Improved conjugates n4 of chelating agents

FIELD: medicine.

SUBSTANCE: invention refers to chelating agents and their technetium complexes to be used as radiopharmaceuticals and characterised by formula I where X is -NR-, -CO2-, -CO-, -NR(C=S)-, -NR(C=O)-, -CONR- or Q; Y represents amino acid, -CH2-, -CH2OCH2-, -OCH2CH2O- or X; Z is an aggregation from peptides, their analogues, substrata, antagonists or enzyme inhibitors, receptor-bonding compounds, oligonucleotides, oligo-DNA- or oligo-RNA-fragments; n is a number 1 to 8; m is a number 0 to 30; R represents H, C1-4alkyl, C2-4alkoxyalkyl, C1-4hydroxyalkyl or C1-4fluoroalkyl; Q represents remains of succinimide , A is a pharmaceutically acceptable anion.

EFFECT: production of new chelating agents applicable for making the technetium complexes.

22 cl, 12 ex, 3 dwg, 2 tbl

 

The scope of the invention

The present invention relates to improved conjugates tetraamine chelat forming agents providing targeted delivery of biological molecules suitable for the formation of metal complexes with radioactive metal99mTc. These radioactive metal complexes useful as99mTc-radiopharmaceuticals funds. Suggested kits and predecessors.

Prior art

In the US 5489425 (Dow Chemical) revealed a number of functionalized tetraamine chelat forming agents with an open-chain and macrocyclic suitable for the formation of metal complexes, particularly complexes of radioactive and non-radioactive rhodium, specifically complexes radioactive105Rh or101mRh. Specific open tetraamine include:

Bifunctional hepatoblastoma agents are described as suitable for conjugation with monoclonal antibodies or their fragments for therapeutic or diagnostic purposes. In the US 5489425 specified (Examples 21, 22 and 23)that chelate conjugate antibody-radiometrically complex receive first formation of the complex metal105Rh, then the interaction with the antibody, followed by purification. In the US 5489425 not mentioned conjugates antibody-helatoobrazutmi agent, which are not in the form of the complex, i.e. have no coordinated radioactive metal. In the US 5489425 no information about how to delineate the lateral amino group and four amino chelat forming agent in such reactions conjugation with the antibody. In the US 5489425 argues that the bifunctional hepatoblastoma agents "could be used also in the formation of complexes of technetium and rhenium", but not disclosed, as this can be achieved not revealed any real complexes of technetium.

In the US 5650134 disclosed conjugate somatostatinomas peptide-chelate forming agent from a number of chelat forming agents. Example 1 describes the conjugation of 6-(p-isothiocyanatobenzene)-1,4,8,11-tetrataenia with octreotide peptide.

In EP 1181936 A1 discloses conjugates of bombezin (i.e. tetradecapeptide) tetraamine chelat forming agents, obtained using bifunctional chelat forming agents BBN-1 and BBN-2, and99mTc-complexes:

where Boc is tert-butoxycarbonyl protective group.

Indicated that the complexes99mTc demonstrated rapid clearance of mouse body through the kidneys and urinary system. In EP 1181936 A1 is not given, however, no description or reference to the synthesis of BBN-1 or BBN-2, except the reference to the stage where they kongugiruut N-end of bombezin. Conjugial is the BBN-2 bombezin and 99mTc-tagging with the formation of a potential radiopharmaceutical tools for visualization of tumors was described by Nock et al. [Eur. J. Nucl. Med., 30(2), 247-258

(2003)]. It is reported that the complex99mTc gives improved hydrophilicity compared to the bombezin-by chelating conjugates of the prior art and it is therefore expected that he favors excretion through the kidneys and urinary system.

Conjugation BBN-1 with octreotide and99mTc-tagging with the formation of a potential radiopharmaceutical tools to visualize tumors in patients-people described Maina et al. [Eur. J. Nucl. Med., 30(9), 1211-1219 (2003)]. None of the above publications relating to BBN-1 or BBN-2, there is shown the synthesis of BBN-1 or BBN-2.

The invention

According to the present invention proposed conjugates tetraamine chelat forming agents providing targeted delivery of biological groups, which are linked through a linker group, and their complexes with technetium as a radiopharmaceutical funds. The linker group is such that the chelate forming agent monofunctionalized in position of the head of the bridge and provides both flexibility and lack of aryl groups to minimize lipophilicity and steric hindrance of obamistas. Proposed suitably protected options gelatobaby the x agents which allow conjugation with a variety of providing targeted delivery of molecules without interactions with the amine nitrogen atoms tetraamines chelat forming agent. Described the syntheses of functionalized chelat forming agent with a bifunctional chelate precursors.

Described radiopharmaceutical compositions containing the metal complexes of technetium according to the invention, and non-radioactive kits for radiopharmaceutical receipt of such funds.

Detailed description of the invention

In the first embodiment of the present invention proposed a cationic complex of technetium99mTc formula (I)

,

where X represents-NR-, -CO2-, -CO-, -NR(C=S)-, -NR(C=O)-, -CONR -, or a group Q;

each Y independently represents a D - or L-amino acid, -CH2-, -CH2OCH2- or-OCH2CH2O-, or group X;

Z is a synthetic, providing targeted delivery of biological grouping;

n means an integer from 1 to 8;

m means an integer from 0 to 30;

R represents H, C1-4alkyl, C2-4alkoxyalkyl,1-4hydroxyalkyl or1-4foralkyl;

Q represents

A represents a counterion;

if mo is a chain of atoms X 1(Y)mnot have a relationship where one heteroatom is directly connected with the other.

A radioactive isotope of technetium can be γ-emitter, such as99mTc, or positron emitter suitable for imaging by means of positron-emission tomography (PET), such as94mTc. Preferably a radioactive isotope of technetium is a99mTc or94mTc, most preferably99mTc.

X preferably represents-CONR-, -NR(C=O)- or a group of Q. Most preferably X is a-CONR -, or-NR(C=O)-, and-CONH -, and-NH(C=O)is particularly preferred.

The linker group -(CH2)n-X-(Y)min the compound of formula (I) is chosen so that the chain of atoms X1(Y)mnot have a relationship in which one heteroatom directly linked to another, where the term "heteroatom" means an atom that is not carbon atom such as nitrogen atom, oxygen or sulfur. This means that this circuit has no such ties, O-O, N-N or O-N.

It seems that the role of the linker group -(CH2)n-X-(Y)min the compound of formula (I) is to distance the complex of technetium from the active binding site providing targeted delivery of biological grouping (Z) in vivo. This gives the opportunity to ensure that the relative volume of the complex is egnazia steric will not inhibit binding to the active sites in vivo. Allenova group -(CH2)n- has the advantage that there are no significant interactions with conjugated providing targeted delivery of biological grouping (Z) with the formation of hydrogen bonds, so that the linker does not wound on Z. In the preferred alkilinity groups n = number from 1 to 6, most preferably from 2 to 4 and particularly preferably 2.

The linker group of the present invention are not aryl rings. This minimizes liquid technologo complex with a linker group that is attached to providing targeted delivery of biological grouping (Z) conjugate. Also minimized steric volume and molecular weight of the linker group (and, therefore, technologo complex), while the flexibility of the connection is stored.

The nature of the linker group can also be used to modify bearsdley visualizing agent. For example, the introduction of a simple ester groups in(Y)m- will help minimize binding plasma proteins. In cases where -(Y)m- contains polietilenglikolya (PEG) structural element or a peptide chain of 1-10 amino acid residues, the linker group may function as a modifier of pharmacokinetics and renal clearance Visualizer is his agent in vivo. Such linker groups"biomodification" can accelerate the excretion technologo imaging agent of the background tissue, such as muscle or liver, and/or from the blood, allowing you to get more high-quality diagnostic images with less background interference. The linker group-biomodification can also be used to promote specific ways of excretion, for example through the kidneys, not the liver. Alternative such linker groups can prolong the period of stay in the blood, allowing the accumulation of a larger amount of the agent in the target site in vivo.

In cases where -(Y)m- contains a peptide chain of amino acids, these amino acid residues preferably selected from glycine, lysine, aspartic acid, glutamic acid or serine. The number of amino acids in the peptide chain is preferably from 1 to 10, most preferably from 1 to 3.

In cases where -(Y)m- contains the grouping PEG, it preferably contains a group of formula (-OCH2CH2O)w-where w denotes an integer having a value of from 3 to 25. Integer w is preferably a number from 6 to 22. Particularly preferred PEG-containing group(Y)m- is the group formed by polymerization of monodisperse PEG-like the structure of 17-amino-5-oxo-6-Aza-3,9,12,15-tetracosapentaenoic acid of formula (IV)

,

where p means an integer from 1 to 10.

The term "foralkyl" refers to an alkyl group with at least one Deputy fluorine, that is, this term covers a group from monitorable (for example, -CH2F) to perforaciones (for example, CF3).

The group -(Y)m- preferably contains grouping diglycolic acid, maleimido grouping, the grouping of glutaric acid, the group of succinic acid, grouping on the basis of polyethylene glycol or PEG-like grouping of the formula IV.

The term "synthetic" has the conventional meaning of this term, that is man-unlike isolated from natural sources, such as from the body of a mammal. Such compounds have the advantage that their production and levels of purity can be fully controlled. Thus, monoclonal antibodies and their fragments are not included in the scope of these claims.

The term "providing targeted delivery of biological grouping" refers 3-100-dimensional peptides or peptide analogs, which can be a linear peptides or cyclic peptides, or combinations thereof; or substrates, antagonists or enzyme inhibitors; synthetic receptor-binding compounds; oligonucleotide is or oligo-DNA or oligo-RNA fragments.

The term "cyclic peptide" means a sequence of 5 to 15 amino acids, in which the two terminal amino acids linked together by covalent bond, which can be a peptide or disulfide bonds, or synthetic ones relationship, such as thioester, fosfomifira, disiloxane or urethane link.

The term "amino acid" refers to L - or D-amino acid analogue of the amino acid or mimetic amino acids, which can be optically pure, then there can be a single enantiomer and, therefore, chiral, or a mixture of enantiomers. Preferably the amino acids of the present invention are optically pure.

The term "mimetic amino acid" refers to synthetic analogues of naturally occurring amino acids, which are isostere, i.e. mimic the steric and the electronic structure of the natural compound. Such isostere well-known in this field and include depsipeptide, retroversive, thioamides, cycloalkanes or 1,5-disubstituted tetrazole [see .Goodman, Biopolymers, 24, 137, (1985)], but not limited to.

Suitable peptides for use in the present invention include:

- somatostatin, octreotide and analogues;

peptides that bind to ST receptor, where ST refers to thermostable Tox is well, produced by E. coli and other microorganisms;

fragments of laminin, for example YIGSR, PDSGR, IKVAV, LRE and KCQAGTFALRGDPQG;

- N-formyl peptides for targeted delivery to the sites of accumulation of leukocytes;

platelet factor 4 (PF4) and its fragments;

- RGD (Arg-Cly-Asp)-containing peptides, which may, for example, aimed to influence angiogenesis [R.Pasqualian et al., Nat Biotechnol. 1997 Jun; 15(6): 542-6; E.Ruoslahti, Kidney Int. 1997 May, 51(5); 1413-7];

peptide fragments α2-antiplasmin, fibronectin or beta-casein, fibrinogen or thrombospondin; amino acid sequence α2-antiplasmin, fibronectin, beta-casein, fibrinogen and thrombospondin can be found in the following publications: the precursor α2-antiplasmin [Mtape et al., J. Biochem, 102, 1033, (1987)], beta-casein [L.Hansson et al., Gene, 139. 193 (1994)], fibronectin [A.Gutman et al., FEBS Lett, 207. 145 (1996)], the predecessor of thrombospondin-1 [V.Dixit et al., Proc. Natl. Acad. Sci., USA, 83, 5449 (1986)], R.F.Doolittle, Ann. Rev. Biochem., 53, 195 (1984);

peptides that are substrates or inhibitors of angiotensin, such as angiotensin II Asp-Arg-Val-Tyr-lle-His-Pro-Phe (E.C.Jorgensen et al., J. Med. Chem., 1979, Vol.22, 9, 1038-1044),

[Sar lie] angiotensin II: Sar-Arg-Val-Tyr-lle-His-Pro-lle (R.K.Turker et al., Science, 1972, 177, 1203),

angiotensin I: Asp-Arg-Val-Tyr-lle-His-Pro-Phe-His-Leu.

