents hydrogen, C1-4alkyl Il is chlorine;

R2represents a C1-5alkyl or C1-4alkoxygroup;

R3represents hydrogen;

R4represents a C1-4alkyl or C1-4alkoxygroup;

R5represents a hydroxy-group, hydroxys2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, -OCH2-CH(OH)-CH2-NR51R52or-OCH2-CH(OH)-CH2-NHCOR54;

R51represents hydrogen, 2-hydroxyethyl or 2-hydroxy-1-hydroxymethylation (in particular hydrogen);

R52represents hydrogen;

R54represents hydroxymethyl; and

R6represents a C1-4alkyl or halogen;

with this option, the value of one or more of the substituents or groups can be replaced with the value(s)given for the named substituent(s) or group(s) in one variation vi-xvi), xxi)to xxv), and xxix-xxxi).

xxxiv) Examples pyridine-3-yl derivatives according to formula (I) is chosen from the group including:

3-{4-[5-(5-Chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol;

N-(3-{4-[5-(5-Chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

3-{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy} prop the n-1,2-diol;

2-Hydroxy-N-(2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide;

N-(3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

3-{4-[5-(5,6-Diisobutylene-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol;

N-(3-{4-[5-(5,6-Diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

2-Hydroxy-N-(2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-3-methylphenoxy}propyl)ndimethylacetamide;

N-(3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-(3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methoxyphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((R)-3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[3-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[5-(6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

(S)-3-{2-Ethyl-4-[5-(5-ethyl-6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

N-(3-{2-Ethyl-4-[5-(5-ethyl-6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphen the XI}-2-hydroxypropyl)-2-hydroxyacetamido;

(R)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

(S)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

N-((R)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxy-ethyl)propionamide;

(R)-3-{2-Ethyl-4-[3-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}propane-1,2-diol;

(S)-3-{2-Ethyl-4-[3-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}propane-1,2-diol; and

3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionic acid.

xxxv) In another embodiment, examples of the pyridine-3-yl derivatives according to formula (I) is chosen from the group including:

(R)-3-{4-[5-(5-Chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol;

(S)-3-{4-[5-(5-Chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol;

N-((R)-3-{4-[5-(5-Chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{4-[5-(5-Chloro-6-isoprop Sipiagin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

(R)-3-{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol;

(S)-3-{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy} propane-1,2-diol;

2-Hydroxy-N-((R)-2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide;

2-Hydroxy-N-((S)-2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide;

N-((R)-3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

(R)-3-{4-[5-(5,6-Diisobutylene-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy} propane-1,2-diol;

(S)-3-{4-[5-(5,6-Diisobutylene-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol;

N-((R)-3-{4-[5-(5,6-Diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy} -2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{4-[5-(5,6-Diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

2-Hydroxy-N-((R)-2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-3-methylphenoxy}propyl)ndimethylacetamide;

2-Hydroxy-N-((S)-2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-3-methylphenoxy}propyl)ndimethylacetamide;

N-((R)-3-{-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((R)-3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methoxyphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methoxyphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((R)-3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[3-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[5-(6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

(S)-3-{2-Ethyl-4-[5-(5-ethyl-6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

N-((R)-3-{2-Ethyl-4-[5-(5-ethyl-6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[5-(5-ethyl-6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

(R)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

(S)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

N-((R)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]shall xavator-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

N-((S)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxy-ethyl)propionamide;

(R)-3-{2-Ethyl-4-[3-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}propane-1,2-diol;

(S)-3-{2-Ethyl-4-[3-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}propane-1,2-diol; and

3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were} propionic acid.

xxxvi) the Following variant of the invention relates to new pyridine-3-yl derivatives of formula (II)

where A, R1, R2and n have the meanings indicated in claim 1; R3represents hydrogen; R4represents a C1-4alkyl or C1-4alkoxygroup; and R6represents a C1-4alkyl or halogen.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical compositions for enteral and parenteral administration.

Preparation of pharmaceutical compositions may be carried out using methods known to anyone skilled in the art (see, for example: Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Helth Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) through the introduction of compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically useful substances, medicinal enter the form together with the appropriate, non-toxic, inert, pharmaceutically acceptable solid or liquid substance used as a carrier, and if necessary, a standard pharmaceutical excipients.

Pharmaceutical compositions comprising a compound of formula (I), are used for prophylaxis and/or treatment of diseases and disorders associated with an activated immune system.

Such illness or disease is chosen from the group comprising: the rejection of transplanted organs, tissues or cells; disease graft-versus-host caused by transplantation; autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; antiphospholipid syndrome; thyroiditis Hashimoto; lymphocytic thyroiditis; multiple sclerosis; heavy pseudoparalysis myasthenia; diabetes type I; uveitis (inflammation of the choroid); episcleritis; scleritis; Kawasaki disease, uveoretinitis; posterior uveitis; uveitis associated with Behcet's disease; syndrome woolright; allergic encephalomyelitis; chronic alltrans antitroy the disorder of vessels; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; psoriatic arthritis; atopic dermatitis; myopathy; myositis; osteomyelitis; contact dermatitis; eczema dermatitis; subarray dermatitis; lichen planus; disease; bullous a disease; congenital bullous bullosa; hives; angioedema; vasculitis; erythema; dermal eosinophilia; acne; scleroderma; alopecia alopecia; keratoconjunctivitis; chronic bilateral conjunctivitis; keratitis; gerpicheskoy keratitis; epithelial corneal dystrophy; lakomy cornea; eye disease; ulcer Moray; ulcerative cerotic; scleritis; ophthalmopathy Graves; syndrome Vogt-Konagi-Harada; sarcoidosis; hay fever; reversible obstructive disease of the Airways; bronchial asthma; allergic asthma; congenital asthma; received asthma, dust asthma, chronic or inveterate asthma, late asthma and hyperphosphorylate respiratory tract; bronchiolitis; bronchitis; endometriosis; orchitis; a stomach ulcer; ischemic bowel disease; inflammatory bowel disease; necrotizing enterocolitis; damage to the intestinal tract associated with thermal burns; disease of the peritoneum; proctitis; eosinophilic gastroenteritis; mastocytosis Crohn's disease; ulcerative colitis, vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fat heart; myocarditis; myocardial infarction; syndrome inflamed aorta; breakdown caused by viral disease; thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; syndrome Guarachera; haemolytic uraemic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; tubulointerstitial jade; interstitial cystitis; dermatomyositis; Guillain-Barre syndrome; disease Miniera; polyneuritis; multiplet neuritis; myelitis; manometric; radiculopathy; hyperthyroidism; graves ' disease; thyrotoxicosis; pure krasnocletocnaya aplasia, aplastic anemia; gipoplasticheskaya anemia; idiopathic thrombocytopenic purple; autoimmune hemolytic anemia; autoimmune thrombocytopenia; agranulocytosis; malignant anemia; megaloblastic anemia; americaplay; osteoporosis; or fibrous lung; idiopathic interstitial pneumonia; dermatitis; Leucoderma vulgaris; diffuse keratome vulgaris; photoallergic sensitivity; cutaneous T-cell lymphoma; Nowotny polyarthritis; horey Huntington; horey Sydenham; micardis; myocarditis; scleroderma; granuloma Wegener; Sjogren syndrome; adipose; eosinophilic fasciitis; povrejdeniar, periodontal, alveoles connective tissue, tooth substance during the treatment; men alopecia alopecia or senile alopecia; muscular dystrophy; pyoderma; syndrome Cesari; hipofisis; chronic adrenal insufficiency; Addison disease; ischemia-reperfusion injury of organs which occur during storage; endotoxic shock; pseudomembranous colitis; colitis caused by drug or radiation; acute ischemic renal failure; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemia; lymphoma; enfisema lungs; cataracts; sideras; inflammation of the retina; senile spotted degeneration; scarring the vitreous body; alkaline burns of the cornea; dermatite erythema, bullous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; disease of peripheral arteries; carcinogens; solid cancer; metastasis carcinoma; Garbaravicius; autoimmune hepatitis; primary liver cirrhosis; sclerotic cholangitis, partial liver resection, acute liver necrosis; cirrhosis; alcoholic cirrhosis; liver failure; fulminant hepatic failure; hidden hepatic failure and "aimed at chronic" liver nedostate the activity.

Preferred diseases and diseases subject to treatment and/or prevention using the compounds of formula (I)are selected from the group including rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; disease graft-versus-host arising from the transplantation of cells of the spinal cord; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, psoriasis, psoriatic arthritis, thyroiditis such as thyroiditis Hashimoto, uveoretinitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; asthma; diabetes type I; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; solid cancers and tumor metastasis.

Particularly preferred diseases or diseases that are subject to treatment and/or prevention using the compounds of formula (I)are selected from the group including rejection of transplanted organs such as kidney, liver, heart and lung; disease graft-versus-host arising from the transplantation of cells of the spinal cord; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease and thyroiditis Hashimoto; and epicheskii dermatitis.

The present invention relates also to a method of prevention or treatment of illness or disease mentioned in the description above, which consists in the introduction of the subject of the pharmaceutically active amount of a compound of formula (I).

In addition, the compounds of formula (I) also apply in combination with one or more immunomodulatory agents used for prophylaxis and/or treatment of diseases or diseases mentioned in the description above. According to a preferred variant of the invention, these agents are selected from the group including immunosuppressants, corticosteroids, NSAIDs, cytotoxic drugs, inhibitors molecular adhesion, cytokines, inhibitors of cytokines, receptor antagonists and recombinant cytokine receptors cytokine.

The present invention relates also to the use of compounds of formula (I) to obtain a pharmaceutical composition, optionally for use in combination with one or more immunomodulatory agents used for prophylaxis and/or treatment of diseases or diseases mentioned in the description above.

The compounds of formula (I) can be obtained by the methods given below, by the methods given in the examples, or similar methods. Optimal reaction conditions vary depending on the reagents Il the solvent, moreover, such conditions may be selected by the expert in the field of technology with the help of a number of optimization techniques.

The compounds of formula (I) according to the present invention can be obtained according to the General sequence of reactions shown below. The following describes just a few of the possible synthetic routes leading to the compounds of formula (I).

When a represents a-CO-CH=CH-, the compounds of formula (I) can be obtained by reaction of compounds of structure (1) with a compound of structure (2) in the presence of base or acid. Functional groups present in the residues R3-R6may need temporary protection or can even be entered on additional stages that follow the reaction of condensation. The compounds of formula (I), where a represents a-CO-CH2-CH2-can be obtained by reaction of compounds of formula (I), where a represents a-CO-CH=CH-, with hydrogen in the presence of a catalyst such as Pd/C, Pt/C, PtO2and the like, in a solvent such as ethanol, methanol, THF, and the like, or their mixtures.

The connection structure (1) can be obtained by reaction of the compound of structure (3) with methyl Grignard reagent is whether by treatment of compounds of structure (4) two equivalents of metallicy in a solvent such as diethyl ether, THF and the like, in the temperature range from -20 to 50°C. Amide Weinrebe structure (3) is obtained by treatment of compounds of structure (4) hydrochloride and N,O-dimethylhydroxylamine in the presence of a condensing reagent such as EDC, DCC and the like (literature: M.Mentzel, ..R.Hoffmann, N-Methoxy-N-methyl amides (Weinreb amides) in modern organic synthesis. Journal for Praktische Chemie/Chemiker-Zeitung, 339 (1997), 517-524; J.Singh, N.Satyamurthi, I.S.Aidhen, The growing synthetic utility of Weinreb's amide, Journal for Praktische Chemie (Weinheim, Germany), 342 (2000) 340-347; V.K.Khiestkin, D.G.Mazhukin, Recent advances in the application of N,O-dialkylhydroxylamins in organic chemistry. Current Organic Chemistry, 7 (2003), 967-993).

The compounds of formula (I), where a represents-CO-NH-CH2-can be obtained by condensation of compounds of structure (5) with a compound of structure (4) using a condensing agent such as EDC, DCC, TBTU, Robot, and the like, or by condensation of compounds of structure (5) with the appropriate acid chloride or bromohydrin acid compound of structure (4).

The compounds of formula (I), a derivative of 5-pyridin-3-yl-[1,2,4]oxadiazole, obtained by reaction of compounds of structure (6) in a solvent such as dioxane, THF, xylene, toluene, benzene, pyridine, DMF, dichloromethane, acetic acid, triperoxonane acid and the like, at room or elevated temperatures in the presence or OUTSTA auxiliary substances such as acids (e.g., TFA, acetic acid, HCl and the like), base (such as NaH, NaOAc, Na2CO3, K2CO3triethylamine and the like), tetraalkylammonium salt, or dehydrating agents (e.g., oxalicacid, carboxylic acid anhydride, POCl3, PCl5P4O10molecular sieves, Burgess reagent, etc.) (literature, for example: A.R.Gangloff, J.Litvak, E.J.Shelton, D.Sperandio, V.R.Wang, K.D.Rice, Tetrahedron Lett. 42 (2001), 1441-1443; T.Suzuki, K.Iwaoka, N.Imanishi, Y.Nagakura, K.Miyta, H.Nakahara, M.Ohta, T.Mase, Chem. Pharm. Bull. 47 (1999), 120-122; R.F.Poulain, A.L.Tartar, B.P.Deprez, Tetrahedron Lett. 42 (2001), 1495-1498; R.M.Srivastava, F.J.S.Oliveira, D.S.Machado, R.M.Souto-Maior, Synthetic Commun. 29 (1999), 1437-1450; E.O.John, J.M.Shreeve, Inorganic Chemistry 27 (1988), 3100-3104; B.Kaboudin, K.Navaee, Heterocycles 60 (2003), 2287-2292).

Compounds of structure (6) can be obtained by reaction of compounds of structure (4) with a compound of structure (7) in a solvent such as DMF, THF, DHM and the like, in the presence or absence of one or more condensing agents such as TBTU, DCC, EKD, hbtu, HOBt, CBI and the like, and in the presence or absence of a base such as triethylamine, DIPEA, NaH, K2CO3etc. (literature, for example: A.Hamze, J.-F.Hernandez, P.Fulcrand, J.Martinez, J. Org. Chem., 68 (2003) 7316-7321; and the literature cited above).

The compounds of formula (I), a derivative of 3-pyridin-3-yl-[1,2,4]oxadiazole, ucaut similarly (literature: for example: C.T.Brain, J.M.Paul, Y.Loong, P.J.Oakley, Tetrahedron Lett., 40 (1999) 3275-3278) using the reaction of compounds of structure (8) with a compound of structure (9) and subsequent cyclization of the corresponding intermediate hydroxyamino ether.

Compounds of structure (7) and (8) can be obtained by reaction of compounds of structure (10) and (11), respectively, with hydroxylamine or one of its salts in a solvent such as methanol, ethanol, pyridine and the like, in the presence or absence of a base such as Na2CO3, K2CO3, tert-butyl potassium, triethylamine and the like (literature: for example, T.Suzuki, K.Iwaoka, N.Imanishi, Y.Nagakura, K.Miyta, H.Nakahara, M.Ohta, T.Mase, Chem. Pharm. Bull., 47 (1999), 120-122; J.Cui, D.Crich, D.Wink, M.Lam, A.L.Rheingold, D.A.Case, W.T.Fu, Y.Zhou, M.Rao, A.J.Olson, M.E.Johnson, Bioorg. Med. Chem., 11 (2003), 3379-3392; R.Miller, F.Lang, Z.J.Song, D.Zewge, WO 2004/035538 (Merck & Co., Inc., USA); B.Kaboudin, K.Navaee, Heterocycles, 60(2003), 2287-2292).

