Pharmaceutical composition comprising the agonist or antagonist of adenosine receptor

 

Proposed: new pharmaceutical compositions containing agonists of adenosine receptors, in particular agonists that bind to the adenosine A3 receptor. These compositions are used for the induction of the production or secretion of G-CSF in the body, prevention or treatment of toxic side effects medicines or treatment of radiation, in particular radiation caused by drugs; and for inhibiting the abnormal growth and proliferation of cells. The invention expands the Arsenal of the declared destination. 7 C. and 29 C.p. f-crystals, 20 ill.

The technical field to which the invention relates.

The present invention relates to the field of cancer and for the treatment of cancer or treatment intended to counteract the side effects of cancer treatment.

The level of technology

Below is a list of works relating to the description of prior art in the field to which the invention relates. The mention of these links in the description is made by indicating in brackets the number of links in the following list.

1. Linden J. The FASEB J. 5:2668-2676 (1991);

2. Stiles, G. L. Clin. Res. 38:10-18 (1990>p>6. Clark C. and M. Coupe Int. J. Cardiol. 23:1-10 (1989);

7. R. K. Dubey et al. Circulation 96:2656-2666 (1997);

8. Soderback U. et al. Clin. Sci. 81:691-694 (1994);

9. Gilbertsen R. B. Agents actions 22:91-98 (1987);

10. Bouma, M. G. et al. J. Immunol. 153:4159-4168 (1994);

11. Rozengurt E. Exp. Cell Res. 139:71-78 (1982);

12. Gonzales F. A. et al., PNAS USA 87:9717-9721 (1990);

13. Sandberg G. and Fredholm B. B. Thymus 3:63-75 (1981);

14. Pastan I. H. et al. Annu. Rev. Biochem. 44:491-495 (1975);

15. WO 99/02143;

16. Fishman P., et al. Cancer Res. 58:3181-3187 (1998);

17. Djaldetti M. et al. Clin. Exp. Metastasis 14:189-196 (1996);

18. Fishman P. et al. Cancer Research 58:3181-3187 (1998).

Background of invention

Myelotoxicity is a common serious complication of chemotherapy and one of the factors limiting the dose of chemotherapeutic drugs that can be entered. It causes life-threatening disease in treated patients and more actual deaths than any other side effect of chemotherapy and can lead to longer patient's stay in hospital. Also called drug myelosuppression restricts the assignment of large, possibly, more effective doses of chemotherapy in patients with malignant diseases. Some approaches to the solution of the question about this side effect include the use of lithium, prostaglandin E, interpolating colony-stimulating factor (G-CSF). At the present time, the use of growth factors such as G-CSF, is a common therapy for cancer patients with neutropenia. This therapy stimulates the proliferation and differentiation of hematopoietic precursors and regulates the functional activity of neutrophils and macrophages. However, treatment with G-CSF is expensive, since G-CSF is a recombinant protein, and is accompanied by side effects.

Endogenous purine nucleoside adenosine is a ubiquitous types of mammalian cells. Adenosine is present in plasma and other extracellular fluids, mediates many of its physiological actions via receptors on the cell surface and is an important regulatory protein. It is released in the extracellular environment from metabolically active or exposed to the external environment of the cells. It is known that adenosine acts through binding with specific associated with G-protein membrane receptors A1, A2 and A3(1-2). Interaction of adenosine from its receptors initiates path signal transduction, mainly adenylyl cyclase effector system, utilizing camp as the second vector. While the A1 receptors is AMR, the A2 receptor, combined with the Gs-proteins, activates adenylate cyclase, and through this increased level of camp(3).

As specific adenosine-surface receptors are found in nearly all cells, almost all organ systems of the body to some extent governed by its local release. These include regulation of the electrophysiological properties of the heart, peace and the suppression of the release of neurotransmitters and regulation of the release of rennin and vascular tone in the kidneys(4-7). Adenosine exerts various effects on the immune system, including anti-inflammatory activity through the inhibition of release of cytokines, inhibition of platelet aggregation, induction of the production of erythropoietin and modulation functions of lymphocytes(8-10). In addition, we discovered that adenosine plays some role in the modulation of some functions of the Central nervous system (CNS) during wound healing when diuresis and alleviating pain. Also it is shown that adenosine can induce the proliferation of different types of healthy cells(11-14). Such modulation of cell growth, likely mediated through adenylate cyclase effector system described is the main means, and this activity is probably connected with its ability to stimulate the proliferation of bone marrow cells. Also found that adenosine exerts an inhibitory action on the proliferation of tumor cells, apparently through the cell cycle arrest GO/G1 and reduction of telomeric signal(17-18). This dual action of adenosine is attractive for the treatment of cancer.

Summary of the invention

According to the present invention found that agonists of adenosine recetor A3 (A3RAg) have a dual effect, manifested in the fact that they inhibit the proliferation of malignant cells, on the one hand, and, on the other hand, counteract the toxic side effects of chemotherapeutic drugs. Specifically, the compounds of the A3RAg inhibit the proliferation and growth of tumor cells, show a synergistic antitumor cytotoxic drug to reduce tumor load, induce proliferation and differentiation of bone marrow cells and white blood cells and counteract the toxic side effects of other drugs, including chemotherapeutic drugs. In addition, according to and is a great introduction and in particular, oral administration. Also discovered according to the invention that some activity A3RAg can be simulated with the help of other agonists and antagonists of adenosine receptors A1 or A2: agonists adenosine receptor A1 (A1RAg) share with A3RAg its ability to induce the secretion of G-CSF; agonist adenosine A2 receptor (A2RAg) shares with A3RAg its ability to inhibit the proliferation of malignant cells; and antagonist of adenosine A2 receptor (A2RAn) shares with A3RAg its ability to counteract the toxic side effects of drugs, for example, in the treatment or prevention of radiation.

The invention, in its broadest sense, refers to the application of the active ingredient with one of the following therapeutic/biological effects: inducing the production or secretion of G-CSF in the body; the prevention or treatment of toxic side effects of the medicinal product or the prevention or treatment of radiation, in particular radiation caused by the drug; and inhibiting the abnormal growth and proliferation of cells. The active ingredient can be an A3RAg or agonist or antagonist of the system adenosine receptors, which is to variants of embodiment of the invention. The first option, referred to in this description "option to induce G-CSF’, includes the use of the active ingredient, which can be an A3Rag or A1Rag, obtaining secretion of G-CSF in the body of the treated subject. It is known that G-CSF stimulates the proliferation and differentiation of hematopoietic precursors and regulates the functional activity of neutrophils and macrophages. Thus, G-CSF-inducing agent, such as what was mentioned above, can be of great therapeutic value, for example, when the counter (i.e., the prevention, reduction, or intensity reduction) mielotoksichnosti.

According to this variant of an embodiment of the invention relates to a method of inducing the secretion of G-CSF in the body of a subject, comprising the introduction of a specified subject an effective amount of the active ingredient selected from the group consisting of A3RAg, A1RAg and combinations A3RAg and A1RAg. According to this variant, the invention also relates to a method of treatment, comprising an introduction to the needy in this subject an effective amount of the specified active ingredient to achieve a therapeutic effect, including the induction of the production or secretion of G-CSF. This option refers to the formation of G-CSF secretion. For this option also includes a pharmaceutical composition for inducing production or secretion of G-CSF in the body, containing an effective amount of the specified active ingredient in a pharmaceutically acceptable carrier.

According to other variant embodiments of the invention, referred to in the description of the "option for the prevention of radiation" or more specifically - "option to prevent neutropenia", active ingredient, which can be an A3RAg or A2RAn, used for the prevention or treatment of radiation, which may be the result mielotoksichnosti.

According to this variant of an embodiment of the invention relates to a method of inducing proliferation or differentiation of bone marrow cells or white blood cells in a subject, comprising the introduction of a specified subject an effective amount of the active ingredient selected from the group consisting of A3RAg, A2RAn adenosine and combinations A3RAg or A2RAn. This option also relates to a method for prevention or treatment of radiation, including an introduction to the needy in this subject an effective amount of the specified active ingredient. According to this variant, the invention also relates to the application of the criminal code and or differentiation of bone marrow cells or white blood cells. Yet according to this variant, the invention also relates to the use of this active ingredient for the manufacture of pharmaceutical compositions for the prevention or treatment of leukopenia. The pharmaceutical composition can be used, in particular, for the prevention or treatment of leukopenia.

According to the related option, referred to in this description "option to prevent toxicity, the above active ingredient (namely one of the A3RAg or A2RAn, as well as their combination) are used to counteract the toxic side effects of drugs, such as chemotherapeutic drugs or neoliticheskie (nemoleptic) medicines.

According to the latest variant, the invention relates therefore to a method for prevention or treatment of toxic side effects of drugs, including introduction to the needy in this subject an effective amount of the active ingredient selected from the group consisting of A3RAg, A2RAn and combinations A3RAg and A2RAn. Also this option refers to the use of this active ingredient for the manufacture of pharmaceutical compositions for the prevention or treatment of toksicnosti.lechenie or treatment of toxic side effects medicines containing an effective amount of the specified active ingredient and a pharmaceutically acceptable carrier.

In General, for the purpose of combating leukopenia caused by drugs, or toxic side effects caused by drugs, it is sometimes desirable to make a composition of the medicinal product with such toxic side effects, together with the specified active ingredient for the combined introduction of both. Thus, the invention also relates to pharmaceutical compositions containing the combination drug, which can cause toxic side effects in the subject, which is treated by him, and the specified active ingredient; and for use of the specified active ingredient for the manufacture of such pharmaceutical compositions. These active ingredients contained in the composition are in amounts effective for the prevention or treatment of toxic side effects.

