Deazapurines and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel deazapurines of formula (I): and pharmaceutically acceptable salts thereof, where n = 0; R1 is H, -NH2, -NHCH3, -NH-Ac, -OH, F, -OCH3, -CN, -NH(C=O)OC2H5; R2 is H, -NRARB, -ORA, C1-20alkyl, C1-20halogenalkyl, C6-10aryl, where RA and RB each independently represents H, C1-20alkyl, where C6-10aryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of C1-20alkyl, C1-20alkoxy and C1-20thioalkyl; each R3 independently represents H, halogen, CN, C1-20alkyl, C1-20alkoxy, C1-20thioalkyl, a -G-RC group, where G is absent or represents CH2-, -(CH2)2-, -CH=CH-CH2-, -CH-CH-, -OC-, -O- or (C=O) and where RC is H, -NRF-RG , -ORF, -SRF, -S(=O)RF, -S(=O)2RF, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, tert-butyl dimethyl silyloxy, heterocycle, C6-10aryl, C5-14heteroaryl with one N atom as a heteroatom, where RF and RG each independently represents H, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-10aryl, 6-member heterocycle with one O atom as a heteroatom, where RF and RG together form a 3-, 4-, 5-, 6-, 7- or 8-member cycloalkyl, cycloalkenyl, where the said heterocycle relates to a non-aromatic 5-, 6-, 7-member ring or bi- or tri-cyclic group containing condensed 6-member rings with 1-2 heteroatoms independently selected from O, S, N; where each of the said alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of O, halogen, OH, -CN, C1-20halogenalkyl, -CH2CF3, C1-20alkyl, C1-20alkoxy, C3-6cycloalkyl, C6-10aryl, 5- or 6-member heterocycle with one or two N atoms as heteroatoms, NHRh, NRhRi, N-ORh, ORh, C(=O)Rh, S(=O)Rh, S(=O)2Rh, =CR4R5, =NR4, where Rh and Rj present C1-20alkyl, C6-10aryl, and each of R4, R5 independently represents H, OH, ORx or C1-6alkyl, where Rx is C1-6alkyl, where the said aryl can be independently further unsubstituted or substituted with one or more substitutes selected from a group consisting of halogen, C1-20alkyl or C1-20alkoxy.

EFFECT: compounds can inhibit cytokine induced expression of adhesion molecules with endothelial cells, which enables their use in pharmaceutical compositions.

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This provisional patent application is related in the process of simultaneous consideration of application No. 60/346598 registered 7 January 2002, and which in its entirety is included in this context as a reference.

Inflammation is a process resulting from dilatation and increased permeability of blood vessels in the area of injury or infection. Chemokines and cytokines released in this area, increase the expression of cell surface proteins on endothelial cells, allowing circulating leukocytes to adhere to the vessel wall and migrate into the site of injury/infection in the tissue. These proteins on the cell surface, called as “cell adhesion molecules”, allow you to be the interaction between leukocytes and endothelial cells and mediate leukocyte migration into the tissue. Additionally, these cell-adhesion molecules necessary for many of the interactions of cells in inflammatory reactions and immune responses. There are three classes of adhesion molecules: selectins, integrins and related immunoglobulin proteins that can be expressed in leukocytes and endothelial cells. Some of adhesion molecules including E-selectin and SAM, induced by cytokines, such the as IL-1 and TNF, and their expression is mediated by transcription factor NF-κB.

Prolonged or inappropriate expression of adhesion molecules may lead to inflammatory or autoimmune disorders. The result of abnormally high expression of E-selectin and/or ICAM may be chronic inflammation, and this expression may be associated with severe inflammatory or autoimmune disorders. Therefore, inhibitors of cell-adhesion molecules may be suitable for the treatment of these diseases.

Inflammatory and autoimmune diseases are not quite amenable to treatment by modern therapy, and therefore there is a need to create the best medicines. For example, rheumatoid arthritis is a chronic state of inflammation in the joint, characterized by destruction of cartilage and bone. Traditional treatment of inflammatory or autoimmune diseases, such as rheumatoid arthritis, include nasteride anti-inflammatory drugs and salicylates, compounds of gold, hydroxychloroquine, sulfasalazin, corticosteroids, oral penicillamine and cytotoxic or immunosuppressive drugs. However, many of these therapies are not always efficient, and are the result of their serious side effects. The relative is tion recently went on sale injectable forms neutralizing TNFa protein, successfully used to treat rheumatoid arthritis and Crohn's disease; however, orally administered inhibitor for these inflammatory or autoimmune diseases is not received.

Obviously, there is still a need for new classes of therapeutic agents for the treatment of inflammatory or autoimmune and proliferative disorders, preferably injected oral route and without serious side effects. It is also desirable, in General, to identify new classes of therapeutic agents for the treatment of inflammatory or autoimmune and proliferative diseases.

Summary of the invention

As discussed above, there is a need to develop new therapeutic agents suitable for the treatment of inflammatory or autoimmune and proliferative diseases. The present invention relates to new compounds of General formula (I):

and pharmaceutical compositions on their basis, as disclosed in the present description, as well as methods of producing and using such compounds.

Description of some preferred embodiments of the invention

Recognizing the need to research and identify new classes of therapeutic agents for the treatment of rheumatoid arthritis and other diseases (according to neatoramanauts implementation inflammatory or autoimmune and proliferative diseases), the present invention relates to new deazapurines and their analogues, as described in more detail in the present description, are generally suitable for the treatment of inflammatory or autoimmune and proliferative disorders. According to some variants of the implementation proposed in the present invention the compounds may be used for the treatment of diseases and disorders, including, but not limited to, rheumatoid arthritis, ulcerative colitis/Crohn's disease, diseases of the Central nervous system (CNS)such as multiple sclerosis, systemic lupus erythematosus, asthma, graft rejection/graft versus host (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, severe myasthenia gravis, diabetes, idiopathic thrombocytopenia, cardiovascular disease and cancer.

1) a General description of the compounds according to the invention

Compounds according to the invention include compounds of the following General formula (I) and their tautomers):

and their pharmaceutically acceptable derivatives,

where

n means an integer from 0 to 4;

R1means a hydrogen atom, -NH2, -NH3, -NH-acyl, -OH, F, -och3, -CN, or-NH(C=O)OS2H5;

R2means the atom in which aroda, -NRARB, -ORA, aliphatic, heteroaromatics, aryl or heteroaryl residue, where RAand RBeach independently mean a hydrogen atom or an aliphatic, heteroaromatics, aryl or heteroaryl residue;

each of R3independently means a hydrogen atom, a halogen atom, a cyano or an aliphatic, heteroaromatics, aryl or heteroaryl residue, or a group-G-RCwhere G is absent or denotes-CH2-, -NRD-, -O - or - (C=O) and where RCmeans a hydrogen atom, -NRFRG, -ORF, -SRFor aliphatic, heteroaromatics, aryl or heteroaryl residue, where RD, RFand RGeach independently mean a hydrogen atom, -NRxRy, aliphatic, cycloaliphatic, heteroaromatics, collegerelations, aryl or heteroaryl residue, -C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue; or where RDand RCor RFand RGtaken together, they form a 3-, 4-, 5-, 6-, 7 - or 8-membered, substituted or unsubstituted cycloaliphatic or collegerelations balance; where each of Rxand Ryindependently means a hydrogen atom, aliphatic, cycloaliphatic, heteroaromatics, qi is logotherapeutic, aryl or heteroaryl residue, -C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue; or where Rxand Rytaken together form a 4-, 5 - or 6-membered, substituted or unsubstituted, saturated or unsaturated cycloaliphatic or collegerelations balance;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the foregoing aryl or heteroaryl residue can be independently substituted or unsubstituted.

According to some variants of implementation, the present invention relates to certain classes of compounds that are of particular interest. For example, one class of compounds of special interest includes compounds substituted by two versions of R3where the compound has the structure:

;

where R3Aand R3beach independently mean a hydrogen atom, a halogen atom, a cyano or an aliphatic, heteroaromatics, aryl or heteroaryl residue, or a group-G-RCwhere G is absent, means-CH2-, -NRD-, -O - or - (C=O) and where RCOSN which denotes a hydrogen atom, -NRFRG, -Or SIGF, -SRFor aliphatic, heteroaromatics, aryl or heteroaryl residue, where RD, RFand RGeach independently mean a hydrogen atom, -NRxRy, aliphatic, cycloaliphatic, heteroaromatics, collegerelations, aryl or heteroaryl residue, -C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue; or where RDand RCor RFand RGtaken together, they form a 3-, 4-, 5-, 6-, 7 - or 8-membered, substituted or unsubstituted cycloaliphatic or collegerelations balance; where each of Rxand Ryindependently means a hydrogen atom, aliphatic, cycloaliphatic, heteroaromatics, collegerelations, aryl or heteroaryl residue, -C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue; or where Rxand Rytaken together form a 4-, 5 - or 6-membered, substituted or unsubstituted, saturated or unsaturated cycloaliphatic or collegerelations balance;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic the sky, linear or branched, saturated or unsaturated, and each of the foregoing aryl or heteroaryl residue can be independently substituted or unsubstituted.

Another class of special interest compounds includes compounds having the structure:

;

where

R3aand R3beach independently mean a hydrogen atom, a halogen atom, a cyano or an aliphatic, heteroaromatics, aryl or heteroaryl residue, or a group-G-RCwhere G is absent, means-CH2-, -NRD-, -O - or - (C=O) and where RCmeans a hydrogen atom, -NRFRG, -ORF, -SRFor aliphatic, heteroaromatics, aryl or heteroaryl residue, where RD, RFand RGeach independently mean a hydrogen atom, -NRxRy, aliphatic, cycloaliphatic, heteroaromatics, collegerelations, aryl or heteroaryl residue, -C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue; or where RDand RCor RFand RGtaken together, they form a 3-, 4-, 5-, 6-, 7 - or 8-membered, substituted or unsubstituted cycloaliphatic or collegerelations balance; where each of Rxand Ryindependent means at the m of hydrogen, aliphatic, cycloaliphatic, heteroaromatics, collegerelations, aryl or heteroaryl residue, -C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue; or where Rxand Rytaken together form a 4-, 5 - or 6-membered, substituted or unsubstituted, saturated or unsaturated cycloaliphatic or collegerelations balance;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the above have shown aryl or heteroaryl residue can be independently substituted or unsubstituted.

The following class of particular interest compounds includes compounds having the structure of formula (I)in which R3Ameans-CH2NRFRGand R3bmeans a hydrogen atom, and the compound has the structure:

where R1, R2, RFand RGhave the meaning as generally above and in classes and subclasses according to the given context.

Another another class of special interest compounds includes compounds having the structure of formula (I), in which the Oh R 3bmeans-CH2NRFRGand R3ameans a hydrogen atom, and the compound has the structure:

where R1, R2, RFand RGhave the meaning as generally above and in classes and subclasses according to the given context.

Another class of special interest compounds includes compounds having the structure of formula (I)in which R3cmeans-CH2NRFRGand R3dmeans a hydrogen atom, and the compound has the structure:

where R1, R2, RFand RGhave the meaning as generally above and in classes and subclasses according to the given context.

The following class of particular interest compounds includes compounds having the structure of formula (I)in which R3ameans -(CH=CH)qCH2(CH2)rNRFRGand R3bmeans a hydrogen atom, and the compound has the structure:

where q and r each independently denote 0 or 1; and R1, R2, RFand RGhave the meaning as generally above and in classes and subclasses according to the given context.

Another class of special interest compounds includes compounds having the structure of formula (I)in which R3a means a hydrogen atom and R3bmeans -(CH=CH)qCH2(CH2)rNRFRGand the compound has the structure:

where q and r each independently denote 0 or 1; and R1, R2, RFand RGhave the meaning as generally above and in classes and subclasses according to the given context.

Another class of special interest compounds includes compounds having the structure of formula (I)in which R3ameans -(C=O)NRFRGand R3bmeans a hydrogen atom, and the compound has the structure:

where R1, R2, RFand RGhave the meaning as generally above and in classes and subclasses according to the given context.

Another another class of special interest compounds includes compounds having the structure of formula (I)in which R3bmeans -(C=O)NRFRGand R3ameans a hydrogen atom, and the compound has the structure:

where R1, R2, RFand RGhave the meaning as generally above and in classes and subclasses according to the given context.

The following class of particular interest compounds includes compounds having the structure of formula (I)in which R3ameans-CH2S(=O) mNRFRGand R3bmeans a hydrogen atom, and the compound has the structure:

where R1and R2have the meaning as generally above and in classes and subclasses according to the context;

m means 0, 1 or 2; and

RFmeans aliphatic, cycloaliphatic, heteroaromatics, collegerelations, aryl or heteroaryl residue;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the foregoing aryl or heteroaryl residue can be independently substituted or unsubstituted.

Another class of special interest compounds includes compounds having the structure of formula (I)in which R3ameans-CH2ORFand R3bmeans a hydrogen atom, and the compound has the structure:

where R1and R2have the meaning as generally above and in classes and subclasses according to the context; and

RFmeans a hydrogen atom, a protective group or an aliphatic, cycloaliphatic, heteroaromatics, collegerelations, aryl or heteroaryl mod is to;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the foregoing aryl or heteroaryl residue can be independently substituted or unsubstituted.

A number of important subclasses of each of the above classes must be specified separately; these subclasses include subclasses of the foregoing classes, where:

i) R1mean NH2;

ii) R1means a hydrogen atom;

iii) R1means NH-methyl;

iv) R1means NH-acyl;

v) R2mean NH2, OH, C1-C6alkyl or C1-C6alkenyl, and the above-mentioned alkyl and alkeneamine group optionally substituted with halogen or hydroxyl;

vi) R2means C1-C2alkyl;

vii) R2means methyl;

viii) R2means a hydrogen atom;

ix) one of RFor RGmeans a hydrogen atom or lower alkyl, and the other denotes alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or hetero is the Rila; or where RFand RGtaken together form a 6-membered, substituted or unsubstituted heterocyclic residue;

x) one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; or where RFand RGtaken together form a 6-membered substituted or unsubstituted, cyclic or heterocyclic residue;

xi) one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means phenyl, pyridyl, (alkyl)phenyl or (alkyl)pyridyl, optionally substituted in each case by one or more halogen atoms, cryptomaterial, methoxy group, trifluoromethyl, methylthiourea; or substituted or unsubstituted lower alkyl, lower heteroalkyl, aryl or heteroaryl; and

xii) one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means a cyclic or acyclic, linear or branched aliphatic residue, optionally substituted by one or more substituted or unsubstituted aryl, heteroaryl, aminogroups, alkoxyl, hydroxyl, thioalkyl, thiol, and the sludge or amino group;

xiii) RFmeans alkyl, cycloalkyl, heteroalkyl, cyclogeranyl, aryl, heteroaryl, alkylaryl or alkylglycerol, optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; and/or

xiv) RFmeans a hydrogen atom, a protective group or alkyl, cycloalkyl, heteroalkyl, cyclogeranyl, aryl, heteroaryl, alkylaryl or alkylglycerol, optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl.

As should be clear of particular interest compounds include, among others, those which possess the characteristic features of one or more of the above subclasses. Some of these subclasses are illustrated by the following connection types:

I) Compounds of the formula (and pharmaceutically acceptable derivatives):

where R1and R2have the meaning as generally above and in classes and subclasses according to the context; G means CH2or -(C=O) and one of RGor RFmeans a hydrogen atom or lower alkyl, and the other denotes alkyl, heteroalkyl is, aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; or where RFand RGtaken together form a 3-8-membered substituted or unsubstituted, cyclic or heterocyclic residue.

According to some variants, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; or where RFand RGtaken together form a 3-8-membered substituted or unsubstituted, cyclic or heterocyclic residue.

According to some other options, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means phenyl, pyridyl, (alkyl)phenyl or (alkyl)pyridyl, optionally substituted in each case by one or more halogen atoms, cryptomaterial, methoxy group, trifluoromethyl, methylthiourea or substituted or unsubstituted lower alkyl, lower heteroalkyl, aryl or heteroaryl.

Coz the ACLs even as other options, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means a cyclic or acyclic, linear or branched aliphatic residue, optionally substituted by one or more substituted or unsubstituted aryl, heteroaryl, aminogroups, alkoxyl, hydroxyl, thioalkyl, thiol, acyl, or amino group.

II) Compounds of the formula (and pharmaceutically acceptable derivatives):

where R1and R2have the meaning as generally above and in classes and subclasses according to the context; G means CH2or -(C=O) and X is O, S, C=O, S=O, C=CR4R5, NR4or CR4R5; where each of R4and R5independently means a hydrogen atom, hydroxyl, halogen atom, cyano, aliphatic, heteroaromatics, aryl or heteroaryl residue, or denotes an acyl residue, substituted aliphatic, heteroaromatics, aryl or heteroaryl residue;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched and each of the foregoing aryl or heteroaryl residue can be independently substituted or unsubstituted.

III) Connection Faure the uly (and their pharmaceutically acceptable derivatives):

where R1and R2have the meaning as generally above and in classes and subclasses according to the context; G means CH2or -(C=O) and one of RGor RFmeans a hydrogen atom or lower alkyl, and the other denotes alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; or where RFand RGtaken together form a 3-8-membered substituted or unsubstituted, cyclic or heterocyclic residue.

According to some variants, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; or where RFand RGtaken together form a 3-8-membered substituted or unsubstituted, cyclic or heterocyclic residue.

According to some other options, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means phenyl, PI is ideal, (alkyl)phenyl or (alkyl)pyridyl optionally independently substituted by one or more halogen atoms, cryptomaterial, methoxy group, trifluoromethyl, methylthiourea or substituted or unsubstituted lower alkyl, lower heteroalkyl, aryl or heteroaryl.

According to another other options, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means a cyclic or acyclic, linear or branched aliphatic residue, optionally substituted by one or more substituted or unsubstituted aryl, heteroaryl, aminogroups, alkoxyl, hydroxyl, thioalkyl, thiol, acyl, or amino group.

IV) Compounds of the formula (and pharmaceutically acceptable derivatives):

where R1and R2have the meaning as generally above and in classes and subclasses according to the context; G means CH2or -(C=O) and X is O, S, C=O, S=O, C=CR4R5, NR4or CR4R5; where each of R4and R5independently means a hydrogen atom, hydroxyl, halogen atom, cyano, aliphatic, heteroaromatics, aryl or heteroaryl residue, or denotes-C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl estato is;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched and each of the foregoing aryl or heteroaryl residue can be independently substituted or unsubstituted.

V) Compounds of the formula (and pharmaceutically acceptable derivatives):

;

where R1and R2have the meaning as generally above and in classes and subclasses according to the context; G means CH2or -(C=O) and one of RGor RFmeans a hydrogen atom or lower alkyl, and the other denotes alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more halogen atoms, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; or where RFand RGtaken together form a 3-8-membered substituted or unsubstituted, cyclic or heterocyclic residue.

According to some variants, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means aryl, heteroaryl, alkylaryl or alkylglycerol optionally independently substituted in each case by one or more atoms ha is ogena, alkoxyl, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl; or where RFand RGtaken together form a 3-8-membered substituted or unsubstituted, cyclic or heterocyclic residue.

According to some other options, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means phenyl, pyridyl, (alkyl)phenyl or (alkyl)pyridyl, optionally substituted in each case by one or more halogen atoms, cryptomaterial, methoxy group, trifluoromethyl, methylthiourea or substituted or unsubstituted lower alkyl, lower heteroalkyl, aryl or heteroaryl.

According to another other options, one of RFor RGmeans a hydrogen atom or lower alkyl, and the other means a cyclic or acyclic, linear or branched aliphatic residue, optionally substituted by one or more substituted or unsubstituted aryl, heteroaryl, aminogroups, alkoxyl, hydroxyl, thioalkyl, thiol, acyl, or amino group.

VI) Compounds of the formula (and pharmaceutically acceptable derivatives):

;

where R1and R2have the meaning as generally above and in classes and subclasses according to the context; G means CH2or -(C=O) their means Of, S, C=O, S=O, C=CR4R5, NR4or CR4R5; where each of R4and R5independently means a hydrogen atom, hydroxyl, halogen atom, cyano, aliphatic, heteroaromatics, aryl or heteroaryl residue, or denotes-C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched and each of the foregoing aryl or heteroaryl residue can be independently substituted or unsubstituted.

VII) Compounds of the formula (and pharmaceutically acceptable derivatives):

;

where RF, R1and R2have the meaning as generally above and in classes and subclasses according to the context; p denotes an integer from 0 to 3; and s denotes an integer from 0 to 4; a, b, D, E and each K, independently, are absent or denote O, S, C=O, S=0, C=CR4R5, NR4or CR4R5where each of R4and R5independently means a hydrogen atom, hydroxyl, halogen atom, cyano, -ORx, -SRx, -NRxRy, aliphatic, heteroaromatics, aryl or het is rarely residue, or means-C(O)Rzwhere Rzrepresents substituted aliphatic, heteroaromatics, aryl or heteroaryl residue; and where a and b, and D, D and E, E and K, and any two adjacent groups can be linked by single or double bond, as valency; where each of Rxand Ryindependently means a hydrogen atom, a protective group, or an aliphatic, heteroaromatics, aryl, heteroaryl, alifaticheskii-aryl, heteroaromatics-aryl, alifaticheskii-heteroaryl or heteroaromatics-heteroaryl residue;

each of the foregoing aliphatic or heteroalicyclic residue can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the foregoing aryl, heteroaryl, alifaticheskii-aryl, heteroaromatics-aryl, alifaticheskii-heteroaryl or heteroaromatics-heteroaryl residue can be independently substituted or unsubstituted.

According to some typical options, the balancemeans substituted or unsubstituted phenyl, pyridyl or furanyl.

According to some other options, the balancemeans substituted or unsubstituted, saturated or unsaturated 3-, 4-, -, 6-, 7 - or 8-membered cycloalkenyl or cyclogeranyl

the residue. According to some typical options, the balance

means substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. According to

some other typical options, the balancemeans

substituted or unsubstituted bicyclic aliphatic residue.

According to some typical options, RFmeans a hydrogen atom or lower alkyl. According to some variants, RFmeans a hydrogen atom or methyl.

You should also take into account that for each of the above sub-groups I-VII of particular interest is the variety of other subclasses, including, without limitation, classes (i)-(xiv)described above, and classes, subclasses and types of compounds as described above and in the examples according to the present context.

Some of the above compounds can include one or more asymmetric centers and can exist in various isomeric forms, such as stereoisomers and/or diastereomers. Thus, the proposed according to the invention compounds and those included in the pharmaceutical composition may be in the form of an individual enantiomer, diastereoisomer or the geometry of the mini-isomer, or may be in the form of a mixture of stereoisomers. According to some variants, the compounds according to the invention are compounds in the form of pure enantiomers. According to some other options, provides a mixture of stereoisomers or diastereomers.

Additionally, the scope of the invention includes any and all tautomers of the above compounds. The invention is not limited to those specified in this context tautomeric structures.

As but one example, the compounds described and represented in General as:

can be described and represented as:

In addition, some compounds, as described in this context may have one or more double bonds, which can be either Z-or E-isomer, unless nothing else. Additionally, the invention encompasses compounds in the form of individual isomers, essentially without other isomers, and alternatively, as mixtures of various isomers, e.g. in form of racemic mixtures of stereoisomers. In addition to the above compounds, in essence, this invention also includes pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds according to the invention and one Il is more pharmaceutically acceptable excipients or additives.

Compounds according to the invention can be obtained by crystallization of the compounds of formula (I) in different conditions and can be in the form of one or a combination of polymorphs of compounds of General formula (I)constituting part of this invention. For example, different polymorphic modifications can be identified and/or obtained through the use of different solvents or mixtures of solvents for recrystallization; through the implementation of crystallization at different temperatures or by using different methods of cooling, ranging from very fast to very slow cooling during kristallizatsii. Polymorphic modifications can also be obtained by heating or melting compounds with subsequent gradual or fast cooling. The presence of polymorphic modifications can be determined by using the solid sample using NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, diffraction X-ray powder pattern and/or using other methods. Thus, the invention covers proposed in the invention compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphic modifications, their pharmaceutically acceptable salts, their pharmaceutically acceptable MES and containing pharmaceutically acceptable composition.

2) Connection and definitions

As indicated above, this invention relates to new compounds which possess a number of biological properties. Compounds according to this invention have biological activities that are suitable for the treatment of inflammatory or autoimmune disorders and/or proliferative disorders. According to some variants proposed in the invention compound suitable for the treatment of rheumatoid arthritis, ulcerative colitis/Crohn's disease, diseases of the Central nervous system (CNS)such as multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection/graft versus host (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, severe myasthenia gravis, diabetes, idiopathic thrombocytopenia, glomerulonephritis, cardiovascular disease and cancer.

Compounds according to this invention include the compounds listed above and described in this context, and partially illustrated according to various classes, varieties and types of disclosed elsewhere in this context.

In addition, the present invention relates to pharmaceutically acceptable derivatives of compounds in accordance with the invention and methods of treatment of a subject with the use of these compounds is s, pharmaceutical compositions based on them, or any of these forms in combination with one or more additional therapeutic agents. The expression “pharmaceutically acceptable derivative”, as used in this context, means any pharmaceutically acceptable salt, ester, or salt of such a complex ester of such compound, or any other adduct or derivative which, after administration to the patient is able to give (directly or indirectly) a compound as otherwise described in this context, or its metabolite or residue. Pharmaceutically acceptable derivatives, thus, include, among others, the prodrugs. A prodrug is a derivative of the compound, usually with little pharmacological activity, which contains additional residue that can leave in vivo with the formation of the main pharmacologically active molecules. An example of a prodrug is an ester which is cleaved in vivo by the formation of interest connections. Proletarienne form a variety of compounds and materials and methods of obtaining derivatives of lead compounds with the receipt of prodrugs are known and can be adapted to this invention. Some typical pharmaceutical compositions and pharmaceutically acceptable derivatives bole is discussed in detail in this context below.

