Dipeptide prodrugs and use thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

 

The present invention relates to prodrugs, which are derivatives of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, method of production thereof, their use for the treatment and/or prophylaxis of diseases and to their use for the manufacture of medicinal products intended for the treatment and/or prophylaxis of diseases, especially cardiovascular diseases.

Prodrugs are derivatives of the active substance, which before the actually release of the active substance undergoing occurring in vivo single-stage or multistage bioperene enzymatic and/or chemical nature. Prodrugs, as a rule, contain chemical group, contributing to the improvement of the properties underlying the active substance [.Ettmayer and others, J. Med. Chem., 47, 2393 (2004)]. For optimal pharmaceutical actions the structure of the specified chemical groups and provided the mechanism of release of the active substance from the prodrug should be extremely exact match with an individual active ingredient, indication for its use, place and method of application. Many drugs used in the form of prodrugs, which is the one from the underlying active substances are characterized by a higher bioavailability, what is achieved, for example, by optimizing the physicochemical characteristics of such prodrugs, and in particular to increase solubility and improve the ability of active and passive absorption or specific for a particular tissue distribution. From the extensive list of related prodrugs literature special mention should be made, for example, .Bundgaard (publisher), Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities, Elsevier Science Publishers B.V., 1985.

Adenosine (a purine nucleoside) is present in all cells and is excreted in free form as one of the many physiological and pathophysiological stimulating substances. Adenosine obraztsa as an intermediate product in the decomposition of adenosine-5'-monophosphate (AMP) and S-adenosylhomocysteine inside the cells, however, can be extracted from them and by attaching to specific receptors to exert influence as a hormonal substance or neurotransmitter. Through adenosine 1 receptors affect essential functions primarily in excitable and/or existing cells of different tissues [see, for example, K.A.Jacobson, Z.-G.Gao, Nat. Rev. Drug Discover., 5, 247-264 (2006)].

2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxy-ethoxy)phenyl]pyridine-3,5-dicarbonitrile [compound of formula (A)] is the eff is active for oral use agonist adenosine receptor 1, currently at the stage of in-depth clinical studies as a potential new pharmaceutical active substance, intended primarily for the prevention and treatment of cardiovascular disease [see WHO Drug Information vol 20, 2 (2006), and the receipt and application of the compounds according to example 6 of the international application WO 03/053441].

However, the compound of formula (A) has low solubility in water and physiological media and organic solvents, as well as limited bioavailability for oral use suspensions of this crystalline substance. These circumstances, on the one hand, responsible for the restricted intravenous administration of the compounds of formula (A) as the active substance with an extremely low dosages, since the preparation of infusion solutions based on physiological salt solutions using conventional hydrotropic of solubilization is very difficult. On the other hand, is difficult is making the appropriate drugs in pill form. Based on the foregoing, the present invention was based on the task to offer derivatives or prodrugs of the compounds of formula (A), which have p is higher solubility in the above environments and/or improved bioavailability for oral use and however after the application is capable of being controlled to be released into the patient's body. Increased the suitability of the compounds of formula (A) for intravenous administration could open up other areas of its therapeutic use as an active substance.

Overview of prodrugs, derivatives of esters of carboxylic acids, and possible properties of these compounds published, for example, in K.Beaumont and in other Curr. Drug Metab., 4, 461-485 (2003).

The object of the present invention are compounds of General formula (I):

in which

RAmeans a group of the formula:

,

or

in which

* indicates the place of attachment to the oxygen atom

L1and L2independently from each other mean a bond or-CH2group

R1, R2and R3independently of one another denote hydrogen or methyl,

R4and R6the same or different and independently of one another denote hydrogen or the side group of a natural α-amino acid or its homologs or isomers,

R5and R7independently of one another denote hydrogen or methyl,

L3denotes unbranched or branched alcander with 2-4 carbon atoms, which is substituted by an amino group,

R8, R9and R10independently of one another denote hydrogen or methyl,

m means 2, 3, 4, 5, and 6,

L4denotes unbranched or branched alcander with 2-4 carbon atoms, which is substituted by a carboxyl group,

R11means hydrogen or methyl, and

n denotes 1, 2, 3,or 4

and also their salts, solvate and solvate salts.