According to another variant embodiment of the invention, referred to in the description of the "option for the inhibition of cell proliferation", the active ingredient, which can be an A3RAg, A2RAg or acheter>According to this variant, the invention relates to a method of inhibiting abnormal cell growth in a subject comprising administration to the subject a therapeutically effective amount of the active ingredient selected from the group consisting of A3RAg, A2RAg and combinations A3RAg and A2RAg. According to this variant, the invention also relates to the use of this active ingredient for the manufacture of a pharmaceutical composition for inhibiting abnormal cell growth. Yet according to this variant, the invention also relates to a pharmaceutical composition for inhibiting abnormal growth of cells that contain the specified active ingredient and a pharmaceutically acceptable carrier.

In one variation of the embodiment of the invention the introduction of the active ingredient is intended to achieve the dual therapeutic effect: inhibition of abnormal cell growth and reduce toxic side effects of drugs, calling such action.

The preferred active ingredient according to the invention is A3RAg. The preferred method of administration of the active ingredient according to the invention is an oral way. However, this preference is not iskluchau ingredient, in particular, when the active ingredient is an A3RAg, preferably less than 100 μg per kg of body weight, typically less than 50 μg, and preferably is in the range of 1-10 µg per kg of body weight.

Detailed description of the invention

According to the invention proposes a new therapeutic use of certain active substances, in particular agonists and antagonists of adenosine receptors. According to one variant embodiment of the invention is a variant to induce G-CSF, some of these substances are used for mediating the production and secretion of G-CSF from the cells. Another option to prevent the toxicity of some of these substances are used to counteract the toxic side effects of drugs, such as chemotherapeutic or nanolattices medicines. Another option - option to prevent leukopenia some such substances used for anti-radiation, in particular radiation caused by drugs. According to another variant - the variant for inhibition of proliferation of some of these substances are used for the selective inhibition of abnormal cell growth.

Leukopenia, which may be a result of reduced production or excessive splenic sequestration of neutrophils may be due to hereditary or congenital diseases. However, it is observed mainly after treatment with drugs such as cytotoxic anticancer drugs, antithyroid drugs, phenothiazines, anti-convulsants, penicillins, sulfonamides and chloramphenicol. Some antineoplastic means cause leukopenia as a predictable side effect.

Hereinafter in this description, the reduction in the number of cells or the number of neutrophils drugs will be called "leukopenia caused by medicines or neutropenia caused by drugs". In addition, when mentioned leukopenia, this term should be understood as referring, in particular, to "neutropenia".

Hereinafter, the term "prevention or treatment of lycopen is to happen otherwise, reduced completely prevented or, if such a reduction occurs, the procedure that leads to an increase in the number of cells. Leukopenia is manifested through many side effects, such as increased possibility of Contracting an infectious factors, and others. The term "prevention or treatment of radiation" should be understood as a designation of improvement of such parameters, which can occur as a result of radiation.

Pharmaceutically or therapeutically effective amount" for the purposes referred to herein, is determined by such considerations, which may be known in the art. The amount must be effective to achieve the desired therapeutic action, which depends on the type and method of treatment. As it is clear to the specialist, the amount must be effective to obtain improved survival rate, more rapid recovery, to obtain reduce or eliminate symptoms or other indicators selected as the appropriate units of measurement specialists in this field. When, for example, the active ingredient is administered to induce the production of G-CSF, an effective amount is AI G-CSF from mononuclear cells of peripheral blood, endothelial cells or fibroblasts, which is produced by G-CSF, through, for example, stimulation of the maturation of precursor cells to Mature neutrophils. When the active ingredient is administered to counteract the radiation caused by drugs, an effective amount of the active ingredient can be a number, which protects the individual from calling drug reduction in the number of leukocytes, in particular neutrophils; the amount of active ingredient that may increase the already reduced content of such cells, for example to restore the content to its normal level, and sometimes even higher; and so on, When the active ingredient is administered in order to reduce toxic side effects of drugs, amount of the active ingredient may constitute, for example, an amount effective to reduce weight loss, due to injected drugs. When the active ingredient is administered in order to inhibit abnormal cell growth that more determined next, an effective amount can be an amount of inhibiting proliferation of such cells in the step of anticancer chemotherapeutic drugs, an effective amount can be an amount that increases or specific anti-cancer toxicity of chemotherapeutic treatment; or an amount effective to reduce the amount of chemotherapy drug or combination of drugs required to achieve the desired action of chemotherapeutic drug or combination of drugs, i.e., reduction of tumor load; etc., an effective amount is the introduction of A3RAg in quantities of less than 100 μg per kg of body weight per day, usually less than 50 μg per kg body weight and, optionally, even less than 10 μg per kg of body weight, for example 3-6 µg per kg of body weight. This number A3RAg, usually administered as a single daily dose, although sometimes the daily dose can be divided into several doses that are given during the day, or sometimes multiple daily doses can be combined into a single dose, which is given to the patient once every few days, particularly if injected composition with delayed release.

The active ingredient according to the invention is preferably A3RAg. A3RAg is agonist, which binds to receptors A3 and then activates them with what Ptolemy, for example, receptors A1 and A2. However A3RAg used according to the invention, exerts its main action through receptor A3 (and it can also be a minor action, manifested through the interaction with other adenosine receptors).

According to one variant embodiment of the invention the active ingredient according to the invention is a nucleoside derivative. The term "nucleoside" refers to any compound containing a sugar, preferably a ribose or deoxyribose, or a purine or pyrimidine base, or a combination of sugars with purine or pyrimidine base, preferably at the expense of N-glycosamino communication. The term "nucleoside derivative" is used to refer to this description of nucleoside occurring in nature, as defined above, a synthetic nucleoside or nucleoside, subjected to chemical modification by inserting/insertions, deletions/s or ekzoticheskogo(them) and endocycles(s) substitution(s) group/groups or conformational modifications, giving the derivative with the desired biological effect.

According to one preferred embodiment variants of the invention the active ingredient in predstavley nucleoside derivative of the General formula (I)

where R1is a (C1-C10)-alkyl, (C1-C10-hydroxyalkyl, (C1-C10-carboxyethyl or (C1-C10-cianelli, or a group of the General formula (II)

where

- Y represents oxygen, sulfur or-CH2-;

- X1represents H, (C1-C10)-alkyl, RaRbNC(=O)- or HORc- where Raand Rbmay be the same or different and selected from the group consisting of hydrogen, (C1-C10)-alkyl, amino, (C1-C10)-halogenoalkane, (C1-C10)-aminoalkyl, (C1-C10)-BOC-aminoalkyl and (C3-C10)-cycloalkyl, or are joined together with formation of a heterocyclic ring containing two to five carbon atoms, and Rcselected from the group consisting of (C1-C10)-alkylene, -NH-, (C1-C10)-halogenation, (C1-C10)-aminoaniline, (C1-C10)-VOS-aminoaniline and (C3-C10)-cycloalkyl;

- X2represents H, hydroxyl, (C1-C10)-alkylamino, (C1-C10)-alkylamino or (C1-C10-hydroxyalkyl;

- X3 is laksi, carboxy, nitrilo, nitro, driftor, aryl, alkaryl, thio, thioester complex group, simple thioester group, -OCOPh, -OC(=S)OPh, or X3and X4both represent oxygen associated with the >C=S with the formation of 5-membered cycle, or X2and X3form a loop of the formula (III)

where R’ and R’ represent, independently, (C1-C10)-alkyl;

- R2selected from the group consisting of hydrogen, halogen, simple (C1-C10)-alkylamino group, amino, hydrazido, (C1-C10)-alkylamino, (C1-C10)-alkoxy, (C1-C10)-dialkoxy, pyridylthio, (C2-C10-alkenyl, (C2-C10)-quinil, thio and (C1-C10)-alkylthio; and

- R3is a group-NR4R5and R4represents hydrogen or a group selected from alkyl, substituted alkyl or aryl-NH-C(Z)-, and Z represents O, S or NRaand Rahas the above values

and R5when R4represents hydrogen, selected from the group consisting of R - and S-1-phenylethylene, benzyl, phenylethylene or anilino groups, unsubstituted or substituted in one or more b>-C10)-halogenoalkane, nitro, hydroxyl, acetamido, (C1-C10)-alkoxy, and sulfonic acid or a salt thereof; or R4is benzodioxolyl, furfuryl, L-propylaminoethyl,-albilineans, T-BOC--albilineans, phenylamino, carbarnoyl, phenoxy or (C3-C10-cycloalkyl, or R5represents a group of the formula

or a suitable salt of the compound, the definition of which is given above, for example it triethylammonium salt; or

when R4represents a group selected from alkyl, substituted alkyl or aryl-NH-C(Z)-, then R5selected from the group consisting of substituted or unsubstituted heteroaryl-NRa-C(Z)-, heteroaryl-(Z)-, aralkyl-NRaWith(Z)-, aralkyl-(Z)-, aryl-NR-C(Z)- and aryl-S(Z)-;

where Z has the values listed above.

According to this variant embodiment of the invention the active ingredient preferably is a nucleoside derivative of the General formula (IV)

where X1, R2and R4have the values specified above.

Preferred active ingredients to ugena, that their derivatives are agonists, selective in respect of the adenosine A3 receptor. Examples of such derivatives are the N6-2-(4-AMINOPHENYL)atelectasis (APNEA), N6-(4-amino-3-iodobenzyl)-adenosine-5'-(N-methyluronamide) (AB-MESA) and 1-deoxy-1-{6-[({3-itfeel}methyl)amino]-N-purine-9-yl}-N-methyl--D-ribofuranoside, the latter also referred to as the N6-3-iodobenzyl-5’-methylcarbamoylmethyl, N6-(3-iodobenzyl)-adenosine-5’-N-methyluronamide, and is referred to above and hereinafter in the description abbreviation IB-MECA, or chlorinated derivative of IB-MECA (R2=CL), called Cl-IB-MECA. Presently particularly preferred IB-MECA and Cl-IB-MECA.

