C-met antagonist and aminoheteroaryl combination for treating cancer

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a composition containing a c-Met antagonist representing an antibody, and an aminoheteroaryl compound and applicable for treating cancer. Besides, the group of inventions represents a pharmaceutical composition containing an anti-c-Met antibody and the aminoheteroaryl compound in the form of combination medications.

EFFECT: using the group of inventions provides more effective inhibition of cancer growth and prolonged absence of a tumour.

15 cl, 2 dwg, 1 tbl, 2 ex

 

The invention relates to compositions containing antagonist of c-Met, representing the antibody, and the connection of aminoheterocycles, in particular as medicine. The present invention also includes a pharmaceutical composition comprising the antibody anti-c-Met and the connection aminoheterocycles as combined preparations for simultaneous, separate or sequential use. The invention relates to the use of a composition according to the invention for the treatment of cancer in a mammal.

c-Met is the prototypical member of the RTK subfamily, which also includes RON and SEA. The family of c-Met RTK is structurally different from other RTK families and is the only known receptor of high affinity growth factor hepatocyte (HGF), also called the scattering factor (scater factor, SF) [D.P. Bottaro et al., Science 1991, 251:802-804; L. Naldini et al., Eur. Mol. Biol. Org. J. 1991, 10:2867-2878]. c-Met and HGF are widely expressed in several tissues, and their expression in normal restricted to cells of epithelial and mesenchymal origin, respectively [M.F. Di Renzo et al., Oncogene 1991, 6:1997-2003; E. Sonnenberg et al., J. Cell. Biol. 1993, 123:223-235]. Both are necessary for normal development of the mammal, and it is shown that they are particularly important in cell migration, morphogenetic differentiation and organization of three-dimensional tubular structures, as well as in growth and angiogenesis [F. Baldt et al., Nature 1995, 76:768-771; .Schmidt et al., Nature. 1995:373:699-702; Tsarfaty et al., Science 1994, 263:98-101]. Although it is shown that the controlled regulation of c-Met and HGF are important in the development of a mammal, maintenance and repair of tissues [Nagayama T, Nagayama M, Kohara S, Kamiguchi H, Shibuya M, Katoh Y, Itoh J, Shinohara Y., Brain Res. 2004, 5;999(2):155-66; Tahara Y, Ido A, Yamamoto S, Miyata Y, Uto H, Hori T, Hayashi K, Tsubouchi H., J Pharmacol Exp Ther. 2003, 307(1):146-51], the violation of their regulation is associated with the progression of cancers.

Aberrant signaling sent inappropriate activation of c-Met, is one of the most frequent changes observed in human cancers and plays a critical role in carcinogenesis and metastasis [Birchmeier et al., Nat. Rev. Mol. Cell Biol. 2003, 4:915-925; L. Trusolino and Comoglio, P. M., Nat Rev. Cancer. 2002, 2(4):289-300].

Activation of C-Met may result from various mechanisms, including : (i) binding of the ligand, ii) overexpression of the receptor, which leads to spontaneous, independent of ligand dimerization, or (iii) mutations, mainly occurring in the intracellular domain of c-Met and resulting in an increased and persistent phosphorylation of c-Met or constitutive activation of the receptor [J. G. Christensen, J. and Burrows Salgia R., Cancer Letters. 2005, 226:1-26].

Activated c-Met recruits effectors of signal transmission in the multiple docking site, localized in the cytoplasmic domain, which results in activation of several key biochemical p. the TEI signal, including Ras-MAPK, PI3K, Src and Stat3 [Gao CF, Vande Woude GF, Cell Res. 2005, 15(1):49-51; Furge KA, Zhang YW, Vande Woude GF, Oncogene. 2000, 19(49):5582-9]. These biochemical pathway that is essential for the proliferation of tumor cells, invasion and angiogenesis and to avoid apoptosis [Furge KA, Zhang YW, Vande Woude GF, Oncogene, 2000, 19(49):5582-9; Gu H, Neel BG, Trends Cell Biol. 2003 Mar; 13(3): 122-30; Fan S, Ma YX, Wang JA, Yuan RQ, Meng Q, Cao Y, Laterra JJ, Goldberg ID, Rosen EM, Oncogene. 2000 Apr 27, 19(18):2212-23]. In addition, a unique aspect of the signal of c-Met relative to other RTK is described interaction with focal adhesion complexes and necesasrily binding partners, such as integrins α6β4 [Trusolino L, Bertotti A, Comoglio PM, Cell. 2001, 107:643-54], CD44v6 [Van der Voort R, Taher THOSE Wielenga VJ, Spaargaren M, Prevo R, Smit L, David G, Hartmann G, Gherardi E, Pals ST, J Biol Chem. 1999, 274(10):6499-506], plexin B1 or semaphorin [Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM, Nat Cell Biol. 2002, 4(9):720-4; Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano's, Blood. 2005, 105(11):4321-9; Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S, Oncogene. 2004, 23:5131-7], which can further add to the complexity of the regulation of cellular functions by their receptor. Finally, recent data demonstrate that c-Met may be involved in the resistance of tumors to gefitinib or erlotinib, suggesting that the combination of compounds intended for EGFR and c-Met, could be of significant interest [Engelman JA at al., Science, 2007, 316:1039-43].

More than 20 mutations discovered in the limits of c-met RTK [Ma R. .et al. Cancer and metastasis rev. 2003, 22:309-25]. Most of these mutations is a missense mutation, localized in the intracellular site of c-Met, within tyrosinekinase domain, and which could affect the affinity or binding properties of therapeutic compounds aimed at this tyrosinekinase domain. Thus, mutations of c-Met may be more or less responsive to therapeutic inhibition. For example, in preclinical studies, SU11274 (low molecular weight tyrosine kinase inhibitor against c-Met) some mutations were divided into susceptible and resistant to the action of this agent [L. Schmidt et al. Nat Genet. 1997, 16:68-73; Zhuang Z. et al. Nat Genet. 1998, 20:66-9]. M1268T and H1112Y are sensitive mutations that showed reduced cell growth and motility. Other mutations, such as L1213V and Y1248 were found as stable and not affected by SU11274 [O. Hahn et al. Hematol Oncol Clin N Am. 2005, 19:343-67]. In these studies demonstrated a direct effect of specific mutations on therapy aimed at c-Met. However, oligomerization of c-Met in the presence or in the absence of ligand is required for the regulation of binding affinity and kinetics of binding kinase with respect to ATP and tyrosinaemia peptide substrates [Hays J.I., Watowich SJ, Biochemistry. 2004, 43:10570-8].

Over the last few years developed many different the strategies to weaken the signal of c-Met in cancer cell lines. These strategies include (i) neutralizing antibodies against c-Met or HGF/SF [Cao, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, Wang LM, Vande Woude GF, Proc Natl Acad Sci USA. 2001, 98(13):7443-8; Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, Lamszus K, Clin Cancer Res. 2006, 12(20):6144-52] or the use of HGF/SF antagonist NK4 to prevent binding of the ligand to c-Met [Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T, Cancer Res., 2000, 60:6737-43], ii) low molecular weight inhibitors of ATP-binding site of c-Met that block the kinase activity [Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB, Cancer Res. 2003, 63:7345-55], iii) the engineered polypeptide SH2 domain, which prevents access to multiple docking site and PHKi or ribozyme, which reduces the expression of the receptor or ligand. Most of these approaches shows selective inhibition of c-Met, resulting in inhibition of the tumor, and shows that c-Met may be of interest for therapeutic intervention in cancer.