Preferably, the peptides of the present invention include peptides antiplasmin or angiotensin II. Peptides antiplasmin containing the amino acid sequence, taken from the N-end:

1) α2-antiplasmin,

that is, NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Thr-Leu-Leu-Lys-OH,

or variants of this sequence, in which one or more amino acids are substituted, added or deleted, such as:

NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Thr-Leu-Leu-Lys-Gly-OH,

NH2-Asn-Gln-Glu-Ala-Val-Ser-Pro-Leu-Thr-Leu-Thr-Leu-Leu-Lys-Gly-OH,

NH2-Asn-Gln-Glu-Gln-Val-Gly-OH, or

2) casein,

that is, Ac-Leu-Gly-Pro-Gly-Gln-Ser-Lys-Val-lle-GIy.

Synthetic peptides of the present invention can be obtained by standard solid-phase synthesis, as described in .Lloyd-Williams, F.Albericio and E.Girald; Chemical Approaches to the Synthesis of Peptides and Proteins, CRC Press, 1997.

Suitable substrates, antagonists or inhibitors of enzymes include glucose and analogues of glucose, such as Tordesillas; fatty acids, or elastase inhibitors, angiotensin II or metalloproteinases. Preferred ones antagonist of angiotensin II is losartan.

Suitable synthetic receptor-binding compounds include estradiol, estrogen, progestin, progesterone and other steroid hormones; ligands for the dopamine D-1 or D-2 receptor or dopamine transporters, for example Trapani, and ligands for the serotonin receptor.

Providing targeted delivery of biological grouping (Z) preferably has a molecular weight less than 5000, the most predpochtitel is about less than 4000, ideally less than 3000. This gives the advantage that improved biological characteristics tetraamine complexes of technetium according to the invention can have an impact on the overall biodistribution, in particular clearance, technologo complex conjugate of formula I. When n is 3 and X contains a nitrogen atom that is directly associated with the group (CH2)nthen Z is selected synthetic and having a molecular weight of less than 4000. Preferred providing targeted delivery of biological groups are 3-20-dimensional peptides or substrates of enzymes, antagonists, enzymes or enzyme inhibitors.

The counterion (A-) represents an anion that is present in equimolar amounts and, therefore, balances the positive charge on the Tc(V) dioxouranium complex of the formula I. the Anion (A), respectively, is a single or multi-charged, provided that there is in balancing the charge quantity. Suitable anion forms an inorganic or organic acid. Examples of suitable anions include halide ions such as chloride or bromide, sulfate, nitrate, citrate, acetate, phosphate and borate ions. Preferred anions are chloride.

Complexes of technetium formula I have the advantage that they are stable after to the plexopathy and contain avidly chelate forming agent (cheland), which links technetium preferably providing targeted delivery of biological grouping. Therefore, it is unlikely that the complex of technetium will be reactions translationunit with biological macromolecules or competing ligands in vivo. Complexes of technetium small and compact, which is useful because they have a minimal steric effect on the conjugate providing targeted delivery of biological grouping (Z). Permanent cationic exchange and Tc(V) dioxolane indicate that the complexes are also hydrophilic and therefore are unlikely to be distributed in other intracellular compartments, and, therefore, will be more quickly removed from the background of organs and tissues in vivo, for example from the bloodstream.

Complexes of technetium formula I can be obtained by reacting a suitable source of technetium with conjugate chelat forming agent having the formula II, as described in the second embodiment below.

In the second embodiment of the present invention proposed a conjugate chelat forming agent of the formula II

where X, Y, Z, n and m are such as defined above;

Q1-Q6independently represent a group Q, where Q represents H or a protective group for amino groups.

These conjugates chelat forming AG the NTA used in obtaining complexes of technetium formula I of the first embodiment.

The term "protective group" means a group which inhibits or suppresses undesired chemical reactions, but which is quite reaktsionnosposobnykh, so it can be split from the functional group in a fairly mild conditions, in which the remainder of the molecule does not undergo modification. After removal of the protective groups to obtain the target product. Protective groups for amino groups are well known to specialists in this field and respectively selected from Boc (Boc means tert-butyloxycarbonyl), Fmoc (Fmoc means fluorenylmethoxycarbonyl), TRIFLUOROACETYL, allyloxycarbonyl, Dde [1-(4,4-dimethyl-2,6-dioxocyclohex)ethyl] or Npys (i.e. 3-nitro-2-pyridylsulfonyl). In some cases, the nature of protection may be such that the protective groups are the groups of Q1/Q2and Q5/Q6then there is the associated nitrogen atom of an amine bond NH is missing. The use of other protective groups described in "Protective Groups in Organic Synthesis", Theorodora W.Greene and Peter G.M.Wuts (John Wiley & Sons, 1991). Preferred protective groups for amino groups are the First and Fmoc, most preferably Vos. If they use Vos, both groups Q1and Q6represent H, and the group Q2, Q3, Q4and

Q5each represent a tert-butoxycarbonyl.

In the conjugates fo the mules II protective groups for amino groups are used primarily for the protection of functional amino groups tetraamines chelat forming agent during chemical synthesis to the formation of a complex with technetium. However, if providing targeted delivery of biological grouping (Z) are able to react with primary and/or secondary amines, these protective groups can also be useful to prevent unwanted chemical reactions between chelat forming amines and Z before the formation of a complex with technetium.

Preferred conjugates of formula II have at least one unprotected amine nitrogen atom (that is, one of the groups Q3or Q4represents H or both groups Q1/Q2or Q5/Q6are H). One or more free amino groups means that the conjugate more quickly dissolves in the water environment, which is the preferred solvent to obtain a complex of technetium formula I. the Free amino group also means that the formation of the complex with technetium occurs more quickly because the complexation does not depend on the prior removal of the protective group, which also would prevent the formation of metal complex. If conjugated providing targeted delivery of biological grouping (Z) is not susceptible to further reaction with amines, it is convenient to use the conjugate of formula II in completely devoid of protection form (i.e. each of the groups Q1-Q6represents N), and that is my chelat forming agent conjugate of formula II is particularly preferred. Completely devoid of protection is more preferable for the complexation obtaining a complex of technetium formula I.

Complexes of technetium formula I according to the present invention can be obtained by interaction of a solution of radioactive metal in a suitable oxidation state with chelat forming agent conjugate of formula II with a suitable pH. A possible solution may contain a ligand that forms a weak complex with technetium (such as gluconate or citrate), i.e. the complex of technetium is produced by the exchange of ligands or translational. Such conditions are often used to suppress undesirable side reactions such as hydrolysis ion technetium, but they are less important when using chelat forming agents of the present invention, because they quickly form complexes with technetium. If a radioactive isotope is a99mTc, then usually the original substance is pertechnetate technetium from99Mo generator. Technetium is present in99mTc-pertechnitat in the oxidation state of Tc(VII)in which it is relatively directionspanel. The preparation of complexes of technetium in a lower oxidation state from Cu(I) to Tc(V) usually requires the addition of a suitable pharmaceutically acceptable reducing agent, such as ditional sodium, sodium bisulfite, serbinova acid, formamidine-Sultanova acid, ion tin, Fe(II) or Cu(I)to facilitate complexation. Pharmaceutically acceptable reducing agent preferably is a salt of divalent tin, most preferably chloride divalent tin fluoride divalent tin or tartrate of divalent tin.

Conjugates chelat forming agent of the formula II can be obtained by conjugation providing targeted delivery of biological molecules (Z) with bifunctional chelat forming agent of the formula III, as described in the fifth embodiment below.

In the third embodiment of the present invention proposed a radiopharmaceutical agent, which contains a complex of technetium first embodiment, where a is a pharmaceutically acceptable counterion, together biocompatible carrier in a form suitable for administration to humans.

The phrase "in a form suitable for administration to man" means that the composition is sterile, aerogene, does not contain compounds that cause toxic and harmful effects, and prepared in the form of a drug with a biocompatible pH (approximately pH 4.0 to 10.5). In such compositions there are no inclusions, which could cause emboli in vivo, and they are prepared so that upon contact with biological fluids (e.g. blood) precipitation is not happening is. In addition, such compositions contain only the biologically compatible excipients and are preferably isotonic.

"Biocompatible carrier" is a fluid medium, in particular liquid, in which the radiopharmaceutical agent suspended or preferably dissolved, such that the composition was physiologically acceptable, i.e. that it was possible to introduce into the body of a mammal without toxicity or undue discomfort. Suitable biocompatible carrier is an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution, such as saline (which may preferably be balanced so that the final product for injection was either isotonic or not hypotonic); an aqueous solution of one or more substances that regulate toychest (for example, salts of plasma cations with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (for example sorbitol or mannitol), glycols (e.g., glycerol) or other non-ionic polyol (e.g. polyethylene glycol, propylene glycols and the like).

The term "pharmaceutically acceptable counterion" refers to the anion (negative ion), which does not cause toxic or in the edno effects when introduced into the body of a mammal in vivo and is compatible chemically and/or toxicologically, with the other ingredients of the pharmaceutical composition. Chemical compatibility for radiopharmaceutical means on the basis of technetium in the present invention means that the anion does not compete effectively with tetraamine chelat forming agent for technetium. Suitable such anions include halides (such as chloride, iodide and bromide);1-2the alkyl sulphonates (e.g. mesilate or ethylsulfonyl); arylsulfonate (for example, phenylsulfonyl or toilet);1-2alkylphosphonate; di(C1-2)alkylphosphate (for example, dimethylphosphate, diethylphosphate or deglycerolized); arylphosphonate; arylphosphate; alkylarylsulfonate; alkylarylsulfonate; C1-2alkylcarboxylic (for example, acetates, propionate, glutamate or glycerate); arylcarboxylic (for example, benzoate) and the like, but are not limited to. Preferred pharmaceutically acceptable counterions include chloride, fluoride, acetate, tartrate, hydroxide and phosphate.

Such radiopharmaceuticals means respectively supplied in the container, which is equipped with a sealing gasket, suitable for single or multiple puncture needle for subcutaneous injections (e.g. crimp sealing gasket lid) and at the same time preserving sterility. Such containers may contain single or multiple doses for patients. Preferred mnogorazovye con is anery are separate bulky bottle (for example, capacity from 10 to 100 cm3), which contains multiple doses for the patient, so a single dose to the patient can be put into clinical syringes through different periods of time during the shelf life of the drug in accordance with the clinical situation. Pre-filled syringes are designed to contain a single dose to humans and, therefore, preferably represent a disposable syringes or other, suitable for clinical use. Pre-filled syringes can be provided with a protective screen to protect the operator from radiation dose. Suitable protective screens for a syringe with a radiopharmaceutical agent known in this field and preferably contain either lead or tungsten.

Radiopharmaceutical means of the present invention contain radioactive isotopes of technetium99mTc or94mTc, most preferably99mTc. If an isotope of technetium is a99mTc, the amount of radioactivity that is suitable for tools radiopharmaceutical for diagnostic imaging, is in the range from 180 to 1500 MBq99mTc depending on the area designated for imaging in vivo absorption and the ratio of target/background.

Radiopharmaceutical-based tools t the tion of the present invention can be obtained in different ways:

1) aseptic manufacturing technology, when education technologo complex described above for the second embodiment is carried out in a room with a clean environment;

2) the final sterilization, when education technologo complex is conducted in aseptic conditions of production and then sterilized at the last stage (for example, gamma radiation or autoclaving);

3) the methodology set when sterile, freeze-dried, non-radioactive drug is the set containing the conjugate chelat forming agent of the formula II and pharmaceutically acceptable reducing agent plus other possible excipients, is subjected to the interaction with the aliquot of sterile99mTc-pertechnitat from generator99mTc.

Method (3) is preferable, and kits for use in the method described in the fourth embodiment (below).

In the fourth embodiment of the present invention proposed a non-radioactive kit for the preparation of a radiopharmaceutical composition described above, which includes a conjugate of formula (II) together with a biocompatible reducing agent. These kits are designed for the preparation of sterile radiopharmaceutical products that are suitable for administration to a person, for example, by injecting directly into the bloodstream. The ligand conjugates and their preferred AU the projects described in the second embodiment above.

For99mTc set preferably dried and is intended for cultivation of sterile99mTc-pertechnitat (TCO4-from the radioisotope generator99mTc to obtain a solution suitable for administration to humans without additional manipulation. Suitable kits comprise a container (e.g. bottle with sealing gasket)containing conjugate chelat forming agent in the form of either a free base or salt with the acid, together with a biocompatible reducing agent, such as dithionite sodium, sodium bisulfite, ascorbic acid, formamidinesulfinic acid, ion tin, Fe(II) or Cu(I). Biocompatible reducing agent preferably is a salt of divalent tin, such as tin chloride or tin tartrate. An alternative set may possibly contain a non-radioactive metal complex, which is adding technetium being transmetallation (i.e. metallocene) to obtain the target product.