Depending on the nature of functional groups present in the residues R3-R6in structures(2), (5), (6), (7), (9) and (10), these functional groups may need temporary protection. Suitable protective groups are known to experts in the field of engineering and include, for example: benzyl or trialkylsilyl group for protection of the alcohol, catalog group for the protection of the diol, etc.. These protective g is uppy can be used in accordance with standard methods (see, for example: T.W.Greene, P.G.M.Wuts, Protective Groups in Organic Synthesis, 3rdEdition, Wiley, New York, 1991; P.J.Kocienski, Protecting Groups, Thieme Stuttgart, 1994). Alternatively, the desired residues R3-R6in particular, R5may also be introduced in the later stages that follow the condensation of pyridine compounds of the structure(1), (4), (8) or (11) with phenyl derivatives of the structure(2), (5), (7), (9) or (10), using the corresponding precursor compound of the structure(2), (5), (7), (9) and (10). Phenyl compounds of the structure(2), (5), (7), (9) and (10) or their precursors are either commercially available or can be obtained according to methods well-known experts from the field of engineering.

The compounds of formula (I)representing derivatives of 2-pyridin-3-yl-[1,2,4]oxadiazole or 2-pyridin-3-yl-[1,3,4]thiadiazole, get similarly using the reaction of compounds of structure (4) with hydrazine (by using a condensing reagent such as TBTU, DCC, EKD, hbtu, HOBt, Robot, CBI, etc.) with the formation of compounds of structure (12), which is then introduced into a condensation reaction with a compound of structure (9), obtaining the compound of structure (13). The compound of structure (13) can also be obtained using the inverse of the reaction sequence, for example, starting with the condensation of compounds of structure (9) with hydrazine, and the like enter into the reaction of the corresponding intermediate hydrazide with a compound of structure (4). The dehydration of compounds of structure (13) with the formation of the desired derivative of 2-pyridin-3-yl-[1,3,4]oxadiazole is carried out by treating the compound of structure (13) using a reagent such as POCl3, CCl4or CBr4in combination with triphenylphosphine, P2O5, Burgess reagent and the like, in a solvent such as toluene, acetonitrile, dioxane, THF or CHCl3in the temperature interval from 20 to 120°C with or without the use of microwave irradiation (literature: for example, M.A.Garcia, S.Martin-Santamaria, M.Cacho, F.Moreno de la Llave, M.Julian, A.Martinez, B.De Pascual-Teresa, A.Ramos, J. Med. Chem., 48 (2005) 4068-4075; Schugar, J.M.Paul, Y.Loong, P.J.Oakley, Tetrahedron Lett. 40 (1999) 3275-3278). Similarly, derivatives of 2-pyridin-3-yl-[1,3,4]thiadiazole obtained by cyclization of compounds of structure (13) with a reagent of Lawesson, optionally in combination with P2S5in the absence or presence of a solvent such as pyridine, toluene, THF or acetonitrile, at elevated temperatures with or without microwave irradiation (literature, for example: A.A.Kiryanov, P.Sampson, A.J.Seed, J. Org. Chem., 66 (2001) 7925-7929).

The compounds of formula (I), a derivative of 5-pyridin-3-isoxazole or 5-pyridin-3-ultisol, obtained by reaction of compounds of structure (14) or POCl3, PCl5, I2in combination with what reperfusion and triethylamine, anhydride triperoxonane acid, Burgess reagent, solvent type, toluene, benzene, dioxane or THF, at temperatures in the range from 20 to 120°C, or with a reagent of Lawesson, optionally in combination with P2S5in the absence or presence of a solvent type, pyridine, toluene, THF or acetonitrile at elevated temperatures with or without microwave irradiation, as described above (literature, for example: N.Sato, T.Shibata, M.Jitsuoka, T.Ohno, T.Takahashi, T.Hirohashi, T.Kanno, H.Iwaasa, A.Kanatani, T.Fukami, Takehiro, Bioorg. & Med. Chem. Lett., 14 (2004) 1761-1764). Compounds of structure (14) are obtained by reaction of compounds of structure (15) with a compound of structure (9). Aminoketone structure (15) can be obtained from compounds of structure (1) by the method described in the literature (see, for example: J.L.LaMattina, J.Heterocyclic Chem., 20 (1983) 533-538; M.Pesson, M.Antoine, P.Girard, J.L.Benichon, S.Chabassier, P. De Lajudie, S.Patte, F.Roquet, G.Montay, Eur. J. Med. Chem., 15 (1980) 263-268). The compounds of formula (I)representing derivatives of 2-pyridine-3-isoxazole or 2-pyridine-3-ultisol receive a similar manner from compounds of structure (16) and compounds of structure (4).

Alternatively, communication between the pyridine or phenyl ring and the Central 5-membered heteroaromatic ring can also be formed using catalyzed the Pallady the m-condensing.

Methods, leading to the conversion of compounds of structure (4) in the connection structure (11), or Vice versa, well-known specialists in the field of technology.

Compounds of structure (4) can be obtained by reaction of the ester of 5,6-dichloronicotinic acid with alkyl Grignard reagent in the presence of Fe(acac)3the solvent type, THF, dioxane, DMF, N-MP or combinations thereof, at temperatures in the range from -78 to 25°C (reaction conditions of Furstner, literature, for example: A.Fürstner, A.Leitner, M.Mendez, H.Krause J. Am. Chem. Soc., 124 (2002) 13856-13863; A.Fürstner, A.Leitner Angew. Chem., 114 (2002) 632-635). Reaction conditions can be selected so that as the principal product was obtained or ester 5-chloro-6-alkynylamino acid, or ester of 5,6-dialkylamino acid. Two atoms of chlorine in the air 5,6-dichloronicotinic acids may also be substituted either sequentially or in one stage, two ALK-1-analnyj groups, which may be identical or different, by processing the broadcast 5,6-dichloronicotinic acid corresponding alkenylboronic derived in terms of conducting the condensation Suzuki, known to experts in the field of engineering. The resulting ester of 5,6-dialkanolamines acid hydronaut next to the corresponding ester of 5,6-dialkylamino acid. In addition, in the method, the reaction conditions of Furstner and Suzuki can be used is sledovatelno. Ester of 5,6-dichloronicotinic acid can also be treated with an alcohol or alcoholate at elevated temperatures with access to the corresponding esters of 5-chloro-6-alkoxyimino acid. Finally, the separation is difficult ester group leads to compounds of structure (4).

Alternatively, compounds of structure (4), where R1represents a methyl group, can be obtained from compounds of structure (17) by obtaining the corresponding esters of 6-chloro-5-methylnicotinic acid by methods known from the prior art, with subsequent derivatization carried out under reaction conditions to Fornero or Suzuki, as described above, and the elimination of hard-ester group. The compound of structure (17) can be obtained from the known 6-chloro-3-formyl-5-methylpyridine (see, for example, EP-0702003) by oxidation of the formyl group to the carboxylic acid using oxidizing agents well known in the prior art, such as water (H2O2in formic acid, KMnO4and the like, in the presence or absence of a solvent type, toluene, THF, MeCN, acetone, in the temperature interval from 0 to 120°C. Compounds of structure (11), where R1represents a methyl group, an alternative can be obtained, as described above, of the compounds of structure (4), where R1represents a methyl group is; or in accordance with literature methods (see, for example: J..Paine III, J. Heterocyclic Chem., 1987, 351-355).

When the compounds of formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known from the prior art, for example by preparation and separation diastereoisomeric salts or by HPLC on a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 μm) column, Daicel ChiralCel OD-H (5-10 μm) column, or Daicel ChiralPak IA (10 μm) or AD-H (5 μm) column. Typical conditions for HPLC are using a mixture of eluent A (EtOH, in the presence or absence of an amine such as NEt3diethylamine) and eluent B (hexane)at the expiration of from 0.8 to 150 ml/min

Experimental part

I) Chemistry

The following examples illustrate the invention, without limiting its scope.

All temperature measured in °C. Compounds are characterized by means of1H-NMR (300 MHz) or13C-NMR (75 MHz) (Varian Oxford; chemical shifts are given in memorial plaques relative to the solvent used; the multiplets: s = single, d = doublet, t = triplet; p = pintle, hex = getset, hept = septet, m = multiplet, br = advanced, constants mates are given in Hz); by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: a 4.6×50 mm, Bond SB-AQ, 5 μm, 120 Å, gradient: 5-95% acetonitrile in water, 1 min, with 0.04% of triflorus the Noah acid, the rate of flow: 4.5 ml/min), tR(retention time) is given in min (retention time marked with * or LC-MS*apply to LC conducted using basic conditions, for example, gradient elution with acetonitrile in water containing 13 mm ammonium hydroxide, or otherwise specified conditions); by TLC (TLC-plates from Merck, Silica gel 60 F254); or by melting point. Compounds purified using preparative WAHI (column: X-terra RP18, 50×19 mm, 5 μm, gradient: 10-95% acetonitrile in water containing 0.5% formic acid) or by using SGH (liquid chromatography medium pressure) (Labomatic MD 80-100 pump, Linear UVIS-201 detector, column: 350×18 mm, Labogel-RP-18-5s-100, gradient: 10% methanol in water to 100% methanol). The racemates can be separated into the enantiomers by using preparative HPLC (column: ChiralPaK AD 20×250 mm, 5 μm, 15% EtOH in hexane).

Abbreviations (used in this description):

aq. water, BSA - bovine serum albumin reagent Burgess - hydroxide of methoxycarbonylmethylene, KX - column chromatography, DNS - carbonyldiimidazole, DC - dicyclohexylcarbodiimide, DHM - dichloromethane, DEAD - diethyldithiocarbamic, DIRAA - diisopropylethylamine, DME - 1,2-dimethoxyethane, DMF - dimethylformamide, DMSO is dimethylsulfoxide, dppf is 1,1/bis(diphenylphosphino)ferrocene, EA - e is ylacetic, The EDC - N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, ether - diethyl ether, EtOH - ethanol, Fe(acac)3- iron(III)acetylacetonate complex, h - hour(s), hbtu - hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea, HOBT - 1-hydroxybenzotriazole, HPLC is high performance liquid chromatography, BB - high vacuum conditions, the reagent Lawesson - 2,4-bis(4-metatithemi)-1,3,2,4-dithiadiphosphetane-2,4-disulfide, LC-MS - liquid chromatography - mass spectrometry, MeCN is acetonitrile, Meon - methanol, min - min(s), SGH - liquid chromatography medium pressure, NaOAc - sodium acetate, NEt3- triethylamine, N-MO - N-methylmorpholin-N-oxide, N-MP - 1-methyl-2-pyrrolidone, SLA - acetate, org. - organic, Ph is phenyl, PPh3- triphenylphosphine, Rev. - preparative, Robot - hexaphosphate benzotriazol-1 yloxy-Tris-pyrrolidinone, rat - racemic, CT room temperature, feast upon. - rich, SIP - sphingosine 1-phosphate, TBME - tert-butyl methyl ether, TBTU - tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,2,3,3-tetramethylurea, tert - tertiary, TPA - triperoxonane acid, THF is tetrahydrofuran, and TLC is thin layer chromatography, tRthe retention time.

Synthesis of intermediate compounds

Nicotinic acid 1

5,6-Dichloronicotinic acid (1,95 g, 10 mmol) are added to a solution of KOtBu (2.28 g, 20 mmol) is isopropanol (20 ml). The mixture is heated at a temperature of 80°C for 15 hours the mixture is Then diluted with water (60 ml) and acidified with 1-molar aqueous solution of model HC1. The aqueous solution is extracted with ether (five times 50 ml) and the combined organic extracts dried (Na2SO4), filtered and evaporated, receiving 5-chloro-6-isopropoxytitanium acid;

1H NMR (d6-DMSO): δ to 1.38 (d, J=6.2 Hz, 7 H), 5,44 (septet, J=6.2 Hz, 1 H), 8,18 (d, J=2.1 Hz, 1 H), 8,65 (d, J=2.1 Hz, 1 H).

Nicotinic acid 2

a) a Suspension of 5,6-dichloronicotinic acid (5,25 g, 27.3 mmol) in toluene (200 ml) is heated to a temperature of 80°C. and then slowly treated with di-tert-butylacetate N,N-dimethylformamide (20,0 g, 98,0 mmol). The mixture becomes slightly yellowish color and transparency. Heating and stirring is continued for 3 h, after which the solution is cooled to CT, diluted with ether and washed with saturated aqueous Na2CO3. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified using SCH (SiO2)to give tert-butyl ether 5,6-dichloronicotinic acid (5,13 g).

1H NMR (CDCl3): δ of 1.62 (s, 9 H), 8,30 (d, J=2.0 Hz, 1 H), 8,83 (d, J=2.0 Hz, 1H).

b) To a solution of tert-butyl methyl ether 5,6-dichloronicotinic acid (3,37 g, 13.6 mmol), Fe(acac)3(719 mg, 2.04 mmol) and N-MP (1,95 ml, 20 mmol) wtgf (300 ml) is added slowly a solution of methylmagnesium in THF (3-molar, of 5.4 ml, 16.3 mmol) at -78°C. the Brown solution becomes turbid and black. Stirring is continued for 1 h at a temperature of -75°C, and the solution was heated to 0°C. After the reaction mixture is again cooled to a temperature of -70°C. the Next portion of methylacrylamide in THF (3-molar solution of 5.4 ml, 16.3 mmol) is added slowly at -70°C. the Dark green mixture is slowly heated to a temperature of -20°C and carefully quenched 0,7-normal aqueous solution of HCl (150 ml). The mixture is then extracted with ether (5 times 60 ml). The combined organic extracts are dried over Na2SO4, filtered and evaporated, to give crude tert-butyl ester 5-chloro-6-methylnicotinic acid as a yellow oil (of 4.66 g);

LC-MS: tR=1,03 min, [M+1]+=228,22.

C) tert-Butyl ester 5-chloro-6-methylnicotinic acid (3,09 g, 13.5 mmol), Fe(ASAS)3(719 mg, 2.04 mmol) and N-MP (1,95 ml, 20 mmol) dissolved in THF (3-molar solution, 500 ml) and cooled to a temperature of -78°C. Then slowly add a solution of isobutylamine in THF (2-molar, 13.6 mmol) at a temperature of -75°C. the Brown solution thus becomes turbid and yellow. Stirring of the solution is continued for 1 h at a temperature of -75°C, after which it slowly heated up to CT. After completion of the reaction add Fe(ASAS)3(719 mg, 2,04 IMO is her) and the mixture is again cooled to a temperature of -70°C. The next portion of methylacrylamide in THF (2-molar solution, 13.6 mmol) is added slowly at -70°C. the Dark green mixture is slowly warmed to room temperature and stirred for 15 hours Then the mixture is carefully quenched 0,7-normal aqueous solution of HCl (150 ml) and extracted with ethyl acetate (6 times 60 ml). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The residue is purified using reverse-phase SGH getting tert-butyl ester 6-methyl-5-isobutylamino acid in the form of a black oil (0.50 g);

LC-MS: tR=0,84 min, [M+1]+=250,14.