Some compounds according to this invention and determine specific functional groups are also described in more detail below. In accordance with this invention, the chemical elements are identified in accordance with the periodic table of the elements, CAS variant, “Handbook of Chemistry and Physics, 75th edition, cover, and specific functional groups are usually determined as described in this context. Additionally, General principles of organic chemistry, as well as specific functional residues and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito, 1999, the full content of which is included in this context as a reference. In addition, the specialist in this field should take into account that the synthesis methods described in this application uses a lot of protective groups. The term “protective group”as used in this context, understand that the specific functional group, such as O, S or N, is temporarily blocked so that a reaction can take place selectively at another reactive position multi-function compounds. According to preferred variants of the protective group reacts selectively in good yield in the formation of a protected substrate that is stable with respect to cover the known reactions; the protective group must be selectively removed in good yield using readily available, preferably nontoxic reagents that do not affect other functional groups; protective group forms legkodelimae derivative (more preferably without the generation of new stereogenic centers); and the protective group has a minimum of additional functionality to avoid further sites of reaction. As specified in detail in this context, can be used for protective oxygen, sulfur, nitrogen and carbon group. For example, according to some variants, as specified in detail in this context, use some common protective oxygen group. These protective for oxygen groups include, but are not limited to, simple methyl ethers, substituted simple methyl esters (for example, you should name a few, as the IOM (methoxymethyl ether), MTM (methylthiomethyl ether), VOM (benzoyloxymethyl ether), RMVB (p-methoxybenzyloxy ether), substituted simple ethyl ethers, substituted simple benzyl ethers, simple Silovye esters (for example, you should name a few, as TMS (trimethylsilyloxy simple ether), TES (triethylsilyl simple ether), TIPS (triisopropylsilyl simple ether), TBDMS (tert-butyldimethylsilyloxy simple ether), three is insincerely simple ether, TBDPS (t-butyldiphenylsilyl simple ether), esters (for example, you should name a few, as formate, acetate, benzoate (Bz), triptorelin, dichloracetate), carbonates, cyclic acetals and ketals. According to some other typical options, use protective for nitrogen group. These protective for nitrogen groups include, but are not limited to, carbamates (including one should mention a few, as methyl-, ethylcarbamate and substituted ethylcarbamate (for example, Troc)), amides, cyclic kidnie derivatives, N-alkyl - and N-arylamine, imino-derivatives and enameloplasty. In this context includes all some other typical protective groups, however, should take into account that this invention is not limited to these protective groups; preferably, the number of additional equivalent protective groups can be easily identified using the above criteria and applicable in accordance with this invention. Additionally, many of the protective groups described in “Protective Groups in Organic Synthesis”, third edition, edited by T.W. Greene and P.G. Wuts, John Wiley and Sons, new York, 1999, the full content of which is included in this context as a reference.

You should take into account that compounds, as described in this context, can be substituted by any number for which estately or functional residues. In General, the term “substituted”, precedes him, the term “optionally” or not, and substituents indicated in the formulas of this invention relate to the replacement of hydrogen radicals with the formation of patterns with specific radical substituent. When more than one position in any given structure may be substituted by more than one Deputy, selected from a precisely defined group, the substituents may be either the same or different in each position. Assume that the term “substituted”used in this context include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. In accordance with this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described in this context that match the valences of the heteroatoms. In addition, have in mind that this invention should not be in any way limited by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invented the Yu, preferably are such that the result is stable compounds suitable for the treatment of, for example, inflammatory or autoimmune and proliferative disorders, including, but not limited to, rheumatoid arthritis, psoriasis, asthma and cancer. The term “stable”as used in this context, preferably refers to compounds which possess stability, allowing them to obtain and retain its integrity for a sufficient period of time for their determination and preferably for a sufficient period of time suitable for use in the detail specified in this context purposes.

The term “aliphatic”as used in this context, includes both saturated and unsaturated, linear chain (i.e. unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted by one or more functional groups. As should be clear to the person skilled in the art, in this context mean that the term “aliphatic” includes, but is not limited to, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl and cycloalkyl. Thus, as used in this context, the term “alkyl” includes linear, branched and cyclic alkyl groups. A similar note is nimo other formed terms such as “alkenyl”, “quinil” and the like. In addition, as used in this context, the terms “alkyl”, “alkenyl”, “quinil” and the like encompass both substituted and unsubstituted groups. According to some variants, the term “lower alkyl”used in this context, is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched), which contain 1-6 carbon atoms.

According to some variants, used in accordance with the invention, alkyl, alkeline and alkyline groups contain 1-20 aliphatic carbon atoms. According to some of the other options used in accordance with the invention, alkyl, alkeline and alkyline groups contain 1-10 aliphatic carbon atoms. According to still other options used in accordance with the invention, alkyl, alkeline and alkyline groups contain 1-8 aliphatic carbon atoms. According to still other options used in accordance with the invention, alkyl, alkeline and alkyline groups contain 1-6 aliphatic carbon atoms. According to still another the following variants used in accordance with the invention, alkyl, alkeline and alkyline groups contain 1-4 carbon atoms. Illustrative al the factual group, thus, include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH2-n-cyclopentyl, hexyl, sec-hexyl, cyclohexyl, -CH2-cyclohexyl and the like, which may also bear one or more substituents. Alkeneamine groups include, but are not limited to, for example, ethynyl, propenyl, butenyl, 1-methyl-2-butene-1-yl and the like. Typical alkyline groups include, but are not limited to, ethinyl, 2-PROPYNYL (propargyl), 1-PROPYNYL and the like.

The term “alkoxy” (or “alkyloxy”) or “thioalkyl”used in this context, refers to an alkyl group, as defined above, associated with the main molecular residue via an oxygen atom or through a sulfur atom. According to some variants, the alkyl group contains 1-20 aliphatic carbon atoms. According to some other options, the alkyl group contains 1-10 aliphatic carbon atoms. According to still some other options used according to the invention alkyl, alkeline and alkyline groups contain 1-8 aliphatic carbon atoms. According to still other variants, the alkyl group contains 1-6 aliphatic the ski carbon atoms. According to still another the following variants, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxyl include, but are not limited to, methoxy, ethoxy-, propoxy-, isopropoxy, h-butoxy-, tert-butoxy, neopentane - and n-hexachrome. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, h-butylthiourea and the like.

The term “alkylamino” refers to a group with the structure-other', where R' is alkyl, as defined in this context. The term “aminoalkyl” refers to a group with the structure of NH2R'-, where R' is alkyl, as defined in this context. According to some variants, an alkyl group containing 1-20 aliphatic carbon atoms. According to some other options, the alkyl group contains 1-10 aliphatic carbon atoms. According to still other options used according to the invention alkyl, alkeline and alkyline groups contain 1-8 aliphatic carbon atoms. According to still other variants, the alkyl group contains 1-6 aliphatic carbon atoms. According to still another the following variants, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, isopropylamino and the like.

Some examples Zam is stitely the above aliphatic (or other) residues of the compounds according to the invention are, not limited to, aliphatic residue, heteroaromatics residue; aryl, heteroaryl, alkylaryl, alkylether, alkoxyl, alloctype, heteroalkyl, heteroanalogues, allylthiourea, Aristocra, generalcologne, heteroanalogues, F, Cl, Br, I, -OH, -NO2, -CN, -CF3, -CH2CF3, -CHCl2, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2SO2CH3, -C(O)Rx, -CO2(Rx), -CON(Rx)2, -OC(O)Rx, -OCO2Rx, -OCON(Rx)2, -N(Rx)2, -S(O)2Rx, -NRx(CO)Rxwhere each of Rxindependently includes, but is not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl or alkylglycerol, each of the above and according to the context of aliphatic, heteroalicyclic, alcylaryl or alkylglycerols substituents may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and each of the above and according to the context of the aryl or heteroaryl substituents may be substituted or unsubstituted. Additional examples of generally suitable substituents are illustrated in accordance with the specific options specified in the examples described in this context.

In General, the terms “the reel” and “heteroaryl”, used in this context, refer to stable mono - or polycyclic, heterocyclic and polyheterocyclic unsaturated residues preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. You should also take into account that aryl and heteroaryl residues, as defined under this context, can be linked through an aliphatic, heteroaromatics, alkyl or heteroalkyl balance and, thus, also include -(aliphatic residue)aryl, -(heteroaromatics balance)aryl, -(aliphatic residue)heteroaryl, -(heteroaromatics balance)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl and (heteroalkyl)heteroaryl. Thus, used in this context, the expression “aryl or heteroaryl” and “aryl, heteroaryl, -(aliphatic residue)aryl, -heteroaromatics balance)aryl, -(aliphatic residue)heteroaryl, -(heteroaromatics balance)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl and (heteroalkyl)heteroaryl” are interchangeable. Substituents include, but are not limited to, any of the above substituents, i.e. substituents listed for aliphatic residues or other residues, as indicated in this context, leading to the formation of stable compounds. According to some the m variants of the present invention, the term “aryl” refers to mono - or bicyclic carbocyclic systems with one or two aromatic cycles, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. According to some variants of the present invention, the term “heteroaryl”used in this context, means a cyclic aromatic radical containing from five to ten atoms in the cycle, of which one atom of the cycle selected from S, O and N; zero, one, or two atoms of the cycle are additional heteroatoms independently selected from S, O and N; and the remaining atoms of the cycle are carbon atoms, and the moiety is bound to the rest of the molecule through any atom of the cycle, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, chinoline, ethenolysis and the like.

You should take into account that aryl and heteroaryl groups (including bicyclic aryl groups) can be unsubstituted or substituted, and substitution means the replacement of one, two, or three hydrogen atoms in them, whether any one or more of the following residues, including, but not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl, alquiler roarer, alkoxyl, alloctype, heteroalkyl, heterokaryosis, allylthiourea, killigrew, heterolytic, heterogroup, F, Cl, Br, I, -OH, -NO2, -CN, -CF3, -CH2CF3, -CHCl2, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2SO2CH3, -C(O)Rx, -CO2(Rx), -CON(Rx)2, -OC(O)Rx, -OCO2Rx, -OCON(Rx)2, -N(Rx)2, -S(O)2Rx, -NRx(CO)Rxwhere each of Rxindependent means, not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl or alkylglycerol, each of the above and according to the context of aliphatic, heteroalicyclic, alcylaryl or alkylglycerols substituents may be unsubstituted or substituted, branched or unbranched, cyclic or acyclic, and each of the above and according to the context of the aryl or heteroaryl substituents may be substituted or unsubstituted. Additional examples of generally suitable substituents are illustrated in accordance with the specific options specified in the examples described in this context.

The term “cycloalkyl”used in this context, refers specifically to groups with the number of carbon atoms from three to seven, the pre is respectfully from three to ten. Suitable cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroalicyclic or heterocyclic residue may be optionally substituted with substituents including, without limitation, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl, alkylether, alkoxyl, alloctype, heteroalkyl, heterokaryosis, allylthiourea, killigrew, heterolytic, heterogroup, F, Cl, Br, I, -OH, -NO2, -CN, -CF3, -CH2CF3, -CHCl2, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2SO2CH3, -C(O)Rx, -CO2(Rx), -CON(Rx)2, -OC(O)Rx, -OCO2Rx, -OCON(Rx)2, -N(Rx)2, -S(O)2Rx, -NRx(CO)Rxwhere each of Rxindependently includes, but is not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl or alkylglycerol, each of the above and according to the context of aliphatic, heteroalicyclic, alcylaryl or alkylglycerols substituents may be unsubstituted or substituted, branched or unbranched, cyclic or acyclic, and each of the above and is under this context, aryl or heteroaryl substituents may be substituted or unsubstituted. Additional examples of generally suitable substituents are illustrated in accordance with the specific options specified in the examples described in this context.

The term “heteroaromatics”used in this context, refers to aliphatic residues, which contain one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon, for example, instead of carbon atoms. Heteroaromatics residues can be branched, unbranched, cyclic or acyclic, and include saturated and unsaturated heterocycles, such as morpholinopropan, pyrrolidinyl etc. According to some variants, heteroaromatics residues substituted by independent replacement in one or more of the hydrogen atoms of one or more residues, including, but not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl, alkylether, alkoxyl, alloctype, heteroalkyl, heterokaryosis, allylthiourea, killigrew, heterolytic, heterogroup, F, Cl, Br, I, -OH, -NO2, -CN, -CF3, -CH2CF3, -CHCl2, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2SO2CH3, -C(O)Rx, -CO2(Rx), -CON(Rx)2, -OC(O)Rx, -OCO2Rx, OCON(Rx)2, -N(Rx)2, -S(O)2Rx, -NRx (CO)Rxwhere each of Rxindependently includes, but is not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl or alkylglycerol, each of the above and according to the context of aliphatic, heteroalicyclic, alcylaryl or alkylglycerols substituents may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and each of the above and according to the context of the aryl or heteroaryl substituents may be substituted or unsubstituted. Additional examples of generally suitable substituents are illustrated in accordance with the specific options specified in the examples described in this context.

The term “halogen”as used in this context, refers to an atom selected from fluorine, chlorine, bromine and iodine.

The term “halogenated” means an alkyl group as defined above containing one, two or three halogen atom associated with it, and illustrated by such groups as chloromethyl, bromacil, trifluoromethyl and the like.

The term “heteroseksualci”used in this context refers to non-aromatic 5-, 6 - or 7-membered cycle or polycyclic group, including, but not limited to, bi - or tricyclic group containing condensive the major six-membered ring with the number of heteroatoms from one to three, independently selected from oxygen atoms, sulfur and nitrogen, where (i) each 5-membered cycle contains from 0 to 1 double bonds and each 6-membered cycle contains from 0 to 2 double bonds; (ii) the heteroatoms nitrogen and sulfur may be optionally oxidized; (iii) the nitrogen heteroatom may be optionally quaternion; and (iv) any of the above-mentioned heterocycles may be condensed with a benzene cycle. Typical heterocycles include, but are not limited to, pyrrolidinyl, pyrazolyl, pyrazolidine, imidazoline, imidazolidine, piperidine, piperazinil, oxazolidinyl, isoxazolidine, morpholine, thiazolidine, isothiazolinones and tetrahydrofuryl. According to some variants, the term “substituted heterocytolysine or heterocyclic group”used in this context, refers to geteroseksualnoe or heterocyclic group, as defined above, substituted by independent replacement of one, two, or three hydrogen atoms in it, is not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl, alkylether, alkoxyl, alloctype, heteroalkyl, heterokaryosis, allylthiourea, killigrew, heterolytic, heterogroup, F, Cl, Br, I, -OH, -NO2, -CN, -CF3, -CH2CF3, -CHCl2, -CH2OH, -CH2CH2OH, -CH2NH2, -CH 2SO2CH3, -C(O)Rx, -CO2(Rx), -CON(Rx)2, -OC(O)Rx, -OCO2Rx, -OCON(Rx)2, -N(Rx)2, -S(O)2Rx, -NRx(CO)Rxwhere each of Rxindependently includes, but is not limited to, aliphatic residue, heteroaromatics residue, aryl, heteroaryl, alkylaryl or alkylglycerol, each of the above and according to the context of aliphatic, heteroalicyclic, alcylaryl or alkylglycerols substituents may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and each of the above and according to the context of the aryl or heteroaryl substituents may be substituted or unsubstituted. Additional examples of generally suitable substituents are illustrated in accordance with the specific options specified in the examples described in this context.

3) the Study and introduction of finished dosage forms

According to this invention proposed in the invention compounds may be tested by any available analysis methods that are known in the prior art to identify compounds with a pre-defined biological activity. For example, the analysis may be cellular or non-cellular, in vivo or in vitro, when is ispolzovanie large or small quantities of material, etc. According to some typical choices in the invention compounds are tested by conducting analyses in order to identify those compounds with antiproliferative/antitumor activity, inhibitory transmission signal of inflammatory cytokine activity, inhibiting expression of adhesion molecule activity and/or anti-inflammatory effect.

Thus, according to one aspect, compounds according to this invention of particular interest include compounds that:

usually are active as inhibitors of the expression of adhesion molecules on endothelial cells after stimulation with inflammatory cytokines;

- show activity as inhibitors of the transmission signal of the inflammatory cytokine;

- show anti-inflammatory effect in respect of the relevant cell lines maintained in vitro, or in animal experiments using acceptable research model;

- show antiproliferative and/or anti-cancer effect in respect of the relevant cell lines maintained in vitro, or in animal experiments using acceptable research model; and

- have a favorable therapeutic profile (for example the EP, safety, efficacy and stability).

As indicated above, some compounds, as described in this context, usually are active as inhibitors of cell-adhesion molecules in endothelial cells (E-selectin and ICAM) and activation of transcription induced by signal transmission of the inflammatory cytokine. More specifically, the compounds according to the invention shown together with immunomodulating activity and, thus, the invention relates further to a method of treating inflammatory or autoimmune disorders, or proliferative disorders. The method includes the introduction of a therapeutically effective amount of the compound or its pharmaceutically acceptable derivative to a subject (including, but not limited to, human or animal)in need of such treatment. According to some variants proposed in the invention compound suitable for the treatment of rheumatoid arthritis, ulcerative colitis/Crohn's disease, diseases of the Central nervous system (CNS)such as multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection/graft versus host (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, severe myasthenia gravis, diabetes, idiopathic thrombocytopenia purpura, glomerulonephritis is, cardiovascular disease and cancer.

According to some variations, the method includes the introduction of a therapeutically effective amount of the compound or its pharmaceutically acceptable derivative to a subject (including, but not limited to, human or animal)in need of it. According to some variants, provides for a pharmaceutical composition that includes proposed in the invention, the compound or its pharmaceutically acceptable derivative), the carrier or diluent and optionally an additional therapeutic agent.

The pharmaceutical composition

As indicated above, this invention relates to new compounds that have biological properties that are suitable for the treatment of inflammatory and proliferative disorders, including, but not limited to, rheumatoid arthritis, ulcerative colitis/Crohn's disease, diseases of the Central nervous system (CNS)such as multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection/graft versus host (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, severe myasthenia gravis, diabetes, idiopathic thrombocytopenia purpura, glomerulonephritis, cardiovascular disease and cancer.

According to another aspect of the present invention, before the book refers to a pharmaceutical composition, which includes any one of the methods in this context, compounds (or Palekastro form, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and optionally a pharmaceutically acceptable carrier. According to some variations, the composition further optionally include one or more additional therapeutic agents. Alternatively, the connection according to this invention can be administered to the patient in need of treatment, in combination with one or more other therapeutic tool. For example, additional therapeutic means for the joint implementation or inclusion in a pharmaceutical composition together with a connection according to this invention can be anti-inflammatory agent (for example, a treatment for rheumatoid arthritis or psoriasis) or cytotoxic agent, or an anti-cancer agent, is indicated for the treatment of cancer, as described in more detail in the context, or it can be any one of a number of funds sanctioned in the book “Food and Drug Administration, which ultimately received approval for the treatment of immune disorders or cancer. You should also take into account that some of the compounds according to this invention may be in free form or, where p is ugodno, in the form of their pharmaceutically acceptable derivative. According to this invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salt, ester, salt of such ester, or prodrug, or any other adduct or derivative compounds according to this invention, which (who) after administration to a patient in need of treatment, able (able) to give, directly or indirectly, a compound as otherwise described in this context, or its metabolite or residue.

The term “pharmaceutically acceptable salt”used in this context, refers to those salts which do not have a toxic action, irritation, allergic response and the like in contact with the tissues of humans and lower animals and conform to acceptable value of benefit/risk. Pharmaceutically acceptable salts of amines, carboxylic acids and other types of connections are well known in the prior art. For example, S.M. Berge and al. describe pharmaceutically acceptable salts in an article in J. Pharmaceutical Sciences,66, 1-19 (1977), included in this context as a reference. Salts can be obtained in situ during the final isolation and purification of the compounds according to the invention or separately by reaction of the free primary or a free carboxyl group with a suitable re is a Gent, as described in General below. For example, free basic functional group can be introduced into an interaction with a suitable acid. In addition, in the case where the compounds according to the invention contain a carboxyl group, suitable pharmaceutically acceptable salts may include metal salts, such as alkali metal salts, for example sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium. Examples of pharmaceutically acceptable non-toxic additive salts of the acids are formed by the amino group of salts derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, Perlina acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the prior art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexane is, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate, and the like. Typical salts of alkali or alkaline earth metal salts are sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts include, when are appropriate, nontoxic ammonium salts, Quaternary ammonium and aminoketones formed using counterions such as halogen, hydroxyl, carboxylate, sulfate, phosphate, nitrate-, (lower alkyl)sulfonate and arylsulfonate-anion.

Additionally, the term “pharmaceutically acceptable ester”as used in this context, refers to esters which are hydrolyzed in vivo and include esters, biodegradable in the human body up to the formation of the compound or its salts. Suitable ester groups include, for example, esters, derivatives, pharmaceutically acceptable aliphatic carboxylic acids, especially alkanovykh, alkenovich, cycloalkanes and arcangioli acid in which each alkyl or canilla part mainly contains not more than 6 carbon atoms. The specific examples of esters include formate, acetate, propionate, butyrate, acrylates and ethylsuccinate.

In addition, the term “pharmaceutically acceptable prodrugs”as used in this context, refers to those prodrugs of the compounds according to this invention, which does not have excessive toxic action, irritation, allergic response and the like, respectively, an acceptable ratio of benefit/risk, in contact with the tissues of humans and lower animals, and effective for their intended use, as well as to zwitterionic forms, where possible, of the compounds according to the invention. The term “prodrug” refers to compounds that are rapidly transformed in vivo with the formation of the compound of the above formula, for example, by hydrolysis in blood. A full discussion is provided in T. Higuchi and V. Stella, “Prodrugs as Novel Delivery Systems, vol.14, A.C.S. Symposium Series, and in the book edited by Edward B. Roche “Bioreversible Carries in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are both included in this context as a reference.

As described above, the pharmaceutical compositions according to the invention additionally include a pharmaceutically acceptable carrier, which, in accordance with the given context, includes any and all solvents, diluents, or other liquid nose is tel, dispersing or suspendresume components, surfactants, isotonic components, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, as suitable for a particular desired dosage form. In “Remington''s Pharmaceutical Sciences, sixteenth edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes the different media used for preparation of pharmaceutical compositions and known methods of obtaining them. Except that any normal the carrier medium is incompatible with the compounds according to the invention, such as by producing any undesirable biological effect or otherwise interacting “harmful manner with any other component (components) of the pharmaceutical composition, considering that their application is included in the scope of this invention. Some examples of substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients such as cocoa butter and waxes for when positories; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters, such as etiloleat and tillaart; agar; sautereau components, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free and no water; isotonic saline; ringer's solution; ethyl alcohol and phosphate buffered solutions, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate; as well as in the composition may be, in accordance with the decision of the manufacturer, dyes, deblokiruyuschee components, components for coatings, sweeteners, taste and flavouring agents, preservatives and antioxidants.

The use and production of finished dosage forms on the basis of the compounds according to the invention

As described in more detail in this context, the present invention mainly relates to compounds suitable for the treatment of inflammatory or autoimmune disorders and treatment of proliferative disorders. Without any connection to any particular theory, more generally, the compounds according to the invention have an inhibitory effect on the expression of adhesion molecules such as E-selectin and ICM-1, on the surface of endothelial cells induced by stimulation with inflammatory cytokines. These cell-surface molecules play a critical role in the infiltration of inflammatory cells and the interactions of cells with inflammatory reactions and immune responses. Connections also reduce the activation of transcription factor NF-κB and inhibit the activation of transcription on the transmission signal of the inflammatory cytokine, which regulates many genes, such as IL-1a and TNFa involved in the pathology of certain inflammatory diseases. More generally, the identification of NF-κB as a key player in the pathogenesis of inflammation suggests that therapy, the target of which is NF-κB, can be effective in inflammatory and immune disorders (see, generally, “NF-κB in Defense and Disease”, J. Clin. Investig.,7, 107 (2001)).

As shown in detail in the examples, when carrying out tests to determine the ability of compounds to inhibit induced by cytokines, expression of adhesion molecules by endothelial cells, some compounds according to the invention (as a rule, where one of R3means a hydrogen atom, and the other of R3means balance, as generally described in this context) show values of the IC50(E-selectin and ICAM-1) is less than 1 Microm. According to the other options, typical compounds show values of the IC50less than 10 Microm.

As indicated above, the compounds according to the invention shown together with immunomodulating activity and possess activity against inhibition of growth of tumor cells. Essentially, the compounds according to the invention is particularly suitable for the treatment of diseases and disorders, including, but not limited to, rheumatoid arthritis, ulcerative colitis/Crohn's disease, diseases of the Central nervous system (CNS)such as multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection/graft versus host (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, severe myasthenia gravis, diabetes, idiopathic thrombocytopenia purpura, cardiovascular disease and cancer.

Thus, as described above, according to another aspect of the invention, methods of treating inflammatory or autoimmune and proliferative disorders include the introduction of a therapeutically effective amount of the compounds of formula (I)as disclosed in this context, to a subject in need of treatment. According to some variants proposed in the invention compound suitable for the treatment of rheumatoid arthritis, ulcerative colitis/Crohn's disease, diseases of the Central the created system (CNS), as, for example, multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection/graft versus host (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, severe myasthenia gravis, diabetes, idiopathic thrombocytopenia purpura, cardiovascular disease and cancer.

You should take into account that compounds and compositions, according to the method of the present invention, can be entered using any amount and any route of administration effective for treating inflammatory or autoimmune and proliferative disorders. Thus, the expression “effective amount”, as used in this context, refers to sufficient funds to stop or inhibit the growth of tumor cells or refers to a sufficient amount to reduce the effects of inflammatory or autoimmune response or violations. Need the exact number may vary from subject to subject, depending on the kind, age and General condition of the subject, the severity of infection, the specific therapeutic agent, its mode of administration and the like. Compounds according to the invention is preferably used to obtain compositions in the form of a single dosage form to facilitate the introduction and dinoor the Zia dosage. The expression “single dosage form”as used in this context, refers to a physically discrete unit of a corresponding therapeutic agent for being treated patient. However, it should be clear that the total daily introduction of the compounds and compositions according to this invention can be defined by the regular physician of the hospital in the evaluation of medical research. The specific therapeutically effective dose for any particular patient or organism will depend on many factors, including being treated with the violation and the severity of the disorder; activity of the specific compound; used concrete composition; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration and the rate of emission of specific compounds; duration of treatment; drugs used in combination or simultaneously with the specific connection; and like factors well known in the field of medical practice (see, e.g., Goodman and Gilman's “The Pharmacological Basis of Therapeutics, tenth edition, edited by A. Gilman, J. Hardman and L. Limbird; McGraw-Hill Press, 155-173, 2001, which in all its totality is included in the context of the present invention as a reference).