According to other variant embodiments of the invention the active ingredient may be a derivative of adenosine, as a rule, mean N6-benzyladenine-5'-alkylaromatic-N1-oxide or N6-benzyladenine-5'-N-dialkylamide-N1-oxide.

In addition, the active ingredient may be a xanthine-7-ribosides derivative of General formula (V)

where X represents O or S;

- R6is an RaRbNC(=O)- or HORc-,

where

- sub>10)-alkyl, amino, (C1-C10)-halogenoalkane, (C1-C10)-aminoalkyl and (C3-C10)-cycloalkyl, or are joined together with formation of a heterocyclic ring containing two to five carbon atoms, and

- Rcchoose among (C1-C10)-alkyl, amino, (C1-C10)-halogenoalkane, (C1-C10)-aminoalkyl, (C1-C10)-VOS-aminoalkyl and (C1-C10)-cycloalkyl;

- R7and R8may be the same or different and are selected from the group consisting of (C1-C10)-alkyl, (C1-C10) -cycloalkyl, R - or S-1-phenylethylene, unsubstituted benzyl or anilide groups and simple phenyl ether benzyl group substituted in one or several positions Deputy selected from the group consisting of (C1-C10)-alkyl, amino, halogen, (C1-C10)-halogenoalkane, nitro, hydroxyl, acetamido, (C1-C10)-alkoxy, and sulfonic acids;

- R9selected from the group consisting of halogen, benzyl, phenyl, (C3-C10)-cycloalkyl and (C1-C10)-alkoxy;

or a salt of such a compound, for example it triethylammonium salt.

Some of these veesee description as references.

The active ingredient in the case of the variant to induce GSF can also be a A1RAg. He is, as a rule, derivatives of adenosine following formula

where R1represents lower alkyl, cycloalkyl, preferably (C3-C8-cycloalkyl (including well-known cyclohexyl - and cyclopentadiene derivatives, known as CPA and SLEEP, respectively), cycloalkyl group can be substituted, for example by hydroxyl or lower alkyl; R1 represents hydroxyl or hydroxyalkyl; phenyl, anilide or lower alkylphenyl, which are all optionally substituted by one or more substituents, for example halogen, lower alkyl, halogenation, such as trifluoromethyl, nitro, cyano, -(CH2)mCO2Ra, -(CH2)mCONR2RaRb, -(CH2)mCORawhere m is an integer from 0 to 6; -SORc, -SO2Rc, -SO3H, -SO2NRaRb, -ORa, -SRa, -NHSO2Rc, -NHCORa, -NRaRbor otheraCO2Rb; where

- Raand Rbrepresent, independently, hydrogen, lower alkyl, alkanoyl, phenyl or naphtalenesulfonic phenyl or fenoxaprop; or, when R1is-NRaRbspecified Raand Rbform together with the nitrogen atom a 5 - or 6-membered heterocyclic ring, optionally containing a second heteroatom selected from among oxygen or nitrogen, and the specified second heteroatom may be optionally also substituted by hydrogen or lower alkyl; or-NRaRbrepresents a group of General formula (VII) or (VIII)

where n is an integer from 1 to 4;

Z represents hydrogen, lower alkyl or hydroxyl;

- Y represents hydrogen, lower alkyl or or' R' represents hydrogen, lower alkyl or lower alkanoyl;

- A represents a bond or a lower alkylene, preferably (C1-C4)-alkenyl; and

- X and X' represent, each independently, hydrogen, lower alkyl, lower alkoxy, hydroxy, lower alkanoyl, nitro, halogenated, such as trifluoromethyl, halogen, amino, mono - or di(lower alkyl)amino, or X and X', taken together, represent methylenedioxy;

- Rcrepresents lower alkyl;

- R2represents hydrogen; halogen; substituted or mezamashi alkoxy; lower alkylamino; NRdRewhere Rdand Rerepresent, independently, hydrogen, lower alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy, halogen or halogenation, such as trifluoromethyl, or alkoxyl; or,- SRfwhere Rfrepresents hydrogen, lower alkyl, lower alkanoyl, benzoyl or phenyl;

W represents a group-och2-, -NHCH2-, -SCH2- or-NH(C=O);

- R3, R4and R5represent, independently, hydrogen, lower alkyl or lower alkenyl, branched or non-branched (C1-C12-alkanoyl, benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen, or R4and R5together form a five-membered cycle, optionally substituted lower alkyl or alkenyl; R3also represents, independently, phosphate, secondary phosphate, or primary phosphate, or alkaline metal or ammonium, or dibasic or diammonium ion;

- R6represents hydrogen, a halogen atom; or

- one of the groups R (i.e. R1-R6) is a sulfur-containing hydrocarbon radical of the formula Rg-SO3-Rhwhere Rgrepresents a group selected from (C1-C10) and unsubstituted, and R11represents a monovalent cation. Suitable monovalent cations are lithium ions, sodium, potassium and ammonium or trialkylamine that make possible dissociation for replacement under physiological conditions. Other groups R are hydrogen or halogen atom, unsubstituted hydrocarbon residue or any other not containing sulfur group, with the above values.

In this case, the hydrocarbon chain may be linear or branched. In particular, the terms "alkyl" or "alkenyl", as used herein, denote an alkyl or alkeneamine group with a linear or branched chain. The terms "lower alkyl" or "lower alkenyl" mean respectively (C1-C10)-alkyl or (C2-C10)-alkeline group, and preferably - (C1-C6)-alkyl and (C2-C6)-alkeline group.

Preferred derivatives of adenosine of formula (VI) are derivatives of N6-cyclopentylamine (CPA), 2-chloro-CPA (SSRA) and N6-cyclohexylbenzene (SLEEP), the receipt of which is well known to specialists in this field. Other derivatives of adenosine, which is known that they are selective in relation R is tamaseni or substituted, for example, hydroxyl, alkyl, alkoxy or the group-CH2C(O)R’, and R’ is a hydroxyl group, -NHCH3, -NHCH2CO2C2H5(ethylglycine), toluidin (where a methyl group substituted halogenosilanes group), or a group-CH2C(O)NHC6H4CH2C(O)R’’ where R’’ represents a group forming mutilatory Deputy (-och3), amide substituent (for example, R’’ represents a group-N3), or R’’ is a hydrazide, Ethylenediamine, -NHC2H5NHC(O)CH3, 4-(hydroxyphenyl)propionyl, biotinylated Ethylenediamine or any other suitable hydrocarbon, which represents the connection A1 agonist.

On the other hand, N6-substituted derivatives of adenosine used according to the present invention as active ingredients, may be a derivative containing an epoxy group and, more specifically, represents cycloalkylation derivatives of adenosine (for example, oxabicyclo, such as norbornanyl, or ocatillo, such as adamantyl). Some of these connections, you can define the General formula (I),

where R1represents a group is e M is a lower alkyl group, with the values specified above.

Options agonist compounds containing epoxide-N6-norbornylene group include endo - and Exo-isomers and, in particular, may constitute one of the four isomers: the form 2R-Exo, 2R-endo, 2S-Exo and 2S-endo.

Another option N6-norbornene derivative may include an oxygen atom at position N1purine cycle. This connection is called the N6-(5,6-apatzingan-2-yl)adenosine 1-oxide.

Sometimes A1RAg can be a derivative of adenosine, which-D-ribofuranosyl group of adenosine replaced by a hydrogen or phenyl group.

A2RAn that can be used according to the invention, are 8-sterilnye derivatives 1,3,7-substituted xantina formula (X)

where R1and R3represent a (C1-C4) -alkyl, allyl or propargyl;

R7represents H, methyl or (C2-C8) -alkyl; n is 1-3;

and X represents a halogen, triptorelin, alkoxy, hydroxy, nitro, amino, dialkylamino, diezani, isothiocyanate, benzyloxy, aminoethoxy, alkoxycarbonyl, acetoxy, acetylamino, succinylamino, 4-(4-RET-BOC-NH -, TRANS-CH2SN=SNSN2O)-3,5-(MeO)2.

A specific example of the compounds of formula (X) is (3,7-dimethyl-1-propargylglycine).

A2RAn can also be a compound of the following formula

or

Obviously, the invention may not be limited to the specific compounds A3RAg, A2RAg or A2RAn specified above.

Active ingredient according to the invention may be as described above, or may be in the form of its salt or solvate, in particular their physiologically acceptable salts and solvate. In addition, when the active ingredient contains one or more asymmetric carbon atoms, it may include isomers and diastereoisomers described above active ingredients or mixtures thereof.

Pharmaceutically acceptable salts of the above-described active ingredients include salts formed pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids are chloromethane, Hydrobromic, sulphuric, nitric, Perlina, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, LiI.

The active ingredient can be introduced in the form of active substances (e.g., prodrugs), and it becomes active only after the future(s) modification(s) in a natural way in a certain area of the body of the subject. In any case, the derivative will be to keep therapeutic functionality of the pharmaceutical compositions of the invention. Such prodrugs are also covered by the term "active ingredient" used in this description. Similarly, the terms "A3RAg", "A1RAg", "A1RAn", "A2RAg" andA2Ranit should be understood to encompass prodrugs that although a priori do not have agonistic or antagonistic activity (such a case may be), be active in vivo.