(d) tert-butyl ether of 6-methyl-5-isobutylamino acid (0.50 g, 2 mmol)dissolved in dioxane (20 ml), add 4-normal solution of HCl in dioxane (30 ml), after which the mixture is stirred for 3 hours the Solvent is then evaporated, obtaining the hydrochloride of 6-methyl-5-isobutylamino acid (0.52 g);

LC-MS: tR=0,54 min; [M+1]+=194,29;1H NMR (d6-DMSO): δ of 0.91 (d, J=6,5 Hz, 6 H), 1.91 a (septet, J=6.5 Hz), 2,68 (d, J=7,3 Hz, 2 H), by 2.73 (s, 3 H), of 8.47 (d, J=1.8 Hz, 1 H), of 8.90 (d, J=2.0 Hz, 1 H).

Nicotinic acid 3

a) To a solution of tert-butyl methyl ether 5,6-dichloronicotinic acid (5,00 g, 20.0 mmol) and complex of 2,4,6-trivinylcyclohexane/pyridine (9,700 mg, 40 mmol) in dioxane (30 ml) is added 2-molar aqueous dissolve the K 2CO3(6 ml)and then Pd(PPh3)4(620 mg, 0.38 mmol) and PPh3(620 mg, 3.8 mmol). The mixture is stirred at a temperature of 100°C for 2 h, cooled to CT and diluted with ether (200 ml)and then extracted with 1-molar aqueous solution of NaOH (twice 50 ml) and brine (50 ml). The organic phase is dried (Na2SO4), filtered and evaporated. The residue is purified using accelerated chromatography (SiO2, ethyl acetate/heptane)to give tert-butyl ester 5-chloro-6-sinilnikova acid (4.0 g) as a yellow oil;

LC-MS: tR=of 1.05 min, [M+1+CH3CN]+=281,36.

b) a Mixture of tert-butyl ester 5-chloro-6-sinilnikova acid (2.0 g), Cs2CO3(3.4 g), three(tert-butyl)phosphine (0,04 equiv.) Tris(dibenzylideneacetone)-diplodia (0.02 EQ.) and 2,4,6-trivinylcyclohexane-pyridine complex (2.0 g) in dioxane (30 ml) Tegaserod and heated at 100°C for 15 h the Mixture was then cooled to CT, diluted with ether (200 ml) and extracted with a 1-molar aqueous solution of NaOH (twice 50 ml) and brine (50 ml). The organic phase is dried (Na2SO4), filtered and evaporated. The residue is purified using accelerated chromatography (SiO2, ethyl acetate/heptane)to give tert-butyl ether 5,6-divinylacetylene acid (0,89 g) in the form of oil.

LC-MS: tR=a 1.01 min, [M+1]+=232,04.

C) To a solution of tert-Buti is a new air of 5,6-divinylacetylene acid (890 mg, 3.8 mmol) in THF (20 ml)containing a number Meon, added Pd/C (100 mg, 10% Pd) and the mixture is stirred under hydrogen pressure (1 ATM) at RT for 3 h the Catalyst was filtered off and the filtrate is evaporated, then the residue purified using accelerated chromatography (SiO2, ethyl acetate/heptane)to give tert-butyl ether 5,6-diethylnicotinamide acid (860 mg) in the form of butter;

LC-MS: tR=0,79 min, [M+1]+=to 236.14.

g) a Solution of tert-butyl methyl ether 5,6-diethylnicotinamide acid (860 mg, 3.65 mmol) in 6 normal aqueous HCl (15 ml) is stirred at 65°C for 3 h, after which the solvent is evaporated. The residue is dried in high vacuum, receiving hydrochloride 5,6-diethylnicotinamide acid (923 mg) in the form of butter;

LC-MS: tR=0,50 min, [M+1]+=180,05.

Nicotinic acid 4

6-Ethyl-5-isobutylamino acid is obtained analogously to receive nicotinic acid (3) from tert-utilaje ester 5-chloro-6-sinilnikova acid and 2,4,6-tri-(2-methylpropenyl)collaboration-pyridine complex, using the methodology described in the publication: F.Kerins, D.F.O''shea, J. Org. Chem., 67 (2002) 4968-4971);

LC-MS: tR=of 0.64 min, [M+1]+=207,98.

Nicotinic acid 5

a) a Solution of 5,6-dichloronicotinic acid (5.0 g, 26 mmol) in dry EtOH (300 ml) and HART is immissione (33 ml, 10 equiv.) stirred at room temperature for 16 h Then the solvent is evaporated, the residue is dissolved in ether (200 ml) and washed with saturated aqueous Na2CO3(75 ml) and brine (50 ml). The organic phase is dried over Na2SO4, filtered and evaporated, obtaining the ethyl ester of 5,6-dichloronicotinic acid (5.8 g) in the form of solids;

LC-MS: tR=to 0.96 min, [M+1]+=219,93.

b) To a solution of ethyl ester of 5,6-dichloronicotinic acid (0.8 g, 3.6 mmol) and 2,4,6-tri-(2-methylpropenyl)collaboration-pyridine complex (1.78 g, 5,49 mmol) in DME (20 ml) is added 2-molar aqueous solution of K2CO3(5 ml)and then Pd(PPh3)4(50 mg, 0,068 mmol) and PPh3(110 mg, 0.68 mmol). The mixture is stirred at a temperature of 100°C for 2 days, then cooled to CT and diluted with ether (100 ml). The phases are then separated and the aqueous phase is extracted with ether (50 ml). The combined organic extracts washed with 1-molar aqueous solution of NaOH (twice 40 ml) and brine (40 ml), dried (Na2SO4), filtered and evaporated. The crude product is purified using accelerated chromatography (SiO2, ethyl acetate/heptane)to give ethyl ester of 5,6-di-(2-methylpropenyl)nicotinic acid (52 mg) as a colourless oil;

LC-MS: tR=1,11 min, [M+1]+=260,24.

b) Ethyl ester of 5,6-di-(2-methylprop who yl)nicotinic acid (52 mg, 0.3 mmol) dissolved in THF (10 ml), added Pd/C (20 mg, 10% Pd) and the mixture is stirred under hydrogen pressure (1 ATM) at room temperature for 15 hours and Then the catalyst is filtered off and the filtrate is evaporated, obtaining the ethyl ester of 5,6-diisobutylamine acid (52 mg) in the form of butter;

LC-MS: tR=1,12 min, [M+1]+=264,19.

g) a Solution of ethyl ester of 5,6-diisobutylamine acid (52 mg, 0.2 mmol) in 6 normal aqueous HCl (2 ml) is stirred at 65°C for 15 h, after which the mixture is cooled to CT and extracted with ether (twice 10 ml). The aqueous phase is evaporated, and the residue dried in high vacuum, receiving hydrochloride 5,6-diisobutylamine acid (0.12 g) as colorless solids;

LC-MS: tR=0,73 min; [M+1]+=236,40.

Nicotinic acid 6

a) phosphorus Oxychloride (183 ml, 2 mol) is heated at a temperature of 90°C and a mixture of commercially available 2-methyl-2-butenonitrile (73 g, and 0.9 mol) and DMF (154 ml, 2 mol) is added slowly, maintaining the temperature in the range from 100 to 110°C. the Mixture was then stirred at 110°C for 15 h, cooled to CT and diluted with dichloromethane (500 ml). After that, the mixture is cooled to 0°C and carefully quenched with water (500 ml). The phases are then separated and the aqueous phase is extracted with dichloromethane (total volume 800 ml). The joint is haunted organic extracts dried (Na 2SO4), filtered and evaporated. The residue is crystallized from cyclohexane, getting 6-chloro-3-formyl-5-methylpyridin (28,3 g) as slightly yellow crystals;

LC-MS: tR=0,76 min, [M+1]+=156,14.

b) a Solution of 6-chloro-3-formyl-5-methylpyridine (10 g, 64 mmol) in formic acid (200 ml) cooled to 0°C and at this temperature add 50%solution of H2O2in water (9.6 ml, 360 mmol). The mixture is stirred at 0°C for 15 h, carefully diluted with water (200 ml) and extracted with dichloromethane (8 times 100 ml). The combined organic extracts washed with 1-molar aqueous solution of HCl (100 ml) (control over the remaining peroxide), dried (MgSO4), filtered and evaporated. The residue is dried, obtaining 6-chloro-5-methylnicotinic acid (9,56 g);

LC-MS: tR=to 0.72 min, [M+1]+=172,0.

C) a Solution of 6-chloro-5-methylnicotinic acid (13,85 g, 80,75 mmol) in dry EtOH (200 ml)containing a few drops of H2SO4mix the contents by heating under reflux for 2 days. Then the solution is cooled to CT, the solvent is evaporated, the residue is dissolved in ethyl acetate (200 ml) and washed with saturated aqueous Na2CO3(double 80 ml), 1-molar aqueous solution of KHSO4(double 80 ml) and brine (50 ml). The organic phase is dried over MgSO4, filtered and evaporated, obtaining the ethyl ester chlor-5-methylnicotinic acid (12,65 g) in the form of solids;

LC-MS: tR=to 0.92 min; [M+1]+=200,10;1H NMR (CDCl3): δ was 1.43 (t, J=7.0 Hz, 3 H), of 2.46 (s, 3 H), 4,43 (q, J=7,3 Hz, 2 H), 8,16 (m, 1 H), 8,84 (d, J=2.0 Hz, 1 H).

g) To a solution of ethyl ester of 6-chloro-5-methylnicotinic acid (to 4.98 g, 24.9 mmol), 2,4,6-tri-(2-methylpropenyl)collaboration-pyridine complex (5,74 g, 17.7 mmol, get similarly to the method described in: F.Kerins, D.F.O''shea, J. Org. Chem., 67 (2002) 4968-4971) and PPh3(to 1.15 g, 4.4 mmol) in DME (60 ml) is added 2-molar aqueous solution of K2CO3(20 ml). The mixture Tegaserod and blow N2, then add Pd(PPh3)4(460 mg, 0.4 mmol). The mixture is then stirred at a temperature of 90°C for 20 h, then cooled to CT, diluted with ethyl acetate (150 ml) and washed with saturated aqueous NaHCO3(twice 50 ml). The organic extract was dried over MgSO4, filtered and evaporated. The crude product is purified using accelerated chromatography (SiO2, heptane/ethyl acetate)to give ethyl ester of 5-methyl-6-(2-methylpropenyl)nicotinic acid (3.98 g) as an orange oil;

LC-MS: tR=to 0.72 min, [M+1]+=220,15.

d) Ethyl ester 5-methyl-6-(2-methylpropenyl)nicotinic acid (3.98 g, 18.2 mmol) dissolved in THF (100 ml) and Meon (100 ml), added Pd/C (500 mg 10% Pd) and the mixture is stirred under hydrogen pressure (1 ATM) at RT for 15 hours the Catalyst is filtered off and the filtrate is evaporated is, getting ethyl ester of 6-isobutyl-5-methylnicotinic acid (3,76 g) as a colourless oil;

LC-MS: tR=0,75 min; [M+1]+=222,15;1H NMR (CDCl3): δ 0,97 (d, J=6.8 Hz, 6 H), of 1.42 (t, J=7,3 Hz, 3 H), 2,20 (septet, J=6,8 Hz, 1H), of 2.38 (s, 3 H), of 2.75 (d, J=7,0 Hz, 2 H), 4.41 (q, J=7,3 Hz, 2 H), 8,03 (d, J=1.8 Hz, 1 H), of 9.00 (d, J=2.0 Hz, 1 H).

e) a Solution of ethyl ester of 6-isobutyl-5-methylnicotinic acid (3.75 g, 16,95 mmol) of 12.5%aqueous HCl (50 ml) is stirred at 65°C for 24 h, after which the solvent is evaporated. The residue is dried in high vacuum, obtaining the hydrochloride of 6-isobutyl-5-methylnicotinic acid (3.55 g) as a white powder;

LC-MS: tR=0,57 min, [M+1]+=194,25.

Nicotinic acid 7

5-Methyl-6-propylenimine acid (1.85 g as hydrochloride) are obtained analogously to receive nicotinic acid (6) of the ethyl ester of 6-chloro-5-methylnicotinic acid (2.0 g) and commercially available TRANS-1-propen-1-Voronovo acid (1.3 g);

1H NMR (d6-DMSO): δ of 0.96 (t, J=7,3 Hz, 3 H), 1,72 (m, 2 H), 3,05 (t, J=7.5 Hz, 2 H), 8,66 (m, 1 H), 8,86 (d, J=1.5 Hz, 1 H).

Nicotinic acid 8

6-Isobutylamino acid is obtained analogously to receive nicotinic acid (2) from commercially available ethyl ester of 6-chloronicotinic acid and isobutyronitrile;

LC-MS: tR=0,52 is in, [M+1]+=180,30.

Nicotinic acid 9

a) To a solution of ethyl ester of 5,6-dichloronicotinic acid (2,40 g, 10.9 mmol) and 2,4,6-Tris-(2-methylpropenyl)cyclotrisiloxane-pyridine complex (2,02 g, 6.22 mmol, obtained using the methods described in: F.Kerins, D.F.O''shea, J. Org. Chem., 67 (2002) 4968-4971) in dioxane (40 ml) and 2-molar aqueous solution of K2CO3(10 ml) was added PPh3(114 mg, 0,436 mmol). The mixture Tegaserod and rinsed with nitrogen, and then add Pd(PPh3)4(160 mg, 0,218 mmol). The mixture is then stirred at a temperature of 100°C for 1.5 h, after which add another portion of 2,4,6-Tris-(2-methylpropenyl)cyclotrisiloxane-pyridine complex (1.01 g, 3.11 mmol). Stirring is continued at a temperature of 100°C for 3 h, and then the mixture is cooled to CT, diluted with ether, washed with 1-normal aqueous solution of NaOH and water, dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane/ethyl acetate in a ratio of 9:1 and getting ethyl ester 5-chloro-6-(2-methylpropenyl)nicotinic acid (2.4 g) as an oil; LC-MS: tR=of 1.05 min, [M+1]+=240,02. To a solution of this compound in dioxane (40 ml) was added 2,4,6-trivinylcyclohexane-pyridine complex (1.84 g, 7,63 mmol), Ca2CO3(4,62g, 14.2 mmol), and then three-tert-butylphosphine (88 mg, 0,436 mmol). The mixture Tegaserod and rinsed with nitrogen, and then add Pd2(dba)3(200 mg, 0,218 mmol). The mixture is then stirred at a temperature of 100°C for 16 h, after which add another portion of 2,4,6-trivinylcyclohexane-pyridine complex (1.84 g, 7,63 mmol) and Pd2(dba)3(200 mg, 0,218 mmol). Stirring is continued at a temperature of 100°C for 24 h, and then the mixture is diluted with ethyl acetate, washed with 1-normal aqueous solution of NaOH, dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane/ethyl acetate in a ratio of 10:1, and receiving the first portion of the ethyl ester of 6-(2-methylpropenyl)-5-sinilnikova acid. In addition, isolated unreacted ethyl ester 5-chloro-6-(2-methylpropenyl)nicotinic acid. This product is again treated with 2,4,6-trivinylcyclohexane-pyridine complex, as described previously. Processing, purification and unification of the two portions gives the ethyl ester of 6-(2-methylpropenyl)-5-sinilnikova acid (1,37 g) in the form of butter;

LC-MS: tR=of 0.87 min, [M+1]+=232,13.

b) To a solution of ethyl ester of 6-(2-methylpropenyl)-5-sinilnikova acid (1,37 g, 6,74 mmol) in THF (20 ml) is added Pd/C (100 mg, 10% Pd), followed by EtOH (20 ml). The mixture is stirred under duress hydrogen (1 ATM) at RT for 24 hours Then the catalyst is removed by filtration and the filtrate concentrated. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane/ethyl acetate in the ratio of 4:1 and getting ethyl ester 5-ethyl-6-isobutylamino acid (970 mg) as a colourless oil;

LC-MS: tR=0,79 min, [M+1]+=236,20;1H NMR (CDCl3): δ 0,97 (d, J=6.8 Hz, 6 H), of 1.27 (t, J=7.5 Hz, 3 H), of 1.42 (t, J=7.0 Hz, 3 H), 2,17-of 2.28 (m, 1 H), 2,69-2,78 (m, 4 H), was 4.42 (q, J=7,0 Hz, 2 H), 8,07 (s, 1 H), of 9.00 (s, 1 H).