Proposed in the invention compounds are the compounds of formula (I), their salts, solvate and solvate salts, the following other compounds of formula (I) and their salts, solvate and solvate salts, as well as in the following examples the invention, other compounds of formula (I), their salts, solvate, and a solvate of salt, if under the following other compounds of formula (I) is not implied salt, solvate and solvate salts.

Proposed in the invention compounds depending on their structure can be in the form of stereoisomers (enantiomers or diastereomers). Thus, the present invention relates to the enantiomers or diastereomers and their mixtures. Individual stereoisomers can be isolated from such mixtures of enantiomers and/or diastereomers known methods.

If proposed in the invention compounds are in the form of the tautomers, the invention relates to any and all tautomeric forms of such compounds.

In accordance with the present invention preferred the salts are physiologically acceptable salts proposed in the invention compounds. Under such salts include salts that are unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the proposed in the invention compounds. In addition to salts containing one salt-forming residue, according to the present invention, if necessary, is also possible to use salts that contain multiple, in particular two or three, salt-forming residue.

Physiologically acceptable salts proposed in the invention compounds are formed by the reactions of addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultancy, toluenesulfonic acid, benzosulfimide, naphthalenedisulfonate, acetic acid, triperoxonane acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts proposed in the invention compounds are salts of conventional bases such as, preferably alkali metal salts (particularly sodium or potassium), salts of alkaline earth metals (in particular, calcium salts or magnesium), and ammonium salts which I have are derived from ammonia or organic amines with 1 to 16 carbon atoms, for example, preferably ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, diethanolamine, triethanolamine, choline, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, research, N-methylmorpholine, arginine, lysine, Ethylenediamine, piperidine and N-methylpiperidine.

In accordance with the present invention under the solvate mean such forms proposed in the invention compounds, which are complexes formed by these are in solid or liquid compounds due to the coordination of solvent molecules. Hydrates are a special form of a solvate and arise from the coordination of these compounds with water molecules. In accordance with the present invention the preferred solvate is a hydrate.

In accordance with the present invention in the absence of specific instructions, the substituents are as follows.

Alcantara with 2-4 carbon atoms in accordance with the present invention is unbranched or branched divalent alkyl residue with 2 to 4 carbon atoms. It is preferable unbranched ascandilwy residue with 2 to 4 carbon atoms. Examples of preferred alcandro are ethane-1,2-diyl (1,2-ethylene), ethane-1,1-diyl, propane-1,3-diyl (1,3-propylene), propane-1,1-diyl, propane-1,Diil, propane-2,2-diyl, butane-1,4-diyl (1,4-butylene), butane-1,2-diyl, butane-1,3-diyl and butane-2,3-diyl. In addition, ascandilwy balance in case of group L3substituted amino group, and in the case of group L4a carboxyl group.

Under the side groups, α-amino acids used as substituents R4and R6assume the side group of a natural α-amino acids and their homologues or isomers. The corresponding α-amino acids can have both L-and D-configuration, or may be a mixture of α-amino acids L - and D-configurations. Examples of suitable side groups are methyl (alanine), propane-2-yl (valine), propane-1-yl (Norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine), butane-1-yl (norleucine), tert-butyl (2-tert-butylglycol), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indole-3-ylmethyl (tryptophan), imidazole-4-ylmethyl (histidine), hydroxymethyl (series), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutane-1-yl (lysine), 4-amino-3-hydroxybutane-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 2-amino-ethyl (2,4-dia is nomalanga acid), aminomethyl (2,3-diaminopropionic acid), 3-guanidinopropionic-1-yl (arginine) and 3-ureidopropionic-1-yl (Citroen). Under the side groups, α-amino acids used as the substituent R4preferably involve methyl (alanine), propane-2-yl (valine), propane-1-yl (Norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine), butane-1-yl (norleucine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine) and 2-carbamoylethyl (glutamine). Under the side groups, α-amino acids used as the substituent R6preferably mean imidazol-4-ylmethyl (histidine), 4-aminobutane-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-amino-ethyl (2,4-diaminopentane acid), aminomethyl (2,3-diaminopropionic acid) and 3-guanidinopropionic-1-yl (arginine). Preferred are the corresponding α-amino acids have L-configuration.