Non-radioactive kits possibly can also include additional components, such as transglutaminase agent, radioprotector, antimicrobial preservative, pH-regulating agent or filler. "Translatorese agent is a compound that quickly communicates with the weak whom the Lex with technetium, and then expelled chelat forming agent. This minimizes the risk of the formation of the restored hydrolyzed technetium (RHT) because of the rapid recovery pertechnitat competing with the formation of a complex with technetium. Suitable such translatorese agents are salts of weak organic acids, organic acid having a pKa in the range from 3 to 7, with a biocompatible cation. The term "biocompatible cation" refers to a positively charged counterion, which forms a salt with ionized negatively charged anionic group, where specified positively charged counterion is also non-toxic and therefore suitable for introduction into the body of a mammal, in particular in the human body. Examples of suitable biocompatible cations include alkali metals, sodium or potassium; alkaline-earth metals, calcium and magnesium, and ammonium ion. Preferred biocompatible cations are sodium and potassium, most preferably sodium. Suitable such weak organic acids are acetic acid, citric acid, tartaric acid, gluconic acid, glucoheptonate acid, benzoic acid, phenols or phosphonic acid. Accordingly, suitable salts are acetates, citrate is, the tartratami, gluconate, glucoheptonate, benzoate, reaction or phosphonates. Preferred such salts are tartratami, gluconate, glucoheptonate, benzoate or phosphonates, more preferably phosphonates, most preferably diphosphonates. Preferred such translatorese agent is a salt MDP, i.e. methylenediphosphonic acid, with a biocompatible cation.

The term "radio protector" means a compound which inhibits degradation reactions, such as redox processes by capturing highly reactive free radicals, such as oxygen free radicals generated by radiolysis of water. Radioprotectors of the present invention respectively selected from ascorbic acid, para-aminobenzoic acid (i.e. 4-aminobenzoic acid or RAVA), hentaimovi acid (2,5-dihydroxybenzoic acid) and their salts with a biocompatible cation as defined above.

The term "antimicrobial preservative" means an agent that inhibits the growth of potentially harmful microorganisms, such as bacteria, yeast or mold. Antimicrobial preservative may also be some bactericidal properties depending on the dose. The main role of antimicrobial(s) preservative(s) by us is oasea the invention consists in suppressing the growth of any such microorganism in a radiopharmaceutical composition after dilution, the most radioactive diagnostic product. However, antimicrobial preservative may also be used to suppress the growth of potentially harmful microorganisms in one or more than one non-radioactive component of the kit of the present invention prior to dilution. Suitable antimicrobial preservatives include parabens, that is, methyl-, ethyl-, propyl - or butylparaben, or mixtures thereof, benzyl alcohol; phenol; cresol; cetrimide and thiomersal. Preferred antimicrobial and preservative(s) are parabens.

The term "pH-regulating agent" means a compound or mixture of compounds used(aja) to ensure that the pH of the diluted set within acceptable limits (approximately pH from 4.0 to 10.5) for the introduction of a human or mammal. Suitable pH-adjusting agents include pharmaceutically acceptable buffers, such as tricin, phosphate or TRIS (i.e. Tris(hydroxymethyl)aminomethane), and pharmaceutically acceptable bases, such as sodium carbonate, sodium bicarbonate or mixtures thereof. When using conjugate in the form of a salt with the acid pH-regulating agent may be present in a separate vial or container, so that the user set could adjust the pH of doing this as part of multistage procedure.

The term "filler" podrazumeva the tsya pharmaceutically acceptable, increasing the amount of agent that can facilitate handling of the material in the production process and lyophilization. Suitable such fillers include inorganic salts, for example sodium chloride, and water-soluble sugar or sugar alcohols such as sucrose, maltose, mannitol or trehalose.

In the fifth embodiment of the present invention proposed a compound of formula III

where Q1-Q6and n are such as defined for formulas I and II above;

E is a functional group suitable for conjugation with providing targeted delivery group (Z) of the first embodiment,

that

1) when n is 3, then at least one of Q1-Q6represents a protective group for amino group;

2) when n is 3 or 5, then E is not IT.

The compound of formula III represents a bifunctional chelate forming agent, i.e. chelate forming agent with one or more attached functional groups (F). Functional group (F) is a group suitable for conjugation with biological providing targeted delivery group (Z). Suitable such functional group (S) include amine, thiocyanate, maleimide and active esters. Preferably E does not contain neaktivirovannye the hydroxyl (-OH) group. The term "active ester" means the ether carboxylic acid derivative, which is the best leaving group and, therefore, provides an easier interaction with nucleophiles present in biological providing targeted delivery of the group, such as amines. Examples of suitable active esters are N-hydroxysuccinimide (NHS), pentafluorophenol, pentafluorothiophenol, para-NITROPHENOL, hydroxybenzotriazole and Rumor (i.e. hexaphosphate benzotriazol-1-electroparadise). Preferred active esters are N-hydroxysuccinimide or pentafluorophenol esters.

E preferably represents a primary amine (-NH2), -CO2M, -NCS, -NCO, maleimide or acrylamide, where M represents H, a cation, a protective group or an active ester. Most preferably, E represents-NH2, -CO2M or maleimide, ideal-NH2or-CO2M

The compounds of formula III is subjected to interaction with the corresponding equivalent functional groups on the biological providing targeted delivery of the group (Z) before the formation of the target conjugate of formula II. Such appropriate functional group on biological providing targeted delivery of the group is clucalc:

the carboxy (for the formation of amide bond with the amine-functionalized chelat forming bifunctional agent);

amines (for the formation of amide linkages with carboxyl or active ester-functionalized chelat forming bifunctional agent);

the halides, mesylates and tozilaty (for N-alkylation of amine-functionalizing bifunctional chelat forming agent), and

thiols (for interaction with maleimide-functionalized bifunctional chelat forming agent).

When E is a group (for example, an active ester), which is intended to interact with biological amino group providing targeted delivery group (Z), it is clear that there is the potential for undesirable side reactions with the amine groups chelat forming agent. For such groups E, Q1-Q6in formula III preferably represent a protective group for nitrogen, such that each of the four nitrogen atoms of amine tetraamines chelat forming agent is protected. When E represents an amino group, it is clear that it is important that the reaction with biological providing targeted delivery of the molecule (Z) occurs only in Amin E, and not on the amine nitrogen atoms tetraamines chelat forming agent. Therefore, in this situation, Q1-Q in formula III preferably represent a protective group for the nitrogen. The protective group for the nitrogen and their preferred examples are described in the second embodiment (above).

The compounds of formula III can be obtained by Schemes 1 and 2. Figure 1 depicts a flexible way of synthesis of carboxy-functionalized N-protected tetraamine chelat forming agents, which can be adapted to many values of n in the formula III. Synthesis of the BOC-protected tetraamine analogue with the Deputy -(CH2)5OH in the head of the bridge described by Turpin et al. [J.Lab. Comp. Radiopharm., 45, 379-393 (2002)]. Figure 2 presents a flexible way of synthesis of amine-functionalized N-protected tetraamine chelat forming agents, which can be adapted to many values of n. Conjugation of biological providing targeted delivery of peptides may be effected in a manner analogous to the methods described Nock et al. [Eur. J. Nucl. Med., 30(2), 247-258 (2003)] and Maina et al. [Ew. J. Nucl. Med., 30(9), 1211-1219 (2003)].

Scheme 1: synthesis of compound 1.

where VOS - tert-butoxycarbonyl protective group

IBX - 1-hydroxy-1,2-benzodioxol-3(1H)-one-1-oxide

NHS - N-hydroxysuccinimide

Bz is benzyl.

Scheme 2: synthesis of compound 2.

where Ts - p-toluensulfonyl.

The invention is illustrated below not about the limits examples. Example 1 describes the synthesis of Compound 1, which represents a carboxy-functionalized N-protected tetraamine chelate forming agent of the present invention. Example 2 describes the synthesis of Compounds 2, which represents an amine-functionalized N-protected tetraamine chelate forming agent of the present invention. Example 3 shows the synthesis of Compound 3, compound, showing conjugation of Compound 1 with the amine (benzylamino). Example 4 describes the synthesis of Compound 6, illustrating the conjugation of Compound 2 with an active complex ether carboxylic acid. Example 5 describes the synthesis of Compounds 4, a conjugate chelat forming agent according to the invention with a derivative of losartan. Example 6 presents a synthesis of the conjugate chelat forming agent with losartan containing linker group PEG. Example 7 describes the synthesis of Compound 8, which represents the conjugate chelat forming agent according to the invention with angiotensinogen peptide. In Example 8 described99mTc-Radiometrie few chelat forming agents according to the invention. In Example 9 presents the results of measurements of the values of lipophilicity (logP) for different99mTc-complexes according to the invention and shown that these complexes are relatively hydrophilic. In Example 10 presents the results of bioracer the division for multiple 99mTc-complexes according to the invention, showing a moderate background liver and high urinary clearance. Example 11 shows the synthesis of Compound 1 with a higher yield. In Example 12 synthesis of protected tetraamine chelat forming agent of the present invention the activated complex ether, conjugated with him (Compound 9).

Example 1: synthesis of Compound 1.

Stage (a): diethyl[2-(benzyloxy)ethyl]malonate

This compound was obtained by modification of the method Ramalingam et al. [Ramalingam et al., Tetrahedron, 51, 2875-2894 (1995)]. Thus, sodium (1.20 g) was dissolved in absolute ethanol (25 ml) in an argon atmosphere. Added diethylmalonate (14,00 g) and the mixture was boiled under reflux for 30 minutes was Added benzylpenicilloyl ether (10 g) and the mixture was stirred at the temperature of reflux distilled for 16 hours. Rotary evaporation of the ethanol was removed and the residue was distributed between ether (100 ml) and water (50 ml). The ether layer was washed with water (3×50 ml) and dried over sodium sulfate. The ether was removed by rotary evaporation and the residue was subjected to distillation under vacuum. Faction Athanasius at 40-55°C, cast (unreacted diethylmalonate). The product was distilled at 140-150°C (1 mm Hg) [lit. BP. 138-140°C (1 mm Hg)]. The output was 12,60 g of a colorless oil.

1H NMR (270 MHz, CDCl3, 25°C, TMS (tetramethylsilane was)) δ=7.28 (m, 5H6 H5), 4.47 (s, 2H, CH2-Ph), 4.16 (m, 4H, SOON2), 3.58 (t, 1H, CH), 3.50 (t, 2H, O-CH2-CH2), 2.21 (t, 2H, O-CH2-CH2), 1.20 (t, 6H, SOON2-CH2).13With NMR (67,5 MHz, CDCl3, 25°C, TMS) δ=169.20 (CO), 138.10, 128.60, at 127.80 (aromatic), 73.00 (CH2Ph), 67.30 (O-CH2-CH2), 61.70 (SOON2), 49.10 (CH), 28.90 (O-CH2-CH2), 14.10 (SOON2CH3).

Stage (b): N,N'-bis(2-amino-ethyl-2-(2-benzyloxyethyl)malonamide

Diethyl[2-(benzyloxy)ethyl]malonate (of 4.00 g) was added to Ethylenediamine (30 ml) and the solution was stirred at room temperature for two days. The excess Ethylenediamine was removed by rotary evaporation and the residue was dried under high vacuum for 2 days before the formation of a yellow oil (4,28 g), which crystallized upon standing. The NMR spectrum showed that the product still contains traces of ethylene diamine.

1H NMR (270 MHz, CDCl3, 25°C, TMS) δ=7.74 (br t, 2H, CO-NH), 7.32 (m, 5H, C6H5), 4.46 (s, 2H, CH2-Ph), 3.50 (t, 2H, och2-CH2-), 3.33 (t, 1H, CH), 3.23 (m, 4H, CO-NH-CH2), 2.74 (t, 4H, CH2-NH2), 2.18 (q, 2H, O-CH2-CH2-), 1.55 (br s, 4H, NH2).13C NMR (67,5 MHz, CDCl3, 25°C, TMS) δ=171.10 (CO), 138.20, 128.30, at 127.70 (aromatic), 73.00 (CH2-Ph), 67.80 (O-CH2-CH2), 51.40 (CH), 42.40 (CO-NH-CH2), 41.20 (CH2-NH2), 31.90 (O-CH2-CH2-).