A3RAg according to the invention can be selected by selection of such compounds, which are qualitatively have activity similar to the activity of IB-MECA. For example, such compounds for use in accordance with the option for inhibition of radiation can be selected based on their ability to stimulate the proliferation of bone marrow cells or white blood cells, and then, based on their ability to manifest their activity in vivo. For application is ERATIO tumor cells and then the manifestation of their activity in vivo.

A1RAn and A2RAn can be tested for their activity and to select for use in the treatment in the same way described for A3RAg, with appropriate modifications.

The pharmaceutical composition of the invention may contain the active ingredient as such, but may contain other ingredients, which can be a pharmaceutically acceptable carrier, diluent, excipient, additive and/or adjuvant, known in the art, for example, for the purpose of making the pharmaceutical compositions of taste, smell, color, lubricity properties or similar properties. Obviously, pharmaceutically acceptable(e) carrier(s), diluent(s), excipient(s), additive(s) used according to the invention, generally should refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material, which preferably do not react with the compounds in the compositions of the invention.

Next, the active ingredient can also be entered in combination with the chemotherapeutic drug, in particular, in the case of options for the prevention of radiation. Thus, the pharmaceutical composition according to the invention may contain, in addition to the specified active ingredient is rapeutique drug is an anticancer chemotherapeutic drug. It should be borne in mind that this term designates any cytotoxic drug or a mixture containing a combination of two or more cytotoxic drugs prescribed to a patient for the purpose of reducing his tumor mass.

One of the conclusions according to the invention is that 3Rg is bioavailable oral and manifests its dual activity (reduction of cell proliferation and the prevention or mitigation of radiation) by oral administration. Thus, according to one preferred options of the pharmaceutical composition of the invention receive for oral administration. This oral composition may also contain a pharmaceutically acceptable carrier, diluent, excipient, additive or adjuvant suitable for oral administration.

In the amount of variant embodiments of the invention to induce G-CSF described pharmaceutical composition is used, in particular, to improve the content of G-CSF secreted by the cells. Such compositions can be used to accelerate the recovery of neutrophils after chemotherapy and bone marrow transplantation or for inhibiting abnormal cell growth. In the present uranim action. Moreover, it is known that the average cost of G-CSF therapy is very high.

Within the scope of a variant embodiment of the present invention to prevent radiation or variants to prevent toxicity described pharmaceutical composition is used, in particular, to improve the subject's level of leukocytes in the bloodstream or other anti-toxic action, such as weight loss. This aspect of the invention is applicable in various clinical situations. It is obvious that a reduced level of white blood cells in the bloodstream, and in particular neutrophils, can lead to weakening of the immune system. An example of the weakening of the immune system, which can be treated according to this aspect of the invention, is such, common in the early stages of cancer, or weakening, resulting leukopenia caused by medicines, or neutropenia caused by drugs.

Option for inhibition of proliferation is useful for the treatment of various abnormalities associated with abnormal cell growth, such as cancer, psoriasis and some autoimmune diseases. In particular, the composition of the invention is used for inhibiting the proliferation of tumor cells is roliferation these cells expressed more clearly, than when exposed to adenosine or agonists ‘A1’ or ‘A2’, although some activity was also observed with A2RAg (see, for example, Fig.5A). These results show that the inhibition of proliferation of tumor cells should be attributed mainly to the binding A3RAg with its corresponding receptor, but this phenomenon to some extent, can also be simulated A2RAg. The above unexpected results also suggest a new therapeutic target for future anticancer cytotoxic drugs.

Also found that A3RAg is a strong inhibitor of the growth of other tumor cells, in addition to the lymphoma cells, such as melanoma or carcinoma of the colon (see, for example, Fig.6). Experienced specialist in this field clearly represent the advantage of the treatment of the subject of non-specific anti-cancer drug is able to inhibit the growth of abnormally dividing cells, and at the same time is able to restore the immune system of a subject by inducing proliferation of bone marrow cells.

Fig.7A-7B, for example, show a differentiating action A3RAg. In this particular case, assess the effect of IB-MECA on tumor and healthy cells. Given dannym. Therapeutic effect A3RAg also changes completely when using the A3 receptor antagonist MRS-1220.

In vivo studies confirm the results obtained in vitro, and show chemotaxin action A3RAg in mice that are processed simultaneously A3RAg and cytotoxic agent, when compared with mice treated only cytotoxic drug (see, for example, Fig.8). In addition, see a decrease in the number of foci in mice treated A3RAg that indicates chemotherapeutic activity A3RAg (see, for example, Fig.9). Figures 10A-10B, and 19A and 19B, for example, show that mice with tumor processed only cytotoxic drug, find the drop in the number of leukocytes and neutrophils peripheral blood, while the introduction 3Rg after chemotherapy leads to the restoration of the total number of white blood cells, manifested in the increase of the percentage of neutrophils.

Thus, we can conclude that 3Rg has a dual therapeutic function, as valid and as chemotherapeutic agent, and as chemotaxins tool. It is clear that the use of A3RAg to achieve this dual action is also in the scope of the present image is medical practice, taking into account the clinical condition of the individual patient, place and route of administration, schedule of administration, age, sex, body mass of the patient, and other factors known to practitioners.

The composition of the invention can be entered in different ways. It can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscularly, administered intraperitoneally, or via the intranasal route, and vnutriobolochechnoe and infusion methods known to experts in this field.

As is known, the course of treatment, people usually longer than that of the animals, i.e. mice, which are used in the examples. The treatment has a length proportional to the duration of the painful process and the effectiveness of the active substance. The treatment regimen includes single or multiple doses over a period of several days or longer. Treatment typically has a duration that depends on the progress of the painful process, the effectiveness of the active substance and the type of patient treated.

When the composition of the present invention is administered parenterally, usually get it in a standard dosage form for injection (solution, suspension, emulsion). Pharmaceutical composition suitable for iknee solutions or suspensions for injection. Used carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, lepidosirenidae and so on), suitable mixtures and vegetable oil.

Non-aqueous media, such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil or peanut oil and esters, such as isopropylmyristate, sometimes also can be used as solvents for the active ingredient.

In addition, you can add various additives that enhance the stability, sterility and isotonicity compositions, including antimicrobial preservatives, antioxidants, chelating agents and buffer substances. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal substances such as parabens, chlorobutanol, phenol, sorbic acid, etc.,

For the purpose of oral administration, the active ingredient can be entered in the applicable form of tablets, suspensions, solutions, emulsions, capsules, powders, syrups, etc. that can be obtained by methods well known to pharmacists.

The present invention opre examples with reference to the accompanying figures. It should be borne in mind that the terminology used is intended to describe and not to limit.

Although in the above description describes only a few specific embodiments of the invention, the experts in this field should be borne in mind that the invention is not restricted by them, and that other changes in form and detail without departing from the scope and essence of the described invention.

Brief description of figures

In order to understand the invention and to imagine how it can be put into practice, will now be described preferred variants of the embodiment of the invention using examples, which are not restrictive, with reference to the accompanying drawings, which depict the following:

Fig.1 is a histogram showing the results of the analysis in vivo, which demonstrates the effect of adenosine (Ad), DPCPX (A1RAn), CPA, SSRA (both A1RAg) or IB-MECA (A3RAg) on the production of G-CSF. Culture-treated modified RPMI serve as control. The results are presented as percent of control (control = 100%).

Fig.2 is a histogram showing the results of the analysis with the inclusion of [3H]-thymidine - experiment, in which propertycategory bars) or without ((-) G-CSF AB - densely shaded bars). The results show the neutralizing effect of antibodies against G-CSF. The results are presented as percent increase compared with the control (control = 0%).

Both figures Fig.3A and Fig.3B are histograms showing the results of the analysis with the inclusion of [3H]-thymidine - experiment, which tested the proliferation of bone marrow cells in the presence of adenosine, adenosine agonists of the receptors (Fig.3A) or adenosine in combination with antagonists of adenosine receptors (Fig.3B). Feel receptor agonists (Fig.3A) are CPA (A1RAg) and IB-MECA (A3RAg); experience receptor antagonists (Fig.3B) are DPCPX (A1RAn), DMPX (A2RAn) and MRS (A3RAn). The results are presented as percent increase of thymidine incorporation compared to the control (control = 0%).

Fig.4 is a histogram showing the results of in vitro experiment, which tested the proliferation of bone marrow cells at three different concentrations of IB-MECA (0.01 µm, 0.1 µm and 1.0 µm). The results are presented as percent increase inclusion of [3H]-thymidine as compared with the control (control = 0%). The numbers under the bars show the concentrations of IB-MECA (in microns).

Fig.5A and 5B represent g is which examine the effect of adenosine and its antagonist on the growth of lymphoma cells (Nb2-11C). In the experiment represented in Fig.5A, check the impact on the growth of lymphoma cells adenosine, CPA (A1RAg), DMPA (A2RAg) or IB-MESA (A3RAg). In the experiment represented in Fig.5V, check the impact on the growth of lymphoma cells adenosine, DPCPX (A1RAn), DPMX (A2RAn) or MRS-1220 (A3RAn). As a control, use the cell lymphoma treated with RPMI. The results are presented as % inhibition of cell growth relative to control (control = 0%).

Fig.6 is a histogram showing the results of in vitro assays, in which the growth of tumour cells of different types (B16 melanoma, carcinoma of the colon NTS 116, lymphoma, Nb2-11C) inhibited in the presence of A3RAg IB-MECA. As a control, cells are treated with RPMI. The results are presented as % inhibition of cell growth relative to control (control = 0%).