Additionally, after receiving the finished dosage form with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions according to this invention it is possible to introduce people and other animals orally, rectally, parenterally, intracisternally, intrawaginalno, administered intraperitoneally, locally (powders, ointments or drops), transbukkalno, in the form of an oral or nasal spray, or the like way, depending on the severity of the infection being treated. According to some variants, the compounds according to the invention can be introduced in dosages of from about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg or from about 0.1 mg/kg to about 10 mg/kg of body weight of the subject per day, one or more times per day, to achieve the desired therapeutic effect. You should also take into account that the subject can be entered dosages lower than 0.001 mg/kg, or greater than 50 mg/kg (e.g., 50-100 mg/kg). According to some variations, the compound is administered orally or parenterally.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the prior art, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzile the initial alcohol, the benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed oil, peanut oil, corn oil, wheatgerm oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, glycols and sorbitane esters of fatty acids, and mixtures thereof. Besides inert diluents, the oral compositions can also include additives, such as humectants, emulsifying and suspendresume components, sweetening, flavoring and aroma additives.

Injectable preparations, for example sterile injectable aqueous or oily suspensions, can be obtained according to known methods using suitable dispersing or moisturizing components and suspendida components. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic mostly acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used include water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, as a solvent or a suspending means usually use sterile non-volatile oil. For this purpose, can be IP is alzavano any “soft” non-volatile oil, including synthetic mono - or diglycerides. In addition, in preparation for injection use fatty acids such as oleic acid.

Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating, to use, sterilizing components in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium.

In order to prolong the effect of the medicinal product, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscularly injected drug. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water-solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral introduced drugs is achieved by dissolution or suspension of the drug in the oil filler. Injectable depot forms are obtained by the formation of microencapsule-matrices of the drug in undergoing biodegradation floor the measures such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the specific polymer can control the rate of release of the drug. Examples of other exposed biodegradable polymers include poly(complex orthoevra) and polyanhydride. Injectable long-acting drugs are also obtained by incorporating the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal injection are preferably suppositories which can be obtained by mixing the compounds according to this invention with suitable, does not cause irritation of the excipients or carriers such as cocoa butter, polyethylene glycol or wax for suppositories, which are solid at ambient temperature but liquid at body temperature and, in addition, melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound mixed with at least one inert, pharmaceutically acceptable excipient or carrier, so the m as sodium citrate or dicalcium phosphate, and/or a) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, C) humectants such as glycerol, d) with dezinfeciruyuhimi components, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution causing prolongation of components, such as paraffin, f) with the absorption accelerators, such as Quaternary ammonium compounds, g) c hydrating ingredients, such as, for example, cetyl alcohol and glycerylmonostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also include tabularasa components.

Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, pills, ka is Sul, pills and granules can be obtained with the applied coatings and shells, such as intersolubility coatings and other coatings well known in the technical field related to obtaining pharmaceutical drugs. They may not necessarily contain opalescent components and can also be a composition from which it is released, only the active ingredient (the ingredient), or, preferably, the release occurs in a certain part of the intestine, optional prolongirovanne. Examples of suitable “for the implementation of” compositions, which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulating form together with one or more excipients, as mentioned above. Solid dosage forms such as tablets, coated tablets, capsules, pills and granules can be obtained coated with coatings and shells, such as intersolubility coatings and other coatings well known in the field of technology pertaining to getting pharmac whitesky drugs. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms can also contain, in normal practice, additional substances other than inert diluents, such as, for example, imparting lubricity tablets lubricants or other auxiliary tabletting AIDS such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also contain tabularasa components. They may not necessarily contain opalescent components and can also be a composition from which it is released, only the active ingredient (the ingredient), or, preferably, the release occurs in a certain part of the intestine, optional prolongirovanne. Examples of suitable “for the implementation of” compositions, which can be used include polymeric substances and waxes.

Dosage forms for local or transdermal injection of the compounds according to this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays; preparations for inhalation or patches. The active ingredient in sterile conditions is mixed with a pharmaceutically acceptable carrier and Liu is diversified needed preservatives or buffers, which may be necessary. Ophthalmic drug, ear drops and eye drops are also considered as included in the scope of this invention. Additionally, this invention relates to the use of transdermal patches, which have the additional advantage of providing controlled flow connection in the body. Such dosage forms are obtained by dissolving or dispersing the compound in a suitable medium. Can also be used amplifiers absorption for increasing the flow of compounds through the skin. Speed can be controlled either by the supply speed control membrane or by dispersing the compound in a polymer matrix or gel.

You should also take into account that the compounds and pharmaceutical compositions according to this invention can be obtained and used in combination therapies, that is, the compounds and pharmaceutical compositions can be obtained in the form of finished dosage forms together with one or more other desirable therapeutic means or administered simultaneously, before or after, or simultaneously, before or after related to conservative treatment procedures. The particular combination of therapies (therapeutic agent or procedure) for use in the combined schemes is ecene can be done based on the compatibility of the desired therapeutics and/or procedures and the achievement of the desired therapeutic effect. You should also take into account that using the applied therapies can achieve desired effect for the same disorder (for example, proposed according to the invention compound may be introduced simultaneously with other anti-inflammatory or anti-cancer) or they can be used to achieve different effects (e.g., control of any adverse effects).

For example, other therapies or anticancer tools that can be used in combination with the compounds according to this invention include surgery, radiation therapy (to name just a few examples, as γ-radiation, radiation therapy, neutron beam radiotherapy, electron beam therapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, biological response modifiers (you can name a few: interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, means to attenuate any adverse effects (e.g., antimimetic), and other recognized chemotherapeutic drugs, including, you can name a few, are not limited to, such as alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolic is s (methotrexate), purine and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabin, gemcitabine), spindle poisons patterns (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoanatabine (carmustin, lomustin), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide and megestrol). Modernized treatment of cancer are disclosed, http:/www.nci.nih.gov./, approved by the FDA list of drugs in Oncology http://www.fda.gov/cder/cancer/druglistframe.htm and the Handbook Merck, seventeenth edition, 1999, the full content of which is included in this context as a reference.

According to some variants proposed in this invention, the pharmaceutical compositions further include one or more additional therapeutically active ingredients (such as chemotherapy and/or palliative ingredient). In accordance with the invention, the term “palliative ingredient” refers to treatment aimed at relieving symptoms of the disease and/or side effects of the regimen, but is not curative. For example, palliative care includes pain relievers, medicines against vomiting and nausea. In addition, chemotherapy, radiation, t is therapy and surgery can all be used palliative (i.e. to reduce symptoms without affecting treatment; for example, for shrinking tumors and low pressure, reduce bleeding, pain and other symptoms of cancer).

Kits for the treatment of

According to other variants of implementation, this invention relates to a kit for the appropriate and effective implementation of the methods according to this invention. Pharmaceutical pack or kit typically includes one or more containers filled with one or more ingredients of the pharmaceutical compositions according to the invention. These kits are mainly convenient for the delivery of solid oral forms such as tablets and capsules. Such a kit preferably includes several doses and may also include a map of dosages that focuses on how to use them. If desirable, may be provided for the reminder, for example, in the form of numbers, letters, or other markings or with the calendar insert, indicating the days of the schedule of treatment, in which you can enter the dosage. Alternatively, the dosage placebo or calcium dietary supplements, either in the form similar to the dosages of the pharmaceutical compositions or different, can be included for collection, according to which the dosage is administered every day. Optionally associated with such container (containers), the statement may be in the form prescribed by the state the state authority in charge of control over the production, the use or sale of pharmaceutical products, which reflects the sanction of the authority for the control of the manufacture, use or sale on the introduction of the man.

Equivalents

The following typical examples are intended to illustrate the invention and do not constitute, and should not be construed as limiting the scope of the invention. Indeed, various modifications of the invention and many further variations in its implementation, except those listed and described in this context should be obvious to the person skilled in the art from the full contents of this document, including the following examples and references to the scientific and patent literature cited in this context. Next, you need to take into account that the content of these cited references are included in this context as a reference for the disclosure of the prior art.

The following examples contain significant additional information, exemplification and guidance that can be adapted to the practice of the present invention in its various embodiments and their equivalents.

Examples

The compounds of this invention and may be clarified further by examples, which illustrate some of the ways in which these connections receive or used is so It should be clear, however, that these examples do not limit the scope of protection of the invention. Variants of the invention, now known or hereinafter disclosed, are considered as falling in the scope of the present invention, as described in this context as presented below in the claims.

According to this invention, for synthesizing or obtaining the proposed according to the invention compounds or including their compositions can be used any means available. For example, can be used many ways of synthesis in solution, such as the methods discussed in detail below. Alternative or additionally, the compounds according to the invention can be obtained by using any of a variety of combinatorial methods, parallel synthesis and/or solid-phase synthesis methods known in the art.

It should be taken into account, as described below, that many proposed according to the invention compounds can be synthesized in accordance with the described in this context means. Source materials and reagents used in the preparation of these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or get their ways, well known to the specialist given in the second area, following the procedures described in such references as Fieser and Fieser, 1991, “Reagents for Organic Synthesis”, vol.1-17, John Wiley and Sons, new York, NY, 1991; Rodd, 1989, “Chemistry of Carbon Compounds”, vol.1-5 and additions, Elsevier Science Publishers, 1989; “Organic Reactions”, vol.1-40, John Wiley and Sons, new York, NY, 1991; March 2001, “Advanced Organic Chemistry”, 5th edition, John Wiley and Sons, new York, NY; and Larock, 1989, “Comprehensive Organic Transformations”, VCH Publishers. These diagrams illustrate only some of the ways through which can be synthesized compounds according to this invention, and various modifications to these schemes can be implemented and can be suggested to the person skilled in the art based on this disclosure.

The ingredients, intermediate products and compounds according to this invention can be isolated and purified using conventional methods, including filtration, distillation, crystallization, chromatography and the like. They can be characterized using conventional methods, including physical constants and spectral data.

1) Typical connection

Some typical compounds according to the invention are listed below and are defined by the connection number, as specified.

2) Experimental methods

As described above, this invention relates to new deazapurine formula (I)as described above, and their derivatives. You should take into consideration that im is s, disclosed in this context, can be applied to any of the compounds mentioned in this context and equivalent. Additionally, some reagents and source materials well known to the person skilled in the art. Although the following examples describe some typical connection, it should be clear that when using an alternate source of substances you can easily get other analogs encompassed by the invention.

Common procedures in relation to the exercise of reactions

If not specified, the reaction mixture is stirred using a magnetic stirrer. The term “inert atmosphere” refers to either the dried argon or dried nitrogen. The reaction mixture is controlled either by thin-layer chromatography, or by using proton nuclear magnetic resonance, when using a suitable sample of the reaction mixture.

General methods of work

If not specified, the reaction mixture is cooled to room temperature or below, then the reaction quenched, if necessary, either water or a saturated aqueous solution of ammonium chloride or sodium bicarbonate. The target products are extracted by the distribution between water and a water-immiscible solvent (such as ethyl acetate, dichloromethane, diethyl ether). Extracts soda is containing the target product, washed, respectively, with water, then with saturated salt solution. In cases where containing product extract is believed to contain residual oxidants, before the above-mentioned washing the extract was washed with 10%solution of sodium sulfite in a saturated aqueous solution of sodium bicarbonate. In cases where containing product extract is believed to contain residual acid, before the above-mentioned washing the extract was washed with saturated aqueous sodium bicarbonate (except in those cases where the target product itself is acidic in nature). In those cases, when the extract containing the product is believed to contain residual basis, before the above-mentioned washing the extract was washed with 10%aqueous citric acid solution (except in those cases where the target product itself is the main character). After washing the extracts containing the target product, dried over anhydrous sodium sulfate or magnesium, then filtered. Raw foods after this release, removing the solvent (the solvent by evaporation in a rotary evaporator under reduced pressure at an appropriate temperature (usually lower than 45°C).

Common cleaning methods

Unless specifically stated, the term “chromatographic purification” refers to flash column chromium is ohafia on silica gel with use of individual solvent or mixed solvent as an eluting funds. Appropriate, containing purified target product eluate combined and concentrated under reduced pressure at an appropriate temperature (usually lower than 45°C) to constant weight.

Obtaining some common compounds

According to some variants, the connection1and2receive in accordance with method C. Temple, B.H. Smithy, J.A. Montgomery, J. Org. Chem.,38, 613-615 (1973).

Dry gaseous HCl bubbled through a 2M solution of nitrile (R2CN) in diethyl ether containing 1 mol-equivalent ethanol, at a temperature of -10°C for 1-2 hours. After stirring an additional hour to overnight at room temperature through a solution bubbled nitrogen to displace excess HCl and diethyl ether. The remaining suspension or the suspension is filtered, washed three times with diethyl ether and then dried in vacuum, obtaining the appropriate ethylenedichloride.

A mixture of compound1(1 mmol) and ethylenedichloride (1.1 mmol) in 5 ml of ethanol is heated at a temperature of 65-70°C. until complete reaction (from 1.5 hours to overnight). The mixture is cooled to room temperature, diluted with 20 ml of water, stirred for 30 minutes, filtered and washed with water. The filter cake is collected and dried in vacuum, olucha target product 3.

A solution of compound3(1 mmol) in 2.8 ml of 57%HI (aqueous solution, 20 mmol) is refluxed until completion of the reaction (12-20 hours). The mixture is cooled to a temperature of 0°C, slowly diluted with 5N NaOH solution (19 mmol) and then with 1 ml of saturated solution of sodium bicarbonate until a pH of approximately 9. The resulting mixture is extracted with either ethyl acetate or a mixture of ethyl acetate and tetrahydrofuran to complete the extraction. The combined extracts dried over sodium sulfate, filtered and concentrated, obtaining the target product4in free form. In some cases, if necessary, to obtain a product with a higher purity rinse product ethylcatechol. Monohydride connection4get after cooling the reaction mixture to room temperature, filtration, washing with water and drying the obtained solid yellow color in high vacuum.

A mixture of compound1(300 mg, 1.3 mmol) and tetraethylorthosilicate (2.6 mmol) in 10 ml of acetic acid was stirred at room temperature overnight and until completion of the reaction. The reaction mixture was concentrated under reduced residual pressure and the residue was diluted with a saturated solution of the m sodium bicarbonate, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated, getting a solid brown color. This solid is dissolved in 24 ml of a mixture of H2O and CH3HE (in the ratio 1:1)containing 1.2 g of KOH and refluxed for 2.5 hours. After cooling to room temperature the mixture is extracted with ethyl acetate. The extracts washed with water, dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (10% methanol/ethyl acetate)to give compound5(45 mg, 16%).

A solution of compound1(203 mg, 0.88 mmol) in triperoxonane acid (2 ml) is heated at 70°C for 12 hours, cooled to room temperature, concentrated and the residue was diluted with a saturated solution of sodium bicarbonate (10 ml) and ethyl acetate (10 ml). The separated aqueous phase is extracted 4 times with 10 ml ethyl acetate and the combined organic layer is dried over sodium sulfate, filtered and concentrated, gaining a solid yellow color. It is a solid yellow color mixed with 3 ml of polyphosphoric acid is heated for 3 hours at 200°C and cooled down to room temperature. The reaction mixture was carefully quenched with a saturated solution of sodium bicarbonate (80 ml) and e is stragiht 4 times with 20 ml of ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated, gaining a solid brownish-yellow color. This solid is dissolved in 5 ml of a 57%aqueous solution of HI and heated at 110°C for 12 hours. After cooling to room temperature the reaction mixture is carefully poured into a saturated solution of sodium bicarbonate (60 ml)containing 3 ml of 1N NaOH solution, and extracted 4 times with 20 ml of ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated and the product purified by chromatography (50% to 100% ethyl acetate/hexane), obtaining the target product6(132 mg, 46% for stage 3).

The mixture methylindol-5-carboxylate (27 g, 155 mmol) (or the corresponding 4-, 6 - or 7-carboxylate), di-tert-BUTYLCARBAMATE (40 g, 1.2 EQ.), (C2H5)3N (26 ml, 1.2 EQ.) and 4-dimethylaminopyridine (DMAP) (0.1 g, 0.005 EQ.) in tetrahydrofuran (165 ml) was stirred at room temperature overnight. The reaction mixture was quenched by adding a saturated solution of sodium bicarbonate (350 ml). The separated aqueous layer is extracted once with ethyl acetate. The combined organic phase is concentrated and the product purified by chromatography (5% and 10% ethyl acetate/hexane), receiving the connection7(42 g, 100%).

To a solution of compound7(42 g, 152 mmol) in dichloromethane (400 ml) at -78°C for 30 minutes add a 1M solution of diisobutylaluminium in toluene (460 ml, 3.0 EQ.). The cooling bath replace the bath with a temperature of -40°C, the reaction mixture is stirred and heated to a temperature of -30°C and by using thin-layer chromatography (TLC) to determine the completeness of the reaction. The reaction is quenched by careful addition of methanol (57 ml, 9,0 EQ.) and water (19 ml, 9,0 equiv.) dilute with ethyl acetate (150 ml) and then warmed to room temperature. The resulting mixture in the form of suspension is filtered through celite, washed with ethyl acetate until then, until the product no longer be detected. The filtrate is concentrated and the product purified by chromatography (15% and 30% ethyl acetate/hexane), receiving the connection8(29 g, 75%).

Methanesulfonanilide (10.1 ml, 1.2 EQ.) within 5 minutes at a temperature of 0°C are added to a solution of compound8(27,0 g, 109 mmol, 1.0 EQ.) and diisopropylethylamine (57 ml, 3.0 EQ.) in dichloromethane (250 ml). After additional stirring for 15 minutes to the reaction mixture are added morpholine (14,3 ml, 1.5 EQ., or cyclic or acyclic R R”NH) and stirred at room temperature overnight. The mixture is then poured into a mixture of saturated sodium hydrogen carbonate solution (100 ml) and water (20 is l), the separated aqueous phase is extracted with 4 times 50 ml of ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (15% to 40% ethyl acetate/hexane), receiving the connection9(34,0 g, 99%).

Method And

To a solution of Diisopropylamine in (17.0 ml, 1.2 EQ.) in tetrahydrofuran (350 ml) at -78°C for 15 minutes, add n-utility (2,5M in hexano, 48.6 ml, 1.2 EQ.) and the reaction mixture was stirred and warmed to room temperature after removal of the cooling bath. The reaction mixture is again cooled to a temperature of -78°C and for 15 minutes using a cannula enter solution connection9(32 g, 101 mmol) in tetrahydrofuran (120 ml). The resulting mixture is stirred and heated to a temperature of -20°C for 15 minutes and then injected (C4H9)3SnCl (31.5 ml, 1.15 EQ.). The mixture is stirred and warmed to room temperature and poured into a saturated solution of NH4Cl (300 ml). The separated aqueous phase is extracted with 3 times 100 ml of ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered, concentrated and the product purified by vacuum chromatography (5% to 50% ethyl acetate/hexane)to give compound 10 (55 g, 89%).

Method In

This reaction is also carried out Ana is ogino in accordance with the methodology used for connection15from the connection14.

Connection11get off exit 86% of tert-butyl methyl ether indole-1-carboxylic acid according to the method used to obtain the connection10from the connection9.

Connection12derived from mono - or disubstituted indole according to such techniques as to produce compounds7and10.

A mixture of compound4(0.4 mmol, 1.0 EQ.; or connection2or5or6), compounds10(1.6 equiv.; or connection11or12) and [(C6H5)3P]4Pd (0.1 EQ.) in degassed dimethylformamide (1 ml) in a nitrogen atmosphere together with K2CO3(1.0 EQ.) or without heated at 110°C for 18-28 hours, cooled to room temperature and concentrated in high vacuum. The residue was diluted with a saturated solution of sodium bicarbonate (10 ml) and ethyl acetate. The separated aqueous phase is extracted many times with ethyl acetate until such time as the product will no longer be detected. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The product was then purified by chromatography (5% or 10% methanol/ethyl acetate)to give the target product13.

To a mixture of compound8(as, for example, tert-butyl ester 5-gidroksimetilglutarovogo acid; 24.4 g, 98,8 mmol), (C2H5)3N (41 ml, 3 EQ.) and DMAP (1.2 g, 0.1 EQ.) in dichloromethane (185 ml) at room temperature add tert-butyldimethylsilyloxy (TBSCl) (23.1 g, 1.5 EQ.) and the resulting mixture is stirred over night. The reaction is quenched with a saturated solution of sodium bicarbonate (200 ml) and the separated aqueous layer is extracted with 3 times 50 ml of dichloromethane. The combined organic phase is dried over sodium sulfate, filtered, concentrated and the product purified by vacuum chromatography (3% ethyl acetate/hexane), receiving the connection14(tert-butyl ether (5-tert-butyldimethylsilyloxy)indole-1-carboxylic acid) as a colourless oil (33,9 g, 95%).

To a solution of compound14(as, for example, tert-butyl ester (5-tert-butyldimethylsilyloxy)indole-1-carboxylic acid; and 33.5 g of 92.7 mmol) in tetrahydrofuran (650 ml) at a temperature below -72°C. dropwise within 45 minutes add tert-utility (63 ml, 1.7m solution in pentane; 1.2 EQ.) and stirring is continued for an additional 40 minutes. Obtained as a result is s brown solution is briefly heated to a temperature of -60°C and then cooled to a temperature below -72°C. After that, the reaction mixture is injected (C4H9)3SnCl (31,6 ml, 1.3 EQ.) and stirred at -40°C for 15 minutes. The reaction is quenched at a temperature of -35°C. a saturated solution of sodium bicarbonate (250 ml) and the separated aqueous layer is extracted with 3 times 50 ml of ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered, concentrated and the product purified by vacuum chromatography (hexane), receiving the connection15(tert-butyl ether (5-tert-butyldimethylsilyloxy)-2-tributylstannyl-1-carboxylic acid) as a colourless oil (60,6 g, 100%).

A solution of compound15(as, for example, tert-butyl ester (5-tert-butyldimethylsilyloxy)-2-tributylstannyl-1-carboxylic acid; 60,6 g, 3.0 EQ.) in dimethylformamide (100 ml) in four portions over 24 hours at a temperature of 110°C and in an atmosphere of nitrogen are added to a solution of compound4(R2=CH3, 8,51 g, was 31.0 mmol), Pd[(C6H5)3P]4(3.2 g, 0.09 EQ.) and (C2H5)3N (26 ml, 3.0 EQ.) in dimethylformamide (100 ml) together with K2CO3(1.0 EQ.) or without it. The resulting mixture is stirred for 20 hours, cooled to room temperature and concentrate. The residue was diluted with a saturated solution of bicarbonate into three is (300 ml) and ethyl acetate (300 ml), filtered and washed with ethyl acetate to remove the sediment, dark grey. Separated from the filtrate, the aqueous phase is extracted 6 times with 200 ml of ethyl acetate until such time as you will not find the target product by TLC. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue is diluted with ethyl acetate and the resulting suspension is filtered, washed with ethyl acetate and 2 times with methanol, receiving the connection16(4,27 g). The filtrate is concentrated and the residual product was then purified by chromatography (0 to 5% methanol/ethyl acetate), obtaining the additional number of connections16(2,59 g). The products comprise receiving the connection16(7-[5-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-ylamine in the form of a solid greenish-gray (6,86 g, 54%).

A solution of potassium tert-butylate in tetrahydrofuran (1,66 mol, 96,3 ml, 9.5 EQ.) at temperatures below -28°C for 40 minutes add to a mixture of compound16(as, for example, 7-[5-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-ylamine; 6,86 g, a 16.8 mmol) and di-tert-BUTYLCARBAMATE (39 ml, 10 EQ.) in tetrahydrofuran (1.1 l). After stirring for 10 minutes the reaction is quenched with a saturated solution of sodium bicarbonate (300 ml) and heating the Ute to room temperature. The separated aqueous layer is extracted with 3 times 150 ml of ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered, concentrated and the product purified by vacuum chromatography (10% to 20% ethyl acetate/hexane), receiving di-BOC-protected intermediate connection.

Di-BOC-protected intermediate compound is then dissolved in 55 ml of tetrahydrofuran containing (C2H5)3N (55 ml), DIBOC (22,5 g, 6.0 EQ.) and DMAP (0.21 g, 0.1 EQ.) and heated at 65°C for 5 hours. After cooling to room temperature the mixture is concentrated and the product purified by vacuum chromatography (10% ethyl acetate/hexane), receiving Tetra-BOC-substituted intermediate connection.

Tetra-BOC-substituted intermediate compound is then dissolved in the solution of HF/pyridine in tetrahydrofuran (0.89 mol, 5.3 equiv., a solution of HF/pyridine is obtained by mixing 10 g 70%HF in pyridine, to 52.5 ml of pyridine and 330 ml of tetrahydrofuran) and stirred at room temperature for 40 hours. The reaction mixture was then carefully quenched with a saturated solution of sodium bicarbonate (250 ml) and the separated aqueous layer is extracted with 3 times 50 ml of ethyl acetate. The combined organic phase washed with brine (50 ml), dried over sodium sulfate, filtered, concentrated and the product purified by vacuum chromatography (10% to 50% of tracecut/hexane), receiving the connection17(tert-butyl ether (5-di(tert-butoxycarbonyl)amino-7-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-indol-2-yl)-2-methylimidazo[4,5-b]pyridine-3-carboxylic acid; 5,64 g, 48% for the three stages) in the form of a slightly yellow solid.

To a mixture of compound17(as, for example, tert-butyl ester (5-di(tert-butoxycarbonyl)amino-7-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-indol-2-yl)-2-methylimidazo[4,5-b]pyridine-3-carboxylic acid; 830 mg, 1.2 mmol) and diisopropylethylamine (2,08 ml, 10 EQ.) in dichloromethane (10 ml) at 0°With add methylsulfonylamino (of 0.14 ml, 1.5 EQ.) and the resulting mixture is stirred and warmed to room temperature. After stirring for 7 hours at room temperature, the mixture was kept at 0°C for two days, warmed to room temperature and concentrated to half its volume. The product is then purified by chromatography (20% to 30% ethyl acetate/hexane), receiving the connection18(tert-butyl ether (5-di(tert-butoxycarbonyl)amino-7-(1-tert-butoxycarbonyl-5-chloromethyl-1H-indol-2-yl)-2-methylimidazo[4,5-b]pyridine-3-carboxylic acid, 770 mg, 90%).

A mixture of compound 17 (as, for example, tert-butyl ester (5-di(tert-butoxycarbonyl)amino-7-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H and the Dol-2-yl)-2-methylimidazo[4,5-b]pyridine-3-carboxylic acid, 122 mg, 0.18 mmol) and periodinane Dess-Martin (223 mg, 3.0 EQ.) in dichloromethane (4 ml) was stirred at room temperature for 1 hour. The resulting mixture is diluted with diethyl ether (60 ml), stirred for 20 minutes and filtered through celite, rinsing with diethyl ether. The filtrate was washed with a saturated solution of sodium bicarbonate (20 ml)containing Na2S2O3(500 mg), and the aqueous phase is again extracted with 2 times 25 ml of diethyl ether. The combined organic layer is dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (10% to 30% ethyl acetate/hexane)to give compound 19 (tert-butyl ether (5-di(tert-butoxycarbonyl)amino-7-(1-tert-butoxycarbonyl-5-formyl-1H-indol-2-yl)-2-methylimidazo[4,5-b]pyridine-3-carboxylic acid; 117 mg, 96%).