Stage (in): N,N'-bis(2-amino-ethyl)-2-(2-benzyloxyethyl)-1,3-diaminopropan the

N,N'-bis(2-amino-ethyl)-2-(2-benzyloxyethyl)malonamide (3.80 g) was dissolved in THF (20 ml) and the flask was immersed in an ice bath. The flask was purged by a stream of argon through the syringe was added THF-bananowy complex (80 ml, 1 M in THF). The reaction mixture was allowed to warm to room temperature, and then stirred it at 40°C for 2 days and boiled under reflux for 1 hour. Was added dropwise methanol (50 ml) and the solution was stirred at 40°C during the night. The solvents were removed on a rotary evaporator and the residue was dissolved in methanol (20 ml). Was added sodium hydroxide (10 g in 15 ml water), and the methanol was boiled off. Stood a colorless oil which was extracted into CH2CH2(3×50 ml). This solution was dried over Na2SO4. After removal of solvent received 3,40 g of a colorless oil.

1H NMR (270 MHz, CDCl3, 25°C, TMS) δ=7.34 (m, 5H, C6H5), 4.49 (s, 2H, CH2-Ph), 3.55 (t, 2H, OCH2-CH2-), 2.76 (t, 4H, N-CH2), 2.63 (m, 8H, N-CH2), 1.84 (m, 1H, CH), 1.58 (m, 2H, CH-CH2-CH2-O), 1.41 (br s, 6H, NH).13C NMR (67,5 MHz, CDCl3, 25°C, TMS) δ=138.60, 128.30, 127.60 (aromatic), 72.80 (CH2-Ph), 68.70 (O-CH2-CH2), 53.50 (N-CH2), 52.80 (N-CH2), 41.60 (N-CH2), 36.40 (CH), 31.30 (CH-CH2-CH2-O). MC-EC (mass spectrometry with ionization by electron impact): 295 [M+H]+, (calc. 295,2).

Stage (d): N,N'-bis(2-tert-buto is starveillance)-2-(2-benzyloxyethyl)-1,3-di(tert-butoxycarbonylamino)propane

N,N'-bis(2-amino-ethyl-2-(2-benzyloxyethyl)-1,3-diaminopropan (3,30 g) was dissolved in CH2Cl2(100 ml) was added triethylamine (of 5.40 g) and tert-BUTYLCARBAMATE (10.30 g). The reaction mixture was stirred at room temperature for 2 days. The mixture was washed with water (100 ml), a solution of citric acid (100 ml, 10% in water) and water (2×100 ml). The organic layer was dried over Na2SO4and the solvent was removed by rotary evaporation to a yellow oil, which was dried to constant weight under high vacuum. The crude product (of 7.70 g) was purified on silikagelevye column (250 g, 230-400 mesh mesh, CH2Cl2CH2Cl2-Et2O, 1:1) to obtain 6,10 g (78,3%) of a clear oil.

1H NMR (270 MHz, CDCl3, 25°C, TMS) δ=7.32 (m, 5H, C6H5), 5.12 (br d, 2H, NH), 4.47 (s, 2H, CH2-Ph), 3.49 (t, 2H, OCH2-CH2-), 3.24 (br, 12H, N-CH2), 2.14 (br, 1H, CH), 1.59 (m, 2H, CH-CH2-CH2-O), 1.45 (s, 18H, t-Bu), 1.42 (s, 18H, t-Bu).13C NMR (67,5 MHz, CDCl3, 25°C, TMS) δ=155.90 (NH-CO), 138.20, 128.30, 127.60, 127.50 (aromatic), 79.90, 78.90 (CME3), 72.80 (CH2-Ph), 68.00 (O-CH2-CH2), 50.00 (br, N-CH2), At 46.90 (br, N-CH2), 39.20 (N-CH2), 34.40 (br, CH), 29.80 (CH-CH2-CH2-O), 28.30 (t-Bu). MS-ES: 695 [M+H]+, (calc. 695,5).

Stage (d): N,N'-bis(2-tert-butoxycarbonylamino)-2-(2-hydroxyethyl)-1,3-di(tert-butoxycarbonylamino)propane

N,N'-bis(2-tert-butoxycarbonylamino)-2-(2-be is siloxides)-1,3-di(tert-butoxycarbonylamino)propane (3,16 g) was dissolved in absolute ethanol (100 ml) was added Pd on charcoal (1,00 g, dry, 10%).

The mixture was first made in the Parr apparatus at a pressure of 35 psi (241,5 kPa) for two days. The catalyst was filtered off, washed with ethanol (3×20 ml). The ethanol was removed by rotary evaporation to obtain a colorless oil, which was dried to constant weight (2.67 g, 97.1 per cent) under high vacuum.

1H NMR (270 MHz, CDCl3, 25°C, TMS) δ=5.25 (br d, 2H, NH), 3.69 (t, 2H, OCH2-CH2-), 3.28 (br, 12H, N-CH2), 2.71 (br, OH), 2.23 (br, 1H, CH), 1.56 (ledge, m, 2H, CH-CH2-CH2-O), 1.48 (s, 18H, t-Bu), 1.44 (s, 18H, t-Bu).13C NMR (67,5 MHz, CDCl3, 25°C, TMS) δ=156.10 (NHCO), 80.00, 79.20 (CME3), 59.60 (O-CH2-CH2), 49.90 (br, N-CH2), 47.00 (br, N-CH2), At 39.34 (N-CH2), 33.80 (CH), 32.30 (CH-CH2-CH2-O), 28.30 (t-Bu). MS-ES: 605 [M+H]+, (calc. 605,4).

Stage (e): N,N'-bis(2-tert-butoxycarbonylamino)-2-(2-carboxymethyl)-1,3-di(tert-butoxycarbonylamino)propane (Compound 1)

Used the way Mazitschek et al. [Ang. Chem. Int. Ed., 41, 4059-4061 (2002)]. Thus, N,N'-bis(2-tert-butoxycarbonylamino)-2-(2-hydroxyethyl)-1,3-di(tert-butoxycarbonylamino)propane (2,60 g) was dissolved in DMSO (dimethyl sulfoxide) (15 ml) and 1-hydroxy-1,2-benzodioxol-3(1H)-one-1-oxide (IBX, 3.50 g). The mixture was stirred at room temperature for 1 hour, then was added N-hydroxysuccinimide (2.50 g). This reaction mixture was stirred at room temperature for 2 days. Added hydroxide solution is of the atrium (2 M, 40 ml) and the mixture was stirred at room temperature for 4 hours. The solution was immersed in an ice bath and acidified with 2 M hydrochloric acid to pH 2. The aqueous layer was extracted with ether (4×100 ml) and the combined ethereal extracts were washed with water (3×50 ml). The ether layer was dried over Na2SO4and the solvent was removed by rotary evaporation to a yellow solid residue, which contained the product and 2-iodobenzoic acid. A large part of iodosobenzene acid (2.1 g) was removed by crystallization from a mixture of chloroform-hexane (1:3) (80 ml). Evaporation of the chloroform-hexane mother liquor gave a yellow oil (3 g), which was applied on silicagel column (300 g, CH2Cl2-Et2O, 1:1). The remaining iodosobenzene acid was suirable ether. The product was suirable a mixture of ether-methanol (9:1). The fractions containing the product were combined and after removal of the solvent was obtained 1.5 g of pale yellow oil. He was subjected to chromatography on silikagelevye column (50 g, Et2O). The product was suirable a mixture of ether-acetic acid (95:5). The fractions containing the product were combined and the solvent was removed by rotary evaporation to obtain oil, which was dried under high vacuum. The output was 1.10 g (41,3%).

1H NMR (270 MHz, CDCl3, 25°C, TMS) δ=7.61 (br s, 1H, COOH), 5.19 (br d, 2H, NH), 3.22 (br, 12H, N-CH2), 2.47 (br m, 1H, CH), 2.26 (br, 2H, CH-CH2-COOH), 141 (s, 18H, t-Bu), 1.37 (s, 18H, t-Bu).13C NMR (67,5 MHz, CDCl3, 25°C, TMS) δ=175.90 (COOH), 156.10 (NHCO), 80.40, 79.10 (CME3), 49.50 (N-CH2), 46.80 (N-CH2), 39.00 (N-CH2), 34.70 (CH-CH2-COOH), 34.20 (CH-CH2-COOH), 28.30, 28.20 (t-Bu). MS-ES: 619 [M+H]+, (calc. 619,4).

Example 2: Synthesis of tert-butyl ester (8-amino-2-{[tert-butoxycarbonyl-(2-tert-carbonylmethyl)amino]methyl}octyl-(2-tert-butyloxycarbonyl)carbamino acid (Compound 2)

Stage (a): 2-(6-chlorhexidine)tetrahydropyran

6-Chlorohexanol (6.85 g, 10 mmol) and p-toluensulfonate acid (500 mg) was dissolved in dry ether (75 ml) and cooled to 0-5°C in an ice bath. Was added dropwise dihydropyran (4.3 g, 10 mmol) in dry ether (25 ml) with constant stirring over a period of time of 30 minutes. After the addition the cooling bath was removed and stirring continued for 16 hours. The solution was extracted with water (50 ml × 2), dried (MgSO4), filtered and the solvent evaporated under reduced pressure to obtain a pale yellow oil.13With NMR spectroscopy showed that this oil sufficiently pure for use without purification in subsequent reactions. The output of 10.1 g (91%).

13With NMR (CDCl3) δ=19.7 (CH2), 25.5 (CH2), 25.6 (CH2), 26.7 (CH2), 29.6 (CH2), 30.8 (CH2), 32.6 (CH2), 45.0 (CH2Cl), 62.3 (och2), 67.4 (och2), 98.8 (GROUND)./p>

1H NMR (CDCl3): δ 1.30-1.71 (14N, m, CH2× 7), 3.24-3.32 (1H), 3.41-3.48 (3H, m, CH and CH2), 3.60-3.67 (1H, m, CH), 3.72-3.82 (1H, bm, CH), 4.44-4.49 (1H, bm BASED).

Stage (b): diethyl ether 2-[6-(tetrahydropyran-2-yloxy)hexyl]malonic acid

Sodium (1.13 g, 49 mmol) in small quantities was dissolved in dry ethanol (100 ml) with constant stirring under your pillow dry nitrogen. One portion was added diethylmalonate (8.0 g, 50 mmol) and the solution was heated at 60°C for 1 hour. One portion was added 2-(6-chlorhexidine)tetrahydropyran (9.3 g, to 42.2 mmol), the temperature was raised to 75-80°C and kept at this temperature for 24 hours. After cooling, the inorganic solid was removed by filtration and the solvent evaporated from the filtrate. The residue was dissolved in CH2Cl2(50 ml), was extracted with water (30 ml × 2), dried (MgSO4), filtered and removed volatile substances with obtaining a light yellow oil. This oil was subjected to chromatography on silica gel using a mixture of petroleum ether (40:60)/ether (200:40) as eluent. The target product was elyuirovaniya with rf=0.15 and was isolated as a colourless oil. Yield 8.7 g (60%).

13With NMR (CDCl3): δ 14.0 (CH3× 2), 19.6 (CH2), 25.5 (CH2), 27.2 (CH2), 28.6 (CH2), 29.0 (CH2), 29.6 (CH2), 30.0 (CH2), 30.8 (CH2), 52.0 (CH), 61.2 (och2× 2), 62.2 (och2/sub> ), 76.4 (och2), 98.8 (OCHO), 169.4 (C=O × 2).

1H NMR (CDCl3): δ 1.10-1.25 (14H, m, CH2× 2, CH2× 4), 1.36-1.50 (6N, bm, CH2× 3), 1.70-1.81 (2H, bm, CH2), 3.17-3.28 (2H, m, CH2), 3.56-3.66 (1H, m, CH), 3.70-3.80 (1H, m, och), 4.04-4.16 (4H, m, OCH2× 2), 4.03-4.08 (1H, m, OCHO).

Stage (in): N,N'-bis-(2-amino-ethyl)-2-[6-(tetrahydropyran-2-yloxy)hexyl]malonamic

Diethyl ether 2-[6-(tetrahydropyran-2-yloxy)hexyl]malonic acid (5,1 g of 14.8 mmol) was dissolved in 1,2-diaminoethane (10 g, 167 mmol) and stirred at room temperature for 16 hours. Volatiles were removed in vacuum (40-50°C at 0.01 mm Hg) to give a light green viscous residue, which was subjected to column chromatography, elwira a mixture of CH2Cl2/MeOH/NH4OH

(50:50:5). Specified in the title compound was loirevalley with rf=0.2 and were collected in the form of light green viscous oil which hardened on standing (yield of 3.9 g, 71%).