Fig.7A and 7B are histograms showing the results of in vitro assays, which test the influence of adenosine or A3RAg IB-MECA on the growth of tumor cells (lymphoma Nb2-11C, Fig.7A) or bone marrow cells (Fig.7B). The results in Fig.7A and 7B are presented as percent inhibition and percent stimulation, respectively, relative to control (control = 0%).

Fig.8 is a histogram showing the results of the experiment ticesim drug (cyclophosphamide). Cyclophosphamide is administered or one (subsectionone bars) or in combination with IB-MECA, administered orally (1 ml) daily, starting 24 hours after administration of chemotherapeutic drugs. As controls are mouse treated with PBS. The number of WBC (WBC) is reported as percent greater than the control (control = 0%).

Fig.9 is a histogram showing the results of the experiment in vivo, which checks the number of foci of melanoma developing in mice after inoculation 2×105of melanoma cells in mice treated with a chemotherapeutic agent cyclophosphamide (SNAME), A3RAg IB-MECA, a combination of IB-MECA, SNAME or phosphate buffered saline (PBS), which serves as a control.

Fig.10A and 10B are histograms showing the results of the experiment in vivo, demonstrating the chemotherapeutic activity of IB-MECA. Shows the content of white blood cells (WBC, Fig.10A) and neutrophils (Fig.10B) as a function of time (hours after administration of the chemotherapy drug cyclophosphamide (SNAME) with IB-MECA (SNAME + IB-MECA) and without IB-MECA). As controls are mouse treated with PBS. The number of neutrophils is given in %, PR and (administration of 5-FU, Cl-IB-MECA or a combination of 5-FU and Cl-IB-MECA) as % of control (untreated mouse = 100%). Processing is the introduction of 5-FU (densely shaded bars), the introduction of 5-FU in combination with Cl-IB-MECA (A3RAg) - subsectionone bars) and one Cl-IB-MECA (where there's no shading columns).

Fig.12A and 12B show the results of an experiment in which test the effect of Cl-IB-MECA at reducing mielotoksichnosti caused by doxorubicin. The experiment carried out on mice ICR. Fig.12A shows the number of white blood cells (WBC), while Fig.12B shows the number of nucleated bone marrow cells. In Fig.12A shows the results of two different treatments at four different points in time, and the level of control shown by the dashed line, while in Fig.12V results in two different moments of time, and the reference level is represented by the column on the left side.

Fig.13 shows the effect of antibodies against G-CSF on the number of white blood cells (WBC) in control mice, mice treated with chemotherapeutic drug, and mice treated with chemotherapeutic drug and Cl-IB-MECA, administered orally (6 μg per kg body weight in 0.2 ml PBS). The number of WBC after injection of antibodies against G-CSF preditah.14 shows the size of the tumor over time, developing the "Nude" mice after injection of carcinoma cells of the colon of human HCT-116, in the control group and in the treated group (oral administration of Cl-IB-MECA).

Fig.15 shows the results of an experiment similar reflected in Fig.14, where measure the size of tumors growing in mice after injection of carcinoma cells of the colon of human HCT-116. Experience four groups: the control group, the group receiving chemotherapy drug 5-FU group, which administered orally Cl-IB-MECA, and the group receiving the combined treatment of 5-FU and Cl-IB-MECA.

Fig.16 is a histogram showing the size of the tumor on the 30th day of the experiment reported in Fig.15.

Fig.17 is a histogram showing the results of an experiment where determine the proliferation of bone marrow cells induced by Cl-IB-MECA, at various concentrations (0.05 mg/ml and 0.5 μg/ml) antibodies against G-CSF (0 - absence of antibody). Proliferation was determined by analysis with the inclusion of [3H]-thymidine.

Fig.18 shows the results of the experiment in vitro, where determine the proliferation or cell melanoma b-16, or bone marrow cells. Proliferation was determined by analysis with the inclusion of [3H]-what do without A3RAg MRS-1523 (gotosection bars). The results are presented as percent of control (control = 100%).

Fig.19A and 19B show the results of an experiment similar reflected in Fig.10A and 10B, respectively, performed with Cl-IB-MECA.

Fig.20 shows the results of the experiment in vitro, determine where the proliferation of bone marrow cells induced IB-MECA or Cl-IB-MECA. These two A3RAg add to the culture of bone marrow cells in concentrations or 1 nm, or 10 nm, with the addition of A3RAn MRS-1523 at a concentration of 10 nm (subsectionone columns - "(+) antagonists") or without addition (gotosection columns - "(-) antagonists"). Proliferation was determined by analysis with the inclusion of [3H]-thymidine. Results are expressed as the percentage of stimulation relative to control (untreated cells in the bone marrow, control = 0%).

Experimental results

Tumor cells

Used murine tumor cell lines (melanoma b-16 and lymphoma rat Nb2 11c). Cells of melanoma b-16 obtained from the American type culture collection (ATSS), Rockville, Maryland. Cell lymphoma rat Nb2-11C [Pines, M., and Gertler, A., J. of Cellular Biochem., 37; 119-129 (1988)] was kindly provided by Dr. A. Gertler, Hebrew University, Israel.

Used cell carcinoma of obodocna cows (FBS, Biological Industries, Beit Haemek, Israel). Twice a week the cells are transferred to fresh medium.

Healthy cells

Used bone marrow cells obtained from the femur of mice C57BL/6J. The cells were obtained as described previously [17].

Medicines connection

Used drugs: adenosine; adenosine agonists of the receptor A1: SRA [2-chloro-N6-cyclopentylacetic], CPA (N-cyclopentylacetyl); A1Ran: DPCPX (1,3-dipropyl-8-cyclopentylacetyl); agonist adenosine A2 receptor: DMPA (N6-[2-(3,5-acid)-2-(2-were)ethyl]adenosine); A2RAn: DMPX (3,7-dimethyl-1-propargylglycine); A3Rag: IB-MECA (1-deoxy-1-{6-[({3-itfeel}methyl)amino]-N-purine-9-yl}-N-methyl--D-ribofuranoside), CE-IB-MECA (2-chloro-N6-3-iodobenzyl)adenosine-5'-N-methyluronamide); and antagonists of adenosine receptor A3: MRS-1523 (5-propyl-2-ethyl-4-propyl-3-ethylsulfanyl)-6-phenylpyridine-5-carboxylate) and MRS-1200 (9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]-triazolo[1,5-C]hinzelin).

Used antibodies against murine G-CSF (rabbit anticavity purified by chromatography for protein A, Cytolab LTD, Basmassovskiy research Institute, Israel).

Cyclophosphamide skupienia BALB/C mice at the age of 3 months with an average weight of 25 g Mice were purchased in Harlan Laboratories, Jerusalem, Israel. Gave standard pelleted diet and tap water.

Example 1. The effect of adenosine and antagonists of adenosine receptors on the production of G-CSF and proliferation of bone marrow cells

In order to test the assumption that adenosine exerts its biological effects through the stimulation of the production of G-CSF, growing healthy cells in the presence of adenosine, agonist or antagonist of adenosine.

For this purpose, bone marrow cells, obtained from the femur of mice C5BL/6J or ICR, first divide, passing through a 25G needle. Then cells (3×105cells per well in 96-well microtiter tablets) incubated with RPMI medium containing 10% serum fetal cow (FBS) in the presence of adenosine (25 μm). Cultures of bone marrow cells in the absence of adenosine add adenosine or agonists of adenosine receptors A1 and A3 CPA (A1RAg, 0.01 µm), SRA (A1RAg, 0.01 µm) or IB-MECA (A3RAg, 0.01 µm); the antagonist of adenosine receptors A1 DPCPX (0.1 ám) added to the culture of bone marrow cells in the presence of adenosine (25 μm).

As a control, the above experiment are culture containing cells suspended in the. For this purpose, after 30 hours of incubation, each well are "charged" with 1 µci [3H]-thymidine. After incubation, generally within 48 hours, cells are harvested and determine the uptake of [3H]-thymidine in liquid LKB scintillation counter (LKB, Piscataway, NJ, USA). The results of this analysis are displayed in Fig.1, which shows that A1RAg or A3RAg have influence on the production of G-CSF, which is similar to the effect obtained in the case of adenosine.

To confirm that adenosine and its agonists appear to act through stimulation of the production of G-CSF, conduct another analysis, where antibodies against G-CSF (62.5 ng/ml) added to the culture of bone marrow cells in the presence of adenosine (25 μm), CPA (0.01 µm) or IB-MECA (0.01 µm). Cell proliferation assessed as described above. The results of this experiment are displayed in Fig.2, which shows that antibodies to G-CSF inhibited the stimulatory effect of adenosine and its agonists on the proliferation of bone marrow cells. These results suggest that at least some of the activities associated with the interaction with adenosine receptors, mediated by through the induction of G-CSF.

Assess cumulative effects on cell proliferation Conte, the results of which are given in Fig.1. Cells are disconnected, incubated in the presence or adenosine (25 μm), CPA (0.01 µm), IB-MECA (0.01 µm), or a combination of IB-MECA and CPA (each at a concentration of 0.01 µm), and then treated as described above. The results are shown in Fig.3A, which shows the increased the combined effect of IB-MECA and CPA.

In order to make a comparative assessment of the influence of agonist adenosine receptor on the proliferation of bone marrow cells, following the same methodology, which is described above, cells incubated with one adenosine or with combination with DMPX (A2RAn), DPCPX (A1RAn), MRS-1220 (A3RAn) or with a combination of DPCPX and MRS-1220. The results are shown in Fig.2B. As you can see, blocking receptor A2 DMPX also leads to increased proliferation of bone marrow cells, which is even higher than in the case of a single adenosine. For comparison proliferation with DPCPX or MRS-1220 reduces the increase of approximately 50% compared to using a single adenosine, while DPCPX in conjunction with MRS-1220 is inhibited proliferation.