Among the molecules that are created to focus on c-Met, some are antibodies.

One of the most widely described is antibody anti-c-Met 5D5 created Genentech [WO96/38557], which acts as a strong agonist, when it is added separately in different models, and the antagonist, when used in the form of a Fab fragment. Another antibody directed n is c-Met, described as Pfizer antibody acting "primarily as an antagonist of c-Met and in some cases as an agonist c-Met" [WO 2005/016382].

The inventor has demonstrated that antibodies, which are antagonists of c-Met, named 224G11, N, S and E, or functional fragment, described in this application and is also described in patent applications EP 073012312 filed July 12, 2007, and US 61/020639, filed January 11, 2008, possess the property of inhibiting the dimerization of c-Met and active in vivo.

Thus, the problem which must be solved by the invention, it is possible to consider the development of a real, and not just the intended combination, are useful for the treatment of cancer.

More specifically the aim of the invention is the development of new and unexpected combinations, able to influence all the factors involved in the activation of c-Met as described above.

In a General aspect, the invention relates to a method of treating cancer in a mammal which comprises the administration to a mammal a therapeutically effective amount of a combination of active ingredients containing antagonist of c-Met and the connection aminoheterocycles.

In another General aspect, the present invention is directed to a composition comprising the antagonist of c-Met, representing the antibody or the functional fragment and the connection of aminoheterocycles, preferably for use as a Lek is rstv.

Further, the present invention is directed to a pharmaceutical composition comprising at least:

i) one antagonist to c-Met, which represents an antibody or functional fragment; and

ii) connection of aminoheterocycles,

as combined preparations for simultaneous, separate or sequential use.

"Simultaneous application" is understood as meaning the introduction of two compounds of the composition according to the invention in a single and the identical pharmaceutical form.

"Private use" is understood as meaning the introduction at the same time two compounds of the composition according to the invention in a separate pharmaceutical form.

"Consistent application" is understood as meaning the sequential introduction of two compounds of the composition according to the invention, each in a separate pharmaceutical form.

According to the invention a combination is preferably mixed with excipients and/or pharmaceutically acceptable carrier.

Also described and claimed composition according to the invention as a medicine.

In another form of the combination according to the invention can be in the form of a set of parts. The invention, therefore, includes a preparation containing antagonist of c-Met, which represents an antibody or one of its functional fragments, and the connection of aminoheterocycles, preferably capable of inhibiting proteinkinase activity of c-Met, as defined above, as a combined preparation for simultaneous, separate or sequential delivery for treatment of cancer in a mammal, in need thereof. In one form of implementation of the drug contains the antagonist to c-Met, representing the antibody or the functional fragment and the connection of aminoheterocycles, as defined above, as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer in a mammal, in need thereof.

In one form of implementation of the invention proposed pharmaceutical packaging, including a course of cancer treatment for one individual mammal that contains (a) at least one antagonist of c-Met, representing the antibody, and (b) at least one compound of aminoethanol in a standard dosage form.

In a more specific aspect the invention relates to a method of treating cancer in a mammal which comprises the administration to a mammal a therapeutically effective amount of a combination of active ingredients in accordance with the present invention, containing antagonist of c-Met, representing the antibody or the functional fragment and the connection is of manageremail.

In a more specific aspect the invention relates to compositions containing antagonist of c-Met, which represents an antibody or functional fragment, and aminoethanol according to the present invention, for the treatment of cancer, preferably from a mammal, more preferably in humans. Anti-cancer therapy comprises administration to a mammal a therapeutically effective amount of the composition according to the present invention. Preferably the composition further comprises a pharmaceutically acceptable carrier and/or excipient.

In a preferred form of implementation, the connection aminoheterocycles capable of inhibiting protein kinase c-Met. More preferred compounds of aminoheterocycles with at least 25%, preferably 40%, 50%, 60%, 75% and 85% of the inhibitory activity of protein kinase c-Met, demonstrated for compounds aminoheterocycles, called PF-02341066, in terms of the same analytical method (see in this application is the complete structure of this compound PF-02341066).

Among the analytical techniques that can be used to determine the activity level of the protein kinase c-Met in the presence of compounds aminoheterocycles, the authors of this invention can quote analysis technique called "continuous coupled spectrophotometric analysis HGFR described nastr in the patent application PCT published under the number WO 2006/021884.

The terms "antibody"and "antibody" or "immunoglobulin" are used interchangeably in the broadest sense and include monoclonal antibodies (e.g., full-length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies or multispecific antibodies (for example, bespecifically antibodies, as far as they exhibit the desired biological activity).

More specifically, this molecule is a glycoprotein containing at least two heavy (H) chains and two light (L) chain, mutually connected by disulfide bonds. Each heavy chain comprises variable region (or domain) of the heavy chain (abbreviated here as HCVR or VH) and a constant region of the heavy chain. The constant region of the heavy chain comprises three domains, CN, CH2 and CH3. Each light chain comprises a variable region light chain (abbreviated here as LCVR or VL) and a constant region light chain. The constant region of the light chain consists of one domain, CL. Region VH and VL can be further subdivided into areas of hypervariability, called parts of the complementarity determining (CDR), separated by areas that are more conservative, called frame regions (FR). Each VH and VL is composed of three CDRs and four FR located from Amin the-end to the carboxy-end in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Variable regions of the heavy and light chains contain a binding domain that interacts with the antigen. The constant region of the antibodies may mediate the binding of immunoglobulin with tissues or host factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

They may also include certain antibody fragments, as described in more detail in this application that may have the desired binding specificity and affinity, regardless of the source or type of immunoglobulin (i.e. IgG, IgE, IgM, IgA, etc).

As a rule, to obtain monoclonal antibodies or their functional fragments, especially of murine origin, it is possible to refer to techniques which are described in particular in the manual "Antibodies" (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp.726, 1988), or the method of obtaining from hybridomas described Kohlerand Milstein (Nature, 256:495-497, 1975).

The term "antagonist" shall mean a compound which is capable of directly or indirectly counteract, to reduce or inhibit the biological activity of c-Met.

Typically, a "therapeutically effective amount" refers to the minimum concentrations or amounts of compounds or compounds that is effective is to prevent, weaken, reduce, or alleviate symptoms of the disease or to prolong the life of the patient to be treated. More specifically, when referring to cancer treatment, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size (or preferably eliminate) the tumor; (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth; and/or (4) weakening to some extent (or, preferably, eliminating) one or more than one symptom caused by cancer.

More specifically, the antagonist of c-Met, representing the antibody or the functional fragment is selected from the group consisting of:

- antibodies (formed from 224G11 antibody or functional fragment comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing the amino acid sequence SEQ ID No. 1, 2 and 3; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, respectively, containing the amino acid sequence SEQ ID No. 10, 11 and 12;

- antibodies (antibodies generated from N) or its functional fragment comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing am nekisnotnice sequence SEQ ID No. 4, 5 and 6; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, respectively, containing the amino acid sequence SEQ ID No. 13, 11 and 14;

- antibodies (antibodies generated from S), comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing the amino acid sequence SEQ ID No. 7, 8 and 9; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, respectively, containing the amino acid sequence SEQ ID No. 15, 16 and 17; and

- antibodies (antibodies generated from A), comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing the amino acid sequence SEQ ID No. 47, 48 and 49; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, respectively, containing the amino acid sequence SEQ ID No. 50, 51 and 52.