13With NMR (CDCl3): δ 19.8 (CH2), 25.5 (CH2), 26.0 (CH2), 27.5 (CH2), 29.2 (CH2), 29.7 (CH2), 30.8 (CH2), 31.9 (CH2), 41.0 (NCH2× 2), 41.9 (NCH2× 2), 54.6 (CH), 62.5 (och2), 67.5 (och2), 98.9 (OCHO), 171.6 (C=O × 2).

1H NMR (CDCl3): δ 1.15-1.28 (6N, bs, CH2× 3), 1.39-1.44 (6N, bm, CH2× 3), 1.69-1.74 (4H, bm, CH2× 2), 2.64 (4H, bs, NH2× 2), 2.73 (4H, t, J=6 Hz, CH2× 2), 3.08-3.29 (6N, m,

CH2× 3), 3.35-3.41 (1H, m, CH), 3.55-3.3 (1H, m, CH), 3.70-3.78 (1H, m, CH), 4.43 (1H, bt, J=4 Hz, OCHO), 7.78 (2H, bt, J=5 Hz, OCNH × 2).

IR (thin film), cm-1: 3417, 3082, 2936, 2862, 1663, 1558, 1439, 1354, 1323, 1261, 1200, 1189, 1076, 1026, 956, 907, 867, 810.

Stage (d): N,N'-bis(2-amino-ethyl)-2-(6-hydroxyhexyl]malonamic

N,N'-Bis(2-amino-ethyl)-2-[6-(tetrahydropyran-2-yloxy)hexyl]malonamide (3,9 g, 10.6 mmol), monohydrate p-toluensulfonate acid (8.5 g, 3 mmol) and ethanol (50 ml) was heated under reflux at 70-75°C for 16 hours. After cooling, was added dropwise concentrated ammonium hydroxide (.880) before reaching a constant value of pH 9. Precipitated precipitated white solid was removed by filtration through celite and the filter cake washed with ethanol (30 ml). The ethanol was removed under reduced pressure (15 mm Hg, 40°C.) to obtain a semi-solid wax. This residue was subjected to chromatography on silica gel, elwira a mixture of CH2Cl2/MeOH/NH4OH (100:50:10), it was found that indicated in the title compound has an rf=0,2. This product was collected and evaporated together with ethanol (100 ml × 3) to remove residual water. Was received light green viscous residue, which solidified upon standing (yield 2.1 g, 69%).

13With NMR (CD3OD): δ 25.4 (CH2), 27.3 (CH2), 28.9 (CH2), 30.4 (CH2), 32.2 (CH2), 40.6 (NCH2× 2), 41.7 (NCH2× 2), 54.1 (CH), 61.6 (CH2OH), 171.7 (C=O × 2).

1H NMR (CD3D): δ 1.28-1.38 (6N, bs, CH2× 3), 1.46-1.55 (2H, bm, CH2), 1.79-1.87 (2H, bm, CH2), 2.73 (4H, t, J=6 Hz, H2NCH2× 2), 3.13 (1H, t, J=7 Hz, CH), 3.27 (4H, dt, J=6 and 2 Hz, HNCH2× 2), 3.53 (2H, t, J=7 Hz, och2).

IR (thin film), cm-1: 3364, 2932, 2862, 2527, 1663, 1558, 1462, 1327, 1223, 1192, 1034.

Mass spectrum (of the Belarusian library Association (fast atom bombardment)) m/e. Calculated for C13H29N4O3(M+H) 289. Found 289.

Stage (d): tert-butyl ether (2-tert-butoxycarbonylamino-2-{[(tert-butoxycarbonyl-(2-tert-butoxycarbonylmethyl)amino]methyl}-8-hydroxyacyl)carboxylic acids

Under the pillow of dry nitrogen pure adduct borane-dimethyl sulfide (15 ml, 150 mmol) was added dropwise via syringe to a stirred mixture of N,N'-bis(2-amino-ethyl)-2-(6-hydroxyhexyl)malonamide (2.1 g, 7,3 mmol) in dioxane (50 ml). After the addition the mixture was carefully heated under reflux at 110°C for 5 days. During this time he remained some amount of white solids. After cooling, volatiles were removed under reduced pressure to obtain a white solid to which was added dropwise methanol (50 ml) to give a colorless solution. This solution was heated under reflux for 3 hours, cooled, was added concentrated HCl (5 ml) and reflux was continued at 70-75°C for 48 hours. Rest ritel removed from the receiving viscous green residue, which were subjected to co-evaporation with methanol (100 ml × 3) to give a light green solid. This solid was again dissolved in dry methanol was added anhydrous potassium carbonate (4.0 g, 30 mmol), and then di-tert-BUTYLCARBAMATE (7.0 g, 32 mmol). The mixture was stirred at room temperature for 48 hours. The inorganic solid was removed by filtration through celite and the solvent evaporated from the filtrate to obtain a viscous residue. This residue was mixed with water (50 ml) and was extracted with CH2Cl2(50 ml × 3). The organic fractions were combined, dried (MgsO4), filtered and the solvent evaporated to obtain a light yellow residue.

Note: at this point it is convenient to control the reaction according to13WITH NMR.

The residue was subjected to chromatography on silica gel using a mixture of CH2Cl2/MeOH (95:5) as eluent. Specified in the title compound was loirevalley with rf=0.41 and it was isolated as a colourless viscous oil (yield 2.5 g, 52%).

13With NMR (CDCl3): δ 25.6 (CH2), 26.4 (CH2), 28.4 (CH2× 12), 29.8 (CH2× 2), 32.6 (CH2), 36.5 (very wide, CH), 39.2 (NCH2× 2 adjacent CH), 46.9 (broad singlet, HNCH2× 2), 50.0 (broad singlet, NCH2× 2), 62.4 (HOCH2), 79.0 (OS × 2), 79.9 (OS × 2), 156.4 (broad singlet, S=O × 4).

1 H NMR (CDCl3): δ 1.05-1.18 (8H, bs, CH2× 4), 1.27 (18H, s, CH2× 6, tert-butyl), 1.31 (18H, s, CH2× 6, tert-butyl), 1.41 (2H, m, CH2), 1.81 (1H, bs, CH), 2.63 (1H, bs, OH), 2.98 (4H, bs, NCH2× 2), 3.11 (8H, bs, NCH2× 4), 3.44 (2H, t, J=8 Hz, CH2O), 5.2 (2H, bs, NH × 2).

IR (thin film), cm-1: 3350, 2976, 2931, 2859, 1674, 1516, 1455, 1418, 1393, 1260, 1250, 1165, 1069, 965, 871, 775.

Mass spectrum (of the Belarusian library Association) m/e. Calculated for C33H65N4O9(M+H) 661. Found 661.

Stage (f): 8-[tert-butoxycarbonyl-(2-tert-butoxycarbonylmethylene]-7-{[tert-butoxycarbonyl-(2-tert-butoxycarbonylmethyl)amino]methyl}oktilovom ester toluene-4-sulfonic acid

tert-Butyl ether (2-tert-butoxycarbonylamino-2-{[(tert-butoxycarbonyl-(2-tert-butoxycarbonylmethyl)amino]methyl}-8-hydroxyacyl)carboxylic acid (2,52 g is 3.82 mmol), p-toluensulfonate (1.0 g, 5.2 mmol), triethylamine (1.3 g, 12.8 mmol) and CH2Cl2(30 ml) was stirred at room temperature for slow evaporation of the solvent. The reaction was controlled by the13With NMR, and after 3 days left a small amount of the original substance. The volume of the reaction mixture is brought to 30 ml by the addition of CH2Cl2, was extracted with water (50 ml × 3), dried (MgsO4), filtered and the solvent evaporated to obtain a brown residue. This residue was subjected to chromatography on silica gel using is the use of a mixture of CH 2Cl2/MeOH (100:5) as eluent. The first was elyuirovaniya unreacted taillored with rf=0,95. Specified in the title compound was loirevalley with rf=0,2, and it was isolated as a pale yellow viscous oil (yield 1.20 g, 39%).

13With NMR (CDCl3): δ 21.7 (CH3tosyl), 25.3 (CH2), 26.3 (CH2), 28.5 (CH2× 12), 28.8 (CH2), 29.5 (CH2), 36.5 (CH very wide), 39.4 (NCH2× 2), 47.0 (wide NCH2× 2), 50.5 (wide, NCH2× 2), 70.6 (TsOCH2), 79.1 (OS × 2), 80.0 (OS × 2), 127.9 (CH × 2), 129.9 (CH × 2), 133.2 (C), 144.7 (C-S Ts), 156.1 (broad, C=O × 4).

1H NMR (CDCl3): δ 1.16 (8H, bs, CH2× 4), 1.35 (M, s, CH2× 6), 1.39 (18H, s, CH3× 6), 1.88 (1H, bs, CH), 2.38 (3H, s, CH2tosyl), 3.10-3.12 (4H, bs, NCH2× 2), 3.19 (8H, bs, NCH2× 4), 3.93 (2H, t, J=7 Hz, CH2OTs), 5.0 (1H, bs, NH), 5.08 (1H, bs, NH), 7.29 (2H, d, J=8 Hz, CH × 2, Ar), 7.72 (2H, d, J=8 Hz, CH × 2, Ar).

IR (thin film), cm-1: 3360, 2974, 2932, 2862, 1693, 1516, 1479, 1418, 1391, 1366, 1250, 1177, 1069, 959, 816, 775.

Mass spectrum (of the Belarusian library Association) m/e. Calculated for C40H71N4O11S (M+H) 815. Found 815.

Stage (f): tert-butyl ether (8 azido-2-{[tert-butoxycarbonyl-(2-tert-carbonylmethyl)amino]methyl}octyl)-(2-tert-butoxycarbonylamino)carbamino acid

8-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylmethylene]-7-{[tert-butoxycarbonyl-(2-tert-butoxycarbonylmethyl)amino]methyl}oktilovom broadcast tolua the-4-sulfonic acid (1,105 g, of 1.36 mmol), sodium azide (350 mg, 5.4 mmol) and methanol (10 ml) was heated under reflux at 70-75°C for 16 hours. After cooling, the methanol was removed at room temperature under reduced pressure until, until all that was left about 1-2 ml of This residue was diluted with water (25 ml) and was extracted with CH2Cl2(25 ml × 4). The organic extracts were combined, dried (MgSO4), filtered, and volatiles evaporated at room temperature (note: azides are potentially explosive, and this stage should be carried out behind a protective screen) to obtain light yellow viscous residue, which was a target compound in a pure state (output 820 mg, 88%).

13With NMR (CDCl3): δ 26.3 (CH2), 26.5 (CH2), 28.3 (CH2× 12), 28.7 (CH2), 29.6 (CH2), 29.8 (CH2), 36.8 (wide, CH), 39.3 (NCH2× 2), 46.9 (wide, NCH2× 2), 50.0 (wide, NCH2× 2), 51.3 (CH2N3), 79.0 (OS × 2), 79.8 (OS × 2), 156.0 (C=O × 4).

1H NMR (CDCl3): δ 1.16 (8H, bs, CH2× 4), 1.29 (18H, s, CH2× 6), 1.33 (D, s, CH2× 6), 1.47 (2H, bt, J=6.5 Hz, CH2adjacent CH), 1.86 (1H, bs, CH), 2.95-3.05 (4H, bs, NCH2× 2), 3.05-3.20 (10H, bs, NCH2× 4 and CH2N3), 5.09 (2H, bs, NH × 2).

IR (thin film), cm-1: 3350, 2974, 2932, 2860, 2097 (strong band N3), 1694, 1520, 1470, 1418, 1391, 1366, 1250, 1167, 1069, 870, 777.

Stage (C): tert-butyl ether (8-amine which is 2-{[tert-butoxycarbonyl-(2-tert-carbonylmethyl)amino]methyl}octyl)-(2-tert-butyloxycarbonyl)carbamino acid (Compound 2)

tert-Butyl ester (8-azido-2-{[tert-butoxycarbonyl-(2-tert-carbonylmethyl)amino]methyl}octyl)-(2-tert-butoxycarbonylamino)carbamino acid (820 mg, 1.20 mmol), 10% palladium on charcoal (100 mg) and methanol (10 ml) was treated with gaseous hydrogen at a pressure of 30 atmospheres (about 3000 kPa) at room temperature for 16 hours. Solids were removed by filtration through celite and the filter cake washed with methanol (50 ml). Volatiles were removed from the filtrate to obtain a viscous oil, which was a target compound in a pure state (yield 700 mg, 89%).