C) a Solution of ethyl ester 5-ethyl-6-isobutylamino acid (970 mg, 4,12 mmol) in 25%aqueous HCl is stirred at a temperature of 95°C for 8 hours the Solvent is evaporated and the residue dried in high vacuum, obtaining the hydrochloride of 5-ethyl-6-isobutylamino acid (1,15 g, presumably in the form of a hydrate) as a colourless resin;

LC-MS: tR=0,62 min, [M+1]+=208,35.

Niacin 10

6-(3-Methylbutyl)nicotinic acid is obtained by reaction of tert-butyl methyl ether of 6-chloronicotinic acid with 3-methylbutylamine under the reaction conditions of Furstner as described upon receipt of nicotinic acid (2);

LC-MS: tR=0,58 min, [M+1]+=194,30.

Nicotinic acid 11

a) To a solution of potassium tert-butylate (1.26 g, 11.3 mmol) in isopropanol (30 ml) was added 2,5-dibromo-3-the peak of the lean (2,89 g, 11.3 mmol). The mixture is stirred at a temperature of 80°C for 15 h, after which add another portion of potassium tert-butylate (2,53 g, 27.5 mmol). Stirring is continued at a temperature of 80°C for 24 h, after which the mixture was diluted with saturated aqueous NaHCO3. The mixture is extracted with ether, the organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane/ethyl acetate in a ratio of 9:1 and receiving 5-bromo-2-isopropoxy-3-methylpyridin (1.24 g) as a colourless oil;

LC-MS: tR=the 1.06 min; [M+1]+=230,00;1H NMR (CDCl3): δ of 1.35 (d, J=6.3 Hz, 6 H), of 2.16 (s, 3 H), 5,27 (septet, J=6.3 Hz, 1H), of 7.48 (d, J=1.5 Hz, 1 H), 8,02 (d, J=2.0 Hz, 1 H).

b) a Solution of 5-bromo-2-isopropoxy-3-methylpyridine (1.24 g, 5.39 mmol) and 2,4,6-trivinylcyclohexane-pyridine complex (1.27 g, 5,26 mmol) in dimethoxyethane (12 ml) and 2-molar aqueous solution of K2CO3(5 ml) Tegaserod and purge with argon, then add Pd(PPh3)4(112 mg, 0,097 mmol). The mixture is stirred at a temperature of 80°C for 15 h, after which it is cooled to CT, diluted with ether (50 ml), washed with saturated aqueous NaHCO3(twice 30 ml), dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica the Le, elwira a mixture of heptane/ethyl acetate in a ratio of 9:1 and getting 2 isopropoxy-3-methyl-5-vinylpyridine (703 mg) as a pale yellow oil;

LC-MS: tR=1,01 min; [M+1]+=178,11.

C) To a solution of 2-isopropoxy-3-methyl-5-vinylpyridine) - derivatives (703 mg, 3.97 mmol) in acetone (80 ml) is added MnO4(1.60 g, 10.1 mmol) and the mixture is stirred at room temperature for 18 hours Dark brown suspension is filtered and the clear, colorless filtrate is evaporated without dried, receiving 6 isopropoxy-5-methylnicotinic acid (1.06 g, in the form of potassium salt) as off-white solids;

LC-MS: tR=0,86 min; [M+1]+=196,09;1H NMR (D2O): δ 1,31 (d, J=6.3 Hz, 6 H), and 2.14 (s, 3 H), 5,15 (septet, J=7,0 Hz, 1H), to $ 7.91 (s, 1 H), 8.34 per (s, 1 H).

N-Hydroxy-6-isobutyl-5-nicotine amide

a) a Solution of ethyl ester of 6-isobutyl-5-methylnicotinic acid (2.86 g, 12.9 mmol) in 7-normal solution of NH3in the Meon (80 ml) is stirred at 60°C for 20 h, after which the solvent is removed in vacuum. The residue is dried, receiving 6-isobutyl-5-nicotine amide (1.89 g) as a yellow oil;

LC-MS: tR=0,66 min, [M+1]+=193,29;1H NMR (D6-DMSO): δ of 0.91 (d, J=6,5 Hz, 6 H), 2,08-of 2.20 (m, 1 H), 2,32 (s, 3 H), 2,65 (d, J=7,3 Hz, 2 H), the 7.43 (s, 1 H), 7,95 (s, 1 H), 8,01 (m, 1 H), 8,78 (s, 1 H).

b) To a solution of 6-isobutyl-5-nicotine amide (1.89 g, 9,85 mmol) in DHM (40 ml) and PI is the one (2.83 g, 39.4 mmol) is added in portions TFA anhydride (5,17 g, 24.6 mmol) at 0°C. the Mixture was then stirred at room temperature for 24 h, diluted with DHM and washed with water, and then 4%aqueous citric acid solution and saturated aqueous NaHCO3. The organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane/ethyl acetate in a ratio of 9:1 and getting 6-isobutyl-5-methylnicotinamide (1.35 g) as a white solid;

LC-MS: tR=to 0.89 min, [M+1]+=175,11.

C) To a solution of potassium tert-butylate (3.04 from g, 27.1 mmol) in Meon (60 ml) is added hydroxylamine hydrochloride (1,62 g, 23.2 mmol) at 0°C. To this suspension is added followed by 6-isobutyl-5-methylnicotinamide (1.35 g, 7.75 mmol). The mixture is heated under reflux for 3 h, cooled to CT, filtered and the filtrate is evaporated without dried. The residue is suspended in a little water and then extracted with ethyl acetate. The organic extract was concentrated and dried in high vacuum, obtaining N-hydroxy-6-isobutyl-5-nicotine amide (1,53 g) as a pale yellow oil;

LC-MS: tR=0,68 min, [M+1]+=208,22;1H NMR (D6-DMSO): δ of 0.91 (d, J=6.8 Hz, 6 H), 2.06 to 2,17 (m, 1 H)to 2.29 (s, 3 H), 2,61 (d, J=7,0 Hz, 2 H), to 5.85 (s extended, 2 H), 7,76 (s, 1 H), at 8.60 (s, 1 H)9,68 (s, H).

N-Hydroxy-6-isopropoxy-5-nicotine amide

Named in the header connection receive similarly, to obtain N-hydroxy-6-isobutyl-5-nicotine amide of nicotinic acid (11);

LC-MS: tR=of 0.64 min, [M+1]+=210,08.

4 Allyloxy-N-hydroxybenzamide

Named in the header connection receive similarly, to obtain 4-allyloxy-N-hydroxy-3,5-dimethylbenzylidene the allilirovanii commercially available 4-hydroxybenzonitrile, followed by conversion of the nitrile in hydroxyamide;

LC-MS: tR=0,59 min, [M+1]+=193,58.

4 Allyloxy-N-hydroxy-2-methylbenzamide

Named in the header connection receive similarly, to obtain 4-allyloxy-3-ethyl-N-hydroxy-5-methylbenzamide proceeding from commercially available 4-hydroxy-2-methylbenzaldehyde;

LC-MS: tR=0,62 min, [M+1]+=207,10;13With NMR (CDCl3): δ 20,72, 68,91, 104,72, 112,75, 116,45, 118,32, 118,53, 132,25, 134,19, 144,09, 161,71.

4 Allyloxy-N-hydroxy-2-methoxybenzamide

Named the title compound is obtained from commercially available 4-hydroxy-2-methoxybenzaldehyde, using literary techniques (references cited in the synthesis of 3-ethyl-4,N-dihydroxy-5-methylbenzylidene);

LC-MS: tR=0,64 min; [M+1]+=223,24; 1H NMR (D6-DMSO): δ was 9.33 (s extended, 1H), 7,30 (d, J=8,2 Hz, 1H), 6,60 (d, J=2.3 Hz, 1H), 6,50 (dd, J=2,3, 8,2 Hz, 1H), 6,10-5,94 (m, 1H), 5,50 (s, 2H), of 5.40 (d, J=17,0 Hz, 1H), 5,24 (d, J=a 10.6 Hz, 1H), 4,57 (d, J=4,7 Hz, 2H), 3,76 (s, 3H).

4 Allyloxy-N-hydroxy-3-methoxybenzamide

Named in the header connection receive similarly, to obtain 4-allyloxy-N-hydroxy-3,5-dimethylbenzylidene the allilirovanii commercially available 4-hydroxy-3-methoxybenzonitrile with subsequent conversion of the nitrile in hydroxyamide;

LC-MS: tR=0,59 min, [M+1]+=223,18.

4 Allyloxy-3-bromo-N-hydroxybenzamide

Named in the header connection receive similarly, to obtain 4-allyloxy-N-hydroxy-3,5-dimethylbenzylidene the allilirovanii commercially available 3-bromo-4-hydroxybenzonitrile with subsequent conversion of the nitrile in hydroxyamide;

LC-MS: tR=0,68 min, [M+1]+=270,96.

4 Allyloxy-3-chloro-N-hydroxy-5-methylbenzamide

Named in the header connection receive similarly, to obtain 4-allyloxy-3-ethyl-N-hydroxy-5-methylbenzamide proceeding from commercially available 3-chloro-4-hydroxy-5-methylbenzaldehyde;

LC-MS: tR=0,69 min, [M+1]+=241,10.

4 Allyloxy-N-hydroxy-3,5-dimethylbenzamide

Named in the title compounds is their get the allilirovanii commercially available 4-hydroxy-3,5-dimethylbenzonitrile allylbromide in the presence of NaOH in isopropanol at RT. The nitrile is then converted into hydroxyamides, using literary techniques (for example: E.Meyer, A.C.Joussef, H.Gallardo, Synthesis 2003, 899-905);

1H NMR (CD3OD): δ 7,27 (s, 2 H), 6,10 (m, 1 H), 5,42 (m, 1 H), of 5.26 (m, 1 H), or 4.31 (dt, J=5,6, 1.5 Hz, 2 H), to 2.29 (s, 6 H).

4 Allyloxy-3-ethyl-N-hydroxy-5-methylbenzamide

Named the title compound is obtained by allilirovanii 3-ethyl-4-hydroxy-5-methylbenzaldehyde, which is obtained from 2-ethyl-6-METHYLPHENOL according to literature methods (see: 3-ethyl-4,N-dihydroxy-5-methylbenzamide). The aldehyde is then converted into the corresponding hydroxyamide according to literature methods (see: 3-ethyl-4,N-dihydroxy-5-methylbenzamide);

LC-MS: tR=0,72 min; [M+1]+=235,09;1H NMR (CD3OD): δ 7,31 (s, 1 H), 7,29 (s, 1 H), 6,10 (m, 1 H), 5,43 (dd, J=of 17.0, 1.5 Hz, 1 H), 5,27 (dd, J=10,3, 1.2 Hz, 1 H), 4,81 (s extended, 3H), or 4.31 (d, J=5.6 Hz, 2 H), to 2.67 (q, J=7,6 Hz, 2 H), of 2.30 (s, 3 H), of 1.23 (t, J=7,6 Hz, 4 H).

4 Allyloxy-3-chloro-N-hydroxy-5-methoxybenzamide

Named the title compound is obtained by allilirovanii commercially available 3-chloro-4-hydroxy-5-methoxybenzaldehyde (see: 4-allyloxy-3-ethyl-N-hydroxy-5-methylbenzamide). The aldehyde is then converted into the corresponding hydroxyamide according to literature methods (see: 3-ethyl-4,N-dihydroxy-5-methylbenzamide);

LC-MS: tR=0,69 min; [M+1]+=257,26.

4,N-Digue is droxi-3,5-dimethylbenzamide

Named the title compound is obtained from commercially available 4-hydroxy-3,5-dimethylbenzonitrile according to literature methods (for example: E.Meyer, A.C.Joussef, H.Gallardo, Synthesis 2003, 899-905);

1H NMR (CD3OD): δ 7,20 (s, 2H), measuring 2.20 (s, 6H).

3-Ethyl-4,N-dihydroxy-5-methylbenzamide

Named the title compound is obtained from commercially available 2-ethyl-6-METHYLPHENOL following literary techniques (see: G.Trapani, A.Latrofa, M.Franco, C.Altomare, E.Sanna, M.Usala, G.Biggio, G.Liso, J. Med. Chem., 41 (1998) 1846-1854; A.K.Chakraborti, G.Kaur, Tetrahedron, 55 (1999) 13265-13268; E.Meyer, A.C.Joussef, H.Gallardo, Synthesis 2003, 899-905);

LC-MS: tR=0,55 min;1H NMR (d6-DMSO): δ 9,25 (s extended, 1H), 7,21 (s, 2H), to 5.56 (s, 2H), by 2.55 (q, J=7,6 Hz, 2H), of 2.15 (s, 3H), 1,10 (t, J=7,6 Hz, 3H).

3,5-Diethyl-4,N-dihydroxybenzamide

Named the title compound is obtained from commercially available 2,6-diethylaniline following literary techniques (G.G.Ecke, J.P.Napolitano, A.H.Filbey, A.J.Kolka, J. Org. Chem., 22 (1957) 639-642; and references cited in obtaining 3-ethyl-4,N-dihydroxy-5-methylbenzylidene);

LC-MS: tR=60 min; [M+1]+=209,46.

3-Chloro-4,N-dihydroxy-5-methoxybenzamide

Named the title compound is obtained from commercially available 3-chloro-4-hydroxy-5-methoxybenzaldehyde, using the literature the sources, quoted in obtaining 3-ethyl-4,N-dihydroxy-5-methylbenzamide;

LC-MS: tR=0,49 min; [M+1]+=216,96;1H NMR (D6-DMSO): δ of 3.84 (s, 3 H), 5,79 (s, 2 H), 7,22 (d, J=1.5 Hz, 1 H), 7,27 (d, J=1.8 Hz, 1 H)9,52 (s, 1 H), 9,58 (s extended, 1 H).

[4-(N-Hydroxycarbamoyl)phenyl]acetic acid

a) To a solution of methyl(4-cyanophenyl)acetate (4,00 g, 27.8 mmol) in Meon (20 ml) is added hydroxylamine hydrochloride (3,17 g, 45.7 mmol) and NaHCO3(of 3.84 g, 45.7 mmol). The suspension is stirred at 60°C for 18 h, after which it is filtered and the filtrate concentrated. The residue is dissolved in DHM, washed with water, then brine, dried over MgSO4, filtered, concentrated and the residue is dried, obtaining methyl [4-(N-hydroxycarbamoyl)phenyl]acetate (3,67 g) as a colourless oil;

LC-MS: tR=0,50 min, [M+1]+=209,05.

b) a Solution of methyl[4-(N-hydroxycarbamoyl)phenyl]acetate (3,67 g, 17.6 mmol) in 25%aqueous HCl (15 ml) is stirred at 65°C for 4 h and Then the solvent is removed in vacuum and the residue is dried in high vacuum, receiving [4-(N-hydroxycarbamoyl)phenyl]acetic acid (3.80 g, presumably in the form of the hydrochloride) as a yellow solid;

LC-MS: tR=0,34 min, [M+1]+=195,05.