In a more preferred form of implementation of the antagonist to c-Met, representing the antibody or the functional fragment is selected from the group consisting of:

- antibodies (formed from 224G11 antibody or functional fragment comprising a heavy chain containing the amino acid sequence of SEQ ID No. 18, and a light chain containing the amino acid sequence of SEQ ID No. 21;

- antibodies (antibodies generated from N) or its functional fragment comprising a heavy chain containing the amino acid sequence of SEQ ID No. 19, and a light chain containing amino acid in sledovatelnot SEQ ID No. 22;

- antibodies (antibodies generated from S), a heavy chain which contains the amino acid sequence of SEQ ID No. 20 and the light chain contains the amino acid sequence of SEQ ID No. 23; and

- antibodies (antibodies generated from A), comprising a heavy chain containing the amino acid sequence of SEQ ID No. 53, and a light chain containing the amino acid sequence of SEQ ID No. 54.

In another specific aspect, the antagonist of c-Met, representing the antibody or the functional fragment is a recombinant, chimeric or humanitariannet antibody or fragment formed from the 224G11 antibody, N, S or E (under educated should involve antibodies or fragments thereof containing at least the 6 CDRs or at least light and heavy chain, as defined above, for each of these antibodies).

More specifically, in the preferred form of the present invention relates to a method or composition according to the invention, where the antagonist to c-Met, which represents an antibody selected from the 224G11, N, S and E.

All of these monoclonal antibodies were secreted by the hybridomas deposited with the CNCM 03/14/2007 numbers CNCM I-3724 (corresponding E), I-3731 (corresponding 224G11), I-3732 (corresponding N) and 07/06/2007 under the number I-3786 (corresponding S). These hybrid of what we consist of mouse hybridoma, resulting from the fusion of splenocytes of immunized mice with cell myeloma line (Sp20Ag14).

Under the CDR regions or CDR imply an indication of the hypervariable region of the heavy and light chains of immunoglobulins, as defined by IMGT.

Unique IMGT numbering defined to compare variable domains independently of the antigen receptor, the type of circuit or of the form [Lefranc M.-P., Immunology Today 18, 509 (1997); Lefranc M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P., Pommie, S., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, Dev. Comp. Immunol., 27, 55-77 (2003)]. In a unique IMGT numbering conservative amino acids always have the same position, for example, cysteine 23 (1st-CYS), tryptophan 41 (CONSERVED-TRP), hydrophobic amino acid 89, cysteine 104 (2nd-CYS), phenylalanine or tryptophan 118 (J-PHE or J-TRP). Unique numbering IMGT provides a standardized definition of the boundaries of the frame regions (FR1-IMGT: position 1-26, FR2-IMGT: 39-55, FR3-IMGT: 66-104 and FR4-IMGT: 118-128) and identify areas of complementarity: CDR1-IMGT: 27-38, CDR2-IMGT: 56-65 and CDR3-IMGT: 105-117. Since the gaps are unoccupied position, the length of the CDR-IMGT (shown between parentheses and separated by dots, for example, [8.8.13]) become critical information. IMGT unique numbering used in 2D graphical representations, designated as IMGT Colliers de Perles [Ruiz, M. and Lefranc, M.-P., Immunogenetics, 53, 857-883 (2002); Kaas, Q. and Lefranc, M.-P., Current Bioinformatics, 2, 21-30 (2007)], and in 3D p is Church in IMGT/3Dstructure-DB [Kaas, Q., Ruiz, M. and Lefranc, M.-P., T cell receptor and MHC structural data. Nucl. Acids. Res., 32, D208-D210 (2004)].

There are three CDRs of the heavy chain and 3 CDR light chain. The term plot CDR or areas CDR used in this application to indicate, depending on the situation, one of these sites, or several, or even all of these sites in General, which contain most of the amino acid residues responsible for binding due to the affinity of the antibody to the antigen or epitope it recognizes.

The following table 1 reclassified items regarding preferred antibodies.

4
TABLE 1
224G11 I-3731227H1 I-3732223C4 I-378611E1 I-3724
Protein SEQ IDN. the SEQ IDProtein SEQ IDN. the SEQ IDProtein SEQ IDN. the SEQ IDThe protein. SEQ IDN. the SEQ ID
CDR-H1124277304755
CDR-H22255288314856
CDR-DK3266299324957
H-chain1841194220435361
CDR-L11033133615385058
CDR-L211343416395159
CDR-L31235143717405260
L-chain2144224523465462

In another preferred form of the method or composition according to the invention, the antagonist of c-Met, representing the antibody is an antibody or one of its functional fragments, formed from antibody called 224G11 (containing at least 6 CDR SEQ ID No. 1, 2, 3, 10, 11 and 12 or at least SEQ ID No. 18 and 21).

As described in the patent application WO 2006/021884, published 2 March 2006 (the provisions of which are incorporated in this application by reference), compounds of aminoheterocycles known as an inhibitor of c-Met and present activity proteincontaining.

As an unexpected result, the author of the crust is of the present application first presents the results illustrating relevant synergies when combining monoclonal antibody antagonist to c-Met, as described above, with the compound of aminoheterocycles, such as described in published patent application WO 2006/021884.

The invention relates to a method or composition for treating cancer in a mammal which comprises the administration to a mammal a therapeutically effective amount of a combination of active ingredients containing at least one antagonist of c-Met, which represents an antibody, as described above, and the connection of aminoheterocycles, preferably selected from those described in published patent application WO 2006/021884.

As a preferred example of the connection of aminoheterocycles compositions of the present invention is an enantiomerically pure compound of formula I

where:

Y represents N or CR12;

R1selected from a hydrogen atom, halogen, C6-12aryl, 5-12-membered heteroaryl,3-12cycloalkyl, 3-12-membered heteroalicyclic, -O(CR6R7)nR4, -C(O)R4, -C(O)OR4, -CN, -NO2, -S(O)mR4, -SO2NR4R5, -C(O)NR4R5, -NR4C(O)R5, -C(=NR6)NR4R5C1-8of alkyl, C2-8alkenyl and C2-8the quinil; and each hydrogen atom in 1optionally substituted by one or more than one group R3;