13With NMR (CDCl3): δ 26.4 (CH2), 26.6 (CH2), 28.4 (CH2× 12), 32.9 (CH2× 2), 36.8 (wide, CH), 39.2 (NCH2× 2), 41.8 (H2NCH2), 46.9 (wide, NCH2× 2), 49.8 (wide, NCH2× 2), 78.9 (OS × 2), 79.7 (OS × 2), 156.0 (C=O × 4).

1H NMR (CDCl3): δ 1.08 (8H, bs, CH2× 4), 1.23 (D, s, CH2× 6), 1.27 (20N, bs, CH2× 6 and CH2), 1.77 (1H, bs, CH), 2.40 (2H, bs, NH2), 2.50 (2H, t, J=7 Hz, CH2NH2), 2.97 (4H, bm, NCH2× 2), 3.00-3.16 (8H, bm, NCH2× 4), 5.21 (1H, bs, NH), 5.30 (1H, bs, NH).

IR (thin film), cm-1: 3360, 1693, 1520, 1459, 1418, 1392, 1367, 1250, 1170, 1068, 964, 922, 871, 775, 733.

Mass spectrum (of the Belarusian library Association) m/e. Calculated for C33H66N5O8(M+H) 660. Found 660.

Example 3: synthesis of Compound 3.

Stage (a): the combination of Compound 1 with benzilate the Ohm

Connection 1 (61,8 mg, 0.1 mmol) in CH2Cl2(5 ml) was treated with benzylamine (10,7 mmol), acid chloride diphenylphosphino acid (25,9 mg) and Diisopropylamine (29 mg, 0.22 mmol) in a round bottom flask with a capacity of 50 ml at 20°C for 18 hours. Then the reaction mixture was diluted with CH2Cl2(20 ml) and washed with 1 N. hydrochloric acid (5 ml) and saturated aqueous potassium carbonate (5 ml). CH2Cl2layer was separated, dried (Na2SO4) and concentrated in vacuum to the resin (approximately 50 mg). This crude substance was then subjected to chromatography on silica gel with a gradient of ethyl acetate in benzene (100 ml each of 50%, 70% and 90%). Collected a small amount of faster current impurities, and then directly to the main faction.

1H and13The NMR spectra were taken in CDCl3. These spectra showed that the main fraction was a pure target compound.

Stage (b): removal of the BOC-protective groups

The product from step (a) (27.8 mg, 0,039 mmol) in CH2Cl2(0.5 ml) was treated triperoxonane acid (0.5 ml) and the reaction mixture was left to stand at room temperature for 3 hours. Then the reaction mixture was concentrated in vacuum to the resin to remove excess acid and weighed (53 mg).1H and13With NMR (CDCl3) spectra showed that the Boc groups were removed by the first stage. A weighted sample of Compound 2 was dissolved in water to obtain 10 malamulo solution of salt triperoxonane acid (TFA), which was used for the experiments on Radiometrie.

Example 4: synthesis of Compound 6.

Stage (a): tert-Butyl ether (8 benzoylamino-2-{[tert-butoxycarbonyl-(2-tert-carbonylmethyl)amino]methyl}octyl)-(2-tert-butyloxycarbonyl)carbamino acid

2,5-Dioxopiperidin-1 silt ester of benzoic acid (20 mg, 0,091 mmol) in dry CH2Cl2was added in one portion to a solution of Compound 2 (50 mg, 008 mmol) in CH2Cl2(1 ml) and the solution was stirred at room temperature for 16 hours. This reaction mixture was diluted with CH2Cl2(10 ml), was extracted with water (15 ml × 2), dried (MgSO4), filtered and the solvent was removed by rotary evaporation. The remaining residue was purified by chromatography on silica gel using a mixture of CH2Cl2/methanol (94:6, rf=0,23) as eluent to obtain a colorless viscous oil (yield 25 mg, 41%).

13With NMR (CDCl3): δ 26.4 (CH2), 26.8 (CH2), 28.5 (CH2× 12), 29.6 (CH2× 2), 29.7 (CH2), 29.9 (CH2), 36.6 (wide, CH), 39.4 (NCH2× 2), 40.0 (O=CNCH2× 2), 47.0 (wide, NCH2× 2), 49.8 (NCH2× 2), 79.7 (OS × 2), 80.0 (OS × 2), 127.0 (Ar CH × 2), 128.5 (Ar CH × 2), 131.3 (Ar CH), 134.9 (Ar C), 156.1 (C=O × 4), 167.6 (ArC=O).

1H NMR (CDCl3): δ 1.28 (8H, bs, CH2× 4), 1.38 (M, s, CH2× 6), 1.42 (20N, bs, CH2× 6 and CH2), 1.95 (1H, bs, CH), 3.1 (4H, bs, NCH2× 2), 3.22 (8H, bs, NCH2× 4), 3.42 (2H, bq, J=6 Hz, CH2N-benzoyl), 5.08 (2H, bs, NH × 2), 6.18 (1H, bs, NH-benzoyl), 7.38-7.45 (3H, m, Ar CH × 3), 7.74 (2H, bd, J=7 Hz, Ar CH × 2).

IR (thin film), cm-1: 3350, 2976, 2932, 2859, 1693 (wide), 1652, 1520, 1419, 1391, 1367, 1251, 1166, 732.

Mass spectrum (of the Belarusian library Association) m/e. Calculated for C40H70N5O9(M+H) 764. Found 764.

Stage (b): removal of the BOC-protective groups

Vos-tetramantane from stage (a) (42 mg, 0,056 mmol) in CH2Cl2(0.5 ml) was treated triperoxonane acid (0.5 ml) and the reaction mixture was left to stand at room temperature for 3 hours. Then the reaction mixture was concentrated in vacuum to remove the excess acid with obtaining resin. The expected mass (45 mg), found the weight of 45.7 mg).1H and13With NMR (CD3OD) spectra showed that the BOC groups were removed completely and that it contained the target compound. A weighted sample of this compound was dissolved in water to obtain 10 malamulo solution of salt triperoxonane acid (TFA) (56 μmol 5.6 ml), which was used for the experiments on Radiometrie.

Example 5. Synthesis of Compound 4.

All reactions were performed in a manual machine-nitrogen bubbler.

Stage (a): addition of losartan to threat the l-derivateservlet solid substrate

Losartan (Merck, 0,236 g, 0,558) and triethylamine (Fluka, 0,233 ml, a rate of 1.67 mmol) was added to a suspension fritillaries resin (Novabiochem, substitution of 1.24 mmol/g, 0,300 g) in DMF (dimethylformamide) (5 ml). After 4 hours the resin was filtered and washed. An aliquot of the resin was split (dichloromethane/TFA/triisopropylsilane, 92,5:5,0:2,5, 15 minutes). HPLC analysis (column Phenomenex Luna C18(2) 3 μm, a 4.6×50 mm, solvents: A=water/0.1% of TFA and B = acetonitrile/0.1% of TFA; gradient 10-40% B over 10 minutes; flow rate 2.0 ml/min, UV detection at 214 and 254 nm) gave a peak with tR6.7 minutes, which corresponds to losartan. The resin was treated with a solution of dichloromethane/methanol/diisopropylethylamine (17:2:1, 20 ml, 1 h), washed with dichloromethane and dried.

Stage (b): the substitution of the hydroxyl group of the azide

Diphenylphosphinite (Aldrich, 0,481 ml of 2.23 mmol) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (0,611 ml, 4.09 to mmol) was added to the suspension associated with the resin losartan from stage (a) (0,372 mmol) in THF (tetrahydrofuran) (10 ml). The reaction mixture was left to stand over night. An aliquot of the resin was digested as described for stage (a). Analysis by LC-MS (liquid chromatography-mass spectrometry) (column Phenomenex Luna C18(2) 3 μm, 50×4,60 mm, solvents: A = water/0.1% of TFA and B = acetonitrile/0.1% of TFA; gradient 20-80% B over 10 minutes; flow rate 1.0 ml/min, UV detection at 214 nm, MS-the RI) gave a peak tR7.3 minutes with m/z 448,1 (MN+)corresponding to the structure.

Stage (): restore the azide group to an amine

To a suspension of resin from step (b) in THF (4 ml) was added tin chloride(II) (Acros, 0,141 g, 0,744 mmol), thiophenol (Fluka, 0,304 ml, 2,976 mmol) and triethylamine (Fluka, 0,311 ml of 2.23 mmol). After 1.5 hours, an aliquot of the resin was split, as described in (a). LC-MS analysis (column Phenomenex Luna C18(2) 3 μm, 50×4,60 mm, solvents: A = water/0.1% of TFA and B = acetonitrile/0.1% of TFA; gradient 20-80% B over 10 minutes; flow rate 1.0 ml/min, UV detection at 214 nm, MS-ERIE) gave a peak at 1,9 minutes with m/z 422,2 (MH+), as expected for Amina.

Stage (d): chelate forming agent losartan-Leu-tetralin (Compound 4)

Fmoc-Leu-OH (Novabiochem, 0,030 g 0,084 mmol) was subjected to a reaction combination with aliquot associated with resin-amino-losartan from stage (b) (0,042 mmol) in DMF using a standard combination of reagents (HATU (hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea) and DIEA (diisopropylethylamine)) and the standard Fmoc Protocol-off (20% piperidine in DMF). The end of the reaction combinations tested standard test Kaiser. Then, this resin bound Compound 1 (0,026 g 0,042 mmol)using the same combination of reagents (HATU and DIEA in DMF. After four hours the product was tsalala from the resin and at the same stage remove the BOC-group (dichloromethane/TFA/treetop episilon, 47,5:50:2,5 solution within one hour). The solution was filtered, concentrated and purified preparative HPLC (column Phenomenex Luna C18(2) 5 μm, a 21.2×250 mm, solvents: A = water/0.1% of TFA and B = acetonitrile/0.1% of TFA; gradient 20-40% B over 60 min; flow rate of 10.0 ml/min, UV detection at 214 nm) to give 5 mg of the product after lyophilization. LC-MS analysis (column Phenomenex Luna C18(2) 3 μm, 50×4,60 mm, solvents: A = water/0.1% of TFA and B = acetonitrile/0.1% of TFA; gradient 10-80% B over 10 minutes; flow rate 0.3 ml/min, UV detection at 214 and 254 nm, MS-ERIE (electrospray ionisation)) tR5.1 minutes, m/z 735,4 (MN+)) confirmed the structure.

Example 6: synthesis of Compound 5

This compound is synthesized on a solid substrate as described in Example 4. Fmoc-Leu-OH (Novabiochem, 0,033 g, 0,092 mmol) and Fmoc-amino PEG diglycolic acid (Polypure, 0,049 mg, 0,092 mmol) sequentially combined with an aliquot associated with resin-amino-losartan from Example 4(C) (0.046 mmol) in DMF using a standard combination of reagents (HATU and DIEA) and standard Fmoc Protocol-off (20% piperidine in DMF). Finish combinations tested standard test Kaiser. This resin is then connected Connection 1 (0,029 g, 0.046 mmol)using the same combination of reagents (HATU and DIEA in DMF. The reaction mixture was left to stand over night, then the product was tsalala from the resin and at the same stage remove the BOC-group (dichlo the methane/TFA/triisopropylsilane, 47,5:50:2,5 solution within one hour). The solution was filtered, concentrated and purified preparative HPLC (column Phenomenex Luna C18(2) 5 μm, a 21.2×250 mm, solvents: A = water/0.1% HCOOH and B = acetonitrile/0.1% HCOOH; gradient 10-40% B over 60 min; flow rate of 10.0 ml/min, UV detection at 214 nm) to give 3.5 mg of product after lyophilization. LC-MS analysis (column Phenomenex Luna C18(2) 3 μm, 50×4,60 mm, solvents: A = water/0.1% HCOOH and B = acetonitrile/0.1% HCOOH; gradient 10-40% B over 10 minutes; flow rate 0.3 ml/min, UV detection at 214 and 254 nm, MS-ERIE) tR4.7 minutes, m/z 1025,4 (MN+)) confirmed the structure.