Cells pre-treated as described above, incubated with various concentrations of IB-MECA (1 μm, from 0.1 μm or 0.01 μm). The percentage of stimulation was determined by analysis with VK bone marrow cells depending on the dose.

Example 2. Modulation of the growth of tumor cells by adenosine and its agonists

Cell lymphoma rat Nb2-11C (1,2×l04cells/ml) incubated for 48 hours in 96-well microtiter tablets with 1 ml of RPMI medium containing 5% serum fetal cows. Add or 25 μm adenosine, or 0.01 μm agonist adenosine receptors (A1RAg CPA; A2RAg DPMA or A3RAg IB-MECA), or 0.1 μm antagonists of adenosine receptors (A1RAn DPCPX; A2RAn DMPX or A3RAn MRS-1220) in combination with adenosine (25 μm).

As a control, the above experiment are culture containing cells suspended in RPMI medium with 5% serum fetal cows. The degree of proliferation is determined by analysis by counting the number of cells.

The results are shown in Fig.5A and 5B, which can be compared with inhibition by adenosine. As you can see, cell proliferation Nb2-11C markedly inhibited after incubation with A3RAg IB-MECA. Imperceptibly the growth inhibition in the presence of A1RAg CPA, and less growth inhibition observed in the presence of A2RAn DMPX. The failure of the CPA in the inhibition of proliferation of these two types of tumor cells suggests that the adenosine A1 receptor in this kind of activity is not involved. However ingibiruya activity as DMPA, and IB-MECA call the AI.

In addition, you can see that A1RAn DPCDX essentially no effect, while in the presence of A3RAn MRS-1220 effect of adenosine on cell proliferation Nb2-11C essentially eliminated. Small, but still noticeable effect manifests A2RAn DMPX. These results lead to the conclusion that the growth of tumor cells can effectively inhibit A3RAg or A2RAn.

In the same way described above, evaluate ingibirovanie A3RAg IB-MECA growth of melanoma cells In-16, carcinoma of the colon HCT-116 and lymphoma Nb2-11C. The results are shown in Fig.6 as the percentage of inhibition of cell proliferation.

Example 3. Agonists adenosine receptor A3 show differeciate effect on tumor and healthy cells

The effect of adenosine, A3RAn and A3RAg on tumor cell growth test, following the experimental procedure described above.

Briefly, cells lymphoma Nb2-11C or bone marrow incubated in the presence or adenosine or IB-MECA. Dual action A3RAg, manifested in the growth inhibition of tumor cells and at the same time, the proliferation of bone marrow cells is reflected in Fig.7A and 7B.

Example 4. In vivo studies

Divided into 4 groups of 40 mice C57BL6/J and each group is treated according to one of opennetwork mouse from the day of inoculation of the tumor to killing of mice.

2. Chemotherapy group: one i.p. injection of cyclophosphamide 24 hours after inoculation of tumor cells, and daily i.p. injection of 1 ml of physiological solution on the mouse from the day of inoculation of the tumor to killing of mice.

3. A group of agonist adenosine receptor A3 (A3RAg):

daily oral administration of IB-MECA from the day of inoculation of the tumor to killing of mice.

4. Group A3RAg + chemotherapy: one i.p. injection of cyclophosphamide 24 hours after inoculation of the tumor and daily administration of 3 μg per kg of body weight IB-MECA.

5 and day 9 mice take blood from the tail vein and get blood samples for counting white blood cells (WBC). The results are shown in Fig.8.

In addition, in the next 18 days mice kill and count the number of tumor foci in the lungs. The results are shown in Fig.9.

Conduct another experiment, in order to assess chemotaxin action A3RAg. Mice treated with cyclophosphamide (50 mg / kg of body weight in 0.3 ml PBS). After 48 and 72 hours after administration of cytotoxic drugs to mice give i.p. injection of adenosine (25 mcg per kg of body weight) or IB-MECA (3 or 6 µg / kg body weight in 0.2 ml PBS). Check the number of white blood cells (WBC) and neutrophils. Results prevedchemical, find the drop in the number of leukocytes and neutrophils in the peripheral blood when compared with the group treated only IB-MECA. When injected adenosine or IB-MECA, the total number of white blood cells is restored, the latter has a more pronounced effect, with full recovery get through 168 hours (7 days).

Example 5. Agonists adenosine receptor A3 prevent weight loss in mice treated with chemotherapeutic drug

Process 4 groups "Nude" mice (origin BALB/C), 10 in each, as described below.

Group 1: mice not treated [confirmed anything]

Group 2: mice give IPR (i.p.) injection of 5-fluorouracil (5-FU, 30 mg / kg body weight in PBS) over the next five days.

Group 3: mice give i.p. injection of 5-FU as in group 2, but starting from 2 days, and then a day later the mice given oral Cl-IB-MECA (6 μg per kg body weight in 0.2 ml PBS).

Group 4: mice receive Cl-IB-MECA, as described above.

The weight of mice was measured at 7, 10 and 14 day. The results are shown in Fig.11.

As you can see, 5-FU strongly affects the weight of mice as compared with control, whereas Cl-IB-MECA, injected with 5-FU, to some extent prevents such poterry, that agonists adenosine receptor A3 have a General protective effect against some toxic action of chemotherapy.

Example 6. Cl-IB-MECA protects mice from mielotoksicnae action of chemotherapeutic drugs doxorubicin

Of ICR mice treated with doxorubicin (i.p. injection of 10 mg/kg in 0.5 ml PBS). After 24, 48 and 72 hours after administration of cytotoxic drugs to mice administered orally Cl-IB-MECA (6 μg per kg of body weight). In points, 72 hours, 96 hours, 120 hours and 144 hours mice kill and take blood samples. In addition, from the femurs of mice suck the bone marrow cells and determine the number of nucleated cells in the resulting sucked away the drugs after application of the drug Kumasi blue.

Have three groups of mice.

Group 1 (control): mice injected with only PBS.

Group 2: mice treated only with doxorubicin.

Group 3: introduction doxorubicin as described above, combined with the introduction of Cl-IB-MECA.

The results of counting the number of white blood cells shown in Fig.12A, and the number of nucleated cells of the bone marrow in Fig.12V. The obtained results clearly show that after the introduction of Cl-IB-MECA there was a notable increase in the number of peripheral white cells is oxychloro action of doxorubicin.

Example 7. Antibodies against G-CSF neutralizing malonamide the effect of Cl-IB-MECA

Mice ICR divided into 6 groups, described below.

Group 1: control, the introduction of only one carrier.

Group 2: control with antibodies against G-CSF (5 µg/mouse).

Group 3: chemotherapy, administration of cyclophosphamide (CYP, 50 mg per kg of body weight).

Group 4: chemotherapy (50 mg per kg of body weight CYP) + antibodies against G-CSF (5 µg/mouse).

Group 5: chemotherapy (50 mg per kg of body weight CYP) + Cl-IB-MECA (6 μg per kg of body weight) + antibodies against G-CSF (5 µg/mouse).

Group 6: chemotherapy (50 mg per kg of body weight CYP) + Cl-IB-MECA (6 μg per kg of body weight) + antibodies against G-CSF (5 µg/mouse).

Each group consists of 10 mice and the experiment was repeated twice.

CYP administered intraperitoneally injected in 0.2 ml PBS, which serves as a carrier.

Cl-IB-MECA give oral (in 0.2 ml PBS) at 48 hours and 72 hours after administration of cyclophosphamide.

Antibodies against G-CSF is injected intravenously (0.2 ml PBS) at 72 hours after administration of chemotherapeutic drugs.

Blood samples taken 124 hours after chemotherapy. The number of white blood cells (WBC) was determined by Coulter counter and the counting of differentiated cells that perform drugs-smears stained with restoreposition, show a fall in the number of WBC in peripheral blood. In the group treated with Cl-IB-MECA, the number of WBC and the percentage of neutrophils is significantly higher compared with the group treated with chemotherapeutic agent (the results regarding neutrophils, not shown). When antibodies against G-CSF is administered control or treated with a chemotherapeutic agent groups, see the expected decrease in WBC. Introduction antibodies against G-CSF to mice treated with a combination of chemotherapeutic drugs and Cl-IB-MECA void protective effect of Cl-IB-MECA, which can clearly be seen in Fig.13. The results obtained lead to the conclusion that the protective effect of C1-IB-MECA on myeloid system is mediated through the ability of C1-IB-MECA promote the production and secretion of G-CSF.

Example 8. Cl-IB-MECA inhibits the development of HCT-116 colon carcinoma colon man in "Nude" mice

Tumors create a subcutaneous injection of 1×106cell carcinoma of the colon of human HCT-116 "Nude" mice (prohozhdenie BALB/C) (Harlan, Jerusalem, Israel). Mice treated orally with 6 µg Cl-IB-MECA per kg of body weight (0.2 ml PBS) in a day. The mouse, which is treated only with vehicle (PBS), constitute the control group. Each group consists of 10 mister tumors evaluated by the formula ¶/6[D1D2]. The results are shown in Fig.14. As you can see, in the treated group, a significant inhibition of tumor growth.

In a separate group of experiments validate combination therapy Cl-IB-MECA and 5-fluorouracil (5-FU). "Nude" mice injected subcutaneously 1×106cells HCT-116. A day later administered intraperitoneally injected with 5-FU (30 mg / kg body weight in 0.2 ml PBS) and subcutaneously in the next 4 days. A day later the mice administered orally 5 mg on kg of weight of a C1-IB-MECA (in 0.2 ml PBS). The mouse, which is treated or only vehicle (PBS), or only 5-FU, serve as control. Each group consists of 10 mice. The rate of tumor growth is determined by measuring two orthogonal diameters of each tumor twice a week, and tumor size was evaluated according to the formula ¶/6[D1D2].