R2represents a hydrogen atom, halogen, C1-12alkyl, C2-12alkenyl,2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nNCR4R5, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)PR5or-C(O)NR4R5and each hydrogen atom in R2optionally substituted R8;

each R3independently represents halogen, C1-12alkyl,

C2-12alkenyl, C2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN,-C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nOR4, -(CR6R7)nC(O)NR4R5, -(CR6R7)nNR 4R5, -C(=NR6)NR4R5, NR4C(O)NR5R6, -NR4S(O)PR5or-C(O)NR4R5each hydrogen atom in R3optionally substituted R8and the group R3on adjacent atoms may be combined with the formation of C6-12aryl, 5-12 membered heteroaryl, C3-12cycloalkyl or 3-12-membered heteroalicyclic group;

each R4, R5, R6and R7independently represents a hydrogen atom, halogen, C1-12alkyl, C2-12alkenyl, C2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl; or any two of R4, R5, R6and R7related to the same nitrogen atom, can be combined together with the nitrogen atom to which they relate, with the formation of a 3-12-membered heteroalicyclic or 5-12-membered heteroaryl group, optionally containing 1 to 3 additional heteroatoms selected from N, O and S; or any two of R4, R5, R6and R7related to the same carbon atom, can be combined with education3-12cycloalkyl, C6-12aryl, 3-12 membered heteroalicyclic or 5-12-membered heteroaryl group; and each hydrogen atom in R4, R5, R6and R7optionally substituted R8;

each Rsup> 8independently represents halogen, C1-12alkyl, C2-12alkenyl, C2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -NH2, -CN, -OH, -O-C1-12alkyl, -O-(CH2)nC3-12cycloalkyl, -O-(CH2)nC6-12aryl, -O-(CH2)n(3-12-membered heteroalicyclic) or-O-(CH2)n(5-12-membered heteroaryl); and each hydrogen atom in R8optionally substituted R11;

each R9and R10independently represents a hydrogen atom, halogen, C1-12alkyl, C3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -OC(O)R4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nNCR4R5, -NR4C(O)NR5R6, -NR4S(O)PR5or-C(O)NR4R5; R9or R10can be combined with a ring atom of a or with the Deputy And with the formation of C3-12cycloalkyl, 3-12-membered heteroalicyclic, C6-12aryl or 5-12-membered heteroaryl ring fused with A; and each hydrogen atom in R9and R10optionally substituted R3 ;

each R11independently represents halogen, C1-12alkyl,

C1-12alkoxy, C3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -O-C1-12alkyl, -O-(CH2)nC3-12cycloalkyl, -O-(CH2)nC6-12aryl, -O-(CH2)n(3-12-membered heteroalicyclic), -O-(CH2)n(5-12-membered heteroaryl) or-CN, and each hydrogen atom in R11optionally substituted with halogen, -OH, -CN, -C1-12the alkyl which may be partially or fully halogenated, -O-C1-12the alkyl which may be partially or fully halogenated, -CO, -SO-or-SO2;

R12represents a hydrogen atom, halogen, C1-12alkyl, C2-12alkenyl,2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nNCR4R5, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)PR5or-C(O)NR4R5and each hydrogen atom in R12optionally substituted R3;

each R13independently represents halogen, C1-12alkyl,

C2-12alkenyl, C2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nOR4, -(CR6R7)nC(O)NR4R5, -(CR6R7)nNCR4R5, -C(=NR6)NR4R5, NR4C(O)NR5R6, -NR4S(O)PR5, -C(O)NR4R5, -(CR6R7)n(3-12-membered heteroalicyclic), -(CR6R7)n(C3-12cycloalkyl), -(CR6R7)n(C6-12aryl), -(CR6R7)n(5-12-membered heteroaryl), -(CR6R7)nC(O)NR4R5or -(CR6R7)nC(O)R4group R13on adjacent atoms may be combined to form with6-12aryl, 5-12 membered heteroaryl, C3-12cycloalkyl or 3-12-membered heteroalicyclic group, and each hydrogen atom in R13optionally substituted R3;

each m independently is 0, 1 or 2;

each n independently is 0, 1, 2, 3 or 4;/p>

each p is independently 1 or 2;

or its pharmaceutically acceptable salt, hydrate or MES.

In another preferred example, the compound of aminoheterocycles is an enantiomerically pure compound of formula Ia:

where:

Y represents N or CH;

R1is a group of furan, thiophene, pyrrole, pyrrolin, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazol, isothiazol, oxadiazole, triazole, thiadiazole, Piran, pyridine, piperidine, dioxane, morpholine, Titian, thiomorpholine, pyridazine, pyrimidine, pyrazin, piperazine, triazine, Titian, azetidin or phenyl; and each hydrogen atom in R1optionally substituted R3;

each R3independently represents halogen, C1-12alkyl,

C2-12alkenyl, C2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nOR4, -(CR6R7)nC(O)NR4R5, -(CR6R7 nNCR4R5, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)pR5or-C(O)NR4R5each hydrogen atom in R3optionally substituted R8and the group R3on adjacent atoms may be combined with the formation of C6-12aryl, 5-12 membered heteroaryl, C3-12cycloalkyl or 3-12-membered heteroalicyclic group;

each R4, R5, R6and R7independently represents a hydrogen atom, halogen, C1-12alkyl, C2-12alkenyl, C2-12quinil,3-12cycloalkyl,6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl; or any two of R4, R5, R6and R7related to the same nitrogen atom, can be combined together with the nitrogen atom to which they relate, with the formation of a 3-12-membered heteroalicyclic or 5-12-membered heteroaryl group, optionally containing 1 to 3 additional heteroatoms selected from N, O and S; or any two of R4, R5, R6and R7related to the same carbon atom, can be combined with education3-12cycloalkyl, C6-12aryl, 3-12 membered heteroalicyclic or 5-12-membered heteroaryl group; and each hydrogen atom in R4, R5, R6and R7optionally substituted R8 ;

each R8independently represents halogen, C1-12alkyl, C2-12alkenyl, C2-12quinil, C3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -NH2, -CN, -OH, -O-C1-12alkyl, -O-(CH2)nC3-12cycloalkyl, -O-(CH2)nC6-12aryl, -O-(CH2)n(3-12-membered heteroalicyclic) or-O-(CH2)n(5-12-membered heteroaryl); and each hydrogen atom in R8optionally substituted R11;

each R9and R10independently represents a hydrogen atom, halogen, C1-12alkyl, C3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -OC(O)R4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nNCR4R5, -NR4C(O)NR5R6, -NR4S(O)PR5or-C(O)NR4R5; R9or R10can be combined with a ring atom of a or with the Deputy And education3-12cycloalkyl, 3-12-membered heteroalicyclic, C6-12aryl or 5-12-membered heteroaryl ring fused with A; and each hydrogen atom in R9and R10NeoMaster is but substituted R 3;

each R11independently represents halogen, C1-12alkyl,

C1-12alkoxy, C3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -O-C1-12alkyl, -O-(CH2)nC3-12cycloalkyl, -O-(CH2)nC6-12aryl, -O-(CH2)n(3-12-membered heteroalicyclic), -O-(CH2)n(5-12-membered heteroaryl) or-CN, and each hydrogen atom in R11optionally substituted with halogen, -OH, -CN, -C1-12the alkyl which may be partially or fully halogenated, -O-C1-12the alkyl which may be partially or fully halogenated, -CO, -SO-or-SO2;

each R13independently represents halogen, C1-12alkyl,

C2-12alkenyl, C2-12quinil,3-12cycloalkyl, C6-12aryl, 3-12-membered heteroalicyclic, 5-12-membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nOR4, -(CR6R7)nC(O)NR4R5, -(CR6R7)nNCR4R5, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)PR5/sup> , -C(O)NR4R5, -(CR6R7)n(3-12-membered heteroalicyclic), -(CR6R7)n(C3-12cycloalkyl), -(CR6R7)n(C6-12aryl), -(CR6R7)n(5-12-membered heteroaryl), -(CR6R7)nC(O)NR4R5or -(CR6R7)nC(O)R4group R13on adjacent atoms may be combined with the formation of C6-12aryl, 5-12 membered heteroaryl, C3-12cycloalkyl or 3-12-membered heteroalicyclic group, and each hydrogen atom in R13optionally substituted R3;

each m independently is 0, 1 or 2;

each n independently is 0, 1, 2, 3 or 4;

each p is independently 1 or 2;

or its pharmaceutically acceptable salt, hydrate or MES.