Example 7: synthesis of Compound 8

Stage (a): synthesis of N-Boc-N-[FmocNH-CH2CH2]-Gly-OH

1 g of N-[FmocNH-CH2CH2]-Gly-OtBu·HCl (Fluka 09660) was treated with 20 ml of 50% triperoxonane acid (TFA) in dichloromethane containing 0.5 ml of triisopropylsilane within 60 minutes. The mixture was evaporated in vacuum and the residue pererestorani in 20 ml of 50% tetrahydrofuran in water. Added 2.6 g of tert-butyloxycarbonyl-anhydride and 1.2 ml of N-methylmorpholine and the mixture was stirred for four days. The tetrahydrofuran is then evaporated in vacuum and the residue pererestorani in dichloromethane. The organic layer was washed with water and dried over MgsO4. Dichloromethane is evaporated in vacuum and the residue pererestorani in 5 ml of dimethylformamide. Dimethylformamide solution was diluted to 400 m is 60% acetonitrile in water and injected on the column for preparative RP-HPLC (HPLC with reversed phase) for cleaning (30-80% B in 40 minutes, where A = H2O/0.1% of TFA and B = CH3CN/0.1% of TFA, at a flow rate of 50 ml/min column Phenomenex Luna 10 MK 18(2) 250×50 mm) to obtain 450 mg of the pure product. The product was analyzed by analytical HPLC (gradient 20-70% B over 10 min where A = N2O/0.1% of TFA and B = CH3CN/0.1% of TFA; flow rate 0.3 ml/min; column, Phenomenex Luna 3 micron C18(2) 50×2 mm; UV detection at 214 nm; retention time of the product 8,66 minutes). Then spent the characterization of the product of mass spectrometry with electrospray ionization (MH+calculated 441,2; MN+found 440,8).

Stage (b): synthesis of N-((CH2)2-NHCOCH2-tetralin)-Glv-Arg-Val-Tvr-lle-His-Pro-lle-OH (Compound 8)

A peptide analogue of angiotensin II were synthesized on a peptide synthesizer Applied Biosystems 433A, starting with 0.1 mmol of resin Fmoc-lle-Wang. An excess of 1 mmol of pre-activated amino acids [using hexaphosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU)] was applied at stages combination with arginine. 123 mg of N-Boc-N-{FmocNH-CH2CH2]-Gly-OH, 114 mg of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanamine

hexaphosphate N-oxide (HATU) and 60 μl of N-methylmorpholine was dissolved in dimethylformamide and stirred for 5 minutes, then added to the resin in the apparatus-nitrogen bubbler. The reagents were removed after 2 hours and the resin was washed with dimethylformamide and dihl what Rotana. The resin was treated with 20% piperidine in dimethylformamide (3×10 ml) and washed with dimethylformamide. 23 mg of Compound 1, 14 mg HATU and 7.5 μl of N-methylmorpholine was dissolved in dimethylformamide for 10 minutes and added to the resin. The reagents were removed after 4 hours and the resin was washed with dimethylformamide and dichloromethane. Simultaneous removal of the protective groups of the side chains and cleavage of the peptide from the resin was performed in 10 ml triperoxonane acid containing 2.5% of triisopropylsilane and 2.5% water for 90 minutes. Triperoxonane acid was removed in vacuo, diethyl ether was added to the residue, the precipitated precipitated product washed with diethyl ether and dried in the air. Purification of the product of preparative RP-HPLC (0-30% B over 40 min where A = N2O/0.1% of TFA and B = CH3CN/0.1% of TFA at a flow rate of 10 ml/min column Phenomenex Luna 10 micron C18(2) 250×21,20 mm) gave 32 mg of pure conjugate chelate-peptide. The product was analyzed by analytical HPLC (gradient, 5-50% B over 20 minutes, where A = N2O/0.1% of TFA and B = CH3CN/0.1% of TFA; flow rate 1 ml/min; column, Phenomenex Luna 3 micron C18(2) 50×2 mm; UV detection at 214 nm; retention time of the product 5,22 minutes). Then spent the characterization of the product of mass spectrometry with electrospray ionization (MH+calculated 1197,8; MH+found 1197,8).

Example 8:99mTc radioactive RET Compounds 3-7

B is l prepared lyophilized set ("Chelakit A plus"), containing the following ingredients:

ComponentMolecular weightmg
SnCl2·2H2O225,630,016
MDP(H4)176,000,025
NaHCO384,014,5
Na2CO3105,990,6
NaPABA159,120,200

25-50 µg connection intended for tagging (dissolved in 25-50 ál of solvent)was added to CHELAKIT IS A plus, and then added to the eluate generator (99mTc4-in physiological solution, 1.0 ml). The solution was mixed and left to stand at room temperature for 20-30 minutes. Compounds 3 and 6 were labelled with technetium at room temperature at pH 9 with the corresponding cationic complexes99mTc high yield (RCP (radiochemical purity) > 90%). Tetraamine complexes were purified HPLC (mobile phase: 0.1% of TFA in water to 0.1% TFA in acetonitrile; column XTERRA RP18of 3.5 μm,a 4.6×150 mm), and they are stable in 50 mm phosphate buffer at 37°C for 2 hours (RCP > 95% HPLC after 2 hours).

Example 9: measurement of lipophilicity (LogP)99mTc complexes

The distribution coefficients octanol-water (LogP)99mTc complexes of Example 8 was defined as follows.

10 ál of HPLC-purified99mTc complex of Example 8 was mixed with 1-octanol (2 ml) and 50 mm phosphate buffer (pH 7.4, 2.0 ml) in a centrifuge tube. The tube was shaken on a vortex at room temperature for 1 minute and then centrifuged at high speed for 60 minutes. 0.1 ml samples of both phases were buried by pipette into other test tubes with appropriate precautions to avoid cross-contamination between phases and read in the gamma counter Wallac Wizzard. The measurement was repeated three times.

The distribution coefficient R was calculated as follows:

P = (imp/min in the octanol - pulse/min background)/(pulse/min in the water pulse/min background).

Usually the final value of the distribution coefficient was expressed as log P.

The results are shown in table 1.

Table 1
Values of Log P technicaly complexes tetraamine connections
99mTc complex Compound No.
3<-2
4+0,6
5-0,1
6-1,8
7<-2

Example 10: the biodistribution99mTc complexes

99mTc complexes of Compounds 4, 5 and 7 were obtained as described in Example 8. The experiments were carried out in two predefined points in time (22 and 120 minutes after injection (ri.) product test normal male Wistar rats (180-220 g). Animals did anesthesia with halothane gas (Halothane) (6% oxygen), making them an injection of 0.1 ml (500 MBq/ml) of the test product, squashed them, analyzed, and samples were analyzed for radioactivity. The results are shown in Table 2.

Table 2
The biodistribution99mTc complexes
% ID/GConnection 4Connection 5Connection 7
Blood 5 min3,261,50,84
Blood 120 min 0,910,260,05
Muscle 120 min0,340,90,1
Liver 120 min6,523,531,55
Easy 120 min1,840,60,4
Heart 120 min0,440,130,1
Heart/blood0,490,52
Heart/lung0,240,210,25
Heart/liver0,070,040,06
Heart/muscle1,3the 1.441
% for the remaining period of 2 hours
Clearance (% ID)
Urine (K, V, U) 120 min21,13accounted for 14.4564,26
HBS 120 min74,6554,21quintiles these figures were 19.63
LogP0,6-0,1<-2

Example 11: an alternative Connection 1

N,N'-Bis(2-tert-butoxycarbonylamino)-2-(2-hydroxyethyl)-1,3-di(tert-butoxycarbonylamino)propane of Example 1, stage (d), was dissolved in carbon tetrachloride (14 ml) and acetonitrile (14 ml). Was added water (21 ml) to obtain the two-phase mixture, then added periodate sodium (45 g, 21 mmol) and the hydrate of ruthenium chloride (35 mg, was 0.026 mmol). The obtained dark brown solution was stirred at room temperature for 1 hour and then diluted with CH2Cl2(40 ml). The organic layer was separated and the aqueous mixture was extracted with additional CH2Cl2(40 ml × 3). All organic extracts were combined, dried (MgSO4), filtered, and volatiles evaporated under reduced pressure to obtain sodium salt of Compound 1 in the form of a dark viscous residue, which use isovale without additional purification (4.15 g, 96%).

13With NMR (CDCl3): δwith28.2 (X12)(CH3), 34.1 (CH2), 34.4 (CH), 38.6 (x2)(NCH2), 46.8 (x2)(NCH2), 49.3 (x2)(NCH2), 79.0 (x2)(OC), 80.2 (x2)(C), 155.9 (x4)(C=O), 175.4 (COOH).

1H NMR (CDCl3): δn1.29 (N, s, CH2× 6), 1.35 (M, s, CH2× 6), 2.19 (1H, br, CH), 2.40 (2H, br, CH2), 3.05-3.23 (12H, br, NCH2× 6), 5.10-5.24 (2H, br, NH × 2).

Mass spectrum (ERIE) m/e. Calculated for (M+Na) C29H54N4Na 641,3738. Found 641,3787.

Example 12: obtain the Compound (9)

1,3-Dicyclohexylcarbodiimide (DCC; 2.16 g, 10.5 mmol) was added in one portion to a stirred solution of Compound 1 (4.15 g, of 6.90 mmol) and N-hydroxysuccinimide (1,81 g, 15.7 mmol) in dry THF (30 ml). This mixture was stirred at room temperature for 16 hours and then precipitated precipitated DCU (1,3-dicyclohexylmethane) was removed by filtration. Volatile substances are evaporated from the filtrate to obtain waxy residue, to which was added dry ether (50 ml), the precipitate fell out additional number of DCU, which was removed by filtration. The ether solution was washed with water (25 ml × 2), dried (MgSO4), filtered and the solvent evaporated under reduced pressure to obtain waxy solids. This solid was purified by chromatography on silica gel, elwira mixture of CH2Cl2/ether (1:1) up until the DCC has not been removed. Eluent was replaced ether is m and the target product (r f=0,4, DCM (dichloromethane)/Et2O 1:1) was isolated as a colourless solid (2.7 g, 57%), TPL 66-68°C.

13With NMR (CDCl3): δwith25.6 (x2)(CH2), 28.4 (x12)(CH2), 31.8 (CH2, 35.2 (CH), 39.3 (x2)(NCH2), 47.1 (x2)(NCH2), 49.1 (x2)(NCH2), 79.9 (x2)(OC), 80.5 (x2)(C), 156.1 (x4)(C=O), 167.7 (C=0), 169.1 (x2)(C=O).

1H NMR (CDCl3): δn1.35 (N, s, CH2× 6), 1.41 (S, s, CH2× 6), 2.52 (3H, brs, CH & CH2), 2.77 (4H, s, CH2× 2), 3.10-3.35 (12H, brs, NCH2× 6), 5.08 (2H, brs, NH×2).

Mass spectrum (ERIE) m/e. Calculated for (M+Na)33H54N6O12Na 738,3896. Found 738,3893.

1. The complex of technetium formula (I)

where X represents-NR-, -CO2-, -CO-, -NR(C=S)-, -NR(C=O)-, -CONR -, or a group Q;
each Y independently represents a D - or L-amino acid, -CH2-, -CH2OCH2- or-och2CH2O-, or group X;
Z is a synthetic, providing targeted delivery of biological grouping selected from 3-100 dimensional peptides or peptide analogs, which can be a linear peptides or cyclic peptides or combinations thereof; or substrates, antagonists or inhibitors of enzymes; synthetic receptor-binding compounds, oligonucleotides or oligo-DNA or oligo-RNA fragments, and Z is a monoclonal antibody or fragm the volume, and has a molecular mass of less than 5000;
n means an integer from 1 to 8;
m means an integer from 0 to 30;
R represents H, C1-4alkyl, C2-4alkoxyalkyl,1-4hydroxyalkyl or1-4foralkyl;
Q is a

Rather it represents a pharmaceutically acceptable anion selected from hydroxide and anions of organic or inorganic acids;
assuming that the chain of atoms X1(Y)mnot have a relationship where one heteroatom is directly connected with the other.

2. The complex of technetium according to claim 1, where a radioactive isotope of technetium is a99mTc or94mVehicle.

3. The complex of technetium according to claim 1, where n denotes a number from 1 to 6, and X is a-CONR -, or-NR(C=O)-.

4. The complex of technetium according to claim 3, where X represents-CONH -, or-NH(C=O)-.

5. The complex of technetium according to claim 1, where -(Y)m- contains PEG group of the formula
(-OCH2CH2O)wwhere w denotes an integer from 3 to 25.

6. The complex of technetium according to claim 5, where w stands for a number from 6 to 22.

7. The complex of technetium according to claim 1, where -(Y)mcontains from 1 to 10 amino acids.

8. The complex of technetium according to claim 7, where the amino acids are independently selected from glycine, lysine, aspartic acid, glutamic acid or serine.

9. The complex of technetium according to claims 1 to 8, wherein Z is selected from:
1) 3-30-dimensional peptide;
2) substrate enzyme antagonist enzyme or ing the inhibitors of the enzyme.