{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl] phenyl} acetic acid is the

Named in the header connection receive on the basis of nicotinic acid (6) and [4-(N-hydroxycarbamoyl)phenyl]acetic acid analogous to obtain the compound of example 13;

LC-MS: tR=to 0.96 min, [M+1]+=352,39.

tert-Butyl ester 3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-were]propionic acid

a) To a solution of 3-ethyl-4-hydroxy-5-methylbenzoic acid (80,3 g, 0,446 mole) is added DMF (500 ml), KHCO3(53,5 g, 0,535 mol), and then benzylbromide (114.3 g, 0,668 mol). The mixture is stirred at 50°C for 18 h, after which it is cooled to CT, diluted with water (250 ml) and extracted with TBME (twice 250 ml). The organic extracts washed with water, and then concentrated. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane/ethyl acetate in the ratio from 19:1 to 9:1 and getting benzyl ester 3-ethyl-4-hydroxy-5-methylbenzoic acid (108,5 g) as a beige solid;

1H NMR (CDCl3): δ of 1.28 (t, J=7.5 Hz, 3 H), is 2.30 (s, 3 H), 2,68 (q, J=7.8 Hz, 2 H), of 5.24 (s, 1 H), lower than the 5.37 (s, 2 H), 7,33 was 7.45 (m, 3 H), 7,45 is 7.50 (m, 2 H), to 7.77 (s, 1 H), 7,79 (s, 1 H).

b) To a solution of benzyl ester 3-ethyl-4-hydroxy-5-methylbenzoic acid (97.5 g, 0,361 mol) and pyridine (57,1 g, 0,721 mol) in DHM (1000 ml) is added dropwise a solution of anhydride triftormetilfullerenov acid (122,1 g, 0,mos) in DHM (100 ml) at 0°C. After the addition the mixture is stirred at room temperature for 2 h, after which it is washed with 2-normal aqueous solution of HCl (500 ml)and then water (500 ml). The organic extract was concentrated and dried, obtaining 3-ethyl-5-methyl-4-triftoratsetilatsetonom acid (to 140.5 g) as an orange oil;

1H NMR: δ of 1.30 (t, J=7.5 Hz, 3 H), of 2.46 (s, 3 H), and 2.83 (q, J=7.5 Hz, 2 H), of 5.39 (s, 2 H), 7,35 is 7.50 (m, 5 H), 7,87 (s, 1 H), to $ 7.91 (s, 1 H).

C) To a solution of 3-ethyl-5-methyl-4-triftoratsetilatsetonom acid (10.0 g, 25 mmol), tert-butyl acrylate (6,37 g, 50 mmol), NEt3(of 5.03 g, 50 mmol) and DPPP (0,82 g, 2 mmol) in DMF (100 ml) is added under nitrogen atmosphere Pd(OAc)2(0.45 g, 2 mmole). The mixture is stirred at a temperature of 115°C for 3 h, then cooled to CT and filtered through a layer of celite, the residue on the filter is washed then TBME (250 ml) and water (500 ml) and the wash water added to the filtrate. The layers are separated and the organic layer washed with water (twice 500 ml), dried over MgSO4and evaporated without dried. To the crude product was added EtOH (100 ml), forming a viscous suspension. The solid is collected, washed with ice EtOH (10 ml) and receive benzyl ester 4-(2-tert-butoxycarbonylamino)-3-ethyl-5-methylbenzoic acid (3.8 g) as off-white solid.

g) To a solution of benzyl ester 4-(2-tert-butoxide Bayliner)-3-ethyl-5-methylbenzoic acid (10.0 g, 26 mmol) in THF (100 ml) in an atmosphere of nitrogen was added Pd/C (0.5 g, 20% Pd). The mixture is stirred at room temperature for 48 h under hydrogen pressure (1 bar). The catalyst is filtered through a layer of celite and the filtrate is concentrated without dried, obtaining 4-(2-tert-butoxycarbonylmethyl)-3-ethyl-5-methylbenzoic acid (of 7.64 g) as a white solid;

1H NMR: δ of 1.29 (t, J=7.5 Hz, 3 H), for 1.49 (s, 9 H), a 2.36-to 2.41 (m, 2 H), to 2.74 (q, J=7.5 Hz, 2 H), 2,99 was 3.05 (m, 2 H), to 7.77 (s, 1 H), 7,80 (s, 1 H).

d) To a solution of 4-(2-tert-butoxycarbonylmethyl)-3-ethyl-5-methylbenzoic acid (36,0 g, 123 mmol) in isopropanol (400 ml) is added HOBT (18,3 g, 135 mmol)and then EDC HCl (27,1 g, 142 mmol). The mixture is stirred at room temperature for 1 h, then add aqueous ammonia solution (69 ml, 25%solution). Stirring is continued for 1 h, after which the mixture was diluted with DHM (500 ml) and washed polysystem aqueous solution of NaHCO3(three times with 400 ml)and then water (400 ml). The organic extract was dried over MgSO4filter and concentrate. The crude product is triturated with TBME (825 ml). The product solids are collected, washed with an additional portion of TBME (50 ml) and dried in high vacuum, obtaining tert-butyl ether 3-(4-carbarnoyl-2-ethyl-6-were)propionic acid (31,91 g) as a white solid.

e) To a solution of tert-butyl Avira-(4-carbarnoyl-2-ethyl-6-were)propionic acid (30.0 g, 103 mmol) and NEt3(31,3 g, 309 mmol) in DHM (300 ml) is slowly added anhydride triperoxonane acid (23,8 g, 113 mmol). The reaction temperature due to ekzotermicheskie support below 5°C. by cooling. After the addition the mixture is stirred at room temperature for 1 h, then washed with water (twice 300 ml) and the organic extract is evaporated without dried, obtaining tert-butyl ether 3-(4-cyano-2-ethyl-6-were)propionic acid (28.4 g) as a pale yellow oil;

1H NMR: δ 1,25 (t, J=7.5 Hz, 3 H), to 1.48 (s, 9 H), 2,32-is 2.37 (m, 2 H), of 2.38 (s, 3 H), 2,70 (q, J=7.5 Hz, 2 H), 2.95 and-to 3.02 (m, 2 H), 7,30 (s, 1 H), 7,34 (s, 1 H).

W) Solution of tert-butyl methyl ether 3-(4-cyano-2-ethyl-6-were)propionic acid (37,0 g, 135 mmol), hydroxylamine hydrochloride (14.1 g, 203 mmol) and NEt3(27.4 g, 271 mmol) in Meon (400 ml) is heated under reflux for 7 h, then cooled to CT. The solvent is evaporated, the residue is transferred to isopropylacetate (500 ml) and washed twice with water (500 ml). The organic extract was dried over MgSO4, filtered, evaporated and dried, obtaining tert-butyl ester 3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-were]propionic acid (40,8 g) as a pale yellow solid;

1H NMR: δ 1.26 in (t, J=7.5 Hz, 3 H), for 1.49 (s, 9 H), 2,33-to 2.41 (m, 5 H), 2,66-to 2.74 (m, 2 H), 2,93-a 3.01 (m, 2 H), is 4.85 (s, 1 H), 7,28 (s, 2 H).

3-[2-Ethyl-4-(N-hydroxyurs imidoyl)-6-were]propionic acid

a) Ethyl ester of 3-(4-cyano-2-ethyl-6-were)propionic acid get similarly obtain tert-butyl ester 3-(4-cyano-2-ethyl-6-were)propionic acid;

1H NMR (CDCl3): δ to 1.21 to 1.31 (m, 6 H), is 2.37 (s, 3 H), 2,41-2,47 (m, 2 H), 2,69 (q, J=7.5 Hz, 2 H), 2,99 was 3.05 (m, 2 H), 4,18 (q, J=7,0 Hz, 2 H), 7,30 (s, 1 H), 7,33 (s, 1 H).

b) a Solution of ethyl ester of 3-(4-cyano-2-ethyl-6-were)propionic acid (55,0 g, 224 mmol) in THF (220 ml) and 1-normal aqueous solution of NaOH (220 ml) was stirred at room temperature for 2 h, after which it is diluted with water (200 ml) and extracted with DHM (twice 200 ml). The aqueous phase is transferred to a 32%aqueous HCl solution (50 ml) at a temperature of 15-30°C, while precipitation. The product solids are collected, washed with water and dried in a high vacuum, obtaining 3-(4-cyano-2-ethyl-6-were)propionic acid (40,87 g) as pale-brown crystals;

1H NMR (D6-DMSO): δ of 1.17 (t, J=7.5 Hz, 3 H), 2,30-2,39 (m, 5 H), to 2.67 (q, J=7,3 Hz, 2 H), 2,87-to 2.94 (m, 2 H), 7,47 (s, 2 H), 12,30 (s, 1 H).

C) To a solution of 3-(4-cyano-2-ethyl-6-were)propionic acid (10.0 g, 46,0 mmol) in EtOH (80 ml) add NEt3(13,97 g, 138,1 mmol)and then hydroxylamine hydrochloride (6,40 g of 92.1 mmol). The mixture is heated under reflux for 7 h, then cooled to CT. The solvent is then removed under vacuum, the residue is dissolved in 2-n is rmalina aqueous HCl solution and adjusted the pH to 5 by addition of 32%aqueous NaOH solution. The precipitate is collected, washed with water and dried in high vacuum at 40°C for 18 h, receiving 3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-were]propionic acid (11.7 g) as a beige crystalline powder;

LC-MS: tR=to 0.60 min, [M+1]+=251,09.

3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionic acid

Named in the title compound derived from nicotinic acid (11) and 3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-were]propionic acid analogous to obtain compounds of example 13;

LC-MS: tR=1,15 min, [M+1]+=410,10.

3-Ethyl-4-hydroxy-5-methylbenzoic acid

a) To a cooled with ice to a solution of H2SO4(150 ml) in water (250 ml) is added 2-ethyl-6-methylaniline (15.0 g, 111 mmol). The solution is treated with ice (150 g), then add dropwise a solution of NaNO2(10.7 g, 155 mmol) in water (150 ml) and ice (50 g). The mixture is stirred at 0°C for 1 h, add a 50%aqueous solution of H2SO4(200 ml) and stirring is continued at RT for 18 h Then the mixture is extracted with DHM, organic extracts are dried over MgSO4and evaporated. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: ethyl shall zitat in the ratio of 9:1 and getting 2-ethyl-6-METHYLPHENOL (8.6 g) in the form of butter raspberry color;

LC-MS: tR=0,89 min;1H NMR (CDCl3): δ 7.03 is-to 6.95 (m, 2H), 6,80 (t, J=7,6 Hz, 1H), 4,60 (s, 1H), 2,64 (q, J=7,6 Hz, 2H, in), 2.25 (s, 3H), 1,24 (t, J=7,6 Hz, 3H).

b) a Solution of 2-ethyl-6-METHYLPHENOL (8,40 g, 61.7 mmol) and hexamethylenetetramine (12,97 g, 92.5 mmol) in acetic acid (60 ml) and water (14 ml) is heated to a temperature of 115°C. the Water is then distilled off at a temperature of 117°C and harvested in unit Dean-stark. Then water separator replace the reflux condenser and the mixture is heated with him for 3 hours the Mixture is cooled to CT, diluted with water (100 ml) and extracted with ethyl acetate. The organic extract was washed with saturated aqueous NaHCO3, dried over MgSO4and evaporated. The remaining solid is dissolved in ethyl acetate and treated with heptane to cause crystallization. The solid is collected and dried, obtaining 3-ethyl-4-hydroxy-5-methylbenzaldehyde (3.13 g) as colorless crystalline powder,

1H NMR (CDCl3): δ 9,83 (s, 1H), 7,58-7,53 (m, 2H), and 5.30 (s extended, 1H), 2,69 (q, J=7,6 Hz, 2H), 2,32 (s, 3H), of 1.28 (t, J=7,6 Hz, 3H).

C) To a solution of 3-ethyl-4-hydroxy-5-methylbenzaldehyde (78.8 g, of 0.48 mol) in DMSO (585 ml) add a solution dihydrate NaH2PO4(17.3 g, 0,144 mol) in water (160 ml) for 13 minutes, the Mixture is stirred at room temperature and add a solution of NaClO2(age of 65.17 g, 0,577 mol) in water (160 ml), cooling the mixture in a bath with ice. With the ect stirred for 1 h, then add the second portion of NaClO2(43,44 g to 0.480 mol) in water (100 ml), maintaining the reaction temperature in the range from 25 to 40°C using an ice bath. The yellow suspension is stirred at room temperature for 24 h, then acidified with 32%HCl to pH 2-3, extracted TBME (250 ml), the organic extract washed with water, and the washing water is extracted with TBME. The solvent of the combined organic extracts evaporated give crude 3-ethyl-4-hydroxy-5-methylbenzoic acid (80,3 g) as a yellow solid.

Hydrazide 4-allyloxy-3,5-dimethylbenzoic acid

To a solution of 4-allyloxy-3,5-dimethylbenzoic acid (see: U.S. Pat 3262946) (5,26 g, 25.5 mmol) in CHCl3(75 ml) was added thionyl chloride (7.5 ml) and the mixture heated under reflux for 2 hours the Mixture was then evaporated and the residue dissolved in DHM (50 ml), transferred to a chilled (0°C) 1-molar solution of hydrazine in THF (75 ml) and DHM (250 ml). The mixture is then slowly heated up to CT for 15 h, diluted with ether (150 ml) and washed with 1-molar aqueous solution of HCl (5 times 50 ml). Aqueous extracts washed with ether (50 ml), the organic phase is separated and the aqueous extracts alkalinized a 33%water solution of KOH and extracted with DHM (5 times 50 ml). The organic extracts are then dried (Na2SO4), f is trout and evaporated, getting named the title compound (5,39 g) as a white solid;

LC-MS: tR=to 0.71 min; [M+1]+=221,20.

2,2-Dimethyl-[1,3]dioxane-5-ymetray ether methanesulfonate acid

Named the title compound is obtained using the methods described in the publications: B.Xu, A.Stephens, G.Kirschenheuter, A.F.Greslin, X.Cheng, J.Sennelo, M.Cattaneo, M.L.Zighetti, A.Chen, S.-A.Kim, H.S.Kim, N.Bischofberger, G.Cook, K.A.Jacobson, J. Med. Chem., 45 (2002) 5694-5709.