The results are shown in Fig.15 and 16. Significant inhibition of tumor growth observed in the groups treated with 5-FU, Cl-IB-MECA and combination therapy Cl-IB-MECA and 5-FU. In 20 days you can see a clear synergistic effect between Cl-IB-MECA and 5-FU when writing tumor mass, as shown in particular in Fig.16 (results shown in Fig.16 are the results at day 30).

Example 9. Cl-IB-MECA stimulates the proliferation of bone marrow cells through the microtiter plates. Add CL-IB-MECA at a final concentration of 10 nm with antibodies against G-SCF at final concentrations of 0.05 and 0.5 μg/ml or without them. Cell proliferation is measured by analysis with the inclusion of [3H]-thymidine. The results are shown in Fig.17.

As you can see, antibodies against G-SCF inhibit the proliferation of bone marrow cells depending on the dose. This experiment also shows that the effect of Cl-IB-MECA mediated through the path of G-SCF (including the secretion of G-SCF of cells).

Example 10. Cl-IB-MECA inhibits the growth of tumor cells and stimulates the proliferation and differentiation of bone marrow cells

Melanoma cells In-16 (5×105cells/ml) and bone marrow cells (3×106cells/ml) incubated in the wells of 96-hole microtiter tablet. Add culture, consisting of RPMI medium with addition of 10% FTS, and Cl-IB-MECA at a concentration of 0.01 μm or 0.1 μm, with the antagonist of adenosine receptor A3 MRS-1523 or without him. Cell proliferation is measured by analysis with the inclusion of [3H]-thymidine mentioned earlier. The results are shown in Fig.18. As you can see, in the presence of MRS-1523 proliferation as melanoma cells and bone marrow cells does not change when compared with control. In contrast, Cl-IB-MECA shows ingibiruet>

The results demonstrate the dual action of agonists adenosine A3 receptor.

Example 11. Cl-IB-MECA acts as chemotaxins tool

Perform the experiment with Cl-IB-MECA, similar to that described in example 4 and the results are shown in Fig.19A and 19B, which shows chemotaxin activity of Cl-IB-MECA.

Example 12. The effect of IB-MECA and Cl-IB-MECA on the proliferation of bone marrow cells

Cells mouse bone marrow were cultured as described above. Cultures add IB-MECA or Cl-IB-MECA at a concentration of 1 or 10 nm in the presence or in the absence of 3Rn MRS-1523. Antagonist added at a concentration of 10 nm. The results are shown in Fig.20.

As can be seen in Fig.20, the effect of IB-MECA and Cl-IB-MECA depends on the dose. In addition, you can also see that the influence is largely inhibited A3RAn.

Claims

1. The use of agonist of adenosine A3 receptor (A3RAg) as an active ingredient in pharmaceutical compositions for inducing the secretion or production of granulocyte colony-stimulating factor (G-CSF)y subject in need thereof, where the agonist of adenosine A3 receptor (A3RAg) exerts its main action through receptor Aden the General formula (I)

where R1is a (C1-C10)-alkyl, (C1-C10-hydroxyalkyl, (C1-C10-carboxyethyl or (C1-C10-cianelli or a group of the General formula (II)

where Y represents oxygen, sulfur or CH2;

X1represents H, (C1-C10)-alkyl, RaRbNC(=O) - or HORc- where R3and R13may be the same or different and selected from the group consisting of hydrogen, (C1-C10)-alkyl, amino, (C1-C10)-halogenoalkane, (C1-C10)-aminoalkyl, (C1-C10)-BOC-aminoalkyl and (C3-C10)-cycloalkyl, or joined together to form heterocyclic ring containing two to five carbon atoms, and Rcselected from the group consisting of (C1-C10)-alkylene, NH-, (C1-C10)-halogenation, (C1-C10)-aminoaniline, (C1-C10)-VOS-aminoaniline and (C1-C10)-cycloalkyl;

X2represents H, hydroxyl, (C1-C10)-alkylamino, (C1-C10)-alkylamino or (C1-C10-hydroxyalkyl;

X3and Xthe Boxing, nitrilo, nitro, driftor, aryl, alkaryl, thio, thioester complex group, simple thioester group, -OCOPh, OC(=S)OPh, or X3and X4both represent oxygen associated with the >C=S with the formation of 5-membered cycle, or X2and X3form a loop of the formula (III)

where Rand Rare independently (C1-C10)-alkyl;

R2selected from the group consisting of hydrogen, halogen, simple (C1-C10)-alkylamino group, amino, hydrazido, (C1-C10)-alkylamino, (C1-C10)-alkoxy, (C1-C10)-dialkoxy, pyridylthio, (C2-C10-alkenyl, (C2-C10)-quinil, thio and (C1-C10) -alkylthio;

R3is a group-NR4R5and R4represents hydrogen or a group selected from alkyl, substituted alkyl or aryl-NH-C(Z)-, Z represents O, S or NRaand Rahas the above meaning, R4represents hydrogen, R5selected from the group consisting of R - and S-1-phenylethylene, benzyl, phenylethylene or anilino groups, nezam the 1-C10)-alkyl, amino, halogen, (C1-C10)-halogenoalkane, nitro, hydroxyl, acetamido, (C1-C10)-alkoxy, and sulfonic acid or a salt thereof, or R5is benzodioxolyl, furfuryl, L-propylaminoethyl,-albilineans, T-BOC--albilineans, phenylamino, carbarnoyl, phenoxy or (C3-C10-cycloalkyl, or R5represents a group of the formula

or an acceptable salt of the compounds defined above, such as its triethylammonium salt; or when R4represents a group selected from alkyl, substituted alkyl or aryl-NH-C(Z)-, then R5selected from the group consisting of substituted or unsubstituted heteroaryl-NRa-C(Z)-, heteroaryl-(Z)-, alkaryl-Nra-C(Z)-, alkaryl-(Z)-, aryl-NR-C(Z)- and aryl-C(Z), where Z has the values listed above.

3. Application under item 1 or 2, where the specified active ingredient is a derivative of the nucleoside of the General formula (IV)

where X1, R2and R5have the values listed in paragraph 2.

4. Application under item 3, where the specified active Ingram is p active ingredient selected from the group consisting of N6-2-(4-AMINOPHENYL)-atelectasia (APNEA), N6-(4-amino-3-iodobenzyl)adenosine-5'-(N-methyluronamide) (AB-MESA) and N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (CI-IB-MECA).

6. Application under item 1, where the active ingredient is an N6-benzyladenine-5'-alkylaromatic-Nl-oxide or N6-benzyladenine-5'-vallorani-N1-oxide.

7. Application under item 1, where the active ingredient is a derivative of xanthine-7-riboside General formula (V)

where X represents O or S;

R6is an RaRbNC(=O)- or HORc- where Raand Rbmay be the same or different and selected from the group consisting of hydrogen, (C1-C10)-alkyl, amino, (C1-C10)-halogenoalkane, (C1-C10)-aminoalkyl and (C3-C10)-cycloalkyl, or joined together to form heterocyclic ring containing two to five carbon atoms, and Rcchoose from a (C1-C10) -alkyl, amino, (C1-C10)-halogenoalkane, (C1-C10)-aminoalkyl, (C1-C10)-VOS-aminoalkyl and (C31-C10)-alkyl, (C3-C10)-cycloalkyl, R - or S-1-phenylethylene, unsubstituted benzyl or anilide groups and simple phenyl ether benzyl group substituted in one or several positions Deputy selected from the group consisting of (C1-C10)-alkyl, amino, halogen, (C1-C10)-halogenoalkane, nitro, hydroxyl, acetamido, (C1-C10)-alkoxy, and sulfonic acids;

R9selected from the group consisting of halogen, benzyl, phenyl,(C3-C10)-cycloalkyl and (C1-C10)-alkoxy,

or a salt of such a compound, for example, it triethylammonium salt.

8. The use of agonist of adenosine A3 receptor (A3RAg) as an active ingredient in pharmaceutical compositions for combating mielotoksichnosti induced drug where A3RAg exerts its primary effect through the A3 receptor.

9. Application under item 8, where the specified drug is a chemotherapeutic drug that is assigned to the subject in the framework of anti-cancer treatment.

10. Application under item 8, where the specified active ingredient is an active ingredient according to any one of paragraphs.2-7.

11. GIP administration.

12. Application A3RAg as an active ingredient in pharmaceutical compositions for inducing proliferation or differentiation of bone marrow cells or white blood cells, where A3RAg exerts its primary effect through the A3 receptor.

13. Application under item 12, where the specified active ingredient is an active ingredient according to any one of paragraphs.2-7.

14. Application under item 12 or 13, where the specified active ingredient included in the preparative form for oral administration.

15. Application A3RAg as an active ingredient in pharmaceutical compositions for the prevention or treatment of radiation, where A3RAg exerts its primary effect through the A3 receptor.

16. Application under item 15 for the prevention or treatment of leukopenia caused by the drug.

17. Application under item 15, where the specified active ingredient is an active ingredient according to any one of paragraphs.2-7.

18. The use according to any one of paragraphs.15-17, where the specified active ingredient included in the preparative form for oral administration.

19. Application under item 16 in combination with a drug that can cause leucopenia in the subject being treated.

20. Application under item 19, where the specified dosage of cogredient pharmaceutical composition for inhibiting abnormal cell growth, where A3RAg exerts its primary effect through A3 receptor.