To a solution of compound 19 (as, for example, tert-butyl ester (5-di(tert-butoxycarbonyl)amino-7-(1-tert-butoxycarbonyl-5-formyl-1H-indol-2-yl)-2-methylimidazo[4,5-b]pyridine-3-carboxylic acid, 958 mg, 1.38 mmol) in tert-butanol (10 ml) at room temperature for 10 minutes, add a solution of KMnO4(436 mg, 2 EQ.) and KN2RHO4(563 mg, 3 EQ.) in water (15 ml) and the resulting mixture is stirred for 30 minutes. The mixture was then diluted with ethyl acetate (20 ml), filtered through celite, about what they with ethyl acetate. The filtrate is diluted with brine (60 ml), water (40 ml) and ethyl acetate (200 ml). The separated aqueous phase is extracted with 3 times 30 ml of ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (30% to 100% ethyl acetate/hexane), receiving the connection20(1-tert-butyl ester 2-(3-tert-butylcarbamoyl-5-di(tert-butoxycarbonyl)amino-2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)indole-1,5-carboxylic acid, 678 mg, 69%).

A mixture of mono - or disubstituted of benzylchloride (or bromide) or bromethalin or chlorodiphenylmethane (20 mmol) and methylamine (22 ml, 40%in water, 10 EQ.) in methanol (18 ml) was stirred at room temperature for 1-5 days to complete the reaction. After concentrating the reaction mixture is diluted with saturated sodium hydrogen carbonate solution (50 ml), extracted with ethyl acetate until then, until you discover the product. The combined extracts dried over sodium sulfate, filtered, concentrated, receiving the product21.

Amines22-26receive according to a modified method described in published PCT application number WO-01/00610-A1.

To a solution of 2-(ethylvanillin)ethanol (1,43 g, 8,65 mmol) and diisopropylethylamine (30 ml, 2.0 EQ.) in dichloromethane (10 ml) at 0°With add methanesulfonanilide (0,80 ml, 1.2 EQ.) and the resulting mixture is stirred for 15 minutes. Then injected ammonia solution (20 ml, 2M in methanol) and the resulting mixture was stirred at room temperature for five days and concentrate. The residue was diluted with 7 ml of 1N HCl and washed 3 times with ethyl acetate. The aqueous phase is treated with 15 ml of 1N NaOH solution and extracted once with ethyl acetate. The extract is dried over sodium sulfate, filtered, concentrated, receiving the product27.

To a solution of 2-benzyloxypyridine-1,3-diol (5.0 g, a 27.4 mmol) in 200 ml of a mixture of tetrahydrofuran and dimethylformamide in a ratio of 5:1 at a temperature of 0°C is added NaH (1.5 g, 2.3 EQ.), then methyliodide (5,1 ml, 3.0 EQ.). The resulting mixture in the form of a white suspension was stirred at room temperature over the weekend. The reaction mixture was quenched with a saturated solution of NH4Cl, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (50% ethyl acetate/hexane), receiving (2-methoxy-1-methoxymethyl-2-ethoxymethyl)benzene (5.6 g, 97%).

A mixture of (2-methoxy-1-methoxymethyl-2-ethoxymethyl)benzene (5.5 g) and Pd(OH)2(0.4 g) in methanol (150 ml) stirred at anatoy temperature in a hydrogen atmosphere until completion of the reaction. The reaction mixture was filtered and concentrated, obtaining 1,3-dimethoxypropane-2-ol (3.0 g, 96%).

To a solution of 1,3-dimethoxypropane-2-ol (0.50 g, 4.14 mmol) and triethylamine (2.3 ml, 4.0 EQ.) in dichloromethane (2 ml) at 0°With add methanesulfonanilide (and 0.61 ml, 2.0 EQ.) and the resulting mixture is stirred for 15 minutes. The reaction is quenched with a saturated solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated. Balance and NaN3(to 0.80 g, 3.0 EQ.) dissolved in dimethyl sulfoxide (10 ml) and heated at 90°C for the weekend. After cooling to room temperature the mixture is diluted with saturated sodium hydrogen carbonate solution and extracted with diethyl ether. The combined extracts dried over sodium sulfate, filtered and concentrated, obtaining the intermediate azide (320 mg, 48%).

A mixture of intermediate azide (320 mg) and Pd(OH)2in methanol (15 ml) was stirred at room temperature in hydrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated, obtaining the connection28(150 mg, 63%).

A mixture of ethylvanillin (4,15 ml, 33 mmol), allylbromide (4.3 ml, 1.5 EQ.) and K2CO3(9,1 g, 2.0 EQ.) in acetone (50 ml) is refluxed for but is I. After cooling to room temperature the reaction mixture was diluted with water (50 ml) and ethyl acetate (100 ml). The separated organic phase is dried over sodium sulfate, filtered and concentrated and the product purified by chromatography (10% ethyl acetate/hexane), receiving arelatively (5.32 g, 100%).

The solution OsO4(7.8 ml 0,1M in water, 0.03 EQ.) at room temperature add to the mixture of arelatively (4,10 g, to 25.3 mmol) and N-methylmorpholin-N-oxide (NMO) (of 5.92 g, 2.0 EQ.) in 40 ml of a mixture of acetone and water in the ratio of 9:1 and the resulting mixture is stirred over night. The mixture is diluted with a saturated solution of NaHCO3(80 ml), a saturated solution of Na2S2O3(20 ml) and 100 ml of a mixture of diethyl ether with hexane in the ratio of 1:1. The separated aqueous phase is extracted with 2 times 30 ml of ethyl acetate and the combined organic phase is dried over sodium sulfate, filtered and concentrated and the product purified by chromatography (30% ethyl acetate/hexane)to give 3-(ethylenediamino)propane-1,2-diol (4,25 g, 86%).

To a solution of 3-(ethylenediamino)propane-1,2-diol (4,22 g, 21.6 mmol) and triethylamine (9,03 ml, 3.0 EQ.) in dichloromethane (20 ml) at -30°C to -35°C add methanesulfonanilide (2.5 ml, 1.5 EQ.) and the resulting mixture is stirred and heated to a temperature of 0°C. the Reaction is quenched with saturated solution of NaHCO3 (30 ml) and the separated aqueous phase is extracted with 2 times 20 ml of dichloromethane and 20 ml of ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated. The residue is dissolved in 30 ml of methanol and treated with sodium methylate (2.3 g, 2.0 EQ.) within 3 hours at a temperature of 65-70°C. After cooling to room temperature the mixture is diluted with a saturated solution of NaHCO3(50 ml) and extracted with 3 times 30 ml of ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated and the product purified by chromatography (10% ethyl acetate/hexane), receiving ethoxytrimethylsilane (1,72 g, 45%).

The solution ethoxymethyleneamino (1,72 g, 9,65 mmol) and sodium methylate (1.04 g, 2.0 EQ.) in methanol (8 ml) is refluxed over the weekend. After cooling to room temperature the mixture is diluted with a saturated solution of NaHCO3(20 ml) and extracted 3 times with 20 ml of ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (30% ethyl acetate/hexane)to give 1-(ethylenediamino)-3-methoxypropan-2-ol (1,95 g, 97%).

A solution of 1-(ethylenediamino)-3-methoxypropan-2-ol (1,95 g to 9.32 mmol) and NMO (2,18 g, 2.0 EQ.) in dichloromethane (15 ml) at room temperature is treated with TRAR (150 mg, of 0.05 EQ.) until completion of the reaction. The reaction mixture was diluted with a saturated solution of NaHCO3(50 ml) and extragear the Ute 3 times 30 ml of ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated and the product purified by chromatography (10% to 15% ethyl acetate/hexane)to give 1-(ethylenediamino)-3-methoxypropan-2-he (0,98 mg, 51%).

A mixture of 1-(ethylenediamino)-3-methoxypropan-2-it (17 mg, 0.08 mmol), hydroxylaminopurine (30 mg) and pyridine (0.3 ml) in methanol (0.4 ml) was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with a saturated solution of NaHCO3and extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated. The residue is dissolved in tetrahydrofuran (0.8 ml) and treated with sociallyengaged (0.3 ml, 1M solution in tetrahydrofuran) at room temperature over night. By processing and purification by chromatography (2M solution of NH3in methanol/dichloromethane in the ratio 5:95), get the connection29in the form of a slightly yellow oil.

Connection30obtained from 3-phenoxypropane-1,2-diol with a total yield of 21%, using the same techniques as for connection29from 3-(ethylenediamino)propane-1,2-Ola.

A mixture of 3-(bromopropyl)benzene or bromeilles (1 mol, 1.0 EQ.) in methanol and 40%-aqueous solution of CH3NH2in water (60 equiv.) stirred at room temp is the temperature or at a temperature of 45°C. until completion of the reaction. After cooling to room temperature the mixture is concentrated and the residue was diluted with a saturated solution of NaHCO3and extracted 3 times with dichloromethane (3 times with ethyl acetate). The combined extracts dried over sodium sulfate, filtered and concentrated, obtaining the connection31or32.

To a mixture of cyclopentanemethanol (1.1 ml, 1.0 EQ.) and ethyldiethanolamine (3.9 ml, 10 EQ.) in dichloromethane (5 ml) at 0°With add methanesulfonanilide (0.8 ml, 1.0 EQ.) and the resulting mixture is stirred and warmed to room temperature. After adding a saturated solution of NaHCO3separated aqueous phase is extracted with dichloromethane and the combined organic layer is concentrated and give crude intermediate mesilate. This mesilate then treated with CH3NH2following the method of producing compounds31/32receiving the connection33.

To a mixture of 1,2-diphenylethanone (307 mg, 1.56 mmol), (C2H5)3N (655 ml) and methylamine (1,02 ml) in tetrahydrofuran (5 ml) at a temperature of 0°C. add a solution of TiCl4in dichloromethane (1M, 1.56 mmol). After stirring for 1.5 hours, add a solution of NaBH4(280 mg, 37.8 mmol) in methanol (8 ml) and the resulting mixture is stirred for 2 hours is. Then add a saturated solution of Na2CO3and the reaction mixture was kept in the camera freezing during the night. After thawing, the organic layer removed and the aqueous layer was extracted 3 times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. After cleaning thin-layer preparative chromatography (80% ethyl acetate/hexane) get the connection34(195 mg, 59%).

Connection35and36get a similar manner from 2-methoxy-1-phenylethanone and cycloheptanone.

37

To a solution of BOC-nortropinone (0.5 g, 2.2 mmol, 1.0 EQ.) in dichloromethane (10 ml) add 10 ml triperoxonane acid. The reaction mixture is stirred for 2 hours and then concentrated. After adding ethyl acetate and a saturated solution of NaHCO3the reaction mixture is extracted 3 times with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated, obtaining the connection37(0.25 g).

To a solution of phenyl ether 2,5-dihydropyrrol-1-carboxylic acid (2 g, 10 mmol, 1.0 EQ.) in 20 ml of a mixture of acetone and water (in the ratio 9:1) add OsO4(4%solution in water; 1 ml) and N-methylmorpholin-N-oxide (2.3 g, 20 mmol, 2 EQ.). The mixture is stirred at room t is mperature during the night, concentrated to remove most of the acetone, poured into a saturated solution of NaHCO3and extracted 3 times with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The crude mixture is purified by chromatography on silica gel (70% to 90% ethyl acetate/hexane), receiving phenyl ether 3,4-dihydroxypyrrolidine-1-carboxylic acid (2,04 g, 88%).

To a solution of phenyl ether 3,4-dihydroxypyrrolidine-1-carboxylic acid (1,93 g, 8.1 mmol, 1.0 EQ.) in methanol (20 ml) is added palladium hydroxide and incubated in an atmosphere of hydrogen for 4 hours. The catalyst is filtered off through celite and washed with methanol. The filtrate is concentrated (25°C), receiving the connection38in the form of a reddish oil (840 mg, 100%).

To a suspension of NaH (8,99 g, 0,225 mol, 4.6 EQ.) in 1,2-dimethoxyethane (70 ml) at a temperature of 0°C. slowly add a solution of 1,4-dioxaspiro[4,5]decane-8-it (7,56 g 0,048 mol, 1.0 EQ.) in 1,2-dimethoxyethane (24 ml). After stirring for 30 minutes, slowly, over 7 hours, enter solution of CH3I (14 ml, 0,225 mol, 4.6 EQ.) in 1,2-dimethoxyethane (70 ml) and the resulting mixture is slowly warmed to room temperature and stirred over night. The reaction is quenched by slowly adding water to it until no more will discover a selection bubble is impressive. The reaction mixture was poured into a mixture of ice water and extracted 3 times with hexane. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by chromatography (100% hexane to remove the oil, then hexane/ethyl acetate in the ratio 5:1), receiving 7,7,9,9-tetramethyl-1,4-dioxaspiro[4,5]decane-8-he (4,16 g, 40%).

To a solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro[4,5]decane-8-she (4.15 g, 0.019 mol, 1.0 EQ.) in tetrahydrofuran (60 ml) is added 30 ml of 1N HCl and the resulting mixture was stirred at room temperature overnight, concentrated to remove most of the tetrahydrofuran, extracted 3 times with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated, obtaining 2,2,6,6-tetramethylcyclobutane-1,4-dione in the form of a solid white color (3,43 g, >100%).

To a solution of 2,2,6,6-tetramethylcyclobutane-1,4-dione (0.40 g, 2.4 mmol, 1.0 EQ.) in tetrahydrofuran (8 ml) was added molecular sieves (4E, 80 mg), 2M solution of CH3NH2in tetrahydrofuran (1.3 ml, 2.6 mmol, 1.1 EQ.) and acetic acid (0.17 ml, 3.0 mmol, 1.2 EQ.). After stirring for 5 minutes added NaBH(OAc)3(0.71 g, of 3.33 mmol, 1.4 EQ.) and the resulting mixture was stirred at room temperature overnight. The reaction is quenched with saturated solution of NaHCO3. Mixture to the center and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers are washed once with saturated solution of NaHCO3, dried over magnesium sulfate, filtered and concentrated, obtaining the crude oil is pale yellow in color, which crystallizes, resulting in the formation of compound39in the form of white crystals (0.40 g, >100%).

To a solution of methyltriphenylphosphonium (17 g, 1.5 EQ.) in tetrahydrofuran (100 ml) at a temperature of 0°C is added dropwise n-utility (2.5m solution in hexane, 18 ml, 1.4 EQ.) and the resulting mixture is stirred for 1 hour. Then injected dropwise a solution of 1,4-dioxaspiro[4,5]decane-8-she (5.0 g, 32 mmol, 1.0 EQ.) in tetrahydrofuran (10 ml) and the resulting mixture is heated to room temperature and stirred over night. The reaction is quenched with saturated solution of NaHCO3and the separated aqueous layer was extracted 4 times with ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (5% to 10% ethyl acetate/hexane), receiving 8-methylene-1,4-dioxaspiro[4,5]decane (to 3.92 g, 79%).

To a solution of 8-methylene-1,4-dioxaspiro[4,5]decane (2.0 g, 13 mmol, 1.0 EQ.) in tetrahydrofuran (10 ml) at a temperature of 0°C is added dropwise 9-borabicyclo[3,3,1]nonan (9-BBN) (0.5m solution in tetrahydrofuran, 104 ml, 4.0 EQ.) and the result with the offer is stirred for 15 minutes and then warmed to room temperature and stirred over night. After this, at a temperature of 0°With portions enter NaBO4·4H2(32 g, 16 EQ.) and the resulting mixture is heated to room temperature and stirred over night, diluted with hexane (30 ml) and the separated aqueous phase is extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (50% to 100% ethyl acetate/hexane), receiving (1,4-dioxaspiro[4,5]Dec-8-yl)methanol (1.5 g, 67%).

To a solution of (1,4-dioxaspiro[4,5]Dec-8-yl)methanol (1.0 g, 5.8 mmol, 1.0 EQ.) and ethyldiethanolamine (17 ml, 3.0 EQ.) in dichloromethane (4 ml) at a temperature of 0°C is added dropwise methanesulfonanilide ones (0.46 ml, 1.0 EQ.) and the resulting mixture is heated to room temperature and stirred for 2 hours. The reaction is quenched with saturated solution of NaHCO3and the separated aqueous phase is extracted 3 times with dichloromethane and 4 times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated give crude 1,4-dioxaspiro[4,5]Dec-8-ymetray broadcast methansulfonate.

A mixture of crude 1,4-dioxaspiro[4,5]Dec-8-Eletropaulo ether methanesulfonate (400 mg) in methanol (2 ml) and an aqueous solution of CH3NH2(40% wt./wt., 5 ml) is refluxed (oil bath, 60°C) during the night. Rea is of quenched with saturated solution of NaHCO 3and the separated aqueous phase is extracted 4 times with dichloromethane and 4 times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated give crude compound40in the form of a brown oil.

To a solution of benzyl ester 4-oxopiperidin-1-carboxylic acid (0.50 g, 2.14 mmol, 1.0 EQ.) in tetrahydrofuran (20 ml) at a temperature of -30°C add dibromodifluoromethane (0,90 ml, 4.5 equiv.) then add hexamethylphosphoramide (NMRA) (1.75 ml, 4.5 EQ.). The cooling bath removed and the reaction mixture was periodically shaken. After 30 minutes add zinc powder (0,63 g, 4.5 EQ.) and NMR (80 μl, 0.4 EQ.) and the mixture is refluxed for 18 hours. After cooling to room temperature, the residue is washed several times with diethyl ether. Combined phase obtained by washing with diethyl ether, washed sequentially with a saturated aqueous solution of copper sulfate (II), brine, dried over sodium sulfate and concentrated. The residue is purified by chromatography (20% ethyl acetate/hexane)to give benzyl ether of 4-differmaterially-1-carboxylic acid (0.32 g, 56%) as a colourless oil.

A mixture of benzyl ester 4-differmaterially-1-carboxylic acid (269 mg) and Pearlman catalyst in methanol (2.5 ml) paramashiva the t in hydrogen atmosphere (filled with hydrogen using a balloon) for 4 hours at room temperature. The reaction mixture was filtered through celite and the filtrate is concentrated and receiving the connection41(138 mg) as a pale yellow oil.

Following the same procedure as for connection41, 2,2-dimethylpropionic ether 4-differmaterially-1-carboxylic acid (368 mg) obtained using 2,2-dimethylpropylene ether 4-oxopiperidin-1-carboxylic acid (500 mg). 2,2-Dimethylpropionic ether 4-differmaterially-1-carboxylic acid (368 mg) in dichloromethane (1.0 ml) at room temperature is treated triperoxonane acid (TFUC, 0.5 ml) for 1.5 hours. After concentrating the reaction mixture, the crude compound42used without other purification.

To a solution of 2-aminocyclohexanol (3.50 g, 23,0 mmol, 1.0 EQ.) in dichloromethane (100 ml) add ethylchloride (2.65 ml, 1.2 EQ.), then an aqueous solution of K2CO3(16.0 g in 200 ml water). The mixture is intensively stirred for 1 hour. The separated aqueous layer is extracted twice with dichloromethane. The combined organic layers are dried over magnesium sulfate, filtered and concentrated, obtaining the ethyl ester of (2-hydroxycyclohexyl)carbamino acid (4,36 g, >100%).

To a solution of ethyl ester of (2-hydroxycyclohexyl)carbamino acid (to 2.06 g, 11.0 mmol, 1.0 EQ.) in tetr is hydrofuran (80 ml) is added LiAlH 4(1,09 g, 28.7 mmol, 2.6 EQ.) and the resulting mixture is heated at 65°C for 2 hours. The reaction mixture is cooled to a temperature of 0°C, quenched with water and the separated aqueous phase is extracted 3 times with ethyl acetate. The combined organic phase is dried over magnesium sulfate, filtered and concentrated, obtaining 2-methylenecycloartanol (1.19 g, 84%).

To a solution of 2-methylenecycloartanol (0,204 g, was 1.58 mmol, 1.0 EQ.) and di-tert-BUTYLCARBAMATE (0,422 g, 1.2 EQ.) in dichloromethane (7.0 ml) is added an aqueous solution of K2CO3(1,09 g of 14.0 ml water) and the resulting mixture is intensively stirred for 1 hour. The separated aqueous layer is extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated, obtaining tert-butyl ether (2-hydroxycyclohexyl)methylcarbamate acid (of 0.332 g, 92%).

To a solution of tert-butyl methyl ether (2-hydroxycyclohexyl)methylcarbamate acid (0,237 g of 1.03 mmol, 1.0 EQ.) in dichloromethane (7.0 ml) at 0°With added molecular sieves (4, 3 ml). The reaction mixture is stirred for 5 minutes and then injected N-methylmorpholin-N-oxide (0,422 g, 3.5 EQ.) and TRAR (0.025 g, 0.07 EQ.). The reaction mixture was stirred at 0°C for 5 minutes and then at room temperature for 40 minutes. After time is Alenia hexanone the reaction mixture was passed through a layer of silica gel, using the first hexane to remove dichloromethane and then using the mixture of hexanol with ethyl acetate in the ratio of 1:1 to obtain the target product. After concentration of the filtrate in a mixture of hexanol with ethyl acetate to obtain tert-butyl ether methyl-(2-oxocyclohexyl)carbamino acid in a solid white color (0,235 g, 100%).

To a solution of tert-butyl ether methyl-(2-oxocyclohexyl)carbamino acid (0,202 g, 0.89 mmol, 1.0 EQ.) in dichloromethane (3.0 ml) add TFOC (1.0 ml) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated, receiving the connection43(0,285 g, >100%).

To a solution of cyclopentylamine (5.8 ml, 59 mmol, 1.0 EQ.) in dichloromethane (250 ml) at room temperature add ethylchloride (7.3 ml, 1.3 EQ.), then an aqueous solution of K2CO3(37 g in 500 ml water). The mixture is intensively stirred for 1 hour. The separated aqueous layer is extracted twice with dichloromethane. The combined organic layers are dried over magnesium sulfate, filtered and concentrated, obtaining the ethyl ester cyclopentylamine acid (9.6 g, 88%).

To a solution of ethyl ester cyclopentylamine acid (6,00 g, 32,4 mmol, 1.0 EQ.) in tetrahydrofuran (250 ml) is added LiAlH4(is 3.08 g, 2.5 EQ.) and R is the result of the mixture is heated at 65°C for 2 hours. The reaction mixture is then cooled to a temperature of 0°C and quenched by adding water. The separated aqueous layer is extracted 3 times with ethyl acetate. The combined organic phases are dried over sulfinol magnesium, filtered and concentrated, obtaining the connection44(2,01 g, 62%).

Connection45-48receive, using the same techniques as for connection44on the basis of the corresponding primary amines.

To a solution of Cyclopentanone (25,0 ml, 0.28 mol, 1.0 EQ.) in toluene (100 ml) add pyrrolidine (27.5 ml, 1.2 EQ.). The reaction flask provided with a nozzle Dean-stark and the reaction mixture refluxed overnight. The reaction mixture is cooled to room temperature and concentrated give crude 1-cyclopent-1-inspiraiton (45,8 g, >100%).

To a solution of Pd(OAc)2(0.06 g, 0.06 EQ.), P(C6H5)3(0.32 g, 0.24 EQ.) and ethyl ester of 2-ethoxycarbonylmethylene ether carboxylic acid (1.23 g, and 5.30 mmol, 1.0 EQ.; receive according to Tetrahedron,54(49), 14885-14904 (1998)) in CH3JV (30 ml) was added 1-cyclopent-1-inspiraiton (1.01 g, 1.4 EQ.) and the reaction mixture is heated at 45°C for 35 minutes. Then add water (15 ml) and the reaction mixture is heated at 50°C for 1 hour, cooled to whom atoi temperature and diluted with 30 ml of ethyl acetate. The separated aqueous phase is extracted twice with ethyl acetate. The combined organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (10% to 15% ethyl acetate/hexane), getting 3-methyltricyclo[3,2,1]Octan-8-he (0.14 g, 70%) as pale yellow liquid.

To a solution of 3-methyltricyclo[3,2,1]Octan-8-she (0.14 g, 1.04 mmol, 1.0 EQ.) in benzene (10 ml) was added ethylene glycol (0.65 g, 16 EQ.) and p-toluensulfonate (0.01 g, 0.06 EQ.). The reaction flask provided with a nozzle Dean-stark and the reaction mixture refluxed overnight. After cooling to room temperature, add (C2H5)3N (0.15 ml) and the resulting mixture is passed through a layer of SiO2and MgSO4. Layer washed with dichloromethane and the combined filtrates concentrated, getting the 3-methyltricyclo[3,2,1]Octan-8-onedimensional (0.21 g, >100%).

Through a solution of 3-methyltricyclo[3,2,1]Octan-8-netinkamas (0.21 g, 1.15 mmol, 1.0 EQ.) in dichloromethane (2 ml) at -78°bubbled With O3up until the reaction mixture will not stay blue color (about 3 minutes). Bubbling About3stopped and the reaction mixture is stirred for 5 minutes at -78°C. the Reaction is quenched by addition of triphenylphosphine (of 0.43 g, 1.4 EQ.) and stirred at pace is the atur -78°C for 10 minutes. The reaction mixture was left to warm to room temperature, stirred for 40 minutes and concentrated. The residue is purified by chromatography on silica gel (10% to 15% ethyl acetate/hexane), receiving bicyclo[3,2,1]octane-3,8-dione-8-atlantal in the form of a colorless oil (0.08 g, 40%).

To a solution of bicyclo[3,2,1]octane-3,8-dione-8-atelectasia (53,1 mg, 0.27 mmol, 1.0 EQ.) in tetrahydrofuran (1.0 ml) at 0°C. add (C2H5)3N (of 0.11 ml, 2.9 EQ.), then add CH3NH2(2.0m solution in tetrahydrofuran, of 0.21 ml, 1.5 EQ.). After stirring at room temperature for 5 minutes dropwise enter TiCl4(0,30 ml, 10.0 EQ.) and the resulting mixture is stirred at 0°C for 45 minutes. Then injected a solution of NaBH4(53,1 mg, 5.1 EQ.) in methanol (2.0 ml) and the resulting mixture is stirred at 0°C for 1 hour. The reaction is quenched with a saturated solution of NaHCO3and the separated aqueous layer is extracted 3 times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated, obtaining in the form of a crude product of 3-methylaminomethyl[3,2,1]Octan-8-onedimensional (24,1 mg).