Synthesis examples

Example 1

a) a Solution of 5-chloro-6-isopropoxyethanol acid (202,9 mg, 0.94 mmol), TBTU (332 mg, 1.04 mmol), base Hunya (607 mg, 4,70 mmol) and 4-allyloxy-N-hydroxy-3,5-dimethylbenzamide (230 mg, 1.04 mmol) in DHM (7 ml) was stirred at room temperature for 24 hours the mixture is Then diluted with ether (150 ml), washed with 1-normal aqueous solution of HCl (twice 20 ml), 1-normal aqueous solution of KHSO4(20 ml) and brine (20 ml), dried over Na2SO4filter and concentrate. The crude product is purified using SJH on silica gel, elwira gradient of ethyl acetate in heptane and getting 4 allyloxy-N-hydroxy-3,5-dimethylbenzimidazolyl ester 5-chloro-6-isopropoxyethanol acid (258 mg) as a white powder;

LC-MS: tR=1,12 min, [M+1]+=418,07.

b) a Solution of 4-allyloxy-N-hydroxy-3,5-dimethylbenzamide ester 5-the ENT-6-isopropoxyethanol acid (200 mg, 0.48 mmol) in dioxane (6 ml) is stirred at 90°C for 2 days. The solvent is then evaporated, to give crude 3-[3-(4-allyloxy-3, 5dimethylphenyl)-[1,2,4]oxadiazol-5-yl]-5-chloro-6-isopropoxypyridine (279 mg);

LC-MS: tR=1,27 minutes

C) To a solution of 3-[3-(4-allyloxy-3, 5dimethylphenyl)-[1,2,4]oxadiazol-5-yl]-5-chloro-6-isopropoxypyridine (191 mg, 0.48 mmol) in acetone (10 ml) and water (1 ml) is added N-MO (97 mg, to 0.72 mmol), and then OsO4(12 mg, 0,048 mmol). The mixture is stirred at 45°C for 16 h, then diluted with 1-normal aqueous solution of KHSO4and extracted with ether (three times 50 ml). The combined organic extracts are dried over Na2SO4filter and concentrate. The sample (15 mg) of the crude product (299 mg) purified using preparative TLC using as additionally separated by a mixture of heptane:ethyl acetate in a ratio of 1:2 and receiving (RS)-3-{4-[5-(5-chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol (10,6 mg);

LC-MS: tR=the 1.06 min, [M+1]+=434,06.

Example 2

To a solution of crude (RS)-3-{4-[5-(5-chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol (265 mg, and 0.61 mmol) in THF (5 ml), add the base Hunya (158 mg, 1.22 mmol), and then methanesulfonanilide (77 mg, 0.67 mmol) at 0°C. then the mixture is stirred at room the Oh temperature for 16 h, add 7-molar solution of ammonia in Meon (2 ml), stirred at 65°C for 16 h, after which the solvent is removed in vacuum to give crude (RS)-1-amino-3-{4-[5-(5-chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propan-2-ol;

LC-MS: tR=0,92 min [M+1+CH3CN]+=474,44.

Example 3

To a solution of (RS)-1-amino-3-{4-[5-(5-chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propan-2-ol (313 mg, 0.6 mmole) in DHM (10 ml) is added glycolic acid (95 mg, 1.25 mmol) and the base Hunya (233 mg, 1.8 mmol). The mixture is cooled to 0°C and add TBTU (236 mg, of 0.74 mmole). Then the mixture is stirred at 0°C for 1 h, then at RT for 16 h, then diluted with ethyl acetate (250 ml), washed with 1-normal aqueous solution of NaOH (three times 25 ml), 1-normal aqueous solution of KHSO4(25 ml) and brine (25 ml), dried over Na2SO4filter and concentrate. The crude product is purified using preparative HPLC, obtaining N-((RS)-3-{4-[5-(5-chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetate (42 mg) as a white powder;

LC-MS: tR=the 1.06 min; [M+1]+=491,48;1H NMR (CD3OD): δ of 1.45 (d, J=6.3 Hz, 6 H), of 2.38 (s, 6 H), 3,47 (dd, J=13,6, 7,3 Hz, 1 H), 3,66 (dd, J=13,6, 4.5 Hz, 1 H), a 3.87 (m, 2 H), Android 4.04 (s, 2 H), 4,14 (m, 1 H), 5,52 (m, 1 H), 7,78 (s, 2 H), 8,43(s, 1 H), cent to 8.85 (s, 1 H).

Example 4

(RS)-3-{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol get similarly obtaining compounds of example 1;

LC-MS: tR=to 0.92 min, [M+1]+=412,21.

Example 5

2-Hydroxy-N-((RS)-2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide get similarly obtaining compounds of examples 2 and 3;

LC-MS: tR=to 0.89 min, [M+1]+=469,57.

Example 6

(RS)-3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol get similarly obtaining compounds of example 1;

LC-MS: tR=of 0.95 min, [M+1]+=426,14.

Example 7

(RS)-1-Amino-3-{2-ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propan-2-ol get similarly obtaining compounds of example 2;

LC-MS: tR=0,82 min, [M+1]+=425,17.

Example 8

N-((RS)-3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido get similarly obtaining compounds of example 3;

LC-MS: tR=of 0.91 min, [M+1]+=483,21.

Example 9

(RS)-3-{2-Ethyl-4-[5-(5-Isobe the Il-6-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol get similarly obtaining compounds of example 1; LC-MS: tR=to 0.96 min, [M+1]+=426,12.

Example 10

(RS)-3-{2,6-Dimethyl-4-[5-(5-methyl-6-propylpyridine-3-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}propane-1,2-diol get similarly obtaining compounds of example 1;

LC-MS: tR=of 0.87 min, [M+1]+=398,54.

Example 11

(RS)-3-{2-Ethyl-6-methyl-4-[5-(5-methyl-6-propylpyridine-3-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}propane-1,2-diol get similarly obtaining compounds of example 1;

LC-MS: tR=of 0.91 min, [M+1]+=412,56.

Example 12

(RS)-3-{4-[5-(5,6-Diisobutylene-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol get similarly obtaining compounds of example 1;

LC-MS: tR=1,01 min; [M+1]+=454,56.

Example 13

To a solution of hydrochloride 5,6-diethylnicotinamide acid (920 mg, 4.3 mmol) and substrate Hunya (2.76 g, 21 mmol) in DHM (50 ml) added TBTU (1,785 g, 5.55 mmol) and the mixture is stirred at room temperature for 5 minutes Then add 3-ethyl-4,N-dihydroxy-5-methylbenzamide (1,14 g, 4.7 mmol), after which the mixture is stirred for 0.5 h, diluted with DHM, washed with saturated aqueous NaHCO3, dried over MgSO4filter and concentrate. Crude 3-ethyl-4,N-dihydroxy-5-methylbenzimidazolyl ester of 5,6-diethylnicotinamide acid (the X-MS: t R=0,79 min) dissolved in dioxane (50 ml) and heated at 100°C for 18 hours the Solvent is evaporated and the crude product purified using rapid chromatography on silica gel, elwira a mixture of heptane: ethyl acetate in a ratio of 10:1 and getting 4-[5-(5,6-diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-METHYLPHENOL (0,42 g) in the form of solids;

LC-MS: tR=1,03 min, [M+1]+=338,09.

Example 14

To a solution of 4-[5-(5,6-diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-METHYLPHENOL (100 mg, 0,296 mmole) in isopropanol (10 ml) and 3-normal aqueous NaOH solution (3 ml) is added (S)-3-chloro-1,2-propandiol (98 mg, of 0.89 mmole). The mixture is stirred at 60°C for 24 h, after which add one more portion (S)-3-chloro-1,2-propane diol (98 mg, of 0.89 mmole). Stirring is continued at 60°C for 2 days. The mixture is then diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic extract was dried over MgSO4, filtered and evaporated. The crude product is purified using preparative TLC using as additionally separated by a mixture of heptane with ethyl acetate and obtaining (S)-3-{4-[5-(5,6-diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}propane-1,2-diol (14 mg) as a red oil;

LC-MS: tR=0,93 min, [M+1]+=412,16.

Example 15

2-{4-[5(5,6-Diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylpenicillin}propane-1,3-diol receive a two-step process similar to obtaining compounds of example 14 using 2,2-dimethyl-[1,3]dioxane-5-Eletropaulo ether methanesulfonate acid as an alkylating agent. Received protected diol (32 mg) was dissolved in THF (5 ml) and water (0.5 ml) and added TFA (0.25 ml). The mixture is then stirred at room temperature for 1 h, diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic phase is evaporated and the residue purified using preparative TLC using as additionally separated by the mixture DHM/Meon and getting 2-{4-[5-(5,6-diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylpenicillin}propane-1,3-diol;

LC-MS: tR=of 0.95 min, [M+1]+=426,09.

Example 16

2-{4-[5-(5,6-Diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}ethanol similarly to obtain compounds of example 14, using bromoethanol as alkylating agent;

LC-MS: tR=1,01 min; [M+1]+=382,17;1H NMR (CDCl3): δ 1,22-of 1.45 (m, 9 H), 2,42 (s, 3 H), 2,72-2,87 (m, 4 H), 2,96 (q, J=7.5 Hz, 2 H), of 4.00 (m, 5 H), 7,89 (s, 1 H), of 7.90 (s, 1 H), 8,24 (s, 1 H), of 9.21 (s, 1 H).

Example 17

a) To a solution of 4-[5-(5,6-diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-METHYLPHENOL (150 mg, 0,445 mmole) in isopropanol (10 ml) and 3-normal aqueous NaOH solution (3 ml) was added epichlorohydrin (164 mg, of 1.78 mmol). The mixture is stirred at room temperature for 20 hours the mixture is Then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 . The organic extract was dried over MgSO4, filtered and evaporated. The crude product is purified using preparative TLC using as additionally separated by a mixture of ethyl acetate with heptane and receiving (RS)-2,3-diethyl-5-[3-(3-ethyl-5-methyl-4-oxiranylmethyl)-[1,2,4]oxadiazol-5-yl] pyridine (92 mg) as oil.

b) (RS)-2,3-Diethyl-5-[3-(3-ethyl-5-methyl-4-oxiranylmethyl)-[1,2,4]oxadiazol-5-yl]pyridine (92 mg) was dissolved in 7-normal solution of NH3in the Meon (20 ml) and heated in a flask with a screw cap at 60°C for 15 hours and Then the mixture is evaporated, give crude (RS)-1-amino-3-{4-[5-(5,6-diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}propan-2-ol (99 mg); LC-MS: tR=0,80 min, [M+1]+=411,09.

Example 18

To a solution of (RS)-1-amino-3-{4-[5-(5,6-diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}propan-2-ol (99 mg, 0.24 mmol), glycolic acid (18.5 mg, 0,244 mmole) and base Hunya (78 mg, and 0.61 mmole) in DHM (5 ml) is added Robot (a 126.7 mg, 0.24 mmol) and the mixture is stirred at room temperature for 30 minutes the mixture is Then diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried over MgSO4filter and concentrate. The crude product is purified using preparative TLC using as additionally separated by the mixture DHM:Meon in the ratio of 10:1 and receiving N-((RS)-3-{4-[5-(5,6-di is terpyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetate (90 mg) in the form of oil;

LC-MS: tR=0,88 min, [M+1]+=469,25.

Example 19

2-Ethyl-4-[5-(6-ethyl-5-isobutylidene-3-yl)-[1,2,4]oxadiazol-3-yl]-6-METHYLPHENOL get similarly obtaining compounds of example 13;

LC-MS: tR=1,09 min, [M+1]+=366,19.

Example 20

(S)-3-{2-Ethyl-4-[5-(6-ethyl-5-isobutylidene-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol get similarly obtaining compounds of example 14; LC-MS: tR=to 1.00 min, [M+1]+=440,20.

Example 21

(S)-2-{2-Ethyl-4-[5-(6-ethyl-5-isobutylidene-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethanol is similar to obtaining the compounds of example 16;

LC-MS: tR=1,08 min, [M+1]+=410,15.

Example 22

(RS)-1-Amino-3-{2-ethyl-4-[5-(6-ethyl-5-isobutylidene-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propan-2-ol get similarly obtaining compounds of example 17;

LC-MS: tR=0,85 min, [M+1]+=439,17.

Example 23

N-((RS)-3-{2-Ethyl-4-[5-(6-ethyl-5-isobutylidene-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido get similarly obtaining compounds of example 18;

LC-MS: tR=of 0.95 min, [M+1]+=497,17.

Example 24

4-[5-(6-Isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-iletiler get similarly obtaining compounds of example 13;

LC-MS: tR=the 1.04 min, [M+1]+=324,36.

Example 25

(RS)-1-Amino-3-{4-[5-(6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propan-2-ol get similarly obtaining compounds of example 17; LC-MS: tR=0,8 minutes

Example 26

2-Hydroxy-N-((RS)-2-hydroxy-3-{4-[5-(6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide get similarly obtaining compounds of example 18;

LC-MS: tR=to 0.89 min, [M+1]+=455,48.

Example 27

(RS)-3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methoxyphenoxy}propane-1,2-diol get similarly obtaining compounds of example 1;

LC-MS: tR=0,94 min, [M+1]+=448,21.

Example 28

a) To a solution of the hydrochloride of 6-isobutyl-5-methylnicotinic acid (50 mg, 0.22 mmol), DIPEA (of 0.12 ml, 0.7 mmole) and TBTU (97 mg, 0.30 mmol) in DHM (5 ml) is added at 0°C hydrazide 4-allyloxy-3,5-dimethylbenzoic acid (50,6 mg, 0.23 mmol) and the mixture is stirred at 0°C for 4 h the mixture is Then diluted with ethyl acetate (15 ml) and washed with 1-molar aqueous solution of NaH2PO4(5 ml), 1-molar aqueous solution of NaOH (5 ml) and water (5 ml). The organic phase is dried (MgSO4), filtered and evaporated, receiving N'-(4-allyloxy-3,5-d is methylbenzoyl)hydrazide 6-isobutyl-5-methylnicotinic acid (85 mg); LC-MS: tR=0,81 min, [M+1]+=396,20.

b) a Solution of N'-(4-allyloxy-3,5-dimethylbenzoyl)hydrazide 6-isobutyl-5-methylnicotinic acid (89 mg, 0,224 mmole) and Burgess reagent (162 mg, 0.68 mmol) in THF (4 ml) is heated in a microwave oven at 110°C for 6 minutes Then the mixture is diluted with ethyl acetate (15 ml) and washed with 1-molar aqueous solution of NaH2PO4(5 ml), 1-molar aqueous solution of NaOH (5 ml) and water (5 ml). The organic phase is dried (MgSO4), filtered and evaporated, to give crude 5-[5-(4-allyloxy-3, 5dimethylphenyl)-[1,3,4]oxadiazol-2-yl]-2-isobutyl-3-methylpyridin (80 mg);

LC-MS: tR=of 1.07 min, [M+1]+=378,3.

in) (RS)-3-{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propane-1,2-diol is obtained from 5-[5-(4-allyloxy-3, 5dimethylphenyl)-[1,3,4]oxadiazol-2-yl]-2-isobutyl-3-methylpyridin similarly, to obtain compounds of example 1;

LC-MS: tR=0,83 min; [M+1]+=412,23;1H NMR (D6-DMSO): δ were 0.94 (d, J=6,5 Hz, 6 H), 2,19 (septet, J=6,5 Hz, 1 H), a 2.36 (s, 6 H), 2,42 (s, 3 H), 2,73 (d, J=7,3 Hz, 2 H), 3,50 (t, J=5.5 Hz, 2 H), 3,76 (m, 1 H), a-3.84 (m, 1 H), the 3.89 (m, 1 H)and 4.65 (t, J=5.5 Hz, 1 H), equal to 4.97 (d, J=5.0 Hz, 1 H), to 7.84 (s, 2 H), 8,24 (d, J=1.0 Hz, 1 H), 9,05 (d, J=1.5 Hz, 1H).

Example 29

On the basis of nicotinic acid (2), (RS)-3-{4-[5-(5-isobutyl-6-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol get the same connection p is the iMER 1;

LC-MS: tR=0,93 min; [M+1]+=412,18.

Examples 30-34

Compounds of the following examples, get similarly obtaining the compounds of example 1, on the basis of nicotinic acid (6).