More specifically, preferred compounds aminoethanol according to the invention is selected from compounds of the aminopyridine or aminopyrazine.

Connection aminoheterocycles preferably in accordance with the form of embodiment of the invention selected from the group consisting of 5-bromo-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-ylamine; 5-iodine-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine; 5-bromo-3-[1(R)-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine; 4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-benzoic acid; (4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-p the Razin-2-yl}-phenyl)-piperazine-1-ylmethanone; 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester; 3-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]-5-[4-(piperazine-1-ylcarbonyl)phenyl]pyridine-2-amine; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; (4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}phenyl)methanol; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}-N-[3-(dimethylamino)propyl]-N-methylbenzamide; tert-butyl 4-(4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}benzoyl)piperazine-1-carboxylate; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-[1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl]-pyridine-2-ylamine; 1-[4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-3-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-hydroxyethane; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyrazin-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1H-pyrazole-4-yl)-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-hydroxyethane; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-[1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl]-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-CFT is henyl)-ethoxy]-pyrazin-2-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-dimethylaminoethanol; 3-[(R)-1-(2-chloro-3,6-differenl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; or their pharmaceutically acceptable salts, MES or hydrate.

In another preferred form of the invention, the connection of aminoheterocycles represents 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine. Another name given to this chemical compound is PF-02341066 (write PF-2341066).

This particular connection is described in detail in Example 13 published patent application WO 2006/021884, and method thereof described in the methodology 62, which is cited below.

General methods 62:

To a solution of 5-bromo-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine (12,83 g, 33,76 mmol) in anhydrous DMF (100 ml) was added di-tert-BUTYLCARBAMATE (each holding 21.25 g, 97,35 mmol) and 4-dimethylaminopyridine (0.793 g, of 6.49 mmol). The reaction mixture was stirred at ambient temperature for 18 hours under nitrogen atmosphere. To the mixture was added a saturated solution of NaHCO3(300 ml) and was extracted with EtOAc (3×250 ml). The combined extracts were washed with water (5×100 ml), saturated NaHCO3and brine, then dried over Na2SO4. After filtration, evaporation and drying under high vacuum, di-BOC-protected 5-bromo-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-Ilam the n received in the form of whitish foamy solid (19,59 g, yield 100%).1H NMR (DMSO-d6, 400 MHz) δ 8.18 (d, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.48 (t, 1H), 6.25 (q, 1H), 1.75 (d, 3H), 1.39 (s, 9H), 1.19 (s, 9H).

To a solution of di-BOC-protected 5-bromo-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine (19,58 g, 33,76 mmol) in DMSO (68 ml) was added potassium acetate (of 11.26 g, 114,78 mmol) and bis(pinacolato)LIBOR (10,29 g, 40,51 mmol). The mixture was degirolami and loaded with nitrogen three times, then was added Pd(dppf)Cl2·CH2Cl2(1,38 g, was 1.69 mmol). The reaction mixture was degirolami and loaded with nitrogen three times and then stirred at 80°C oil bath under nitrogen atmosphere for 12 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (100 ml) and filtered through a layer of Celica, which was washed with ethyl acetate. United an ethyl acetate solution (700 ml), washed with water (5×100 ml), brine (100 ml) and dried over Na2SO4. After filtration and concentration the residue was purified on a column of silica gel, elwira EtOAc/hexane (0%-50%), with di-BOC-protected 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-ylamine in the form of a foamy solid (20,59 g, yield 97%).1H NMR (DMSO-d6, 400 MHz) δ 8.20 (d, 1H), 7.70 (d, 1H), 7.63 (dd, 1H), 7.47 (t, 1H), 6.20 (q, 1H), 1.73 (d, 3H), 1.50-1.13 (m, N).

To a solution of di-BOC-protected 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-yl)-pyridine-2-ylamine (20,34 g, 32,42 mmol) in CH2Cl2(80 ml) was added a solution of dry HCl in dioxane (4 N., of 40.5 ml, 162 mmol). The reaction solution was stirred at 40°C. oil bath under nitrogen atmosphere for 12 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (400 ml), then carefully but quickly washed with saturated NaHCO3up until the aqueous layer became basic (pH>8). The organic layer was washed with brine and dried over Na2SO4. After filtration, evaporation and drying under high vacuum, 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-ylamine obtained in the form of whitish foamy solid (13,48 g, yield 97%).1H NMR (DMSO-d6, 400 MHz) δ 8.01 (d, 1H), 7.27 (dd, 1H), 7.17 (d, 1H), 7.03 (t, 1H), 6.12 (q, 1H), 5.08 (bs, 2H), 1.81 (d, 3H), 1.30 (s, 6H), 1.28 (s, 6H).

To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-ylamine (4,2711 g, 10.0 mmol) and 4-(4-bromopyrazole-1-yl)-piperidine-1-carboxylic acid tert-butyl ether (3,9628 g, 12,0 mmol) in DME (40 ml) was added a solution of Na2CO3(3,1787 g, 30.0 mmol) in water (10 ml). The solution was degirolami and loaded with nitrogen three times. To the solution was added Pd(PPh3J2Cl2(351 mg, 0.50 mmol). The reaction solution was again degirolami and loaded with nitrogen three times. The reaction solution was stirred at 87°the oil bath for about 16 hours (or until the expenditure of pinacolone borane ester), was cooled to ambient temperature and diluted with EtOAc (200 ml). The reaction mixture was filtered through a layer of cellite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4and concentrated. The crude product was purified on a column of silica gel, elwira system of EtOAc/hexane (0% EtOAc to 100% EtOAc), to obtain 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-3-yl}-pyrazole-1-yl)-piperidine-1-carboxylic acid tert-butyl ether (3,4167 g, yield 65%, purity ~95%) with Rf of 0.15 (50% EtOAc/hexane). MS m/e 550 (M+1)+.

To a solution of 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-3-yl}-pyrazole-1-yl)-piperidine-1-carboxylic acid tert-butyl ether (566,7 mg of 1.03 mmol) in methanol (5 ml) or dichloromethane (30 ml) was added 4 N. HCl/dioxane (15 ml). The solution was stirred for about 1 hour or until complete removal of protection. The solvents are evaporated, and the residue was dissolved in methanol and purified on preparative HPLC C-18 reversed-phase elwira a mixture of acetonitrile/water with 0.1% acetic acid, from 5% to 30% with a linear gradient. After lyophilization 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine acetate was obtained as a white solid (410 mg, yield 78%, 100% purity by HPLC, 96,4% Hey).1H NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.68 (d, 1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (q, 1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m, 2H), 1.88 (m, 2H), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e 450 (M+1)+.

In a particular aspect of the invention discussed the composition of the present invention, where the connection aminoethanol is a compound of formula Ib:

In another aspect, the invention relates to a method where the cancer is selected from cancers with overexpression of c-Met and/or exhibit autophosphorylating c-Met.

More specifically, the cancer is selected from prostate cancer, osteosarcoma, lung cancer, breast cancer, endometrial cancer, glioblastoma, or colon cancer.

In a preferred form of implementation, the invention relates to compositions, as mentioned above, where the antagonist to c-Met, which represents an antibody selected from the antibodies formed from 224G11, N, S and E or their functional fragments.

More specifically, the antagonist of c-Met, representing the antibody formed from 224G11 antibody.