To a solution of 3-methylaminomethyl[3,2,1]Octan-8-netinkamas (94,5 mg, 0.48 mmol, 1.0 EQ.) in acetone (2.0 ml) is added 1N HCl (1.5 ml) and the reaction mixture stirred for the eyes at room temperature. The reaction mixture was neutralized with saturated solution of NaHCO3to pH values higher than 7, extracted 3 times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated, obtaining the connection49(40,0 mg, 54%).

To a solution of (3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)methylaminopropane (1.0 g, 4 mmol, 1.0 EQ.) in tetrahydrofuran (12 ml) is added di-tert-BUTYLCARBAMATE (1.1 ml, 1.2 EQ.), the triethylamine (2 ml) and 4-dimethylaminopyridine (DMAP) (catalytic amount). The resulting mixture is heated at 90°C for 6 hours, cooled to room temperature, poured into a saturated solution of NaHCO3and the separated aqueous layer is extracted 3 times with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (10% ethyl acetate/hexane)to give tert-butyl ether (3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)methylcarbamate acid (1.4 g, 91%) as a solid white color.

To a solution of tert-butyl methyl ether (3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)methylcarbamate acid (1.27 g, 3.63 mmol, 1.0 EQ.) in a mixture of acetone (40 ml) and water (20 ml) add pyridine-4-toluensulfonate (PPTS) (228 mg, 0.25 EQ.) and the resulting reaction mixture is boiled with milk products is a diversified fridge over night, cooled to room temperature, concentrated to a volume of 20 ml, poured into a saturated solution of NaHCO3and extracted 3 times with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (from hexanol to a mixture of 20% ethyl acetate/hexane)to give tert-butyl ether methyl-(4-oxocyclohexyl)carbamino acid (735 mg, 88%) as a solid white color.

To a solution of tert-butyl ether methyl-(4-oxocyclohexyl)carbamino acid (0,69 g, 3.04 from mmol, 1.0 EQ.) in tetrahydrofuran (25 ml) at a temperature of -30°With type CBr2F2(1.25 ml, 4.5 equiv.) then slowly add P(N(CH3)2)3. The resulting mixture is heated to room temperature for 0.5 hours and add Zn. The resulting mixture is stirred at the boil under reflux for 16 hours, cooled to room temperature and diluted with diethyl ether. The organic phase is decanted and the aqueous phase is extracted 2 times with diethyl ether. The combined organic phase was washed with a saturated solution of CuSO4until then, until it will remain blue, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (20% ethyl acetate/hexane)to give tert-butyl ester (4-shall ivermectinandcollies)methylcarbamate acid (475 mg, 60%) as a solid white color.

To a solution of tert-butyl methyl ether (4-diversityecological)methylcarbamate acid (150 mg, or 0.57 mmol, 1.0 EQ.) in dichloromethane (1.5 ml) add TFOC (1.5 ml). The reaction mixture is stirred for 4 hours and then concentrated, receiving the connection50(85 mg). The crude compound is used at the next stage without further purification.

To a solution of cyclopropylamine (5.0 g, of 87.5 mmol) and triethylamine (30 ml) in dichloromethane (100 ml) at a temperature of 0°C is added dropwise benzylchloride (15.0 ml, 10.5 mmol) and the resulting mixture is stirred for 2 hours. Add additional benzylchloride (1 ml) and the resulting reaction mixture is stirred over night. Then the reaction quenched with saturated solution of NaHCO3and the separated aqueous phase is extracted several times with dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (100% ethyl acetate to 5% methanol/ethyl acetate)to give benzyl ether cyclopropylamino acid (11.8 g, 71%).

To a solution of benzyl ether cyclopropylamino acid (11.8 g) and under the conditions (in excess) in a mixture of tetrahydrofuran (80 ml) and dimethylformamide (20 ml) at 0°With added NaH (2.20 g, to 91.6 shall mol) and the resulting mixture is heated to room temperature and stirred over night. The reaction is then quenched at a temperature of 0°C with saturated solution of NaHCO3. The separated aqueous phase is extracted several times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (5% to 20% ethyl acetate/hexane)to give benzyl ether cyclopropylmethanol acid (11,32 g, 91%).

A mixture of benzyl ether cyclopropylmethanol acid (10.7 g) and Pd(OH)2in methanol (100 ml) was stirred at room temperature in an atmosphere of hydrogen from a cylinder for 17 hours, diluted with concentrated HCl (4.8 ml), filtered through celite and concentrated. The residue is repeatedly subjected to azeotropic distillation with toluene, getting cyclopropanecarbonitrile (connection51, 5.75 g). The crude product is used without further purification.

To a solution of (tetrahydrofuran-3-yl)methanol (1,00 g, 9,79 mmol, 1.0 EQ.), P(C6H5)3(3,85 g, 1.5 EQ.) and imidazole (1,33 g, 2.0 EQ.) in dichloromethane (15 ml) at 0°With type I2(of 3.73 g, 1.5 EQ.) and the resulting mixture is stirred at 0°C for 30 minutes and then at room temperature for 30 minutes. The reaction mixture was diluted with a saturated solution of Na2S2O3and the separated aqueous layer extra is irout 3 times with ethyl acetate and 4 times with dichloromethane. The combined extracts dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (15% ethyl acetate/hexane), getting 3-iodmethylenetrialkyl in the form of a yellow oil (1,59 g, 76%).

A mixture of 3-admitistration (500 mg, 2.36 mmol, 1.0 EQ.) and CH3NH2(40%solution in water, of 1.62 ml, 8.0 EQ.) in methanol (1 ml) is heated at 60°C for 3 hours. After cooling to room temperature the reaction mixture is diluted with excess amounts (2H5)3N and concentrate. This process is repeated until, while using1H NMR will not detect CH3NH2. The residual yellow oil (compound52directly used without further purification.

To a solution of 1-methoxymethamphetamine (2.50 g, a 24.3 mmol, 1.0 EQ.) in dioxane (15 ml) is added an aqueous solution of K2CO3(15 g in 15 ml water) and the mixture is cooled to 0°C. After that enter CBZ-CL (4,16 ml, 1.2 EQ.) and the resulting mixture is heated to room temperature and stirred for 3 hours, extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (hexanol to a mixture of 40% ethyl acetate/hexane)to give benzyl ether (1-metoxi ylpropyl)carbamino acid (4.4 g, 76%) as a solid white color.

To a solution of benzyl ether (1-methoxymethyl)carbamino acid (4.4 g, 18.5 mmol, 1.0 EQ.) and under the conditions (6.9 ml, 111 mmol, 6 equiv.) in a mixture of tetrahydrofuran and dimethylformamide (4:1, 50 ml) at a temperature of 0°C. slowly added NaH (1.35 g, of 55.5 mmol, 3 EQ.). The resulting mixture is heated to room temperature and stirred over night. The reaction is carefully quenched by slowly adding water until, until you have to observe the allocation of bubbles (N2). The reaction mixture was poured into a mixture of water and ice and extracted 3 times with ethyl acetate. The combined organic phase is purified by chromatography on silica gel (30% to 50% ethyl acetate/hexane)to give benzyl ether (1-methoxymethyl)methylcarbamate acid (4.4 g, 94%).

To a solution of benzyl ether (1-methoxymethyl)methylcarbamate acid (4.4 g, 17.5 mmol, 1.0 EQ.) in methanol (30 ml) is added palladium hydroxide and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 1.5 hours. The mixture was then filtered through celite and washed with methanol. The filtrate is treated with concentrated HCl (1.6 ml, 1 EQ.) and concentrate, receiving the connection53(2.67 g, 100%).1H-NMR confirms the structure of this compound. The crude compound is used at the next study is without further purification.

Connection54get out of the benzyl ether (1-benzyl-2-hydroxyethyl)carbamino acid using the same methods stage 2 and stage 3 for connection53.

Benzyl ether (1-cyclohexylmethyl-2-hydroxyethyl)methylcarbamate acid is obtained from benzyl ether (1-cyclohexylmethyl-2-hydroxyethyl)carbamino acid, following the same methodology stage 2 for connection53. Benzyl ether (1-cyclohexylmethyl-2-hydroxyethyl)methylcarbamate acid is then treated with a mixture of TFWC and dichloromethane (1:1) at room temperature for 4 hours. The mixture was then concentrated, receiving the connection55.

To a solution of (R)-(-)-leucinol (2.0 g, 17 mmol, 1.0 EQ.), (C2H5)3N (3.6 ml, 1.5 EQ.) and DMAP (10 mg) in tetrahydrofuran (2 ml) at room temperature add di-tert-BUTYLCARBAMATE (Re2O) (4.5 g, 1.2 EQ.). After stirring for 5 hours the reaction is quenched with water and the separated aqueous phase is extracted 4 times with diethyl ether. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (20% to 30% ethyl acetate/hexane)to give tert-butyl methyl ether (1-hydroxymethyl-3-methylbutyl carb is mirovoi acid (1.9 g, 53%).1H-NMR confirms the structure of this connection.

Connection56obtained from tert-butyl methyl ether (1-hydroxymethyl-3-methylbutyl)carbamino acid using the same methods as for connection55.

To a solution of 4-hydroxycyclohexanecarboxylate acid (mixture of CIS-/TRANS-isomers) (5,00 g, 1 EQ.) in tetrahydrofuran (350 ml) at -78°With add motility (1M solution in tetrahydrofuran). After stirring at -78°C for 45 minutes the cooling bath is removed and the resulting mixture is heated to room temperature and stirred over night. After a full 24 hours the reaction mixture is poured into a mixture of ice water (800 ml). The mixture is intensively stirred. The separated aqueous phase is extracted with a mixture of methanol and ethyl acetate (in a ratio of about 1:20). The combined organic layer is dried over sodium sulfate, filtered and concentrated. The crude product is purified by chromatography (50% to 100% ethyl acetate/hexane)to give 1-(4-hydroxycyclohexyl)alanon (2,08 g, 42%).

A mixture of 1-(4-hydroxycyclohexyl)ethanone (2.24 g, 1 EQ.), toluene (160 ml), neopentyl glycol (1,96 g, 1.2 EQ.) and p-toluenesulfonic acid (TsOH) (150 mg, of 0.05 EQ.) in a flask equipped with a nozzle Dean-stark refluxed over night. Sociofluid to room temperature and concentrate. The crude product is purified column chromatography on silica gel (25% to 50% ethyl acetate/hexane)to give 4-(2,5,5-trimethyl[1,3]dioxane-2-yl)cyclohexanol (2,23 g, 62%).

To a solution of 4-(2,5,5-trimethyl[1,3]dioxane-2-yl)cyclohexanol (2,22 g, 1 EQ.) and N-methylmorpholin-N-oxide (2.28 g, 2 EQ.) in CH3CN (65 ml) add TRAR (161 mg, of 0.05 EQ.). The reaction mixture was stirred at room temperature overnight. To the mixture is added saturated aqueous solution of Na2S2O3and the resulting mixture is intensively stirred for 15 minutes. The separated aqueous phase is extracted with dichloromethane. The combined organic layer is dried over sodium sulfate, filtered through celite and concentrated. The crude product is purified column chromatography on silica gel (25% to 50% ethyl acetate/hexane)to give 4-(2,5,5-trimethyl[1,3]dioxane-2-yl)cyclohexanone (1,87 g, 85%).

Connection57obtained from 4-(2,5,5-trimethyl[1,3]dioxane-2-yl)cyclohexanone, following the method for obtaining compounds of34of the 1.2-diphenylethanone.

To a suspension of (3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)methylaminopropane (6,9 g, 27.6 mmol, 1.0 EQ.), (C2H5)3N (15 ml, 4.0 EQ.) and 4-dimethylaminopyridine (DMAP) (catalytic amount) in 100 ml of a mixture of tetrahydrofuran and MDF (in the ratio 1:1) is added di-tert-BUTYLCARBAMATE (7,6 ml, 1,2 E. the century) and the resulting mixture is heated at 90°C for 6 hours. After cooling to room temperature the reaction mixture was diluted with a saturated solution of NaHCO3and the separated aqueous layer is extracted 2 times with ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated. The crude product is purified by chromatography (10% to 20% ethyl acetate/hexane)to give tert-butyl ether (3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)methylcarbamate acid in a solid white color (at 9.53 g, 99%).

A solution of tert-butyl methyl ether (3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)methylcarbamate acid (at 9.53 g of 27.2 mmol, 1.0 EQ.) and pyridine-4-toluensulfonate (2.1 g, 0.3 EQ.) 500 ml of a mixture of acetone and water (2:1) is heated at a temperature of 80°C for 18 hours, cooled to room temperature and concentrated to remove acetone. The residual aqueous solution was diluted with a solution of NaHCO3and extracted 2 times with ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated. The crude product is purified by chromatography (20% to 50% ethyl acetate/hexane)to give tert-butyl ether methyl-(4-oxocyclohexyl)carbamino acid in a solid white color (5,38 g, 87%).

To a solution of tert-butyl ether methyl-(4-oxocyclohexyl)carbamino acid (134 mg, 0.59 mmol, 1.0 EQ.) in dichloromethane (0.5 ml) at room t is mperature add (CH 3Och2CH2)2NSF3(217 μl, 2.0 EQ.), then ethanol (10 μl, 0.3 EQ.). After stirring for 1 hour the reaction is carefully quenched with saturated solution of NaHCO3and stirred until the gas evolution stops. The separated aqueous phase is extracted with dichloromethane. The combined organic extracts dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by chromatography (5% to 10% ethyl acetate/hexane), receiving a mixture of tert-butyl methyl ether (4,4-diverticulosis)methylcarbamate acid tert-butyl ester (4-diverticulosis-3-enyl)methylcarbamate acid. To a solution of a mixture of products in dichloromethane (1.5 ml) at room temperature add triperoxonane acid (1.5 ml) and the resulting mixture is stirred for 2.5 hours and concentrated, obtaining a mixture of compounds58and59(in the ratio of 2:1 according to the1H-NMR).

To a solution of 3-chloro-2-chloromethyl-1-propene (20,0 g, 160 mmol, 1.0 EQ.) in tetrahydrofuran at a temperature of 0°C. add sodium methylate (100 ml 25%solution in methanol, 2.8 EQ.). After removal of the cooling bath the reaction mixture is stirred at room temperature for 20 hours and at a temperature of 35°C for 20 hours. The reaction is quenched with saturated solution of NH4Cl (10 ml), the mixture is diluted with etilovym ether (200 ml) and filtered, washing with diethyl ether. The filtrate is concentrated by distillation, diethyl ether, tetrahydrofuran and ethanol at atmospheric pressure, getting slightly yellow liquid residue. By fractional distillation of the residue obtained 3-methoxy-2-methoxymethyl-1-propene (8,9 g, 43%); BP. = 120-130°C.

To a solution of 3-methoxy-2-methoxymethyl-1-propene (3.5 g, 30 mmol, 1.0 EQ.) in tetrahydrofuran (10 ml) at a temperature of 0°C type NR3.THF (1M solution in tetrahydrofuran (THF, 18 ml, 0.6 EQ.) and the resulting mixture is stirred for 40 minutes. The reaction is quenched with water, then add perborate sodium (10.6 g, 2.3 EQ.), warmed to room temperature, stirred overnight, diluted with dichloromethane and filtered through celite. The filtrate is diluted with brine and the separated aqueous layer is extracted with dichloromethane. The combined extracts dried over sodium sulfate and filtered. The filtrate is distilled under atmospheric pressure, getting slightly yellow liquid residue. By fractional distillation of the residue under a pressure of 40 mtorr get 3-methoxy-2-methoxymetopon-1-ol (1,93 g, 48%); BP. = 90-110°C.

To a solution of 3-methoxy-2-methoxymetopon-1-ol (0,90 g, 6.7 mmol, 1.0 EQ.) in dichloromethane (10 ml) at 0°With add (C2H5)3N (1.9 ml, 2.0 equiv.) then methanesulfonanilide (MsCl) (0.63 ml, 1.2 EQ.). After moving the air traffic management within 40 minutes the reaction is quenched with methylamine (40%solution in water). After concentration of the reaction mixture at room temperature, the residue is diluted with methanol (2 ml) and methylamine (3 ml, 40%solution in water), heated at 50°C for 18 hours, cooled to room temperature, saturated with Na2CO3and extracted with diethyl ether. The combined extracts dried over sodium sulfate and filtered. The filtrate is distilled at atmospheric pressure to give crude product60(0,78 g, 80%) as a slightly yellow liquid.

To a solution of TRANS-4-aminocyclohexanecarboxylic (5.0 g, from 32.9 mmol, 1.0 EQ.) in a mixture of water (80 ml) and tetrahydrofuran (60 ml) at room temperature add NaHCO3(6.4 g, 2.3 EQ.) and di-tert-BUTYLCARBAMATE (of 14.8 ml, 2.0 EQ.). After stirring for 48 hours the greater part of the tetrahydrofuran from the reaction mixture is removed by concentration and the aqueous residue extracted with ethyl acetate. The combined organic extracts dried over sodium sulfate, filtered and concentrated. The crude product is crystallized from a mixture of ethyl acetate and hexanol (in the ratio 9:1)to give tert-butyl ester (4-TRANS-hydroxycyclohexyl)carbamino acid (5.2 g, 75%).

To a solution of tert-butyl methyl ether (4-TRANS-hydroxycyclohexyl)carbamino acid (3.0 g, a 13.9 mmol, 1.0 EQ.) and under the conditions (4.3 ml, 5.0 EQ.)in N-methyl-2-pyrrolidinone (NMP) (50 ml) at 0°With added 60%NaH in mineral oil (1,67 g, 3.0 EQ.) in a known manner controlled portions and the resulting mixture is stirred for 3 hours at room temperature. The reaction mixture was quenched with methanol (3.0 ml), stirred for 30 minutes, diluted with a saturated solution of NH4Cl and the mixture is extracted three times with ethyl acetate. The combined organic extracts dried over sodium sulfate, filtered and concentrated. The crude mixture is purified by chromatography on silica gel (20% ethyl acetate/hexane)to give tert-butyl ester (4-TRANS-methoxycyclohexyl)methylcarbamate acid (3.25 g, 96%).

To a solution of tert-butyl methyl ether (4-TRANS-methoxycyclohexyl)methylcarbamate acid (445 mg, to 1.83 mmol, 1.0 EQ.) in dichloromethane (2 ml) at room temperature add triperoxonane acid (TFUC) (2 ml). After stirring for 2 hours the reaction mixture was concentrated, receiving the connection61(685 mg, 145%, contains residual TFUC).1H-NMR confirms the structure and the product used without further purification.

Alternatively, the connection61can be obtained according to the following scheme:

Thus, the oxidation of 4-methoxycyclohexanone in suitable conditions (for example, TRAR NMO) in a suitable solvent (e.g. dichloromethane) leads to the corresponding ketone. Reset movieline amination of 4-methoxycyclohexanone in suitable conditions (for example, dimethylamine, NaBH(OAc)3acetic acid in tetrahydrofuran) allows to obtain the corresponding amine61with good stereoselectivity (i.e., the TRANS-configuration).

To a suspension of tert-butyl ether methyl-(4-oxocyclohexyl)carbamino acid (intermediate compound for producing compounds58and59, 580 mg, 2.56 mmol, 1.0 EQ.) in tetrahydrofuran (8 ml) at -78°With add triazolylmethyl lithium (1M solution in tetrahydrofuran (THF, 5.7 ml, 2.2 EQ.). After stirring for 2.5 hours the reaction mixture is heated to a temperature of 0°C and stirred for 30 minutes. The reaction is quenched with a saturated solution of NH4Cl and the separated aqueous layer is extracted with a mixture of ethyl acetate and hexanol (1:1). The combined organic extracts dried over sodium sulfate, filtered and concentrated. The crude mixture is purified by chromatography on silica gel (from 33% to 50% ethyl acetate/hexane)to give tert-butyl ester (4-CIS-hydroxycyclohexyl)methylcarbamate acid (391 mg, 67%).

Connection62obtained from tert-butyl ether (4-CIS-hydroxycyclohexyl)methylcarbamate acid following the same procedure as for connection61from tert-butyl ether (4-TRANS-hydroxycyclohexyl)methylcarbamate acid.

To a solution of tert-butyl methyl ether (4-CIS-hydroxycyclohexyl)methylcarbamate acid (1,95 g, charged 8.52 mmol, 1.0 EQ.) in dimethylformamide (20 ml) at 0°With added NaH (559 mg, 2.5 EQ.). After stirring for 10 minutes introduce methyliodide (3.9 ml, 7.6 equiv.) and the cooling bath removed. After stirring for 5 hours at room temperature the reaction is quenched with methanol (1.5 ml), the reaction mixture is stirred for 15 minutes and diluted with a saturated solution of NH4Cl. The mixture is extracted with a mixture of ethyl acetate and hexanol (1:1). The combined organic extracts dried over sodium sulfate, filtered and concentrated. The crude mixture is purified by chromatography on silica gel (10% to 25% ethyl acetate/hexane)to give tert-butyl ester (4-CIS-methoxycyclohexyl)methylcarbamate acid (1.73 g, 84%).

To a solution of tert-butyl methyl ether (4-CIS-methoxycyclohexyl)methylcarbamate acid (1.73 g, 7,12 mmol, 1.0 EQ.) in dichloromethane (4 ml) at room temperature add triperoxonane acid (4 ml). After stirring for 3.5 hours, the reaction mixture was concentrated, give crude product. This product is dissolved in dichloromethane (50 ml) and washed with saturated solution of Na2CO3(40 ml). The aqueous layer was again extracted 5 times with dichloromethane. The combined organic extracts dried over Sul is a sodium atom, filtered and concentrated, obtaining the free amine63(1.12 g, 109%, contains residual dichloromethane).

A mixture of compound18(0,01-0,1M, 1.0 EQ.), diisopropylethylamine (5.0 equiv.) and any one amine compound21-63or other commercially available primary or secondary alkylamine (3-10 equiv.) in dichloromethane was stirred at room temperature or at 40°C for from several hours to five days until completion. The reaction mixture was concentrated and the intermediate product, or when carrying out purification by chromatography (ethyl acetate/hexane), or without it, dissolved in a mixture in the ratio of 1:1 dichloromethane and triperoxonane acid (0,05M) and stirred at room temperature with anisole (5-10 EQ.) or without it for 3-4 hours until completion of the reaction. The reaction is then carefully quenched with a saturated solution of NaHCO3, extracted with ethyl acetate until such time as you will not find the product. The combined extracts dried over sodium sulfate, filtered, concentrated and the product64purify by high-performance liquid chromatography (HPLC) with reversed phase (methanol/water).

The following methodology is used to produce aromatic amines (RFand/or RG= aryl). To a solution of N-atilan is Lina (47 μl, 6 EQ.) in tetrahydrofuran (1 ml) at a temperature of -78°C. add n-utility (148 μl, 2.5m solution in hexano, 6 equiv.) then hexamethylphosphoramide (HMPA) (200 μl) and stirred for 10 minutes. Enter solution connection18(44 mg, holding 0.062 mmol) in tetrahydrofuran (0.7 ml) when washing with tetrahydrofuran (0.3 ml). After stirring for 10 minutes the reaction mixture was quenched with a saturated solution of NaHCO3(15 ml), extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (ethyl acetate)to give the intermediate compound. The intermediate connection and anisole (100 μl) dissolved in 2 ml of a mixture of dichloromethane and triperoxonane acid in the ratio of 1:1 and stirred at room temperature for 3 hours. The reaction is then carefully quenched with a saturated solution of NaHCO3, extracted 4 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product64clean HPLC with reversed phase (methanol/water).

To a solution of compound20(0,03-0,05M, 1.0 EQ.) and TOTU (1.5 EQ.) in dimethylformamide at room temperature add diisopropylethylamine (1.6 EQ.) and stirred for 15 minutes. To the resulting mixture add one amine and the connection 21-63or other commercially available primary or secondary amine (1.5 EQ.). The reaction mixture is stirred for from several hours to overnight until the completion of the reaction. The reaction mixture was concentrated and the intermediate product, or when carrying out purification by chromatography (ethyl acetate/hexane), or without it, dissolved in a mixture of 1:1 dichloromethane and triperoxonane acid (0,01-0,05M) and stirred at room temperature with anisole (5-10 EQ.) or without it for 3-4 hours until completion of the reaction. The reaction is then carefully quenched with a saturated solution of NaHCO3, extracted with ethyl acetate until such time as you will not find the product. The combined extracts dried over sodium sulfate, filtered, concentrated and the product65clean HPLC with reversed phase (methanol/water).

Listed in the following table, the compounds are produced either by following the method of obtaining compounds of13or compounds64or65.

To a solution of compound17(20 mg, 0.03 mmol, 1.0 EQ.), triphenylphosphine (15 mg, 2.0 EQ.) and phthalimide (8.5 mg, 2.0 EQ.) in toluene (2 ml) at room temperature add diethylazodicarboxylate (9,1 μl, 2.0 EQ.) and the resulting mixture is stirred for 19 hours. The reaction mixture was concentrated and the intermediate connection purified by chromatography (30% ethyl acetate/hexane), getting to 19.3 mg (81%) of product. This intermediate compound is dissolved in 2 ml 1:1-mixture of dichloromethane and triperoxonane acid and stirred at room temperature for 2 hours until completion of the reaction. The reaction is then carefully quenched with a saturated solution of NaHCO3(15 ml), extracted 7 times with 10 ml of ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified HPLC with reversed phase (methanol/water)to give compoundER-806286(2.4 mg, 24%). MS (ES): 423,2 (M+N)+.

ConnectionER-806287obtained from 4-triptoreline, following the same methodology as for connectionER-806286. MC (ES): 438,2 (M+N)+.

A mixture of compound 18(12.5 mg, 0.018 mmol), diisopropylethylamine (0.2 ml, 65 EQ.) and thiophenol (10 μl, 5.5 EQ.) in dimethylformamide (0.5 ml) at room temperature and stirred for two days. The reaction mixture was concentrated and purified by chromatography (30% ethyl acetate/hexane), obtaining an intermediate compound in the amount of 12.7 mg (92%). This intermediate connection and anisole (100 μl) dissolved in 2 ml of a mixture in the ratio of 1:1 dichloromethane and triperoxonane acid and stirred at room temperature for 40 minutes. The reaction is then carefully quenched with a saturated solution of NaHCO3(15 ml), extracted 7 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (5% methanol/ethyl acetate)to give compoundER-806311(4.5 mg, 65%). MC (ES): 386,2 (M+N)+.