ExampleRaRbRcLC-MS
tR[min][M+H]+
30NNN0,83384,50
31CH3NN0,86398,48
32NOch3N0,75414,20
33NBr N0,93462,20
34NCH3Cl0,95432,26

Example 34

1H NMR (CDCl3): δ 1,01 (d, J=6.8 Hz, 6 H), 2,18-2,31 (m, 1 H), of 2.45 (s, 3 H), of 2.46 (s, 3 H), 2,80 (d, J=7,3 Hz, 2 H), 3,82-of 3.96 (m, 2 H), 4,06 is 4.13 (m, 2 H), 4,15-to 4.23 (m, 1 H), 7,95 (d, J=0.8 Hz, 1 H), 8,09 (d, J=1.5 Hz, 1 H), 8,21 (s, 1 H), 9,19 (s, 1 H).

Examples 35-39

Compounds of the following examples, get similarly obtaining compounds of example 2.

ExampleRaRbRcLC-MS
tR[min][M+H]+
35CH3NN0,78397,07
36NOch3 N0,68413,17
37NCH3Cl0,82431,49
38NOch3Cl0,81447,15
39NCH3CH3

Examples 40-43

Compounds of the following examples, get similarly obtaining compounds of example 3.

N
ExampleRaRbRcLC-MS
tR[min][M+H]+
40CH3N0,84455,45
41NOch3N0,73471,22
42NCH3Cl0,90489,20
43NOch3Cl0,90505,16

Example 40

1H NMR (CDCl3): δ 1,01 (d, J=6,5 Hz, 6 H), 2,17-of 2.30 (m, 1 H), of 2.46 (s, 3 H), 2,68 (s, 3 H), 2,80 (d, J=7,3 Hz, 2 H), 3,13-3,19 (m, 1 H), 3,47 of 3.56 (m, 1 H), 3.72 points-of 3.80 (m, 1 H), 3,99-4,08 (m, 2 H), 4,17-4,24 (m, 3 H), 6,85-of 6.90 (m, 2 H), was 7.08 (t advanced, J=5.5 Hz, 1 H), of 8.06 (d, J=8,3 Hz, 1 H), 8,21 (s, 1 H), 9,20 (s, 1 H)

Example 44

(RS)-1-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methoxyphenoxy}-3-(2-hydroxy-ethylamino)propan-2-ol get proceeding from a compound of example 27 is similar to obtaining the compounds of example 2 by reaction methysulfonylmethane intermediate connection ethanolamines;

LC-MS: tR=0,82 min, [M+1]+=491,06;1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6 H), 2,18-to 2.29 (m, 1 H), of 2.46 (s, 3 H), and 2.79 (d, J=7,3 Hz, 2 H), 2,83 of 2.92 (m, 4 H), 3,68-to 3.73 (m, 2 H), to 4.01 (s, 3 H), 4.04 the-4,16 (m, 2 H), 4,24-or 4.31 (m, 1 H), of 7.64 (s, 1 H), 7,87 (s, 1 H), 8,21 (s, 1 H), 9,18 (s, 1 H).

Examples 45 and 46

Racemic compound obtained in example 8, decompose to pure enantiomers using preparative HPLC, using a chiral stationary phase (ChiralPak ADH is 4.6×250 mm, 5 μm, 20% EtOH containing 0.1% diethylamine in heptane, 40 min, speed expiration: 0.8 ml/min).

Example*ChiralityRetention time [min]
45R13,5
46S11,8

Example 47

2-Ethyl-4-[3-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-METHYLPHENOL derived from N-hydroxy-6-isobutyl-5-nicotine amide and 3-ethyl-4-hydroxy-5-methylbenzoic acid analogous to obtain compounds of example 13;

LC-MS: tR=1,02 min, [M+1]+=352,09.

Examples 48-53

On the basis of example 47, the compounds of the following examples, get similarly obtaining the previous examples.

Example Similarly, theRLC-MS
exampletR[min][M+H]+
48140,99425,82
49140,99425,90
50170,74425,08
51170,74425,24
52180,92483,12
53180,92 483,07

Example 49

1H NMR (CDCl3): δ 1.00 each (d, J=6.3 Hz, 6 H), of 1.33 (t, J=7,3 Hz, 3 H), 2,17-of 2.27 (m, 2 H), 2,43 (s, 6 H), and 2.79 (m, 4 H), 2,90 (s extended, 1 H), 3,82-4,01 (m, 4 H), 4,15-4,24 (m, 1 H), of 7.93 (s, 1 H), 7,94 (s, 1 H), 8,18 (s, 1 H)to 9.15 (s, 1 H).

Example 53

1H NMR (CDCl3): δ 1,01 (d, J=6,5 Hz, 6 H), of 1.33 (t, J=7,3 Hz, 3 H), 2,16-of 2.28 (m, 1 H)to 2.41 (s, 3 H), of 2.44 (s, 3 H), 2,74-2,82 (m, 4 H), 3,39 (s extended, 1 H), 3,49-to 3.58 (m, 1 H), of 3.77-3,95 (m, 3 H), 4,20-4,27 (m, 3 H), 7,01 (s extended, 1 H), of 7.93 (s, 1 H), 7,94 (s, 1 H), 8,19 (s, 1 H)to 9.15 (s, 1 H).

Example 54

a) To a solution of nicotinic acid (6) (50 mg, 0,218 mmol) in DHM (5 ml) add a solution of TBTU (97 mg, 0,301 mmol), and then DIPEA (90 mg, 0,696 mmol) in DHM (5 ml). The mixture is stirred and cooled to 0°C, then add hydrazide 4-allyloxy-3,5-dimethylbenzoic acid (51 mg, 0,232 mmol). Then the mixture is stirred at 0°C for 16 h, then diluted with ethyl acetate (15 ml), washed with saturated aqueous NaHCO3(5 ml) and 1 molar aqueous solution of NaOH (5 ml), dried over MgSO4, filtered, concentrated and dried in vacuum, obtaining the intermediate hydrazide;

LC-MS: tR=0,81 min, [M+1]=396,37. To a solution of this compound in THF (3 ml) is added a reagent Lawesson (129 mg, 0,318 mmol) and the mixture is heated in a microwave oven at 110°C for 5 minutes the mixture is Then diluted with ethyl acetate (30 ml), washed with saturated aq is m solution of Na 2CO3, dried over Na2SO4filter and concentrate. The crude product is purified using preparative TLC using as additionally separated by DHM containing 10% 7-normal solution of NH3in Meon, and receiving 5-[5-(4-allyloxy-3, 5dimethylphenyl)-[1,3,4]thiadiazole-2-yl]-2-isobutyl-3-methylpyridin (67 mg) as a yellow solid; LC-MS: tR=the 1.04 min, [M+1]+=394,10.

b) 5-[5-(4-Allyloxy-3, 5dimethylphenyl)-[1,3,4]thiadiazole-2-yl]-2-isobutyl-3-methylpyridin process OsO4as described in stage C) of example 1, obtaining (RS)-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,3,4]thiadiazole-2-yl]-2,6-dimethylphenoxy} propane-1,2-diol;

LC-MS: tR=0,78 min, [M+1]+=428,50;1H NMR (CDCl3): δ 1.01 (d, J=6,5 Hz, 6 H), 2,17-of 2.28 (m, 1 H), 2,39 (s, 6 H), 2,43 (s, 3 H), was 2.76 (d, J=7,3 Hz, 2 H), 3,82-to 3.99 (m, 4 H), 4,14-is 4.21 (m, 1 H), of 7.70 (s, 2 H), 8,13 (s, 1 H), of 8.90 (s, 1 H).

Example 55

To a solution of {4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]phenyl}acetic acid (50 mg, 142 μmol) in DMF (3 ml) is added EDC HCl (33 mg, 171 μmol), HOBT (23 mg, 171 μmol) and DIPEA (28 mg, 213 μmol). The mixture is stirred at room temperature for 5 minutes, then add ethanolamine (10 mg, 157 μmol). Stirring is continued at RT for 72 h Then the mixture is diluted with ethyl acetate, washed with water and concentrated. The crude product is purified using preparative TLC, use as eluent DHM, containing 10% Meon, and receiving N-(2-hydroxy-ethyl)-2-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]phenyl}ndimethylacetamide (26 mg) as a white solid;

LC-MS: tR=0,82 min, [M+1]+=395,15;1H NMR (CDCl3): δ 1,01 (d, J=6,5 Hz, 6 H), 2,19-to 2.29 (m, 1 H), of 2.46 (s, 3 H), 2,53 (s extended, 1 H), 2,80 (d, J=7,3 Hz, 2 H), 3,44 (q, J=4,8 Hz, 2 H), of 3.69 (s, 2 H), 3,71 of 3.75 (m, 2 H), 5,96 (s extended, 1 H), 7,46 (d, J=7.5 Hz, 2 H), 8,18 (d, J=7.8 Hz, 2 H), 8,17 (s), 8,19 (s), by 8.22 (s, 1 H), 9,20 (s, 1 H).

Example 56

N-(2-Hydroxy-1-hydroxymethyl-ethyl)-2-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]phenyl}ndimethylacetamide get similarly obtaining compounds of example 55, using 2-aminopropan-1,3-diol;

LC-MS: tR=0,78 min, [M+1]+=425,19.

Example 57

1-(2-{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]phenyl}acetyl)azetidin-3-carboxylic acid is obtained from {4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]phenyl}acetic acid and methyl ester of azetidin-3-carboxylic acid analogously to obtain compounds of example 55; mixing of this product in 3-normal aqueous solution with NaOH in dioxane at RT for 20 h gives the desired connection;

LC-MS: tR=0,60, [M+1]+=434,96.

Example 58

(RS)-3-{4-[5-(6-Isobutylpyrazine-3-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propane-1,2-diol receive is similar to obtaining compounds of example 28 from nicotinic acid (8);

LC-MS: tR=0,85, [M+1]+=398,36.

Example 59

(RS)-1-Amino-3-{4-[5-(6-isobutylpyrazine-3-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propan-2-ol is obtained from the compound of example 58 similarly, in a compound of example 2;

LC-MS: tR=0,75, [M+1]+=397,29.

Example 60

(RS)-2-Hydroxy-N-(2-hydroxy-3-{4-[5-(6-isobutylpyrazine-3-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide produced from compound of example 59 similarly, in a compound of example 3;

LC-MS: tR=0,80, [M+1]+=455,19;1H NMR (CD3OD): δ 0,97 (d, J=6,7 Hz, 6 H), 2.06 to of 2.20 (m, 1 H), of 2.38 (s, 6 H), was 2.76 (d, J=7,0 Hz, 2 H), 3,38 is 3.57 (m, 1 H), 3,59-to 3.73 (m, 1 H), 3,78-of 3.94 (m, 2 H), to 4.01 (s, 2 H), 4,05-4,16 (m, 1 H), 7,50 (d, J=7.9 Hz, 1 H), 7,81 (s, 2 H), to 8.41 (dd, J=8,2, 2.1 Hz, 1 H), 9,16 (d, J=2.1 Hz, 1 H).

Examples 61-70

Compounds of the following examples, get similarly obtaining the previous examples, on the basis of nicotinic acid (8).

Approx.Similarly, theRaRbRcLC-MS
exampletR[min][M+H]+
6113CH3CH3HE1,04324,36
6213Och3ClOH1,03360,01
6317CH2CH3CH30,81411,47
6417CH2CH3CH30,81411,41
6518CH2CH3CH3 0.92469,25
6618CH2CH3CH30,92469,24
6717Och3Cl0,81433,12
6817Och3Cl0,81433,10
6918Och3Cl0,91491,02
7018Och3Cl 0,91491,04

Example 66

1H NMR (CDCl3): δ 0,99 (d, J=6,5 Hz, 6 H), of 1.33 (t, J=7.5 Hz, 3 H), 2,15-of 2.26 (m, 1 H), that is 2.40 (s, 3 H), 2,72-and 2.83 (m, 4 H), 3,49-to 3.58 (m, 1 H), 3,78-of 3.94 (m, 3 H), to 4.17-4.26 deaths (m, 3 H), 6,98 (s extended, 1 H), 7,34 (d, J=8,3 Hz, 1 H), 7,88 (s, 1 H), 7,89 (s, 1 H), 8,39 (dd, J=8,0, 2.0 Hz, 1 H), 9,37 (d. J=1.3 Hz, 1 H).

Examples 71-77

Compounds of the following examples derived from nicotinic acid (9) and 3-ethyl-4,N-dihydroxy-5-methylbenzamide similarly obtaining the compounds of the previous examples.

ExampleSimilarly, theRLC-MS
exampletR[min][M+H]+
7113HE1,08366,10
72161,06410,15
7316 1,09424,32
74140,98440,29
75151,01454,37
76170,85439,28
77180,94497,36

Example 75

1H NMR (CDCl3): δ 1,01 (d, J=6.8 Hz, 6 H), of 1.33 (m, 6 H), 2,15 (s extended, 1 H), 2,22-of 2.34 (m, 2 H), 2,42 (s, 3 H), 2,73-to 2.85 (m, 4 H), 3,51 (s, 1 H), of 3.96-4.09 to (m, 5H), 7,89 (s, 1 H), 7,92 (s, 1 H), of 8.25 (d, J=a 1.8 Hz, 1 H), of 9.21 (d, J=2.0 Hz, 1 H).

Examples 78-81

Compounds of the following examples derived from nicotinic acid (10) and 3-ethyl-4,N-dihydroxy-5-methylbenzamide similarly obtaining the compounds of the previous examples.

ExampleSimilarly, theR LC-MS
exampletR[min][M+H]+
7813HE1,05352,52
79161,04396,15
80140,96426,11
81150,99440,24

Example 81

1H NMR (CDCl3): δ 1,01 (d, J=6.0 Hz, 6 H), of 1.33 (t, J = 7.8 Hz, 3 H), 1,67-to 1.77 (m, 2 H), and 2.14 (s extended, 1 H), and 2.27 to 2.35 (m, 1 H), 2,42 (s, 3 H), 2,77 (q, J=7.5 Hz, 2 H), 2,93-to 2.99 (m, 2 H), to 3.99-4.09 to (m, 5 H), 7,86-to $ 7.91 (m, 3 H), 7,94 (s, 1 H), 8,79 (d, J=5.0 Hz, 1 H).

Examples 82-88

Compounds of the following examples get similar to the previous examples of nicotinic acid (11) and 3-ethyl-4,N-dihydroxy-5-methylbenzamide.

ExampleSimilarly, theRLC-MS
exampletR[min][M+H]+
8213HE1,18354,14
83141,08428,21
84141,08428,21
85170,88427,13
8617
8718 1,03485,28
88181,03485,23

Example 88

1H NMR (CDCl3): δ of 1.32 (t, J=7.5 Hz, 3 H), of 1.42 (d, J=6.0 Hz, 6 H), of 2.28 (s, 3 H), 2,39 (s, 3 H), of 2.75 (q, J=7.5 Hz, 2 H), to 3.41 (m, 1 H), 3,48-to 3.58 (m, 1 H), 3,76-3,93 (m, 3 H), 4,17-of 4.25 (m, 3 H), 5,43-5,52 (m, 1 H), 7,03 (t advanced, J=4.3 Hz, 1 H), the 7.85 (s, 1 H), 7,87 (s, 1 H), 8,14 (s, 1 H), 8,84 (s, 1 H).