In another form of the invention in this application is described composition, where the connection aminoheterocycles selected from compounds of the aminopyridine or aminopyrazine.

More specifically, the connection aminoethanol is a compound of formula Ib:

The invention also relates to the use of a composition as defined in this application, to ensure the aka in a mammal.

In a specific preferred form of implementation of the cancer is selected from cancers with overexpression of c-Met and/or exhibit autophosphorylating c-Met. More specifically, the cancer is selected from prostate cancer, osteosarcoma, lung cancer, breast cancer, endometrial cancer, glioblastoma, or colon cancer.

The invention will be better understood on reading the following examples, where:

Figure 1 illustrates the activity in vivo 224G11 and activity in vivo PF-2341066 on NCI-H441 NSCLC, and

Figure 2 illustrates the synergistic activity in vivo combination 224G11 and PF-2341066 on NCI-H441 NSCLC.

Example 1: Activity in vivo 224G11 and PF-02341066 in the form of individual therapies

To verify that the model NCI-H441 in vivo, available in the laboratory, are sensitive both to the 224G11 antibody and the compound PF-2341066, used mice with immune deficiency, transplanted subcutaneously NCI-H441. Briefly, cells NCI-H441 NSCLC from ATCS were cultured in medium RPMI 1640, 10% FTS, 1% L-glutamine. The cells were divided for two days prior to transplantation, so that they were in the exponential growth phase. Ten million cells NCI-H441 were injected with s.c. Nude mice. Five days after implantation, tumors were measurable, and animals were divided into groups of 6 mice with comparable tumor size. For antibody treatment, mice were treated I.P. Pavlova. saturating dose of 2 mg 224G11 Mab/mouse, and then twice a week on 1 mg of antibody/mouse is. 50 mg/kg PF-02341066 was introduced r.o. (oral probe), daily during the week, and then 5 days a week with a double dose on the fifth day. Treatment was continued throughout the experiment. Tumor volume was measured twice a week and calculated by the formula: π/6 X length X width X height.

The results described in figure 1, showed a significant difference in tumor growth in mice treated as 224G11 and PF-02341066. In this experiment 224G11 and PF2341066 showed comparable anti-tumor activity.

Example 2: Activity in vivo combination 224G11 and PF-02341066

Cells NCI-H441 from ADS routinely cultured in medium RPMI 1640, 10% FTS, 1% L-glutamine. The cells were divided for two days prior to transplantation, so that they were in the exponential growth phase. Ten million cells NCI-H441 were injected with s.c. Nude mice. Five days after implantation, tumors were measurable, and animals were divided into groups of 6 mice with comparable tumor size. For antibody treatment, mice were treated I.P. Pavlova. saturating dose of 2 mg 224G11 Mab/mouse, and then twice a week on 1 mg of antibody/mouse. 50 mg/kg PF-02341066 was introduced r.o. (oral probe), daily during the week, and then 5 days a week with a double dose on the fifth day. The group of mice receiving and 224G11, and PF-2341066, processed, by the same methods as described above for each connection. Tumor volume was measured is vital in a week and calculated by the formula: π/6 X length X width X height, and monitoring of body weight of the animals was performed daily during the whole period of treatment.

Statistical analysis was performed on each dimension, using the criterion of Mann-Whitney. In this experiment, the control group mice were killed on day 53 for ethical reasons. On day 53 after the first injection, the average tumor size groups treated one way, decreased by 64%, 73% and 93% for 224G11, PF-2341066 and 224G11+PF-2341066, respectively. On day 53, combination therapy significantly improved tumor growth compared with the same therapy (p≤0,002 compared with one PF-2341066 and p≤0,002 compared with one 224G11), and one of the 6 mice in the combination therapy group was not a tumor. Significant differences were not observed between the 2 treatments one treatment.

These results are presented in figure 2, were confirmed within 14 days after the end of treatment (D67), where tumor volume of the group receiving combination therapy remained significantly lower than those, which were injected with the way one therapy, and where 16% of mice receiving the combined therapy was still free from tumor.

1. Composition for treating cancer containing the antagonist to c-Met, representing the antibody or the functional fragment and the connection of aminoheterocycles, where the specified connection aminoheterocycles selected from the group which ostoja from:
5-bromo-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-ylamine; 5-iodine-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine; 5-bromo-3-[1(R)-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine; 4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-benzoic acid; (4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazine-1-ylmethanone; 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester; 3-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]-5-[4-(piperazine-1-ylcarbonyl)phenyl]pyridine-2-amine; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; (4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}phenyl)methanol; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}-N-[3-(dimethylamino)propyl]-N-methylbenzamide; tert-butyl 4-(4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}benzoyl)piperazine-1-carboxylate; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-[1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl]-pyridine-2-ylamine; 1-[4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-3-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-hydroxyethane; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperid is n-4-yl-1H-pyrazole-4-yl)-pyrazin-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1H-pyrazole-4-yl)-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-hydroxyethane; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-[1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl]-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-dimethylaminoethanol; 3-[(R)-1-(2-chloro-3,6-differenl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; or their pharmaceutically acceptable salts, MES or hydrate.

2. The composition according to claim 1 as a medicine.

3. Pharmaceutical composition for treating cancer containing at least:
i) one antagonist of C-Met, which represents an antibody or functional fragment; and
ii) connection of aminoheterocycles,
in the form of combination products, where the specified connection aminoheterocycles selected from the group consisting of:
5-bromo-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-ylamine; 5-iodine-3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine; 5-bromo-3-[1(R)-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-2-ylamine; 4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-benzoic acid; (4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazine-1-ylmethanone; 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-benzoyl)-piperazine-1-carbon is Oh acid tert-butyl ester; 3-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]-5-[4-(piperazine-1-ylcarbonyl)phenyl]pyridine-2-amine; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; (4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}phenyl)methanol; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}-N-[3-(dimethylamino)propyl]-N-methylbenzamide; tert-butyl 4-(4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-forfinal)ethoxy]pyridine-3-yl}benzoyl)piperazine-1-carboxylate; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-[1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl]-pyridine-2-ylamine; 1-[4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyridine-3-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-hydroxyethane; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyrazin-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-(1H-pyrazole-4-yl)-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-hydroxyethane; 3-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-5-[1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl]-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-forfinal)-ethoxy]-pyrazin-2-yl}-pyrazole-1-yl)-piperidine-1-yl]-2-dimethylaminoethanol; 3-[(R)-1-(2-chloro-3,6-differenl)-ethoxy]-5-(1-Pipa is one-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine; or their pharmaceutically acceptable salts, MES or hydrate.

4. Composition according to any one of claims 1 to 3, where the antagonist to c-Met, representing the antibody or the functional fragment is selected from the group consisting of:
the antibody or functional fragment comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing the amino acid sequence SEQ ID No. 1, 2 and 3; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, respectively, containing the amino acid sequence SEQ ID No. 10, 11 and 12;
the antibody or functional fragment comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing the amino acid sequence SEQ ID No. 4, 5 and 6; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, respectively, containing the amino acid sequence SEQ ID No. 13, 11 and 14;
the antibody or functional fragment comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing the amino acid sequence SEQ ID No. 7, 8 and 9; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, respectively, containing the amino acid sequence SEQ ID No. 15, 16 and 17; and
the antibody or functional fragment comprising a heavy chain contains the CDR-H1, CDR-H2 and CDR-H3, respectively, containing the amino acid sequence SEQ ID No. 47, 48 and 49; and a light chain contains the CDR-L1, CDR-L2 and CDR-L3, operasie respectively amino acid sequence of SEQ ID No. 50, 51 and 52.