To a solution of compound17(40.5 mg, 0,058 mmol) and diisopropylethylamine (100 μl, 10 EQ.) in dichloromethane (1 ml) at 0°With add methylsulfonylamino (9 μl, 2 EQ.) and stirred for 30 minutes. Add 4-hydroxypiperidine (30 mg, 5.0 EQ.) and dimethylformamid the d (0.5 ml) and the reaction mixture is heated to room temperature and stirred for 2.5 days. The reaction is quenched with a saturated solution of NaHCO3(10 ml) and the separated aqueous phase is extracted 4 times with ethyl acetate. The combined organic extracts dried over sodium sulfate, filtered and concentrated and the product purified HPLC with reversed phase (methanol/water)to give the intermediate compound (25 mg, 65%). This intermediate compound was dissolved in dichloromethane (0.5 ml) and treated with TRAR (5 mg) and NMO (20 mg) at room temperature for 10 minutes. The reaction is quenched with water and Na2S2O3and extracted 4 times with ethyl acetate. The combined organic extracts dried over sodium sulfate, filtered and concentrated and the product purified by chromatography (15% ethyl acetate/hexane), receiving the intermediate compound (13,7 mg). This intermediate connection and anisole (100 μl) dissolved in dichloromethane (1 ml) and treated triperoxonane acid (1 ml) at room temperature for 4 hours. The reaction is then carefully quenched with a saturated solution of NaHCO3(15 ml), extracted 4 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified HPLC with reversed phase (methanol/water)to give compoundER-806355(3.4 mg, 16% over three stages).1H-NMR (DMSO-d6) δ (ppm): 2,35 (t, J=6 Hz, 4H), 2.49 USD (s, 3H), 2,70 (t, J=6 Hz, 4H), to 3.67 (s, 2H) 5,74 (s, 2H), 6.73 x (s, 1H), 7,16 (DD, J=8,2 Hz and 1.2 Hz, 1H), 7,28 (d, J=1.2 Hz, 1H), 7,53 (d, J=8,2 Hz, 1H), 7,55 (s, 1H).

To a solution of thiomorpholine (1.0 g, 9.7 mmol) in acetic acid (12 ml) at room temperature add hydrogen peroxide (4 ml, 30%solution in water, 3.6 EQ.). The resulting mixture is stirred at a temperature of 100°C. over night, cooled to room temperature and concentrate. Thiomorpholine of the residue crystallized from ethanol in the form of a dark solid. Following the General method for obtaining compounds of64connectionER-806401produced from compound18and teamoriented. MC (ES): 417,2 (M+Na)+.

A mixture of compound18(5 mg) and benzyl alcohol (100 ml) is treated with tert-butyl potassium (1 ml, 1,66 M in tetrahydrofuran) at room temperature over night. The reaction mixture was quenched with a saturated solution of NaHCO3and extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the crude intermediate product and anisole (50 μl) dissolved in dichloromethane (0.5 ml) and treated triperoxonane acid (0.5 ml) at room temperature for 3 hours. The reaction is then carefully quenched with a saturated solution of NaHCO3then the reaction see what camping is extracted 4 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified by thin-layer chromatography (10% methanol/ethyl acetate)to give compoundER-806404(1.0 mg, 37%). MC (ES): 384,2 (M+N)+.

To a solution of 5-yogendra (5.0 g, to 20.6 mmol), phenylacetylene (3.4 ml, 1.5 EQ.) and diethylamine (10 ml) in dimethylformamide (2 ml) is added Pd[(C6H5)3P]4(120 mg, 0.005 EQ.) and CuI (39 mg, 0.01 EQ.) in nitrogen atmosphere at a temperature of cooling water bath and the resulting mixture is stirred for 3 hours at room temperature. The reaction mixture was diluted with a saturated solution of NaHCO3(50 ml), extracted 4 times with 30 ml of ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered, concentrated and the product purified by chromatography (15% to 20% ethyl acetate/hexane), receiving 5-phenylethynyl-1N-indole (to 4.41 g, 98%).

tert-Butyl ester 5-phenylalaninol-1-carboxylic acid is obtained from 5-phenylethynyl-1N-indole, according to the method for obtaining compounds of7(as, for example, 5-methyl ester and 1-tert-butyl ether indole-1,5-dicarboxylic acid) of methylindol-5-carboxylate.

tert-Butyl ester 5-phenylethynyl-2-tributylstannyl-1-carboxylic acid is obtained from tert-butyl ether 5-phenylalaninol-1-carboxylic acid according to the but the method for obtaining compounds of 10from the connection9.

ConnectionER-806644get out of the tert-butyl ester 5-phenylethynyl-2-tributylstannyl-1-carboxylic acid and compounds4(R1=CH3according to the method for obtaining compounds of13. MC (ES): 364,2 (M+N)+.

A solution of compoundER-806644(6.5 mg) and Lindlar catalyst (50 mg) in tetrahydrofuran (2 ml) was stirred at room temperature in an atmosphere of hydrogen gas for 1 hour. The resulting mixture was filtered through celite and the filtrate concentrated. The residual solid is washed several times with ethyl acetate, receiving the connectionER-806645in the form of a slightly yellow solid (2.0 mg, 31%). MC (ES): 366,3 (M+N)+.

A solution of compoundER-806644(5 mg) and Pd(OH)2(10 mg) in 2 ml of tetrahydrofuran was stirred at room temperature in an atmosphere of hydrogen gas overnight. The resulting mixture was filtered through celite and the filtrate is concentrated and the product purified HPLC with reversed phase (methanol/water)to give compoundER-806646(1.3 mg, 26%). MC (ES): 368,3 (M+N)+.

A solution of compound16(20 mg) in 3 ml of a mixture in the ratio of 1:1 tetrahydrofuran and methanol at room temperature is treated with 1N hydrochloric acid (0.5 ml) for 30 minutes. Reacciona the mixture is diluted with a saturated solution of NaHCO 3and extracted with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified HPLC with reversed phase (methanol/water)to give compoundER-806095(2.6 mg, 18%).1H-NMR.

A solution of compoundER-806393(1.3 ml) in 0.5 ml of methanol at room temperature is treated with 1N solution of LiOH (0.1 ml) over night. The reaction mixture was then neutralized with 1N hydrochloric acid (0.1 ml) to pH=5 and concentrate. The residue is treated with a mixture in the ratio of 1:1 methanol and ethyl acetate and filtered. The filtrate is concentrated and the residue purified HPLC with reversed phase (methanol/water)to give compoundER-806420(0.5 mg, 40%). MC (ES): 496,3 (M-N)-.

A mixture of compound18(15,5 mg, 0.02 mmol) and methylamine (of 0.11 ml, 2.0m solution in tetrahydrofuran, 1.0 EQ.) in dichloromethane (0.5 ml) was stirred at room temperature overnight, diluted with a saturated solution of NaHCO3and extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated. The residue is dissolved in dimethylformamide (0.5 ml) as solution A.

To a solution of benzoic acid (3.4 mg, 1.3 EQ.) and TOTU (10 mg, 1.4 EQ.) in dimethylformamide (0.3 ml) at room temperature add diisopropylate the min (5,3 μl, 1.4 equiv.) and stirred for 15 minutes. Then enter solution And when washing 3 times with 0.5 ml of dimethylformamide and the resulting mixture is stirred overnight, concentrated, diluted with a saturated solution of NaHCO3and extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated. Balance and anisole (50 μl) dissolved in dichloromethane (0.5 ml) and treated triperoxonane acid (0.5 ml) at room temperature for 3 hours. The reaction mixture was carefully quenched with saturated solution of NaHCO3and ethyl acetate and the separated aqueous phase is extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified HPLC with reversed phase (methanol/water)to give compoundER-806432(1.4 mg, 16% over three stages). MC (ES): 411,2 (M+N)+.

tert-Butyl ester 5-nitroindole-1-carboxylic acid is obtained from 5-nitroindole, following the same procedure as such for connection7from methylindol-5-carboxylate.

A solution of tert-butyl ester 5-nitroindole-1-carboxylic acid (0.50 g) and catalytic amount of Pd(OH)2in a mixture of methanol and ethyl acetate was stirred at room temperature in hydrogen atmosphere for 1 hour. The reaction to shift the ü filtered through celite and the filtrate is concentrated, getting tert-butyl ester 5-amino-2,3-dihydroindol-1-carboxylic acid (0,44 g, 98%).

To a solution of tert-butyl ester 5-amino-2,3-dihydroindol-1-carboxylic acid (407 mg, of 1.74 mmol) and triethylamine (1.2 ml, 5.0 EQ.) in dichloromethane (5 ml) at 0°With add benzoyl chloride (305 μl, 1.5 EQ.) and the resulting mixture is stirred for 15 minutes. The reaction is then quenched with saturated solution of NaHCO3and the mixture is extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (20% to 100% ethyl acetate/hexane)to give tert-butyl ester 5-benzoylamino-2,3-dihydroindol-1-carboxylic acid (588 mg, 100%).

To a mixture of tert-butyl ester 5-benzoylamino-2,3-dihydroindol-1-carboxylic acid (570 mg, 1,68 mmol) and under the conditions (of 0.42 ml, 4.0 EQ.) in dimethylformamide (10 ml) at a temperature of 0°C. add sodium hydride (60 mg, 1.5 EQ.) and the resulting mixture is stirred for 20 minutes. After concentration the residue from the reaction mixture is diluted with saturated solution of NaHCO3and extracted 3 times with ethyl acetate. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified by chromatography (30% ethyl acetate/hexane)to give tert-butyl ester 5-(benzoylmethylene)-2,3-dihydroindol-1-carboxylic acid (547 mg, 93%).

The mixture is tert-butyl ester 5-(benzoylmethylene)-2,3-dihydroindol-1-carboxylic acid (500 mg) and MnO 2(5 g) in toluene (20 ml) is heated at a temperature of 80°C for 1 hour. Enter the additional amount MnO2(5 g) and the resulting mixture is stirred at a temperature of 80°C for 1 hour. After cooling to room temperature the mixture is filtered through celite and the filtrate concentrated. The product was then purified by chromatography (30% ethyl acetate/hexane)to give tert-butyl ester 5-(benzoylmethylene)indole-1-carboxylic acid (372 mg, 75%).

tert-Butyl ester 5-(benzoylmethylene)-2-tributylstannyl-1-carboxylic acid is obtained from tert-butyl ester 5-(benzoylmethylene)indole-1-carboxylic acid according to the method for obtaining compounds of10from the connection9.

ConnectionER-807313get out of the tert-butyl ester 5-(benzoylmethylene)-2-tributylstannyl-1-carboxylic acid and compounds4(R1= methyl), following the method for obtaining compounds of13. MS (ES): 397,2 (M+H)+and 419,1 (M+Na)+.

ConnectionER-807015get as a by-product during get connection65from the spatial difficult amines, and it gives satisfactory1H-NMR-spectrum.

A mixture of compound18(51 mg, 1.0 EQ.), (3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)methylaminopropane (71 mg, 4.0 EQ.), utilisable the amine (0.25 ml, 20 EQ.) and dimethylformamide (0.3 ml) in dichloromethane (2.5 ml) was stirred at room temperature for 23 hours. After concentration the residue is dissolved in 0.6 ml of 1N hydrochloric acid and 0.6 ml of acetone and refluxed for 16 hours. After cooling to room temperature, the reaction then carefully quenched with a saturated solution of NaHCO3, extracted with ethyl acetate until such time as you will not find the product. The combined extracts dried over sodium sulfate, filtered, concentrated and the product purified HPLC with reversed phase (methanol/water)to give compoundER-807586(6.4 mg, 22%).1H-NMR and MS (ES): 403,5 (M+N)+.

ConnectionER-807759receive by following the same procedure as for connection13(as, for example,ER-805639) by the reaction of a combination of Still and connectionER-807586by hydrolysis of ketala.1H-NMR and MS (ES): 389 (M+N)+.

To a suspension compoundER-807586(5 mg, 0,0124 mmol, 1.0 EQ.) in 0.5 ml of water is added NH2OCH3.HCl (5.2 mg, 0,623 mmol, 50 EQ.). The solid is dissolved, slowly add a saturated solution of NaHCO3(0.3 ml) and the resulting mixture is stirred over night. The reaction mixture was diluted with ethyl acetate and a saturated solution of NaHCO and extracted 4 times with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated. The crude mixture is purified by chromatography on silica gel (10% methanol/ethyl acetate)to give compoundER-807789in a solid white color (5.3 mg, 100%).1H NMR and MS (ES): 432 (M+N)+.

To a solution of compoundER-807586(15 mg) in 1 ml of a mixture in the ratio of 1:1 methanol and tetrahydrofuran are added 20 mg of NaBH4and the mixture is stirred for 30 minutes, diluted with a saturated solution of NaHCO3and extracted 4 times with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified HPLC with reversed phase (methanol/water)to give compoundER-807790.1H-NMR and MS (ES): to 405.5 (M+N)+.

To a solution of n-utility (1,6M in hexano, 0.35 ml of 0.56 mmol, 31,3 EQ.) in tetrahydrofuran (2.0 ml) at 0°With add methyltriphenylphosphonium (0.20 g, 0,56 mmol, 31 EQ.). The reaction mixture is heated to room temperature and stirred for 40 minutes. Part of the solution (0.6 ml) was transferred into another flask and add connectionER-807586(7.2 mg, 0,0179 mmol, 1.0 EQ.). The resulting mixture was stirred at room temperature for 18 hours, water is added and the mixture was EXT Airout 3 times with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified HPLC with reversed phase (methanol/water)to give compoundER-807835(0.8 mg, 12%).1H-NMR and MS (ES): is 401.5 (M+1N).

To a solution of compoundER-807586in (11.5 mg, 0,0286 mmol, 1.0 EQ.) in tetrahydrofuran (2.0 ml) at 0°With add CH3MgCl (3.0 m in tetrahydrofuran, 0.25 ml, 0.75 mmol, 26,3 EQ.). The reaction mixture is heated and stirred at room temperature for 18 hours. The reaction is quenched with a saturated solution of NaHCO3and then extracted 3 times with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated. The resulting mixture was purified by chromatography on silica gel (100% ethyl acetate, then 10% to 30% methanol/ethyl acetate)to give compoundER-807837(0.8 mg, 7%).1H-NMR and MS (ES): 419,4 (M+1N).

tert-Butyl ester 5-charmerende-1-carboxylic acid is produced from compound8following the method for obtaining compounds of9but without the additive of the research.

A mixture of tert-butyl ester 5-charmerende-1-carboxylic acid (0,82 g, 3.10 mmol, 1.0 EQ.), cyclohexylaniline (of 0.53 ml, 1.4 EQ.) and K2CO3(from 0.90 g, 2.0 EQ.) in dimethylformamide (6 ml) is heated under the temperature is 40°C. until completion of the reaction. The reaction mixture is cooled to room temperature, diluted with a saturated solution of NH4Cl and extracted with diethyl ether. The organic extracts are dried over magnesium sulfate, filtered and concentrated. The resulting mixture was purified by chromatography (5% ethyl acetate/hexane)to give tert-butyl ester 5-cyclohexanedimethanol-1-carboxylic acid (0,79 g, 74%).

ConnectionER-808036get out of the tert-butyl ester 5-cyclohexanedimethanol-1-carboxylic acid according to the methods for obtaining compounds of16from the connection14.

To a solution of compoundER-808036(60 mg, 0.15 mmol, 1.0 EQ.) in a mixture of tetrahydrofuran (2.5 ml) and methanol (1.5 ml) at-78º add a solution of m-chloroperoxybenzoic acid (60 mg, about 70%, 1.6 EQ.) in tetrahydrofuran. After stirring for 2 hours the reaction is quenched with saturated solution of Na2S2O3and a saturated solution of NaHCO3. The separated aqueous layer was extracted 5 times with ethyl acetate and the combined organic phase is dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by chromatography (5% to 10% methanol/ethyl acetate)to give semifinished products (18 mg and 32 mg each). After further purification HPLC with reversed phase (methanol/water) receive connectionER-808082(3.2 m is) and ER-808083(3.2 mg).1H-NMR confirms the structure of both products.

A mixture of tert-butyl ester 5-charmerende-1-carboxylic acid (0,41 g, 1.55 mmol, 1.0 EQ.), cyclohexanol (of 0.82 ml, 5.0 EQ.) and Ag2O (1.80 g, 5.0 EQ.) in diethyl ether (5 ml) is stirred at 35°C for the weekend. After cooling to room temperature the reaction mixture was filtered through celite, rinsing with diethyl ether. The filtrate is concentrated and the residue purified by chromatography (3% ethyl acetate/hexane)to give N-BOC-5-cyclohexanedimethanol (160 mg, 28%) as a colourless oil.1H-NMR confirms the structure.

ConnectionER-808103get out of the tert-butyl ester 5-cyclohexanedimethanol-1-carboxylic acid according to the methods for obtaining compounds of16from the connection14. Both spectrum MS (ES) and1H-NMR confirmed the structure.

To a suspension compound3(R = methyl, 300 mg of 1.03 mmol, 1.0 EQ.) in tetrahydrofuran (5 ml) at room temperature is added dropwise LiAlH4(1.0m solution in tetrahydrofuran, of 2.56 ml, 2.5 EQ.) and the resulting mixture is then heated at 65°C for 30 minutes. After cooling to a temperature of 0°C. the reaction is quenched with methanol (1.2 ml, 30 EQ.) and water (30 equiv.) stirred, heated to whom atoi temperature and filtered through celite, rinsing with ethyl acetate. The filtrate is concentrated and the residue purified by chromatography on silica gel (ethyl acetate, then 10% methanol/ethyl acetate)to give 7-chloro-2-methyl-5-methylamino-3N-imidazo[4,5-b]pyridine in the form of a solid white color (190 mg, 94%).

ConnectionER-808040obtained from 7-chloro-2-methyl-5-methylamino-3N-imidazo[4,5-b]pyridine and tert-butyl ester 5-[(cyclohexylethylamine)methyl]-2-tributylstannyl-1-carboxylic acid (produced from compound8and cyclohexylethylamine according to the methods for obtaining compounds of10), following the method of obtaining compounds of13.1H-NMR confirms the structure.

To a solution of compoundER-807790(17 mg, 0,042 mmol, 1.0 EQ.) in dichloromethane (1 ml) at 0°With add (CH3Och2CH2)2NSF3(14 μl, 1.8 equiv.) and the resulting mixture is stirred for 1 hour at 0°C and for 1 hour at room temperature. The reaction is quenched with a saturated solution of NaHCO3and the separated aqueous layer is extracted with dichloromethane, then with a mixture of ethyl acetate and tetrahydrofuran in the ratio of 1:1. The combined organic extracts dried over sodium sulfate, filtered and concentrated. The residue is purified HPLC with reversed phase (methanol/water)to give compoundER-80128 (2 mg, 13%).1H-NMR and MS confirmed the structure.

tert-Butyl ester 5-formylindole-1-carboxylic acid or tert-butyl methyl ether 6-formylindole-1-carboxylic acid

To a solution of compound8(8.0 g, 32,4 mmol, 1 EQ.) in dichloromethane (24 ml) was added in several portions reagent Dess-Martin (17.9 g, 1.3 EQ.) at a temperature of 0°C and the resulting mixture was slowly warmed to room temperature and stirred for 30 minutes. The reaction mixture was diluted with diethyl ether (100 ml), filtered through celite, washing with diethyl ether (50 ml). The filtrate was washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product is subjected to azeotropic distillation with toluene, getting tert-butyl ester 5-formylindole-1-carboxylic acid (7,3 g, 95%) or, similarly, tert-butyl ester 6-formylindole-1-carboxylic acid (7,3 g, 95%).

Magnesium (turnings) is activated by washing 1N hydrochloric acid and diethyl ether and dried in high vacuum over night. To an activated magnesium (418 mg, 3 EQ.) in diethyl ether (10 ml) while maintaining the internal temperature at 30-33°C, slowly add bromeilles (0.8 ml, 1 EQ.) in diethyl ether (4 ml). The resulting reaction mixture is heated at a temperature of 34°C in ECENA 1 hour and cooled to a temperature of 0°C. After that enter the solution tert-butyl ester 5-formylindole-1-carboxylic acid (900 mg) in diethyl ether (15 ml) and the resulting mixture was warmed to room temperature for 4 hours, heated at a temperature of 30-32°C, cooled to room temperature and then the reaction quenched with saturated solution of NH4Cl. The separated aqueous phase is extracted with ethyl acetate, the combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by chromatography (10% to 25% ethyl acetate/hexane)to give the corresponding alcohol (949 mg, 85%).

To a mixture of alcohol (513 mg, 1 EQ.) and (C2H5)3N (625 μl, 3 EQ.) in dichloromethane (15 ml) at a temperature of 0°C add the anhydride of methansulfonate (390 mg, 1.5 EQ.). The cooling bath removed and the mixture stirred for 2.5 hours and diluted with a saturated solution of NaHCO3. The separated aqueous layer is extracted with dichloromethane. The combined organic layer is dried over sodium sulfate, filtered and concentrated. The crude product is purified by chromatography (hexanol to 10% ethyl acetate/hexane)to give tert-butyl ester 5-(2-cyclohexylphenol)indole-1-carboxylic acid (380 mg, 78%).

ConnectionER-808281get out of the tert-butyl ester 5-(2-cyclohexylphenol)indole-1-carboxylic acid by following the procedures for obtaining the compounds is of 16from the connection14. MS (ES) and1H-NMR confirmed the structure.

A solution of compoundER-808281(about 10 mg, 1 EQ.) in methanol (5 ml) with 10%palladium-on-coal (catalyst) stand in an atmosphere of hydrogen overnight at room temperature. The mixture was then applied onto a silica gel, elwira with solvent from ethyl acetate to 20% methanol/ethyl acetate, receiving the connectionER-808469(7.5 mg). MS (ES) and1H-NMR confirmed the structure.

tert-Butyl ester 5-winrental-1-carboxylic acid or tert-butyl methyl ether 6-winrental-1-carboxylic acid

To a suspension of methyltriphenylphosphonium (8,1 g, 22.7 mmol) in tetrahydrofuran (140 ml) at 0°C for 10 minutes, added dropwise n-utility (1.6 m solution in hexano, of 14.2 ml, 22.7 mmol). After stirring for 20 minutes is injected slowly over 20 minutes, a solution of tert-butyl ester 5-formylindole-1-carboxylic acid (4,63 g of 14.8 mmol) in tetrahydrofuran (20 ml). The reaction mixture is slowly warmed to room temperature, stirred for 30 minutes. The reaction mixture was poured into a saturated solution of ammonium chloride and the separated aqueous phase is extracted with 3 times 100 ml of ethyl acetate. The combined organic phase is dried over sulfate is m sodium filtered and concentrated. The residue is purified by chromatography (dichloromethane to 1% acetone/dichloromethane)to give tert-butyl ester 5-winrental-1-carboxylic acid (4.7 g, 100%) or, similarly, tert-butyl ester 6-winrental-1-carboxylic acid.

tert-Butyl ester 5-(2-hydroxyethyl)indole-1-carboxylic acid or tert-butyl ester 6-(2-hydroxyethyl)indole-1-carboxylic acid

To a solution of tert-butyl ester 5-winrental-1-carboxylic acid (4.5 g, 18.5 mmol, 1.0 EQ.) in tetrahydrofuran (46 ml) at 0°C for 10 minutes add 9-borabicyclo[3,3,1]nonan (9-BBN) (0.5m solution in tetrahydrofuran, 87 ml, 2.4 EQ.). The resulting reaction mixture is stirred for 2.5 hours and diluted with tetrahydrofuran (150 ml) and water (150 ml), maintaining the temperature at 0°C. Then injected NaBO3.4H2O (44 g) and the resulting reaction mixture is stirred and warmed to room temperature and stirred. The reaction mixture was diluted with dichloromethane (100 ml) and the separated aqueous layer is extracted with 3 times 100 ml of dichloromethane. The combined organic layers dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (dichloromethane to 5% acetone/dichloromethane)to give tert-butyl ester 5-(2-hydroxyethyl)indole-1-carboxylic acid (3.2 g, 76%) or, similarly, tert-butyl ester 6-(2-hydroxyethyl)indole-1-carboxylic acid.

tert-Butyl ester 5-(2-morpholine-4-retil)indole-1-carboxylic acid or tert-butyl ester 5-[2-(cyclohexylethylamine)ethyl]indole-1-carboxylic acid or tert-butyl ester 6-(2-morpholine-4-retil)indole-1-carboxylic acid or tert-butyl ester 6-[2-(cyclohexylethylamine)ethyl]indole-1-carboxylic acid

To a solution of tert-butyl ester 5-(2-hydroxyethyl)indole-1-carboxylic acid (260 mg, 1 mmol, 1.0 EQ.), triphenylphosphine (391 mg, 1.5 EQ.) and imidazole (136 mg, 2 EQ.) in dichloromethane (5 ml) at room temperature for 20 minutes in small portions add iodine (328 mg, 1.3 EQ.). The reaction mixture was poured into water and extracted 4 times with 100 ml dichloromethane. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (20% ethyl acetate/hexane), receiving semifinished iodide (600 mg). This iodide is then dissolved in methanol (10 ml) and treated with morpholine (1.73 ml, 20 EQ.) at a temperature of 60°C during the night. The reaction mixture is cooled to room temperature, poured into water and extracted with dichloromethane. The combined organic layers dried over sodium sulfate, filtered and concentrated. The residue is purified to lodochnoy chromatography on silica gel (dichloromethane to 15% acetone/dichloromethane), getting tert-butyl ester 5-(2-morpholine-4-retil)indole-1-carboxylic acid (290 mg, 88%) or, similarly, tert-butyl ester 5-[2-(cyclohexylethylamine)ethyl]-indole-1-carboxylic acid or tert-butyl ester 6-(2-morpholine-4-retil)indole-1-carboxylic acid or tert-butyl ester 6-[2-(cyclohexylethylamine)ethyl]indole-1-carboxylic acid.

tert-Butyl ester 5-(2-methoxycarbonylbenzyl)indole-1-carboxylic acid or tert-butyl ester 6-(2-methoxycarbonylbenzyl)indole-1-carboxylic acid

To a solution of tert-butyl ester 5-formylindole-1-carboxylic acid (3.4 g, of 13.8 mmol, 1.0 EQ.) in toluene (35 ml) at room temperature add (C6H5)3P=SNCO2CH3(5.5 g, 1.2 EQ.) and the resulting mixture is stirred over night. After concentration the crude product was purified column chromatography on silica gel (dichloromethane to 1% acetone/dichloromethane)to give tert-butyl ester 5-(2-methoxycarbonylbenzyl)indole-1-carboxylic acid (5,03 g, 90%) or, similarly, tert-butyl ester 6-(2-methoxycarbonylbenzyl)indole-1-carboxylic acid.

tert-Butyl ester 5-(3-hydroxypropyl)indole-1-carboxylic acid or tert-butyl ester 6-(3-hydroxypropyl)indole-1-carboxylic acid

To a solution of tert-butyrolacetone methyl-5-(2-methoxycarbonylbenzyl)indole-1-carboxylic acid (with 4.64 g, of 15.3 mmol, 1.0 EQ.) in tetrahydrofuran (87 ml) at a temperature of -30°C using a syringe pump over 20 minutes add LiAlH4(1N solution in tetrahydrofuran, 18.6 ml, 1.2 EQ.) and the resulting mixture is stirred and heated to a temperature of -5°C. After cooling again to a temperature of -30°C. the reaction is then quenched by slow addition of acetone (10 ml), keeping the temperature below -15°C, the mixture was poured into a solution of Rochelle salt at a temperature of 0°C, stirred for 1 hour and the separated aqueous layer is extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified column chromatography (dichloromethane to 2% acetone/dichloromethane)to give tert-butyl ester 5-(3-hydroxypropyl)indole-1-carboxylic acid (2,89 g, 70%) or, similarly, tert-butyl ester 6-(3-hydroxypropyl)indole-1-carboxylic acid.

tert-Butyl ester 5-(3-morpholine-4-ylpropyl)indole-1-carboxylic acid or tert-butyl ester 6-(3-morpholine-4-ylpropyl)indole-1-carboxylic acid

To a solution of tert-butyl ester 5-(3-hydroxypropyl)indole-1-carboxylic acid (0.95 mg, of 3.48 mmol, 1.0 EQ.) and (C2H5)3N (1.8 ml, 3.0 EQ.) in dichloromethane (10 ml) at 0°With add methanesulfonanilide (and 0.40 ml, 1.5 EQ.). Received MES stirred for 30 minutes, warmed to room temperature and stirred for an additional hour. Then enter cyclohexylethylamine (8,3 ml, 18 equiv.) and the resulting mixture is stirred over the weekend, diluted with a saturated solution of NaHCO3and the separated aqueous phase is extracted 3 times with ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (50% ethyl acetate/hexane)to give tert-butyl ester 5-(3-morpholine-4-ylpropyl)indole-1-carboxylic acid, or, similarly, tert-butyl ester 6-(3-morpholine-4-ylpropyl)indole-1-carboxylic acid.