10. Conjugate chelat forming agent, suitable for the production of complexes of technetium according to claims 1 to 9, and the said conjugate is a conjugate of formula II

where X, Y, Z, n and m are such as defined in claim 1;
Q1-Q6independently represent a group Q, where Q represents H or a protective group for amino groups.

11. Conjugate chelat forming agent of claim 10, where each of Q1-Q6represents N.

12. Conjugate chelat forming agent of claim 10, where Q1and Q6both represent H, and Q2, Q3, Q4and Q5represent tert-butoxycarbonyl.

13. Radiopharmaceutical agent, which contains a complex of technetium formula I according to any one of claims 1 to 9, together with a biocompatible liquid carrier selected from water and aqueous solutions.

14. Radiopharmaceutical means indicated in paragraph 13, where a radioactive isotope of technetium is a99mTc or94mVehicle.

15. Kit for radiopharmaceutical preparation tools PP and 14, which includes:
1) conjugate chelat forming agent p-12;
2) a biocompatible reducing agent selected from dithionite sodium, sodium bisulfite, ascorbic acid, formamidine-sulinowo acid, ion of divalent tin, Fe(II) or Cu(II).

16. Set on 15, where is biocompatible is the first reducing agent contains ion tin.

17. Set on 15, where each of Q1-Q6represents N.

18. Set on 15, where Z is as defined in item 9.

19. The compound of formula III

where Q1-Q6and n are such as defined in claim 10;
E is a functional group suitable for conjugation with providing targeted delivery of biological grouping (Z), as defined in claim 1, to obtain chelat forming agent conjugate of claim 10, where E is selected from the group CO2N, NH2and CO2(NHS), where (NHS) is an N-hydroxysuccinimidyl residue, provided that when n=3, then at least one of Q1-Q6represents a protective group for amino groups.

20. The connection according to claim 19, where E represents-NH.

21. The connection according to claim 19, where E represents-CO2N.

22. The connection according to claim 19, where n denotes a number from 1 to 6.



 

Same patents:

FIELD: chemistry; biochemistry.

SUBSTANCE: present invention pertains to biotechnology and is an oligopeptide, capable of blocking invasion and metastasis of cancerous cells, containing an oligopeptide series (given in the application) or its fragment. The invention is also a pharmaceutical composition for preventing or treating degenerative diseases, or pathological conditions, caused by destruction of the extracellular matrix (ECM) by matrix metalloproteinase (MMP), and a diagnostic composition for diagnosing degenerative diseases or pathological conditions, caused by destruction of the extracellular matrix (ECM) by matrix metalloproteinase (MMP). The invention is also a vaccine for treating or preventing degenerative diseases, or pathological conditions, caused by destruction of extracellular matrix (ECM) by matrix metalloproteinase (MMP).

EFFECT: provision for oligpeptides, which can effectively block invasion or metastasis of cancerous cells and which can be used for preventing or treating degenerative diseases or pathological conditions, caused by destruction of extracellular matrix by matrix metalloproteinase.

8 cl, 4 dwg, 1 tbl, 5 ex

FIELD: biotechnology, medicine, oncology, peptides.

SUBSTANCE: invention relates to a method based on phage display for preparing peptides interacting specifically with mammary Ehrlich tumor and can be used in therapy and diagnosis of malignant neoplasm. Peptides are prepared by affinity selection from phage peptide libraries comprising ten millions of different peptides of size 15 amino acid residues, the group of nine peptides wherein each peptide shows ability for accumulation in Ehrlich tumor. For practice using mimetic-peptides selected by such manner can be prepared by chemical synthesis and to use for preparing conjugates on their basis with the known cytotoxic preparations, radioactive isotopes and they can be incorporated in the composition of liposomal preparations for visualization of tumor neoplasm also.

EFFECT: valuable medicinal properties of peptides.

2 dwg, 2 ex

The invention relates to a new autoantigen and its derived peptides, their use in the treatment of chronic articular cartilage in autoimmune diseases, pharmaceutical compositions containing these peptides, diagnostic method detection self-reactive T cells in the analyzed sample and the analytical set used in said method

FIELD: chemistry.

SUBSTANCE: invention claims novel compounds with inhibition effect on HCV (hepatitis C virus) protease, and methods of obtaining the claimed compounds.

EFFECT: pharmaceutical compositions including these compounds, and methods of compound application in treatment of HCV protease related diseases.

23 cl, 5 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention is related to improved method for preparation of manganese oxalate (II) by means of direct interaction of metal with acid in bead mill in presence of liquid phase, in which manganese and oxalic acid are loaded into bead mill in stoichiometric ratio in amount of 0.75-2.4 mole/kg of load at mass ratio of load and glass beads of 1:1.2, liquid phase dissolvent used is water or organic substance, or mixture of organic substances; loading is carried out in the following sequence: liquid phase dissolvent, acid, then metal; process is started at room temperature and is carried out under conditions of forced cooling in the temperature range of 18-39°C with control over procedure by sampling method to practically complete spend of loaded reagents for product making, afterwards mixing and cooling are terminated, suspension of reaction mixture is separated from glass beads and filtered, salt deposit is sent for product cleaning from traces of non-reacted metal, and filtrate is returned into repeated process.

EFFECT: method makes it possible to produce target product in absence of manganese dioxide and stimulating additive at temperatures close to room temperature.

2 cl, 13 ex, 2 tbl

FIELD: chemical industry; methods of production of the manganese salts with the organic acids.

SUBSTANCE: the invention is pertaining to production of the manganese salts with the organic acids in particular, to the salt of the divalent manganese and formic acid. The method is exercised by interaction of manganese, its oxides in the state of the highest valence with the formic acid solution in the organic solvent in the presence of iodine as the stimulating additive. The production process is conducted in the bead grinder of the vertical type having the revertive cooler-condenser, the high-speed paddle stirrer and the glass beads of in the capacity of the grinding agent loaded in the mass ratio to the loading of the liquid phase as (1÷2): 1. The liquid phase consists of the formic acid solution in the organic solvent. The concentration of the acid is taken within the range of 3.5÷10.8 mole/kg. In the loaded liquid phase they dissolve the stimulating additive of iodine in the amount of 0.025-0.100 mole/kg of the liquid phase. The ratio of the masses of the liquid phase and the total of the metallic manganese and the manganese oxide are as(4.9÷11):1. The molar ratio of the metal and the oxide in the loading is as (1.8÷2.,2):1. The metal and the oxide are loaded the last. It is preferable in the capacity of the dissolvent to use the butyl alcohol, ethyl acetate, ethylene glycol, 1.4-dioxane, dimethyl formamide. The production process is started and conducted at the indoor temperature up to practically complete(consumption of the whole loaded manganese oxide. Then the stirring is stopped, the suspension of the salt is separated from the beads and the nonreacted manganese and after that conduct filtration. The filtrate and the nonreacted manganese are returned into the repeated production process, and the filtered out settling of the manganese salt is exposed to purification by recrystallization. The technical result of the invention is - simplification of the method at usage of accessible reactants.

EFFECT: the invention ensures simplification of the method at usage of accessible reactants.

16 ex, 2 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: chemical industry; methods of production of the bromine derivatives of fullerene С60.

SUBSTANCE: the invention is pertaining to the method of production of the bromine derivatives of fullerene С60. The process consists in the interaction of the bromoform and the tetra bromomethane with fullerene С60 at presence of the rhodium-containing catalyst - Wilkinson's complex [RhCl(PPh3)3] at the temperature of 100°С within 10-20 hours, at the molar ratio of [Rh]:[C60]:[CHBr3 or CBr4]= 1:100:100-500. The technical result of the invention is the increased output of the product, the reduced amount of the wastes, the insignificant consumption of the catalyst.

EFFECT: the invention ensures the increased output of the product, the reduced amount of the wastes, the insignificant consumption of the catalyst.

3 ex, 1 tbl

FIELD: chemical technology.

SUBSTANCE: invention relates to technology for synthesis of acetic acid inorganic salts. Method involves interaction of metallic manganese or its dioxide with acetic acid in the presence of oxidizing agent. Process is carried out in beaded mill of vertical type fitted with reflux cooling-condenser, high-speed blade mixer and glass beads as grinding agent loaded in the mass ratio to liquid phase = 1.5:1. Liquid phase represents glacial acid solution in ethylcellosolve, ethylene glycol, 1,4-dioxane, isoamyl alcohol and n-butyl alcohol as a solvent. The concentration of acid in liquid phase is 3.4-4 mole/kg. Then method involves loading iodine in the amount 0.025-0.070 mole/kg of liquid phase, metallic manganese and manganese dioxide in the mole ratio = 2:1 and taken in the amount 11.8% of liquid phase mass. The process starts at room temperature and carries out under self-heating condition to 30-38°C to practically complete consumption of manganese dioxide. Prepared salt suspension is separated from beads and unreacted manganese and filtered off. Filtrate is recovered to the repeated process and prepared precipitate is purified by recrystallization. Invention provides simplifying method using available raw and in low waste of the process.

EFFECT: improved method of synthesis.

3 cl, 9 ex

FIELD: catalyst preparation methods.

SUBSTANCE: invention relates to preparation of manganese (III) acetylacetonate, which can be used as catalyst as well as vinyl monomer polymerization initiator. Method is implemented in aqueous medium with ammonium acetylacetonate freshly prepared by mixing acetylacetone with aqueous ammonia solution. Hydrogen peroxide is used as oxidant and sodium bicarbonate is additionally introduced into reaction mixture. Following consecutive operations are carried out: reaction of manganese (II) chloride tetrahydraye with sodium bicarbonate; separating thus formed manganese (II) bicarbonate in the form of paste; adding ammonia acetylacetonate and then hydrogen peroxide aqueous solution to the paste; and recovering manganese (III) acetylacetonate with yield 95%.

EFFECT: improved economical and environmental characteristics of process.

FIELD: organic chemistry, medicine, physiology.

SUBSTANCE: invention relates to agents for regulation (maintaining or suppression) of physical working ability and/or adaptation to different variants represented by solvated complex compounds of the general formula (I): Katm+[L1qEL2]Ann- x p.Solv (I) wherein L1 means aminothiols of the formula: R1NHCH(R2)(CH2)1-2SR3 wherein R1 means hydrogen atom (H), (C1-C20)-alkyl or RCO; R means (C1-C19)-alkyl; R2 means H or carboxyl; R3 means H, (C1-C20)-alkyl, (C2-C20)-alkenyl or benzyl; q = 1, 2 or 3; L2 means halogen atom, water and/or organic ligand. For example, bis-(N-acetyl-L-cysteinato)aquozinc (II) diheptahydrate suppresses physical working ability and in the dose 50 mg/kg increases reviving time of mice by 6 times and cats - by 2.8fold under conditions of acute hypoxia with hypercapnia, and increases reviving time of mice by 4 times under conditions of acute hypobaric hypoxia. Under the same conditions the known antihypoxic agents amtizol, acizol or mexidol are inactive or less active significantly by their activity. Bis-(N-acetyl-L-cysteinato)-ferrous (II) pentahydrate is more active as compared with the known antihypoxic agents and protects experimental animals in 4 variants of hypoxia. Bis-(N-acetyl-L-cysteinato)zinc (II) sulfate octahydrate is similar to enumerated compounds by its antihypoxic activity.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 dwg, 11 tbl, 33 ex

The invention relates to the objects of the invention characterized in the claims, i.e

The invention relates to a new method of obtaining metallizovannyh derived bacteriochlorophyll for use in the methods of photodynamic therapy (PDT) and in vivo diagnostics and photodynamic destruction of viruses and microorganisms in vitro, as well as some new metallosalen derived bacteriochlorophyll

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds of series 2-propen-1-on of general formula or their tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, where Q stands for heteroaryl cycle, containing up to 2 nitrogen atoms. Compounds I induce HSP-70 and are useful in treatment of diseases accompanying pathologic process in organisms of mammals, including humans.

EFFECT: novel compounds possess useful biological properties.

26 cl, 7 tbl, 179 ex

FIELD: chemistry.

SUBSTANCE: in derivatives of 1,2-di(cyclo)substituted benzole of general formula I, their salts and hydrates , R10 is 5-10 member cycloalkyl, optionally substituted, or 5-10 member cycloalkenyl, optionally substituted, n=0, 1 or 2; XI is CH or nitrogen.

EFFECT: inhibiting activity with respect to cell adhesion or cell infiltration and application as therapeutic or preventive agent for inflammatory and autoimmune diseases, connected with adhesion and infiltration of leucocytes.

22 cl, 3 tbl, 118 ex

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