Example 89

3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxyethyl)propionamide obtained from 3-{2-ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionic acid analogous to obtain compounds of example 55;

LC-MS: tR=1.07, and [M+1]+=453,23;1H NMR (CDCl3): δ is 1.31 (t, J=7,3 Hz, 3 H), of 1.42 (d, J=5.5 Hz, 6 H), of 2.28 (s, 3 H), 2,38-2,48 (m, 5 H), 2,53 (s extended, 1 H), 2,77 (q, J=7,3 Hz, 2 H), 3,06-3,14 (m, 2 H), 3,42-to 3.50 (m, 2 H), 3,71-with 3.79 (m, 2 H), 5,42-5,52 (m, 1 H), of 5.89 (s extended, 1 H), of 7.82 (s, 1 H), the 7.85 (s, 1 H), of 8.15 (s, 1 H), cent to 8.85 (s, 1 H).

Examples 90-92

Compounds of the following examples get analogously to example 13 from 3-ethyl-4-hydroxy-5-methylbenzoic acid and N-hydroxy-6-isopropoxy-5-nicotine amide.

Example Similarly, theRLC-MS
exampletR[min][M+H]+
9013HE1,18354,10
91141,12428,05
92141,12428,06

Example 92

1H NMR (CDCl3): δ of 1.34 (t, J=7.5 Hz, 3 H), of 1.41 (d, J=6.0 Hz, 6 H), 2,03 (t, J=6.0 Hz, 1 H), and 2.27 (s, 3 H), 2,43 (s, 3 H), 2,70 (d, J=5.0 Hz, 1 H), and 2.79 (q, J=7,3 Hz, 2 H), 3,82-to 3.99 (m, 4 H), 4,15-is 4.21 (m, 1 H), 5,41-5,49 (m, 1 H), 7,92 (s, 1 H), of 7.96 (s, 1 H), 8,11 (s, 1 H), 8,79 (s, 1 H).

II) Biology

GTPγS analysis determine EC50values

Analyses GTPγS binding is carried out in 96-cellular tablets titration (Nunc, 442587) for a final volume of 200 µl, using membrane preparations of Cho cells expressing recombinant human S1P1 receptor. Condition analysis: 20 mm Hepes (company Fluka, 5441), 100 mm NaCl (company Fluka, 71378), 5 mm MgCl2(the company Fluka, 63064), 0.1% of BSA (firm Calbiochem, 126609), 1 μm GDP (firm Sigma, G-7127), 2.5% DMSO, Fluka, 41644), 50 pM35S-GTPγS (firm Amersham Biosciences, SJ1320), a pH of 7.4. Test compounds are dissolved and diluted with 100% DMSO and pre-incubated at room temperature for 30 min in 150 μl of the above buffer for analysis, in the absence of35S-GTPγS. After adding 50 μl of35S-GTPγS, analyzed the mixture incubated for 1 h at room temperature. The analysis is stopped by transferring the reaction mixture into Multiscreen tablet (Millipore, MAHFC1H60)using the collector cells from firms Packard Biosciences, after which the tablets are washed with ice with a solution of 10 mm Na2HPO4/NaH2PO4(in the ratio of 70%:30%), dried, sealed in the lower division and after adding 25 μl MicroScint20 (Packard Biosciences, order# 6013621), sealed at the top. Membrane binding35S-GTPγS was measured using TopCount from the company Packard Biosciences.

EU50represents the concentration of agonist, comprising 50% of the maximum specific35S-GTPγS binding. Specific binding is determined by subtracting nonspecific binding from the maximum binding. The maximum binding represents the number of pulses per minute associated with Multiscreen tablet in the presence of 10 μm S1P. Nonspecific shall wezwanie represents the number of binding in the absence of the agonist in the analysis.

Were also measured agonistic activity (EC50values) of the compounds of examples 62-92. Found EU50values are in the range of from 0.1 to 9410 nm with a mean of 492 nm. Agonistic activity of selected compounds are presented in table 1.

Table 1
Connection exampleEU50[nm]
10,6
52,7
420,6
434,0
771,2
880,1
893,5
925,1

Assessment of the effectiveness of in vivo

The effectiveness of compounds of the formula (I) was estimated by the measurement of circulating lymphocytes after oral administration of from 3 to 30 mg/kg of the compounds of formula (I) normotensive male individuals of Wistar rats. The animals were kept in a controlled climate with 12-hour light/dark cycle and had access to armalloy rat food and water. Blood was sampled before and after 3, 6 and 24 h after drug administration. Whole blood was subjected to haematological analysis using the Advia Hematology system (Bayer Diagnostics, Zürich, Switzerland).

All data are presented as mean ±SEM. Statistical analyses were performed using variance analysis (ANOVA) using Statistica (StatSoft) and Student-Newman-Keuls method for multiplet comparisons. Reduced to zero, the hypothesis is discarded, when p<0,05.

In the example in table 2 shows the effect on lymphocytes, after 6 h after injection of 10 mg/kg of some compounds of the present invention normotensive male individuals of Wistar rats compared to animals treated only with solvent. The number of lymphocytes after 6 h after oral administration was measured for 6 exemplary compounds were in the size range from -77% to -61% with an average value of -68%.

84
Table 2
Connection exampleThe number of lymphocytes
3-71%
8-61%
12-61%
74-77%
-76%

1. The compound of formula (I)

where a is a *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-,
,,or

where the asterisks indicate the bond through which the connection to the pyridine group of formula (I);
R1represents hydrogen, C1-4alkyl or chlorine;
R2represents a C1-5alkyl or C1-4alkoxygroup;
R3represents hydrogen or C1-4alkyl;
R4represents hydrogen, C1-4alkyl, C1-4alkoxygroup or halogen;
R5represents-CH2-(CH2)n-CONR51R52, -CO-other51, 1-(3-carboxyethylidene)-2-acetyl, hydroxy-group, hydroxys2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxypropan, -OCH2-CH(OH)-CH2-NR51R52or-OCH2-CH(OH)-CH2-NHCOR54;
R51represents hydrogen, C1-3alkyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylene or 2,3-dihydrodiol;
R52represents hydrogen;
R54represents hydroxymethyl;
n PR is dstanley a 0 or 1; and
R6represents hydrogen, C1-4alkyl or halogen;
and salt of such compounds.

2. The compound according to claim 1, where a is a
;
and salt of such compounds.

3. The compound according to claim 1 or 2, where R1represents a C1-4alkyl or chlorine; and a salt of such compounds.

4. The compound according to claim 1 or 2, where R1represents a C1-4alkyl; and the salts of such compounds.

5. The compound according to claim 1 or 2, where R2represents a C1-5alkyl; and the salts of such compounds.

6. The compound according to claim 1 or 2, where R2represents n-propyl or isobutyl; and the salt of such compounds.

7. The compound according to claim 1 or 2, where R2represents a C1-4alkoxygroup; and the salt of such compounds.

8. The compound according to claim 1 or 2, where R3represents hydrogen; and the salts of such compounds.

9. The compound according to claim 1 or 2, where R3represents hydrogen; and R4represents a C1-4alkyl or C1-4alkoxygroup; and R6represents a C1-4alkyl or halogen; and salts of such compounds.

10. The compound according to claim 1 or 2, where R3represents hydrogen, R4represents a C1-3alkyl or methoxy group, and R6represents methyl, ethyl, or halogen; and salts of such compounds.

11. The compound according to claim 1 or 2, where the R 5represents-CH2-(CH2)n-CONR51R52, -CO-other51the hydroxy-group, hydroxy2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl,
-OCH2-CH(OH)-CH2-NR51R52or-OCH2-CH(OH)-CH2-NHCOR54; and the salt of such compounds.

12. The compound according to claim 1 or 2, where R5represents-CH2-(CH2)n-CONR51R52, -CO-other51hydraxis2-5alkoxygroup, di-(hydraxis1-4alkyl)-C1-4alkoxygroup, 2,3-dihydroxypropyl, -OCH2-CH(OH)-CH2-NR51R52or-OCH2-CH(OH)-CH2-NHCOR54; and the salt of such compounds.

13. The compound according to claim 1 or 2, where R5is hydraxis2-5alkoxygroup, di-(hydraxis1-4alkyl)1-4alkoxygroup, 2,3-dihydroxypropyl, -OCH2-CH(OH)-CH2-NR51R52or-OCH2-CH(OH)-CH2-NHCOR54; and the salt of such compounds.

14. The compound according to claim 1 or 2, where R5is a 3-hydroxy-2-hydroxymethylpropane, 2,3-dihydroxypropyl or-OCH2-CH(OH)-CH2-NHCOR54; and the salt of such compounds.

15. The compound according to claim 1, selected from the group including:
3-{4-[5-(5-Chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propane-1,2-diol;
N-(3-{4-[5-(5-Chloro-6-isopropoxypyridine-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
3-{4-[5-(6-Isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy} propane-1,2-diol;
2-Hydroxy-N-(2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide;
N-(3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
3-{4-[5-(5,6-Diisobutylene-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy} propane-1,2-diol;
N-(3-{4-[5-(5,6-Diethylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
2-Hydroxy-N-(2-hydroxy-3-{4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-3-methylphenoxy}propyl)ndimethylacetamide;
N-(3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
N-(3-{2-Chloro-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methoxyphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
N-((R)-3-{2-Ethyl-4-[5-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
N-((S)-3-{2-Ethyl-4-[3-(6-isobutyl-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
N-((5)-3-{2-Ethyl-4-[5-(6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
(S)-3-{2-Ethyl-4-[5-(5-ethyl-6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;
N-3-{2-Ethyl-4-[5-(5-ethyl-6-isobutylpyrazine-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
(R)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;
(S)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;
N-((R)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
N-((5)-3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxyethyl)propionamide;
(R)-3-{2-Ethyl-4-[3-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}propane-1,2-diol;
(S)-3-{2-Ethyl-4-[3-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}propane-1,2-diol; and
3-{2-Ethyl-4-[5-(6-isopropoxy-5-methylpyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionic acid;
and salt of such compounds.

16. Pharmaceutical composition for prevention or treatment of diseases or disorders associated with an activated immune system, including a connection according to one of claims 1 to 15 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

17. The connection according to one of claims 1, 2 and 15, or its pharmaceutically acceptable salt, or a pharmaceutical composition according to item 16 for use in the prevention or treatment of illness is her or diseases, associated with an activated immune system.

18. The use of compounds according to one of claims 1 to 15 or its pharmaceutically acceptable salt to obtain a pharmaceutical composition for the prevention or treatment of diseases or disorders associated with an activated immune system.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 and salts thereof, fungicidal compositions based on said compounds, a plant disease control method using compounds of formula , as well as intermediate compounds of formulae and . Values of radicals are given in the description.

EFFECT: high efficiency of the compounds.

14 cl, 20 dwg, 284 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) X represents NH, n means a number equal to 0-3, Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-, p means a number equal to 0-2, q means a number equal to 1-3, R1 represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents 5~6-member heteroaryl or heterocyclyl each of which has 1 -3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulphonyl 6~12-member aryl, R3 represents R7-X-B-X'-, B represents a direct bond or represents 5~6-member heterocyclyl or heteroaryl each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S. Also the invention refers to a pharmaceutical composition for glucokinase activation and a method for preparing it.

EFFECT: use of the compounds of formula (I) as glucokinase activators.

22 cl, 11 dwg, 3 tbl, 222 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3,3'-bi-1,5,3-dithiazepinane of formula (1) having fungicidal activity against Bipolaris sorokiniana, Aspergillus fumigates, Aspergillus niger and Paecilomyces variotii. The method involves reaction of a mixture of ethanedithiol and formaldehyde with hydrazine hydrate (60%) with molar ratio aldehyde: ethanedithiol: hydrazine = 40:20:10 at temperature 25°C and atmospheric pressure for 2-4 hours.

EFFECT: improved method.

2 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3,4-thiadiazolines (I), thiadiazinones (II) and thiadiazepines (III), obtained based on thiohydrazides of oxamic acids, which can be used to inhibit pathogenic bacteria, and can particularly affect type III secretion system in pathogens, having general formula:

, , ,

where R denotes H; R1 denotes H, pyridinyl; phenyl, substituted with alkyl C1-C5, Hal, CF3; a group , where X denotes S, substituted with alkyl C1-C5, COOR4; R2, R3 denotes alkyl C1-C5, pyridinyl, phenyl, substituted Hal, OH, OR4, a R4 denotes unsubstituted alkyl C1-C4.

EFFECT: obtaining compounds which can be used to inhibit pathogenic bacteria.

2 cl, 2 dwg, 6 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R denotes a substituted or unsubstituted thiazolyl group of formula or ; R4 and R5, each independently, are selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl; iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteratoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; or R4 and R5 can be taken together to form a saturated or unsaturated ring, having 5-7 atoms; said substitutes are independently selected from one or more groups, selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R6 denotes a group selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteroatoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R1 is selected from i) hydrogen; ii) C1-C6 linear or C3-C6 branched alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted benzyl; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R2 is selected from i) C1-C6 linear or C3-C6 branched alkyl or ii) C1-C6 linear or C3-C6 branched alkoxy; R3 denotes hydrogen or C1-C4 linear or C3-C6 branched alkyl.

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20 cl, 10 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present inventions refers to a new crystalline form of tetomilast hydrate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 20=10.6°, 12.9°, 21.1°, 22.3° and 25.0°, to a new crystalline form of anhydrous tetomilast type C of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=4.2°, 8.2°, 12.0°, 16.4°, 24.7° and 25.9°, to a new crystalline form of acetonitrile tetomilast solvate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=3.6°, 7.1°, 10.6°, 14.2° and 24.8°, to based pharmaceutical compositions and to methods for preparing.

EFFECT: new crystalline forms shows useful processing characteristics with relation to preparing pharmaceutical drugs of them.

13 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula

wherein A, R1, R2, R3, R4, R5 and R6 are presented in the description, preparing and using them as pharmaceutically active compounds as immunomodulatory agents.

EFFECT: preparing the pharmaceutical composition showing agonist activity with respect to S1P1/EDG1 receptor and using it for prevention and treatment diseases or disorders associated with activated immune system.

20 cl, 244 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I

,

where A represents S or Se; B represents H or ; R1 represents aryl selected from the following structures:

R2 represents H or ; R3 represents H or C1-C8 alkyl; R4 and R5 independently represent H or C1-C8 alkyl; R6 represents H, C1-C8 alkyl, C2-C7 alkenyl, alkaline metal or alkaline earth metal; R11 and R12 independently represent H, C1-C8 alkyl or halogen; R21 represent H, halogen or C1-C7 alkyl; m and n independently represent integers having values 1-4; p represents an integer having a value of 1-5; q represents an integer having a value of 1-4; r represents an integer having a value of 1-3; s represents an integer having a value of 1-5; as an activator of peroxisome proliferator-activated receptor (PPAR) and its hydrate, solvate, stereoisomer and pharmaceutically acceptable salt, and to a pharmaceutical composition.

EFFECT: preparing an agent for muscle strengthening, an agent for memory improvement, a therapeutic agent for dementia and Parkinson's disease.

15 cl, 8 tbl, 348 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a salt of 2-ethyl-6-methyl-3-hydroxypyridine with nicotinic acid, a method of producing said salt, as well as a method of correcting metabolic disorders in case of sugar diabetes with diabetes with exogenous hypercholesteremia and morphofunctional disorders and brain during acute ischemia.

EFFECT: novel salt of 2-ethyl-6-methyl-3-hydroxypyridine with nicotinic acid is described, which has hypoglycemic, hypolipidemic and neuroprotective activity and can be used in endocrinology, cardiology, neurology, emergency treatment and intensive care.

4 cl, 3 ex

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