5. Composition according to any one of claims 1 to 3, where the antagonist to c-Met, representing the antibody or the functional fragment is selected from the group consisting of:
the antibody or functional fragment comprising a heavy chain containing the amino acid sequence of SEQ ID No. 18, and a light chain containing the amino acid sequence of SEQ ID No. 21;
the antibody or functional fragment comprising a heavy chain containing the amino acid sequence of SEQ ID No. 19, and a light chain containing the amino acid sequence of SEQ ID No. 22;
the antibody or functional fragment, a heavy chain which contains the amino acid sequence of SEQ ID No. 20 and the light chain contains the amino acid sequence of SEQ ID No. 23; and
the antibody or functional fragment comprising a heavy chain containing the amino acid sequence of SEQ ID No. 53, and a light chain containing the amino acid sequence of SEQ ID No. 54.

6. Composition according to any one of claims 1 to 3, where the antagonist to c-Met, representing the antibody or the functional fragment is selected from the group consisting of monoclonal antibodies secreted by the hybridomas deposited with the Collection Nationale de Cultures de Microorganismes (CNCM, Institut Pasteur, Rue du Docteur Roux, Paris, France) March 14, 2007 under the numbers I-3724, I-3731, 3732 and July 6, 2007 under the number I-3786.

7. HDMI is tion according to claim 6, where the antagonist to c-Met, representing the antibody is a monoclonal antibody, named 224G11, Sekretareva hybridomas deposited in the CNCM on March 14, 2007 under the number I-3731, or the antibody or functional fragment formed from the 224G11 antibody, including:
- at least 6 CDR having the sequence SEQ ID No. 1, 2, 3, 10, 11 and 12; or
at least a heavy chain containing the amino acid sequence of SEQ ID No. 18, and a light chain containing the amino acid sequence of SEQ ID No. 21.

8. Composition according to any one of claims 1 to 3, where the connection aminoethanol is a compound of formula Ib:

9. Composition according to any one of claims 1 to 3, where the cancer is selected from cancers with overexpression of c-Met and/or exhibit autophosphorylating c-Met.

10. Composition according to any one of claims 1 to 3, where the cancer is selected from prostate cancer, osteosarcoma, lung cancer, breast cancer, endometrial cancer, glioblastoma, or colon cancer.

11. The composition according to any one of claims 1-3 for the treatment of cancer in a mammal, preferably human.

12. The use of the pharmaceutical composition according to claim 3, containing in combined preparations at least the antagonist to c-Met, representing the antibody or the functional fragment and the connection of aminoheterocycles as defined in any of claims 4 to 9 to obtain drugs for cancer treatment.

13. The application indicated in paragraph 12, where the cancer is selected from cancers with overexpression of c-Met and/or exhibit autophosphorylating c-Met.

14. The application indicated in paragraph 12, where the cancer is selected from prostate cancer, osteosarcoma, lung cancer, breast cancer, endometrial cancer, glioblastoma, or colon cancer.

15. The use according to any one of p-14 for the treatment of cancer in a mammal, preferably human.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to methods for reducing B-cell count or treating a disease or disorder related to pathological activity of B-cells. That is ensured by administering a therapeutically effective amount of CD37-specific binding molecule and a therapeutically effective amount of mTOR or PI3K inhibitor into an individual. There are also presented a composition and a kit for treating non-Hodgkin lymphoma.

EFFECT: group of inventions provides a synergetic effect in administering CD37-specific binding molecules (SMIP) in a combination with mTOR or PI3K inhibitors for treating or preventing the B-cell related hyperproliferative disease.

36 cl, 9 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and concerns using a peptide conjugated with a protein representing a keyhole limpet hemocyanin (KLH) protein used as an immunogen for preparing antibodies specifically recognising any of prevailing versions of beta-amyloid peptide Aβ40 and Aβ42; or using an antibody, or an active fragment, or an antibody derivative of the above peptide in preparing a therapeutic agent for preventing and/or treating a disease characterised by amyloid accumulation in the patient's brain.

EFFECT: group of inventions provides effective immunisation, reduces an amyloid load and a quantity of brain amyloid plaques.

5 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to experimental cardiology and pharmacology, and concerns correction of endothelial dysfunction. That is ensured by administering a mixture of solutions of homoeopathic dilutions of monoclonal antibodies to vascular endothelium growth factor (VEGF) intragastrically into Wistar white male rats 2 times a day in a dose of 4.5 mg/kg for 28 days with underlying intraperitoneal administration of L-NAME in a dose of 12.5 mg/kg a day.

EFFECT: administering homoeopathic dilutions of monoclonal antibodies to VEGF prevents developing L-NAME induced endothelial dysfunction.

1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to experimental cardiology and pharmacology, and concerns correction of endothelial dysfunction. That is ensured by administering a mixture of solutions of homoeopathic dilutions of monoclonal antibodies to interleukin-1 intragastrically into Wistar white male rats 2 times a day in a dose of 4.5 mg/kg for 28 days with underlying intraperitoneal administration of L-NAME in a dose of 12.5 mg/kg a day.

EFFECT: administering homoeopathic dilutions of monoclonal antibodies to interleukin-1 prevents developing L-NAME induced endothelial dysfunction.

1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and pharmacology, and concerns correction of endothelial dysfunction. That is ensured by administering an activated potentiated form of vascular endothelial growth factor (VEGF) antibodies in an effective amount.

EFFECT: correction of endothelial dysfunction.

5 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of biotechnology. Claimed is a method of obtaining a high-titre antimicrobial serum. Method includes application of strain S.aureus No1991, characterised by immunogenicity ED50=(50-100)×106 microbial cells, weak virulence LD50=(0.5-2.0)×109 microbial cells; its inactivation and drying with dimethylketone by double processing with 3 volumes of dimethylketone. After that, immunisation of animals is carried out: two times subcutaneously and two times intravenously. In conclusion serum isolation is carried out.

EFFECT: invention can be used in medicine for estimation of antigen activity of anti-staphylococcal vaccines.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to cardiology, and deals with treatment and prevention of arterial hypertension. For this purpose pharmaceutical composition, containing activated potentiated antibodies to angiotensin II receptor and to endothelial NO-synthase, is introduced.

EFFECT: method ensures effective treatment of arterial hypertension due to synergic antihypertensive action of composition components.

11 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group relates to medicine, namely to cardiology, and deals with treatment of chronic heart failure. For this purpose pharmaceutical composition, containing activated potentiated forms of antibodies to angiotensin II receptor and to endothelial NO-synthase is introduced.

EFFECT: synergic action of pharmacological composition components ensures improvement of systolic function of left ventricle and increase of tolerance to physical load in said group of patients.

11 cl, 2 ex, 2 tbl

Antibody to epha2 // 2525133

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of immunology, medicine and biotechnology. Claimed are versions of anti-EPHA2 antibodies. Claimed antibodies are bound with polypeptide, consisting of amino acids 426-534 in SEQ ID NO:8. Also described are hybridomes, which produce such antibodies, and pharmaceutical compositions and methods of application of said antibodies and compositions.

EFFECT: invention can be used in medicine.