AnalogsER-808501, ER-808514, ER-808542, ER-808544get out of the tert-butyl ester 5-(2-morpholine-4-retil)indole-1-carboxylic acid tert-butyl ester 5-(3-morpholine-4-ylpropyl)indole-1-carboxylic acid tert-butyl ester 6-(3-morpholine-4-ylpropyl)indole-1-carboxylic acid tert-butyl ester 6-(2-morpholine-4-retil)indole-1-carboxylic acid using the same techniques as for connection16or connection14.

A solution of compound20(51 mg) in dichloromethane (1 ml) is treated at room temperature triperoxonane acid (1 ml) for 3 hours and concentrated. The solid residue is washed of diet the gross ether and methanol, give crude product (18.2 mg). The crude product is then purified HPLC with reversed phase (methanol/water)to give compoundER-809047(9.6 mg, 44%). MS (ES),19F and1H-NMR confirmed the structure.

A mixture of 7-chloro-3N-imidazo[4,5-b]pyridine (J. Heterocyclic. Chem.,19, 513 (1982)) (250 mg, contains 25% 5-chloro-3H-imidazo[4,5-b]pyridine), tert-butyl methyl ether 2-tributylstannyl-1-carboxylic acid (compound11, 822 mg) and tetrakis(triphenylphosphine)palladium(0) (188 mg) in dimethylformamide (10 ml) is heated at a temperature of 120°C for 6 hours. The reaction mixture was extracted with ethyl acetate and washed with water and brine. The organic layer is dried over magnesium sulfate and evaporated. The residue is purified by chromatography (ethyl acetate/hexane)to give 7-(1N-indol-2-yl)-3N-imidazo[4,5-b]pyridine (compoundIC-261) (28 mg) as a solid pale brown.1H-NMR confirms the structure.

A mixture of compound2(1.66 g, 6 mmol), tert-butyl methyl ether 2-tributylstannyl-1-carboxylic acid (compound11, 3.6 g, 7 mmol), triethylamine (of 0.83 ml, 6 mmol) and tetrakis(triphenylphosphine)palladium(0) (600 mg, 10% mol.) in dimethylformamide (10 ml) is heated at a temperature of 130°C for 6 hours. During reaction, add connection11two on the operations (2 x 1.01 g). The reaction mixture was extracted with ethyl acetate, the extract washed with water and dried over anhydrous magnesium sulfate. After filtering to the residue add silica gel (400 mesh) and concentrated. The residue is purified by chromatography (ethyl acetate/methanol)to give compoundIC-395(240 mg) and the compoundIC-375(80 mg).1H-NMR confirms the structure.

Ethyl ester (7-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-yl)carbamino acid

To a solution of diethyl 4-chloro-5-nitro-2,6-pyridinedicarboxylate (intermediate product to obtain the connection1) (500 mg) in ethanol (50 ml) is added Raney Nickel (1 g) and stirred for 12 hours in an atmosphere of hydrogen at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue is dissolved in propan-2-Ola (10 ml) and stirred for 60 hours while boiling under reflux. The reaction mixture is cooled to room temperature and the precipitate filtered off. The filtrate is concentrated, receiving 250 mg of ethyl ether (7-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-yl)carbamino acid in a solid gray color.1H-NMR confirms the structure.

A mixture of ethyl ether (7-chloro-2-oxo-2,3-dihydro-1N-imidazo[4,5-b]pyridine-5-yl)carbs the new acid (240 mg), tert-butyl ester 2-tributylstannyl-1-carboxylic acid (compound11, 472 mg), and tetrakis(triphenylphosphine)palladium(0) (54 mg) in dimethylformamide (10 ml) is heated at a temperature of 120°C for 4 hours. Introduce additional tert-butyl ester 2-tributylstannyl-1-carboxylic acid (compound11, 472 mg) and tetrakis(triphenylphosphine)palladium(0) (54 mg) and the resulting mixture is heated at a temperature of 120°C for an additional 12 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by chromatography (ethyl acetate/methanol)to give compoundIC-380(20 mg) as a solid pale grey.1H-NMR confirms the structure.

Ethyl ester of (2-amino-7-chloro-3N-imidazo[4,5-b]pyridine-5-yl)carbamino acid

To a stirred solution of ethyl 5,6-diamino-4-chloro-2-pyridinecarboxamide (intermediate product to obtain the connection1are 1.00 g, 4.3 mmol) in 20 ml of ethanol at room temperature add ciambrone (0.55 g, 5.2 mmol). The solution is stirred for 3 hours and then at 60°C for 3 hours. The precipitate is filtered off and washed with diethyl ether, obtaining the ethyl ester of (2-amino-7-chloro-3N-imidazo[4,5-b]pyridine-5-yl)carbamino acid (0.55 g, 38%) as yellow powder.1H-NMR confirmed the t structure.

ConnectionIC-416obtained from the ethyl ester of (2-amino-7-chloro-3N-imidazo[4,5-b]pyridine-5-yl)carbamino acid and connection11when using typical techniques described for connectionIC-380.1H-NMR confirms the structure.

7-iodine-2-alkyl-3N-imidazo[4,5-b]pyridine

The compound 7-iodine-2-alkyl-3N-imidazo[4,5-b]pyridine (7-iodine-3N-imidazo[4,5-b]pyridine, 7-iodine-2-methyl-3N-imidazo[4,5-b]pyridine, 7-iodine-2-ethyl-3N-imidazo[4,5-b]pyridine) and/or its hydroiodide is obtained from 4-chloropyridine-2,3-diamine (Recueil,88, 1263-1274 (1969)by the same procedure as for obtaining compounds2and4from the connection1.

5-fluoro-7-iodine-2-methyl-3H-imidazo[4,5-b]pyridine

To a solution of compound4(R2= methyl; monohydrate, 300 mg, 0.75 mmol, 1.0 EQ.) in HBF4(48-51%in water, 3 ml) at 0°With add NaNO2(1.0 g, 19 equiv.) portions over 1 hour while maintaining the reaction temperature below 4°C. the resulting mixture was stirred at 0°C for 40 minutes and at room temperature for 30 minutes. The reaction is then quenched with a saturated solution of NaHCO3and the resulting mixture is extracted 5 times with diethyl ether. The combined organic phase is dried over sulfate n is sodium, filtered and concentrated, gaining 5-fluoro-7-iodine-2-methyl-3N-imidazo[4,5-b]pyridine in the form of solids slightly brown (170 mg, 86%).19F-NMR,1H-NMR and MS confirmed the structure.

Connection66obtained from 7-iodine-2-alkyl-3N-imidazo[4,5-b]pyridine (or monogenoidea) or 5-fluoro-7-iodine-2-methyl-3N-imidazo[4,5-b]pyridine and connection15according to the same procedure as for connection13or64.

Connection67obtained from 7-iodine-2-methyl-3N-imidazo[4,5-b]-pyridine and connection15according to the same procedure as for connection65.

7-Iodine-2-methyl-1,4-dihydroimidazo[4,5-b]pyridine-5-he

To a solution of compound4(R = methyl, 160 mg, 0.59 mmol) in 10 ml of 20%aqueous H2SO4when the temperature is ur 0°C in small portions add sodium nitrite (1.54 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was neutralized with a saturated aqueous solution of NH3to pH=7-8 and collect the precipitation, getting a solid yellow color. This solid is then crystallized from water, receiving 140 mg of product 7-iodine-2-methyl-1,4-dihydroimidazo[4,5-b]pyridine-5-it (87%) with satisfactory MS spectra and1H-NMR.

ConnectionER-807546obtained from 7-iodine-2-methyl-1,4-dihydroimidazo[4,5-b]pyridine-5-she and connection10(R'=C6H5CH2; R”=methyl) in the same procedure as for connection13. To connectER-807546get satisfactory MS spectra and1H-NMR.

AnalogsER-809251andER-809252obtained from 7-iodine-2-methyl-3N-imidazo[4,5-b]pyridine and, accordingly, tert-butyl ester 6-[2-(cyclohexylethylamine)ethyl]indole-1-carboxylic acid tert-butyl ester 5-[2-(cyclohexylethylamine)ethyl]indole-1-carboxylic acid using the same techniques as for connection16from the connection14.

3) Biological tests

The test Protocol HUVEC

Produce a crop of the total human endothelial cells of the umbilical vein (HUVEC, Clonetics, Inc.) in 96-well tablets 5×104cells/ml and incubated at 37°C. the next day cells add 20 is CL dilution of each compound and incubated for 30 minutes followed by stimulation with TNFa (a-tumor necrosis factor) (1 ng/ml) for four hours at 37°C. After stimulation with TNF tablets washed with phosphate buffered saline containing 0.5% bovine serum albumin, fixed with the help of 0.025% glutaraldehyde and stained with primary and secondary antibodies to determine the expression of E-selectin and ICAM. Tablets incubated with 100 ál of primary mouse antibodies against human E-selectin and against human ICAM (R&D Systems, Minneapolis, MN)diluted in the ratio 1:500 in phosphate buffered saline containing 0.5% bovine serum albumin and 5% fetal calf serum for one hour, after which the tablets are washed and incubated with 100 μl of secondary peroxidase conjugated goat antibodies against mouse IgG (Pierce, Rockford, IL)diluted in the ratio of 1:10000 in phosphate buffered saline solution containing of 0.5% bovine serum albumin and 5% fetal calf serum for 30 minutes. The tablets are then washed, add 100 ál of TMB substrate (3,3',5,5'-tetramethylbenzidine) and left to leak color reaction for 15-20 minutes. The reaction is quenched with 50 μl of 1N H2SO4and determine the optical density (OD) using a microplate spectrophotometer for at a wavelength of 450 nm. The values of the IC50(causing 50%inhibition concentration) determined Aut, based on the percentage of inhibition as calculated by the following formula:

% inhibition = {1-[(mean OD in the presence of compounds is the average OD value of the blank experiment)/(mean OD in the presence of TNF - average OD of the blank experiment)]}·100.

The INHIBITORY activity of the ANALOGUES IKKI

connectionStructureIC50(µM) (ELAM)
805600
(IC375)
1<IC50≤10
805894
(IC 400)
1<IC50≤10
806006>10
8059851<IC50≤10
8059841<IC50≤10
806002>10

805969>10
805971>10
805996>10
805639
(IC 397)
1<IC50≤10
805895
(IC 405)
1<IC50≤10
8060071<IC50≤10

8059761<IC50≤10
8059751<IC50≤10
805999>10
806011 1<IC50≤10
805970>10
805972>10

805997>10
806010>10
806014≤1
806094≤1
8060951<IC50≤10
806097>10

806107>10
806123 1<IC50≤10
806136>10
8061811<IC50≤10
8062211<IC50≤10
8062201<IC50≤10
8062241<IC50≤10
8062281<IC50≤10

8062761<IC50≤10
8062751<IC50≤10
8062741<IC50≤10
8062731<IC50≤10
806286>10
806287>10
8063111<IC50≤10
8063171<IC50≤10

8063201<IC50≤10
806329>10
8063331<IC50≤10
8063361<IC50≤10
806355≤1
8063581<IC50≤10
806359≤1
806363>10

8063621<IC50≤10
8063611<IC50≤10
8063681<IC50≤10
806372≤1
8063731<IC50≤10
8063741<IC50≤10
806375 1<IC50≤10
8063831<IC50≤10

806393≤1
8064011<IC50≤10
806402≤1
8064041<IC50≤10
8064171<IC50≤10
8064191<IC50≤10
8064201<IC50≤10
806421≤1

1<IC50≤10
8064351<IC50≤10
8064371<IC50≤10
8065691<IC50≤10
806609≤1
8066101<IC50≤10
8066441<IC50≤10
806645>10

8066461<IC50≤10
806647
8066531<IC50≤10
8066711<IC50≤10
806781≤1
8067901<IC50≤10
806796>10

806820≤1
806839≤1
806840≤1
806841≤1
806842≤1
8068431<IC50≤10
806844≤1
806860≤1

td align="center"> 806903
806874>10
8068751<IC50≤10
806878≤1
8068991<IC50≤10
8069001<IC50≤10
8069011<IC50≤10
8069021<IC50≤10
1<IC50≤10

806904≤1
806905≤1
8069871<IC50≤10
8070141<IC50≤10
8070151<IC50≤10
807139≤1
8071401<IC50≤10
807183≤1
807240≤1

807313≤1
8073771<IC50≤10
8073921<IC50≤10
8074001<IC50≤10
807401≤1
8073991<IC50≤10
807447≤1
8074481<IC50≤10
8074491<IC50≤10

807450 1<IC50≤10
8074511<IC50≤10
8074521<IC50≤10
807453≤1
807454≤1
807457≤1
8074581<IC50≤10
8074591<IC50≤10
8074601<IC50≤10

8074621<IC50≤10
807463 1<IC50≤10
8074641<IC50≤10
807465>10
807466≤1
807467≤1
807469≤1
8074961<IC50≤10

807497≤1
8074981<IC50≤10
8075051<IC50≤10
807506 1<IC50≤10
8075281<IC50≤10
8075311<IC50≤10
807532≤1
807543>10
807544>10

807546>10
8075481<IC50≤10
8075491<IC50≤10
8075501<IC50≤10
807562 1<IC50≤10
8075711<IC50≤10
807573≤1
8075841<IC50≤10

8075851<IC50≤10
807586≤1
8075871<IC50≤10
8076361<IC50≤10
8076491<IC50≤10
8076601<IC50≤10
807662 1<IC50≤10
8076631<IC50≤10

8077031<IC50≤10
8077041<IC50≤10
8077481<IC50≤10
807749≤1
8077501<IC50≤10
807751≤1
807754≤1
807758≤1

807759≤1
8077621<IC50≤10
807779≤1
8077871<IC50≤10
8077881<IC50≤10
8077891<IC50≤10
8077901<IC50≤10
807794>10

807835≤1
807836 1<IC50≤10
8078371<IC50≤10
8078621<IC50≤10
8078651<IC50≤10
8078761<IC50≤10
8078921<IC50≤10
8079201<IC50≤10

8079301<IC50≤10
8079311<IC50≤10
8079521<IC50≤10
807956 1<IC50≤10
8079621<IC50≤10
8079761<IC50≤10
807977≤1
8079781<IC50≤10

8079801<IC50≤10
8080091<IC50≤10
808028≤1
8080361<IC50≤10
8080391<IC50≤10
8080401<IC50≤10
8080411<IC50≤10

808069≤1
8080781<IC50≤10
8080791<IC50≤10
8080801<IC50≤10
8080811<IC50≤10
8080821<IC50≤10
8080831<IC50≤10
808084 ≤1

8080851<IC50≤10
808086≤1
808101≤1
808102>10
8081031<IC50≤10
808107≤1
808128≤1
808151≤1

8081521<IC50≤10
808153 1<IC50≤10
808160≤1
8081641<IC50≤10
808247≤1
8082541<IC50≤10
8082551<IC50≤10
808256≤1

8082571<IC50≤10
8082591<IC50≤10
8082601<IC50≤10
8082611<IC50≤10
8082621<IC50≤10
8082661<IC50≤10
8082681<IC50≤10
8082691<IC50≤10
808281>10

8082831<IC50≤10
8082841<IC50≤10
8082851<IC50≤10
8082861<IC50≤10
808287>10
808288>10
8082891<IC50≤10
8082901<IC50≤10
8082911<IC50≤10

8083101<IC50≤10
808311>10
8083121<IC50≤10
8083131<IC50≤10
808319 1<IC50≤10
808322>10
8083461<IC50≤10

8083471<IC50≤10
8083551<IC50≤10
8083561<IC50≤10
8083611<IC50≤10
808362>10
808363>10
8083641<IC50≤10
808365 1<IC50≤10

8083701<IC50≤10
808371≤1
8083721<IC50≤10
8083851<IC50≤10
8083861<IC50≤10
808387≤1
8083881<IC50≤10
808469>10
808470>10

808473≤1
8084961<IC50≤10
8084971<IC50≤10
808498>10
808499>10
808500>10
8085011<IC50≤10
808513>10
8085141<IC50≤10

8085411<IC50≤10
1<IC50≤10
8085431<IC50≤10
8085441<IC50≤10
8085481<IC50≤10
8085711<IC50≤10
808576>10
8086001<IC50≤10
8086171<IC50≤10

8086201<IC50≤10
808622 1<IC50≤10
8086231<IC50≤10
8086241<IC50≤10
8086271<IC50≤10
808628≤1
8086291<IC50≤10
8086311<IC50≤10
808635≤1

8086361<IC50≤10
808637≤1
808658 >10
8086601<IC50≤10
8086611<IC50≤10
8086631<IC50≤10
8086651<IC50≤10
8086721<IC50≤10

808673>10
8086751<IC50≤10
8086911<IC50≤10
8086921<IC50≤10
8087021<IC50≤10
8087031<IC50≤10
8087041<IC50≤10
8087051<IC50≤10

8087111<IC50≤10
8087121<IC50≤10
8087131<IC50≤10
8087141<IC50≤10
8087171<IC50≤10
8087191<IC 50≤10
808720>10
8088331<IC50≤10
808834≤1
8088351<IC50≤10

808836≤1
8088491<IC50≤10
8089831<IC50≤10
8089841<IC50≤10
8090471<IC50≤10
809187 1<IC50≤10
809189≤1
809190>10
809191≤1

8091921<IC50≤10
8091931<IC50≤10
8091961<IC50≤10
8091971<IC50≤10
8091981<IC50≤10
809199>10
809200 1<IC50≤10
8092011<IC50≤10
8092021<IC50≤10

8092031<IC50≤10
8092041<IC50≤10
8092051<IC50≤10
809206>10
809207>10
809208>10
809209>10
809210img src="https://img.russianpatents.com/1045/10455690-s.jpg" height="31" width="62" /> >10
809211>10

809212>10
809213>10
809214>10
8092151<IC50≤10
8092161<IC50≤10
8092171<IC50≤10
8092181<IC50≤10
8092191<IC50≤10
809220 1<IC50≤10
809221>10

8092221<IC50≤10
8092231<IC50≤10
809224≤1
809225>10
8092261<IC50≤10
8092271<IC50≤10
809228≤1
8092291<IC50≤10
809230 1<IC50≤10

8092311<IC50≤10
8092321<IC50≤10
8092331<IC50≤10
809234>10
809235>10
809236>10
8092371<IC50≤10
8092381<IC50≤10
8092511<IC50≤10
809252 1<IC50≤10

ConnectionStructureIC50(µM) (ICAM-1)
IC2611<IC50≤10
IC3751<IC50≤10
IC3801<IC50≤10
IC395>10
IC396≤1
IC400≤1
IC4011<IC50≤10
IC402>10

IC403≤1
IC404≤1
IC4151<IC50≤10
IC416>10

1. The compound having the structure (I):

and its pharmaceutically acceptable salts, where
n means an integer from 0 to 4;
R1means a hydrogen atom, -NH2, -N3, -NH-Ac, HE, F, -och3, -CN, or-NH(C=O)OC2H5;
R2means a hydrogen atom, -NRARB, -Or SIGAWith1-20alkyl, C1-20halogenated,6-10aryl, where RAand RBeach independently mean a hydrogen atom or a C1-20alkyl,
where C6-10aryl may not be independently substituted or substituted by one or more substituents selected from the group consisting of C1-20of alkyl, C1-20alkoxy and
With1-20thioalkyl;
each of R3independently means a hydrogen atom, a halogen atom, CN, C1-20alkyl,
With1-20alkoxy, C1-20thioalkyl or group-G-RC where G is absent or denotes-CH2-, -(CH2)2-, -CH=CH-CH2-, -CH-CH-, -C≡C-, -O - or - (C=O) and
where RCmeans a hydrogen atom, -NRF-RGgroup, -ORF, -SRF, -S(=O)RF, -S(=O)2RF,
With1-20alkyl, C1-20alkenyl,1-20quinil,3-10cycloalkyl,3-10cycloalkenyl, trebuie.mentionez, heterocycle, With6-10aryl or5-14heteroaryl with one nitrogen atom as heteroatom,
where RFand RGeach independently mean a hydrogen atom, a C1-20alkyl, C1-20alkenyl,1-20quinil,3-10cycloalkyl,3-10cycloalkenyl,6-10aryl, 6-membered heterocycle containing one atom of O as heteroatom,
where RFand RGtaken together, they form a 3-, 4-, 5-, 6-, 7 - or 8-membered cycloalkyl, cycloalkenyl,
moreover, the above-mentioned heterocycle refers to non-aromatic 5-, 6-, 7-membered ring or a bi - or tricyclic group comprising kondensirovannye 6-membered ring having 1-2 heteroatoms independently selected from oxygen, sulfur, nitrogen;
each of the above alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl can independently be unsubstituted or substituted by one or more substituents selected from the group consisting of oxygen, halogen, HE, -CN, C1-20is halogenoalkane, -CH2CF3With1-20of alkyl, C1-20alkoxy, C3-6cycloalkyl,6-10aryl, 5 - or 6-membered heterocycle with one or two nitrogen atoms as heteroatoms, otherh, NRhRi, N-ORhORhC(=O)Rh, S(=O)Rh, S(=O)2Rh, =CR4R5, -NR4,
and Rhand Rirepresent1-20alkyl, C6-10aryl, and each R4and R5independently means hydrogen, HE, ORxor C1-6alkyl, where Rxis1-6alkyl;
moreover, the above-mentioned aryl may independently optionally be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C1-20the alkyl or C1-20aloxi.

2. The compound according to claim 1, where the compound has the structure:

where R3aand R3beach independently mean a hydrogen atom, a C1-20alkoxy, or one of them denotes a hydrogen atom and the other denotes a halogen atom, CN, C1-20alkyl,
With1-20alkoxy, or a group - G-RC,
where G is absent or denotes-CH2-, -(CH2)2-, -CH=CH-, -C≡C-, -O - or - (C=O), and
where RCmeans a hydrogen atom, -NRFRG; -ORF, -SRF, -S(=O)RF, -S(=O)2RFWith1-20alkyl, C1-20alkenyl,1-20quinil,3-10cyclol the sludge, With3-10cycloalkenyl saturated 3-7-membered heterocycle containing one or two heteroatoms selected from oxygen, nitrogen, sulfur, a 5 - or 6-membered heteroaryl with one nitrogen atom as heteroatom;
where RFand RGeach independently mean a hydrogen atom, a C1-20alkyl, C1-20alkenyl,1-20quinil.

3. The compound according to claim 1, where the compound has the structure:

where R3aand R3beach independently mean a hydrogen atom, or R3Ameans1-20alkyl, substituted or means a group-G-RC,
where G denotes-CH2-and
where RCmeans-NRFRG,
where RFand RGindependently mean C1-20alkyl, C3-10cycloalkyl, 6-membered
a heterocycle with one oxygen atom as the heteroatoms, or RFand RGtaken together with the nitrogen atom, form a 5 - or 6-membered heterocycle, and 6-membered heterocycle contains an oxygen atom as a second heteroatom;
R3bmeans hydrogen;
moreover, the above alkyl may be substituted or substituted With one6-10by aryl; or R3ameans hydrogen, and R3bmeans1-20alkyl substituted by phenyl which can be substituted C1-20alkoxy.

4. The compound according to claim 1, where the compound has the structure:

where R1, R2, RFand RGhave the meaning as indicated in claim 1.

5. The compound according to claim 1, where the compound has the structure:

where R1, R2, RFand RGhave the meaning as indicated in claim 1.

6. The compound according to claim 1, where the compound has the structure:

where R1, R2, RFand RGhave the meaning as indicated in claim 1.

7. The compound according to claim 1, where the compound has the structure:

where q and r each independently denote 0 or 1; and R1, R2, RFand RGhave the meaning as indicated in claim 1.

8. The compound according to claim 1, where the compound has the structure:

where q and r each independently denote 0 or 1; and R1, R2, RFand RGhave the meaning as indicated in claim 1.