22. Application on p. 21 for inhibiting the growth or proliferation of cancer cells.

23. Application under item 21 or 22, where the specified active ingredient is an active ingredient according to any one of paragraphs.2-7.

24. The use according to any one of paragraphs.21-23, where the specified active ingredient included in the preparative form for oral administration.

25. Application A3RAg as an active ingredient in pharmaceutical compositions for the treatment of cancer, and A3RAg exerts its primary effect through the A3 receptor and exerts a dual effect for inhibiting the proliferation of cancer cells, and to counter the toxic side effects when treating of the same subject chemotherapeutic drug.

26. Application on p. 25, where the specified active ingredient works synergistically with the specified drug for more strong antitumor action.

27. Application under item 25 or 26, where the active ingredient is an active ingredient according to any one of paragraphs.2-7.

28. The use according to any one of paragraphs.25-27, where the specified active ingredient included in the preparative form for oral Vvedenie. Application on p. 29, where the dosage A3RAg is less than 50 mg/kg of body weight.

31. Application on p. 30, where the dosage A3RAg is from 1 to 10 mcg/kg of body weight.

32. The use according to any one of paragraphs.1, 2, 8, 12, 15, 21, 25, 29, 30 or 31, where the specified active agent selected from the group consisting of

N6-(3-iodobenzyl)-9-methyladenine;

N6-(3-iodobenzyl)-9-hydroxyethylidene;

R-N6-(3-iodobenzyl)-9-(2,3-dihydroxypropyl)adenine;

S-N6-(3-iodobenzyl)-9-(2,3-dihydroxypropyl)adenine;

N6-(3-iodobenzylamine-9-yl)acetic acid;

N6-(3-iodobenzyl)-9-(3-cyanopropyl)adenine;

2-chloro-N6-(3-iodobenzyl)-9-methyladenine;

2-amino-N6-(3-iodobenzyl)-9-methyladenine;

2 hydrazido-N6-(3-iodobenzyl)-9-methyladenine;

N6-(3-iodobenzyl)-2-methylamino-9-methyladenine;

2-dimethylamino-N6-(3-iodobenzyl)-9-methyladenine;

N6-(3-iodobenzyl)-9-methyl-2-Propylenediamine;

2 hexylamino-N6-(3-iodobenzyl)-9-methyladenine;

N6-(3-iodobenzyl)-2-methoxy-9-methyladenine;

N6-(3-iodobenzyl)-9-methyl-2-methylthioadenosine;

N6-(3-iodobenzyl)-9-methyl-2-(4-pyridylthio)adenine;

(1S, 2R, 3S, 4R)-4-(6-amino-2-phenylethylamine-N-purine-9-yl)cyclopentane-1, 2, 3-triol;

(1S, 2R, 3S, 4R)-4-(6-amino"0">-dihydroxy-4-(N-methylcarbamoyl)cyclopent-1-Il)]N6-(3-iodobenzyl)adenine;

2-chloro-9-(2'-amino-2',3'-dideoxy-D-5'-methylamino-furosemide)-N6-(3-iodobenzyl)adenine;

2-chloro-9-(2',3'-dideoxy-2'-fluorine--D-5'-methylamino-furosemide)-N6-(3-iodobenzyl)adenine;

9-(2-acetyl-3-deoxy--D-5-methylisophthalic)-2-chloro-N6-(3-iodobenzyl)adenine;

2-chloro-9-(3-deoxy-2-methanesulfonyl-D-5-Metallbau-furosemide)-N6-(3-iodobenzyl)adenine;

2-chloro-9-(3-deoxy--D-5-methylisophthalic)-N6-(3-iodobenzyl)adenine;

2-chloro-9-(3,5-1,1,3,3-tetraisopropyldisiloxane-D-5-ribofuranosyl)-N6-(3-iodobenzyl)adenine;

2-chloro-9-[2',3'-O-thiocarbonyl-D-5-methylisophthalic)N6-(3-iodobenzyl)adenine;

9-(2-phenoxythiocarbonyl-3-deoxy--D-5-methylisophthalic)-2-chloro-N6-(3-iodobenzyl)adenine;

1-(6-benzylamino-N-purine-9-yl)-1-deoxy-N,4-dimethyl--D-ribofuranose the Enina;

2-chloro-9-(2'-azido-2',3'-dideoxy-D-5'-methylaminopropyl)-N6benzyladenine;

2-chloro-9-(-D-erythropoietic)-N6-(3-iodobenzyl)adenine;

N6(benzodioxolyl)adenosine;

1-(6-furfurylamine-N-purine-9-yl)-1-deoxy-N-methyl--D-ribofuranosylpurine;

N6-[3-(L-propylamino)benzyl]adenosine-5'-N-methyluronamide;

N6-[3-(-alaninemia)benzyl]adenosine-5'-N-methyluronamide;

N6-[3-(N-T-BOC--alaninemia)benzyl]adenosine-5'-N-methyluronamide;

N6[N'-phenylhydrazine)purine-9--ribofuranoside-5'-N-methyluronamide;

6-(O-phenylhydroxylamine)purine-9--ribofuranoside-5'-N-methyluronamide;

9-(-D-2',3'-dimethoxyacetophenone)-N6-(3--alaninemia)benzyl]adenosine;

9-(-D-erythropoietic)-2-methylamino-N6-(3-iodobenzyl]adenine;

2-chloro-N-(3-iodobenzyl)-9-(2-tetrahydrofuryl)-N-purine-6-amine;

2-chloro-(2’-deoxy-6’-thio-L-arabinosyl)adenine;

2-chlorine is -(2,4-dichlorobenzophenone)adenosine-5'-N-ethyleneamine;

N6-(4-methoxyphenylethylamine)adenosine-5'-N-ethyleneamine;

N6-(4-chlorophenethylamine)adenosine-5'-N-ethyleneamine;

N6(phenylcarbonylamino)adenosine-5'-N-ethyleneamine;

N6(benzylcarbamoyl)adenosine-5’-N-ethyleneamine;

N6-(4-sulfonamidophenylhydrazine)adenosine-5'-N-ethyleneamine;

N6-(4-acetylpenicillamine)adenosine-5'-N-ethyleneamine;

N6-((R)--phenylethanol)adenosine-5'-N-ethyleneamine;

N6-((S)--phenylethanol)adenosine-5'-N-ethyleneamine;

N6-(5-methylisoxazol-3-yl-carbarnoyl)adenosine-5'-N-ethyleneamine;

N6-(1,3,4-thiadiazole-2-yl-carbarnoyl)adenosine-5'-N-ethyleneamine;

N6-(4-n-propoxyethanol)adenosine-5'-N-ethyleneamine;

N6bis-(4-nitrophenylamino)adenosine-5'-N-ethyleneimine; and

N6bis-(5-chloropyridin-2-yl-carbarnoyl)adenosine-5'-N-ethyleneamine.

33. The use according to any one of paragraphs.1, 2, 3, 8, 12, 15, 21, 25 or 29, 30 and 31, where the specified active ingredient selected from the group consisting of compounds of the formula (IV), where X1is an RaRbNC(=O) Raand Rbcan be Odin is 10) halogenoalkane, (C1-C10)-aminoalkyl, and (C3-C10)cycloalkyl; R2selected from the group consisting of hydrogen, halogen, (C1-C10)alkoxy, amino, (C2-C10)alkenyl and (C2-C10)quinil, and R5selected from the group consisting of R - and S-1-phenylethyl, unsubstituted benzyl group and a benzyl group substituted in one or more of the provisions of the Deputy selected from the group consisting of (C1-C10)-alkyl, amino, halogen, (C1-C10)halogenoalkane, nitro, hydroxy, acetamido, (C1-C10)alkoxy, sulfo.

34. Application under item 33, where the specified active ingredient selected from the group consisting of compounds of the formula (IV), where Raand Rbmay be the same or different and selected from the group consisting of hydrogen, (C1-C10)-alkyl, and R2is hydrogen or halogen; Rais hydrogen, R2is hydrogen and R5is unsubstituted benzyl; Rbis (C1-C10) alkyl or (C3-C10) cycloalkyl and R5in R or S-1-phenylethyl or benzyl substituted in one or more of the provisions of the Deputy selected from the group consisting of halogen, amino, acetamide (C2-C10) alkylen formula Rd-C=C-, where Rdis (C1-C8) alkyl, or R2represents halogen, (C1-C10) alkylamino, or (C1-C10) alkylthio; Rais hydrogen, Rbis (C1-C10)alkyl and R5- substituted benzyl.

35. The use according to any one of paragraphs.1, 7, 8, 12, 15, 21, 25 or 29, 30 and 31, where the specified active ingredient selected from the group consisting of compounds of the formula (V), where X1represents Oh, R6- RaRbNC(=O) Raand Rbmay be the same or different and selected from the group consisting of hydrogen, (C1-C10)alkyl, amino, (C1-C10)halogenoalkane, (C1-C10) -aminoalkyl, (C3-C10) cycloalkyl, and R7and R8may be the same or different and selected from the group consisting of (C1-C10)alkyl, R - and S-1-phenylethylene, unsubstituted benzyl group and a benzyl group substituted in one or several positions Deputy selected from the group consisting of (C1-C10)alkyl, amino, halogen, (C1-C10)halogenoalkane, nitro, hydroxy, acetamido, (C1-C10)alkoxy and sulfopropyl, and R9selected G of PP.1-31 or 32-35, where the active ingredient is presented in the form of a salt of triethylamine.

Priority items:

23.12.1999 on PP.1-11, 13-14, 17, 19-20, 23, 25-36;

10.09.1999 on PP.12, 15-16, 18, 21-22 and 24.



 

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