74 cl, 14 dwg, 14 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the field of immunology. Disclosed is a method of treating rheumatoid arthritis, chronic arthritis in children or Castelman's disease, application of an antibody in the said method, as well as application of an antibody in production of a medication for treatment of rheumatoid arthritis, chronic arthritis in children or Castelman's disease. The antibody by the claimed invention possesses an improved antigen-neutralising ability, pharmacokinetics, immunogenicity, safety and physicochemical properties and can be further applied in therapy of diseases, associated with the activation of the receptor IL-6.

EFFECT: claimed is the medication for treatment of rheumatoid arthritis, chronic arthritis in children or Castelman's disease, representing the antibody against the receptor IL-6, obtained on the basis of the antibody TOCILIZUMAB.

12 cl, 5 dwg, 2 ex

FIELD: genetic engineering, immunology, medicine.

SUBSTANCE: invention relates to new antibodies directed against antigenic complex CD3 and can be used in therapeutic aims. Antibody IgG elicits the affinity binding with respect to antigenic complex CD3 wherein heavy chain comprises skeleton of the human variable region in common with at least one CD3 taken among amino acid sequences SEQ ID NO 2, 4 and 6 and their corresponding conservatively modified variants. Light chain comprises skeleton of the rodent variable region in common with at least one CD3 taken among amino acid sequences SEQ ID NO 8, 10 and 12 and their corresponding conservatively modified variants. Antibody is prepared by culturing procaryotic or eucaryotic cell co-transformed with vector comprising recombinant nucleic acid that encodes antibody light chain and vector comprising recombinant nucleic acid that encodes antibody heavy chain. Antibody is administrated in the patient suffering with malignant tumor or needing in immunosuppression in the effective dose. Invention provides preparing chimeric antibodies against CD3 that are produced by expression systems of procaryotic and eucaryotic cells with the enhanced yield.

EFFECT: improved preparing methods, valuable medicinal properties of antibody.

33 cl, 5 dwg, 1 ex

FIELD: medicine, pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a composition eliciting an antiviral effect. The composition comprises hydrophilic conglomerate of immunoglobulins consortium adsorbed with polyethylene glycol 4000-6000, recombinant interferon-α2 and a special additive taken among the following substances: glycine, glucose, maltose, sodium chloride taken in the definite ratio of components. Invention provides elevating solubility of composition eliciting an antiviral effect and enhanced release of biologically active substances to solution.

EFFECT: valuable medicinal properties of composition.

5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a composition eliciting an antibacterial effect. Composition comprises hydrophilic conglomerate of immunoglobulins consortium adsorbed with polyethylene glycol 4000-6000 and a special additive taken among the following substances: glycine, glucose, maltose, sodium chloride taken in the definite ratio of components. Invention provides sufficient desorption of biologically active substances in resuspending the composition eliciting an antibacterial effect and comprising consortium of immunoglobulins.

EFFECT: valuable medicinal properties of composition.

5 ex

FIELD: immunology.

SUBSTANCE: the innovation deals with new immunogenic conjugates of beta-propionamide-bound polysaccharide and N-propionamide-bound oligosaccharide with protein, and the method to obtain these conjugates has been suggested, as well. Conjugates should be applied to obtain vaccines against infectious diseases and cancer that enables to broaden the number of preparations applied in treating the above-mentioned diseases.

EFFECT: higher efficiency.

1 dwg, 2 ex, 8 tbl

FIELD: microbiology and immunology, in particular immunodiagnosis.

SUBSTANCE: atypical strain of melioidose Burkholderia pseudomallei-111-6-1 with altered phenotype defected with respect to synthesis of 8 antigen and acting as immunosuppressor is used as antigen for animal immunization. Immune serum is obtained after 2 immunization cycles of animal-producer with titer in gel immunodiffusion reaction not less than 1:128.

EFFECT: immune serum with increased specific activity.

2 tbl, 2 ex

FIELD: medicine and immunology, in particular treatment and prevention immunodeficiency conditions and diseases associated with bacterial or viral aggression.

SUBSTANCE: claimed method includes administration to a patient immunoglobulin drug (e.g., pharmaceutical composition containing 6-12 % of specific heterologous secreted immunoglobulin A, isolated from milk or foremilk of immunized ungulates). Administration is performed parenterally wherein single dose is at least 10 IU/kg of patient weight for treatment or at least 5 IU/kg for prophylaxis; or perorally in dose of 0.2-0.5 g and/or topically one-two times per day for 1-5 days. Method of present invention makes it possible to decrease dose of administrating immunoglobulin due to prolonged retention of its high titers in body fluids.

EFFECT: enlarged range of application and assortment of immunoglobulin drugs.

4 cl, 5 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with cryoprotective ointment containing recombinant interferon-α2. The suggested cryoprotective ointment contains recombinant interferon-α2, glycerol, polyethylene glycol 300-6000, polyglucin, buffered 0.02%-Trilon B solution at pH of 5.5-7.0 and ointment foundation at a certain content of components per 1.0 g ointment. Additionally, cryoprotective ointment could contain glycine 3,7-bis(dimethylamino)phenothiazonium chloride, dry immunoglobulin preparation or dry immunoglobulin preparation for enteral application. Ointment foundation of cryoprotective ointment could contain water-free lanolin, Vaseline and Vaseline oil, at the following ratio of components: 2.5;3.5:1 - 6.5:0.5:1. The innovation provides maximal safety of recombinant interferon-α2 activity in cryoprotective ointment at multiple alteration of positive and negative environmental temperature and at keeping cryoprotective ointment under these conditions.

EFFECT: higher efficiency of application.

8 cl, 8 ex

FIELD: medicine, pharmaceutics, pharmacology.

SUBSTANCE: one should apply mammalian anti-HBP-antibodies. The ways are being suggested to identify monoclonal antibody bound, at least, with one epitope upon native HBP (heparin-binding protein) and methods to detect whether a mammal produces HBR being bound with a monoclonal antibody and, also, the kits for the above-mentioned purpose. The present innovation provides the opportunity to apply the mentioned antibodies in preventing and treating disorders associated with bradykinin releasing.

EFFECT: higher efficiency of application.

25 cl, 11 dwg, 3 ex, 1 tbl

FIELD: veterinary science.

SUBSTANCE: animals should be introduced with antihistamine serum (AHS) subcutaneously at the dosage of 4.0-5.0 ml in combination with myxoferon at the quantity of 60-75 dosages and vitamin C at the dosage of 1.0-1.5 ml/animal, once daily, thrice at interval of 5-7 d. Application of AHS in combination with myxoferon and ascorbic acid provides active stimulation of immunological reactivity, increases total body resistance I animals and causes no toxic effects and allergic reactions.

EFFECT: higher efficiency of correction.

3 tbl

FIELD: immunology, biotechnology, medicine.

SUBSTANCE: invention relates to antiidiotypical monoclonal antibody or fragment thereof for BSW17 antibody effecting on LgE Cε3-region bonding to high affinity LgE receptor. Amino acid sequence is as described in specification. antiidiotypical antibody is useful as pharmaceutical composition ingredient for LgE-mediated disease treatment. Invention make in possible to prevent allergic disorders and inflammations due to inhibiting interaction between LgE Cε3-region with high affinity receptor by claimed antibody.

EFFECT: new agent for allergic and inflammation disorder treatment.

7 cl, 32 dwg, 5 tbl, 10 ex

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