9. The compound according to claim 1, where the compound has the structure:

where R1, R2, RFand RGhave the meaning as indicated in claim 1.

10. The compound according to claim 1, where the compound has the structure:

where R1, R2, RFand RGhave the meaning as indicated in claim 1.

11. The compound according to claim 1, where the compound has the structure:

where R1and R2have the meaning as indicated in claim 1;
m means 0, 1 ili; and
RFmeans3-10cycloalkyl,6-10aryl.

12. The compound according to claim 1, where the compound has the structure:
;
where R1and R2have the meaning as indicated in claim 1; and
RFmeans a hydrogen atom, a C1-20alkyl, substituted phenyl, C3-10cycloalkyl,6-10aryl, substituted C1-20halogenation.

13. The compound according to claim 1, where the compound has the structure:

where R1and R2have the meaning as indicated in claim 1;
G means CH2, - (CH2)2-, -CH=CH-, -C≡C - or -(C=O); and
RCmeans6-10aryl, C3-10a heterocycle with one nitrogen atom as a heteroatom or a residue of formula:
,
where X is O, S, C=O, S=O, C=CR4R5, NR4or CR4R5,
where each of R4and R5independently means a hydrogen atom, hydroxyl, halogen atom, -C(=O)Rz,
where Rzis6-10aryl, and
each of these groups,
heterocycle, With6-10the aryl may be independently unsubstituted or substituted Deputy selected from the group consisting of halogen, HE1-20of alkyl, C1-20alkoxy, 5 - or 6-membered saturated heterocycle with one nitrogen atom as heteroatom, C(=O)Rhwhere hrepresents a C6-10aryl, optionally substituted by one or more substituents selected from the group consisting of C1-20alkyl, C1-20alkoxy, halogen.

14. The compound according to claim 1, where the compound has the structure:

where R1and R2have the meaning as indicated in claim 1;
G means CH2, -(CH2)2-, -CH=CH-, -C≡C - or -(C=O); and RCmeans3-10a heterocycle with one nitrogen atom as a heteroatom or a residue of formula:
,
where X is Oh, and each of these groups,
With3-10the heterocycle may be independently unsubstituted or substituted by one Deputy, selected from the group consisting of C(=O)Rhwhere Rhrepresents a C6-10aryl, optionally substituted with halogen.

15. The compound according to claim 1, where the compound has the structure:

where R1and R2have the meaning as indicated in claim 1;
G means CH2, -(CH2)2-, -CH=CH-, -C≡C - or -(C=O); and RCmeans saturated With5-6a heterocycle with one nitrogen atom as a heteroatom or a residue of formula:
,
where X is O.

16. The compound according to claim 1, where the compound has the structure:

where R1, R2and Rfhave the meaning as indicated in claim 1;
p means an integer equal 0-2;
s indicates an integer of 0;
one of a, b, D, E and K-means O-C=O, -C=CR4R5,- (C=NR4or-CR4R5and other means-CR4R5each R4and R5independently means hydrogen, HE, ORxor1-6alkyl, where Rxis1-6alkyl.

17. The compound according to any one of claims 1 to 16, where R1mean NH2.

18. The compound according to any one of claims 1 to 16, where R1means a hydrogen atom.

19. The compound according to any one of claims 1 to 16, where R2mean NH2HE1-C6alkyl, with the specified alkyl may be unsubstituted or substituted by one or more Halogens.

20. The compound according to any one of claims 1 to 16, where R2means1-C2alkyl.

21. The compound according to any one of claims 1 to 16, where R2means methyl.

22. The compound according to any one of claims 1 to 16, where R2means a hydrogen atom.

23. The compound according to any one of claims 4 to 10, where one of RFor RGmeans a hydrogen atom or a C1-6alkyl, and the other means C1-20alkyl, C6-10aryl, where each of the above C1-20alkyl, C6-10the aryl may be independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C1-20of alkyl, C1-206-10aryl,
where RFand RGtaken together, they form a 3-, 4-, 5-, 6-, 7 - or 8-membered cycloalkyl, cycloalkenyl.

24. The compound according to any one of claims 4 to 10, where one of RFor RGmeans a hydrogen atom or a C1-6alkyl, and the other means6-10aryl,
where the above With6-10aryl can be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C1-20of alkyl, C1-20alkoxy,
where RFand RGtaken together, they form a 3-, 4-, 5-, 6-, 7 - or 8-membered cycloalkyl, cycloalkenyl.

25. The connection point 24, where one of RFor RGmeans a hydrogen atom or a C1-6alkyl, and the other means phenyl, where phenyl may be independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, metoxygroup,1-6the alkyl.

26. The compound according to any one of claims 4 to 10, where one of RFor RGmeans a hydrogen atom or a C1-6alkyl, and the other means1-20alkyl, C1-20alkenyl,1-20quinil,3-8cycloalkyl that can be independently unsubstituted or substituted by one or more substituents selected from the group consisting of C6-10aryl, C1-20alkoxy, HE, S(=O)Rhand S(=O)2Rh,
each Rhand Rhindependently isone 1-20alkyl, C6-10aryl.

27. Connection to item 11, where RFmeans3-10cycloalkyl or6-10aryl.

28. The connection section 12, where RFmeans a hydrogen atom, a C1-20alkyl, substituted phenyl, C3-10cycloalkyl,6-10aryl, substituted C1-20halogenation.

29. The compound according to claim 1, selected from the following compounds:












its pharmaceutically acceptable salt.

30. The compound according to claim 1, where the specified compound has the structure:
.

31. The compound according to claim 1, where the compound is selected from the group consisting of

32. The compound having the structure:

and its pharmaceutically acceptable salt.

33. The compound having structural formula II

and his farm is citiesi acceptable salt,
where R1HE is a or O-TBS (tert-butyldimethylsilyloxy ether).

34. Pharmaceutical composition having the ability to inhibit induced by cytokines, expression of adhesion molecules by endothelial cells, comprising the compound according to any one of claims 1 to 33 and a pharmaceutically acceptable carrier or diluent.

35. The pharmaceutical composition according to clause 34, where the connection is in the amount effective for inhibiting the pathway of cytokine associated with inflammation; cell proliferation; for the manifestation of anti-inflammatory effect.

36. The pharmaceutical composition according to clause 34, where the compound has a structure as claimed in any of claim 2 to 33.

37. Pharmaceutical composition for treating inflammatory or autoimmune disorders, or proliferative disorders, comprising a compound having a structure as claimed in any one of claims 1 to 33, and a pharmaceutically acceptable carrier or diluent.

38. The composition according to clause 37, where the inflammatory or autoimmune disorder, or a proliferative infringement is rheumatoid arthritis, ulcerative colitis/Crohn's disease, a disease of the Central nervous system (CNS)such as multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection/graft versus host (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, diabetes, idiopathic purple thrombocytopenia, glomerulonephritis, cardiovascular disease or cancer.

39. The composition according to clause 37, where inflammatory infringement is rheumatoid arthritis.

40. The composition according to clause 37, where inflammatory infringement is ulcerative colitis/Crohn's disease.

41. The composition according to clause 37, where inflammatory infringement is multiple sclerosis.

42. The composition according to clause 37, where inflammatory infringement is asthma.

43. The composition according to clause 37, where inflammatory infringement is psoriasis.

44. The composition according to clause 37, where inflammatory infringement is allograft rejection/graft versus host (GVHD).

45. The composition according to clause 37, where inflammatory infringement is idiopathic purple thrombocytopenia.

46. The composition according to clause 37, where inflammatory infringement is allergic rhinitis.

47. The composition according to clause 37, where inflammatory infringement is atopic dermatitis.

48. The composition according to clause 37, where inflammatory violation is systemic lupus erythematosus.

49. The composition according to clause 37, where inflammatory infringement is glomerulonephritis.

50. The composition according to clause 37, where inflammatory infringement is diabetes.

51. The use of compounds according to any one of paragraphs.-33 to obtain drugs for the treatment of inflammatory or autoimmune disorders, or proliferative disorders.

52. The intermediate connection representing

53. The intermediate connection representing

54. The intermediate connection representing



 

Same patents:

Organic compounds // 2379309

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (I) in free or salt form, where Q is a bond, R1 and R2 independently represent H or C1-C8alkyl, or R3 is C1-C8alkyl, R4 and R5 independently represent halogen, C1-C8alkyl, C1-C8haloalkyl, C3-C15carbocyclic group, nitro group, cyano-group, C1-C8alkylsulphonyl group, R6 is H or C1-C8alkyl; W is a group of formula (Wa1) or (Wa2), where A independently represents C or N, or W represents a group of formula (Wb); where Y independently represents C or N; and Z represents N, O or S, or W represents a group of formula (Wc), where Y independently represents C or N; and Z represents O or S; X represents -SO2-, -CH2-, -CH(C1-C8alkyl)- or a bond; m and n each independently represents an integer from 0 to 3; and p is 1, to a pharmaceutical composition with CRTh2 antagonist activity, as well as to use thereof as a medicinal agent and production method thereof.

EFFECT: new compounds which can be used in medicine are obtained and described.

10 cl, 153 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns compounds of general formula I or to their pharmaceutically acceptable salts, where X1 - CH; X2 - N or CH; Q1 represents ,

where X11 - CH or C-halogen; X12 - CH, C-halogen or C-CF3; X13 - CH; X14 - C-E11, and E11 represents C0-10alkyl or C0-10alkoxy; X15 - CH or N; X16 - N or N+ -0; G1 - phenyl or 5-6-members unsaturated ring containing one heteroatom N or S; R1 - C0-10alkyl, cycloC3-10alkyl or piperidinyl, any of which is optionally substituted with 1-2 independent substitutes G11, or R1 represents phenyl; G11 is chosen from: OR21 where R21 represents C0-10alkyl; -oxo; -cycloC3-8alkyl; -C0-10alkyl optionally substituted with group N(C0-10alkyl)(C0-10alkyl) wherein C0-10alkyl is optionally substituted with group N(C0-10alkyl)C(O)C0-10alkyl; group OR2221, where R2221 - C0-10alkyl; group N(C0-10alkyl)C(O)C0-10alkyl; group N(C0-10alkyl)SO2(C0-10alkyl); group -N(C0-10alkyl)C(O)N(C0-10alkyl)(C0-10alkyl); group -N(C0-10alkyl)C(=O)R3331, where R3331 - C1-10alkoxy C1-10alkyl or tetrahydrofuranyl; -N(R21)R31 where R21 and R31 independently represent C0-10alkyl optionally substituted with thiophenyl, morphlinyl, furanyl; cycloC3-8alkyl; C1-10alkoxyC1-10alkyl; tetrahydropyranyl; piperidylC0-10alkyl; or piperidyl optionally substituted with C0-10alkyl; or R21 and R31 optionally taken together with nitrogen atom whereto attached, form 3-10-members saturated ring optionally substituted with one or more independent substitutes G1111, and optionally including one or more heteroatoms different from nitrogen whereto R21 and R31 are attached; where G1111 - C0-10alkyl optionally substituted with group OR77 where R77 - C0-10alkyl, or G1111 represents C1-10alkoxyC1-10alkyl, pirimidinyl, pyrazinyl, imidazolylmethyl; C(O)N(R21)R31 where R21 and R31 independently represent C0-10alkyl; -C(O)O(C0-10alkyl); -C(O) C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or halogen; -heterocyclylC0-10alkyl where heterocyclyl represents 4-6-members saturated ring containing 1 or 2 heteroatoms, independently chosen from N, O or S optionally substituted with a substitute chosen from: 1) OR2221, where R2221 - pyrimidinyl or C0-10lkyl; 2) C(O)OR2221, where R2221 - C0-10alkyl or phenyl-C0-10alkyl; 3) C(O)C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or C1-10alkoxy C1-10alkyl; 4) C(O)N(C0-10alkyl)(C0-10alkyl); 5) S(O)2C0-10alkyl; 6) SO2N(C0-10alkyl)(C0-10alkyl); 7) -NR2221R3331, where R2221 and R3331 taken together with nitrogen atom whereto attached, form pyrrolidinyl; or G11 represents C, which taken together with carbon whereto attached, forms C=C double bond substituted with R5 and G111 where R5 and G111 are hydrogens. The invention also specifically concerns cys-3-[8-amino-1-(2-phenylquinoline-7-yl)-imidazo[1,5-α]pyrazine-3-yl]-1-methl-cyclobutanole or its pharmaceutically acceptable salt. The specified compounds and their pharmaceutically acceptable salts are applicable in treatment of conditions mediated by activity IGF-1R proteinkinase, particularly angiogenesis, vascular permeability, immune response, cell apoptosis, tumour growth or inflammation. The invention also concerns a pharmaceutical composition.

EFFECT: improved efficiency of the composition and method of treatment.

14 cl, 3 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrrolo[3,2-c]pyridine derivatives of formula (I) or their pharmaceutically acceptable salts in which R1 is hydrogen; straight or branched C1-C6alkyl group optionally substituted with one or more substitutes selected from a group consisting of C1-C5alkoxy, hydroxyl, C3-C7 cycloalkyl, C1-C3 alkylthiazolyl and 1,3-dioxolanyl; straight or branched C2-C6 alkenyl group; straight or branched C2-C6 alkynyl group; C3-C7cycloalkyl group; or benzyl group optionally substituted with one or more substitutes selected from a group consisting of halogen, C1-C3alkyl and C1-C3alkoxy, R2 is a straight or branched C1-C6 alkyl group, R3 is hydrogen; straight or branched C1-C6 alkyl group; straight or branched C2-C6alkenyl group; or a benzyl group optionally substituted with one or more halogens, and R4 is 1,2,3,4-tetrahydroisoquinolinyl group; a benzyloxy group optionally substituted with one or more halogens; or an amine group substituted with one or two substitutes selected from a group consisting of hydrogen, straight or branched C1-C5alkylcarbonyl, phenoxycarbonyl, benzyl, optionally substituted with one or more halogens, and benzoyl, optionally substituted with one or more halogens, as well as to method of producing said compounds and a pharmaceutical composition with inhibitory effect on a proton pump containing these compounds.

EFFECT: new compounds are obtained and described, which exhibit excellent inhibitory effect on a proton pump and can provide reversible inhibitory effect on a proton pump.

7 cl, 82 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-H-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazole[3,4-b]pyridine-5-carboxamide, which is a compound of formula or its pharmaceutically acceptable salt, as well as to a method of producing said compounds. The invention also relates to use of the said compound or its pharmaceutically acceptable salt as phosphodiesterase IV (PDE4) inhibitor, for example in treatment and/or prevention of inflammatory and/or allergic disease, cognitive impairment or depression in mammals. The invention particularly pertains to use of the compound or its pharmaceutically acceptable salt in treating and/or preventing atopic dermatitis in mammals, for example via external local administration to a mammal, for example a human being.

EFFECT: pharmaceutical compositions are also provided, which contain the said compound or its pharmaceutically acceptable salt, particularly suitable for external local administration.

35 cl, 1 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: present invention is related to new crystalline forms of salt of mesylate2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidaso[1,2-a]pyridine-6-carboxamide and to their mixture. Besides the present invention is also related to methods of their preparation, application and pharmaceutical composition for inhibition of gastric acid secretion, which contains them. Production of new salt of 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidaso[1,2-a]pyridine-6-carboxamide and its crystalline forms for production of medicinal agent for use in treatment or prophylaxis of gastrointestinal disorders such as gastritis, gastric ulcer, duodenal ulcer, peptic ulcerous diseases, reflux-esophagitis, Zollinger-Ellison syndrome, ulcerogenic adenomas of pancreas, acute bleeding from upper compartments of gastrointestinal tract.

EFFECT: wider area of compounds application.

33 cl, 1 tbl, 12 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to monohydrate of sodium salt S-tenatoprazol, which complies with the following formula: . Invention is also related to method for production of monohydrate of sodium salt of S-tenatoprazol, to application and pharmaceutical composition on its basis for treatment of gastrointestinal pathologies.

EFFECT: production of new compound and pharmaceutical composition on its basis, which may be used in medicine for production of medicinal agents for treatment of gastrointestinal pathologies, gastroesophageal reflux and gastrointestinal haemorrhages in patients, which are prescribed polymedicamental therapy.

19 cl, 9 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns methods and compositions for inducing apoptosis of cancer cells. Substance of the invention includes the modified antibodies-DR-5 agonists which in combination with apoptosis-inducing agents, synergetically induce apoptosis of cancer cells.

EFFECT: intensified antineoplastic activity.

19 cl, 51 ex, 2 tbl, 35 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely oncology and can be used in treatment of tumours. The method involves introduction of an autologous vaccine representing heat-shock proteins recovered from tumour tissue of the patient in a complex with tumour antigens. Thus treatment with the autologous vaccine is preceded with introduction of an oncolytic attenuated Newcastle disease virus as an adjuvant.

EFFECT: application of the invention allows improving clinical effectiveness in tumours ensured by formation of a vaccine-induced specific immune response against tumour and additional stimulation of nonspecific immunity combined with cytolytic activity of the adjuvant.

2 cl, 4 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention concerns pharmacology and medicine, namely to preparations based on Saint-Mary-thistle extracts, and can be used for therapy of hepatic pathologies and malignant neoplasms. The composition represents a noncovalent complex wherein as an excipient, human or mammal blood plasma protein is used with the flavolignane to protein ratio (1-150): 1. In the composition as human or mammal blood plasma protein, albumin, prealbumin, alpha-fetoprotein, alpha- or beta-globulin or their peptide fragments are used. Besides as alpha globulin, the composition contains lipoproteins, transcortin, acidic glycoprotein, thyroxine-binding globulin, haptoglobin, plasminogen, macroglobulin, retinol-binding protein, vitamin D-binding protein, while beta globulin is as follows - lipoproteins, transferrin, globulin binding connecting sex hormones, transcobalamin.

EFFECT: ensured double therapeutic action: realisation of hepatoprotective or antineoplastic activity combined with the plasma-substituting therapy in hypoproteinemia accompanying an underlying disease.

4 cl, 3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention includes description of novel pharmaceutical combination, pharmaceutical composition, which includes said combination, application of said combination for obtaining medication and commercial packing. Combination includes (a) at least one anti-inflammatory agent, selected from group, which includes inhibitors of topoisomerase I and inhibitors of topoisomerase II, and (b) epothilone B derivative of formula (I), and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or successive application.

EFFECT: obtaining of effective combination for treatment of proliferative disease, namely disease connected with considerable tumor and resistant to other medications.

12 cl

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns pharmaceutical composition for prevention and treatment of diseases and disease states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), which contains mixture of extract obtained from Scutellariae and enriched with flavonoids with free B-ring, which include baicalein, and extract obtained from Acacia and enriched with flavans, which include catechine and epicatechine. Claimed invention also relates to method of body weight loss and control over glucose level in blood. Methods by claimed invention include introduction to person, who needs it, of efficient amount of composition by claimed invention together with pharmaceutically acceptable carrier. Claimed invention mainly relates to prevention and treatment of diseases and states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), including, but not confining to it, stopping discomfort and pain in joints, induced by such states as osteoarthritis, rheumatoid arthritis and other injuries caused by overload.

EFFECT: composition possesses high efficiency.

35 cl, 22 ex, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinoline derivatives of formula I or pharmaceutically acceptable salts thereof or esters with tyrosine kinase inhibitor properties. In formula I , R1 is selected from hydroxy, C1-C4-alkoxy, hydroxy(C2-C4-alkoxy), C1-C3-alkoxy-(C2-C4-alkoxy) or from a group of formula Q2-X3 - in which X3 is O, and Q2 is azetidin-1-yl-C2-C4-alkyl, pyrrolidin-1-yl- C2-C4-alkyl, piperidino-C2-C4-alkyl, piperazino-C2-C4-alkyl or morpholino-C2-C4-alkyl; b is 1, 2, or 3; each R2, which can be identical or different, is selected from fluorine, chlorine, bromine, C1-C4-alkyl, C2-C4-alkenyl and C2-C4-alkenyl; Q1 is piperidinyl; a is 0; X1 is CO; X2 is a group of formula: -(CR12R13)P-(Q5)m-, where m is 0 or 1, p is 0, 1, 2, 3 or 4; each of R12 and R13, which can be identical or different, is selected from hydrogen, C1-C6-alkyl, amino, C1-C6-alkylamino and di-[C1-C6-alkyl]amino, and Q5 is C3-C7cycloalkylene; Z is selected from hydroxy, amino, C1-C6-alkylamino, di-[C1-C6-alkyl]amino, C1-C6-alkoxy and a group of formula: Q6-X9-, in which X9 is a single bond and Q6 is heterocyclyl or heterocyclyl-C1-C4 alkyl; under the condition that, if m and p are equal to 0, Z is heterocyclyl.

EFFECT: proposed derivatives can be used in treating proliferative diseases, particularly for treating malignant growths.

32 cl, 4 dwg, 2 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted derivatives of N-(3-benzoylaminophenyl)-4-pyridyl-2-pyrimidine amine of general formula (I), with inhibitory activity towards protein kinase, method of producing said derivatives and pharmaceutical compositions based on the derivatives. In the compound of formula 1 R1 is hydrogen and R2 is NR5R6, or R1 is NR5R6 and R2 is hydrogen; R3 is trifluoromethyl; R4 is lower alkyl; and R5 and R6 are independently hydrogen, lower alkyl, di(lower alkyl)amino-lower alkyl, N-lower alkylpiperidinyl, N-lower alkylpyrrolidinyl, or lower alkyl, or NR5R6 together represent pyrrolidino, piperidino, morpholino, N-lower alkylpiperazino, 1N-imidazolyl, 1H-2-lower alkylimidazolyl, 1H-4-lower alkylimidazolyl or 1H-2,4-di-lower alkylimidazolyl, or a pharmaceutically acceptable salt of such a compound.

EFFECT: compounds can be used in treating diseases related to inhibition of protein kinase activity, such as neoplastic diseases or leukaemia.

13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted derivatives of N-(3-benzoylaminophenyl)-4-pyridyl-2-pyrimidine amine of general formula (I), with inhibitory activity towards protein kinase, method of producing said derivatives and pharmaceutical compositions based on the derivatives. In the compound of formula 1 R1 is hydrogen and R2 is NR5R6, or R1 is NR5R6 and R2 is hydrogen; R3 is trifluoromethyl; R4 is lower alkyl; and R5 and R6 are independently hydrogen, lower alkyl, di(lower alkyl)amino-lower alkyl, N-lower alkylpiperidinyl, N-lower alkylpyrrolidinyl, or lower alkyl, or NR5R6 together represent pyrrolidino, piperidino, morpholino, N-lower alkylpiperazino, 1N-imidazolyl, 1H-2-lower alkylimidazolyl, 1H-4-lower alkylimidazolyl or 1H-2,4-di-lower alkylimidazolyl, or a pharmaceutically acceptable salt of such a compound.

EFFECT: compounds can be used in treating diseases related to inhibition of protein kinase activity, such as neoplastic diseases or leukaemia.

13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel sulphonamide derivatives of general formula (I) , where R1 is phenyl, thiophenyl or furanyl, unsubstituted or substituted with one or two substitutes selected from a group consisting of halogen, lower alkyl, lower alkyl substituted with halogen, -O-lower alkyl substituted with halogen, NO2 or CN; R2-R4 and R2'-R4' is hydrogen, lower alkyl, phenyl or lower alkyl substituted with halogen; R5 is phenyl, pyridinyl, benzo[1,3]dioxolyl or benzofuranyl, unsubstituted or substituted with 1-3 substitutes selected from a group consisting of halogen, lower alkyl, lower alkyloxy, CN, nitro, amino, hydroxy, lower alkyl substituted with hydroxy, lower alkyl substituted with halogen, or substituted with -C(O)-NR"2, -(CR2)m-C(O)-R', -(CH2)m-heteroaryl, unsubstituted or monosubstituted -(CH2)m-lower alkoxy, lower alkyl, -(CH2)m-O-benzene or CH2OH, -O-C(O)-lower alkyl, -O-C(O)-NR2, -O-(CH2)m-C(O)OH, -O-lower alkynyl, -O-lower alkyl, substituted with halogen, -O-(CH2)m-heterocyclyl, -O-(CH2)m-phenyl, unsubstituted or monosubstituted hydroxy, -O-(CH2)m-heteroaryl, unsubstituted or monosubstituted with lower alkyl, -(CH2)m-NH-C(O)R', -(CH2)m-NH-S(O)2-R', -S(O)2-lower alkyl, -S(O)2-heterocyclyl, -S(O)2NH-cycloalkyl, or is C3-6cycloalkyl; R' is hydrogen, lower alkyl, lower alkynyloxy, hydroxy, C3-6cycloalkyl, heterocyclyl, which is unsubstituted or substituted with one or two substitutes selected from COOH, -C(O)O-lower alkyl, halogen or lower alkyl, or is phenyl, benzyl, heteroaryl, -(CH2)m-lower alkoxy or -(CHR)m-C(O)O-lower alkyl; R" is hydrogen, C3-6cycloalkyl, which is unsubstituted or substituted with one or two substitutes selected from halogen, or is lower alkyl, lower alkyl substituted with halogen, lower alkyl substituted with hydroxy, -(CH2)m-heterocyclyl, -NR2, heteroaryl, benzyl or -(CHR)m-C(O)O-lower alkyl; R is hydrogen or lower alkyl; X is -CHR-; m equals 0, 1, 2 or 3; and its pharmaceutically acceptable salts of an acid compound, optically pure enantiomers, racemates or diastereomeric mixtures. The invention also relates to medicine containing a formula I compound.

EFFECT: obtaining novel compounds which inhibit γ-secretase.

16 cl, 230 ex

Organic compounds // 2379309

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (I) in free or salt form, where Q is a bond, R1 and R2 independently represent H or C1-C8alkyl, or R3 is C1-C8alkyl, R4 and R5 independently represent halogen, C1-C8alkyl, C1-C8haloalkyl, C3-C15carbocyclic group, nitro group, cyano-group, C1-C8alkylsulphonyl group, R6 is H or C1-C8alkyl; W is a group of formula (Wa1) or (Wa2), where A independently represents C or N, or W represents a group of formula (Wb); where Y independently represents C or N; and Z represents N, O or S, or W represents a group of formula (Wc), where Y independently represents C or N; and Z represents O or S; X represents -SO2-, -CH2-, -CH(C1-C8alkyl)- or a bond; m and n each independently represents an integer from 0 to 3; and p is 1, to a pharmaceutical composition with CRTh2 antagonist activity, as well as to use thereof as a medicinal agent and production method thereof.

EFFECT: new compounds which can be used in medicine are obtained and described.

10 cl, 153 ex, 1 tbl

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