Preferred are the compounds of formula (I)in which:

RAmeans a group of the formula:

,

or,

in which

* indicates the place of attachment to the oxygen atom

L1means of communication,

L2means bond or-CH2group

R1and R3/sup> independently of one another denote hydrogen or methyl,

R4means hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methylpropan-1-yl, butane-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl,

R6means hydrogen, imidazol-4-ylmethyl, 4-aminobutane-1-yl, 3-aminopropan-1-yl, 2-amino-ethyl, aminomethyl or 3-guanidinopropionic-1-yl,

L3means unbranched alcander with 2-4 carbon atoms, which is substituted by an amino group,

R8and R10independently of one another denote hydrogen or methyl,

m represents 2, 3 or 4,

L4means unbranched alcander with 2-4 carbon atoms, which is substituted by a carboxyl group,

R11means hydrogen or methyl, and

n represents 2, 3 or 4,

and also their salts, solvate and solvate salts.

Especially preferred are the compounds of formula (I), in which

RAmeans a group of the formula:

,

or

in which

* indicates the place of attachment to the oxygen atom

L1and L2accordingly, means of communication,

R4means hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methylpropan-1-yl, butane-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-yl is ethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl,

R6means imidazol-4-ylmethyl, 4-aminobutane-1-yl, 3-aminopropan-1-yl, 2-amino-ethyl, aminomethyl or 3-guanidinopropionic-1-yl,

L3means a group of the formula-CH(NH2)-CH2-, -CH2-CH(NH2)-, -CH2-CH(NH2)-CH2-, -CH(NH2)-CH2-CH2- or-CH2-CH2-CH(NH2)-,

m represents 2, 3 or 4,

L4means a group of the formula **-CH2-CH(COOH)- or-CH2-CH2-CH(COOH)-, in which

** means the place of connection to the adjacent carbonyl group,

and

n represents 2 or 3,

and also their salts, solvate and solvate salts.

Even more preferred are the compounds of formula (I)in which:

RAmeans a group of the formula:

in which

* indicates the place of attachment to the oxygen atom

L1and L2accordingly, means of communication,

R4means hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, hydroxymethyl or 1-hydroxyethyl, and

R6means imidazol-4-ylmethyl, 4-aminobutane-1-yl, 3-aminopropan-1-yl, 2-amino-ethyl, aminomethyl or 3-guanidinopropionic-1-yl,

and also their salts, solvate and solvate salts.

Even more preferred are also the compounds of formula (I)in which:

RAmeans a group of the formula

in which

* indicates the place of attachment to the oxygen atom

L3means a group of the formula-CH(NH2)-CH2-, -CH2-CH(NH2)-, -CH(NH2)-CH2-CH2- or-CH2-CH2-CH(NH2), and

m represents 2 or 3,

and also their salts, solvate and solvate salts.

Another object of the present invention is a method of obtaining a offer in the invention compounds of formula (I), characterized in that the compound of formula (A):

[And] in an inert solvent in the presence of means of condensation atrificial carboxylic acid of formula (II), (III) or (IV):

in which

L1L3L4, R1, R4, R5and R11respectively, such as described above

PG1means a temporary aminosidine group, such as tert-butoxycarbonyl, and

PG2means a temporary carboxylate group, such as tert-butyl,

obtaining the compounds of formula (V), (VI), (VII):

in which L1L3L4, R1, R4, R5, R11, PG1and PG2accordingly, the hat, as indicated above,

then otscheplaut protective group PG1accordingly PG2and in an inert solvent in the presence of means of condensation combine in the case of compound (V) with the compound of the formula (VIII)in the case of compound (VI) with the compound of the formula (IX) in the case of compound (VII) with the compound of the formula (X):

in which

L2, R6, R7, R8, PG2, m and n, respectively, such as described above, and

R2aand R3aand R9aand R10arespectively the same or different are as defined above for R2, R3, R9accordingly, R10or mean temporary aminosidine group, such as tert-butoxycarbonyl,

then remove, if necessary, present protective groups,

or

[In] in an inert solvent in the presence of means of condensation combined with the compound of the formula (XI), (XII) or (XIII):

in which

L1L2L3L4, R1, R4, R5, R6, R7, R8, R11, m and n, respectively, such as described above

R2aand R3aand R9aand R10aaccordingly, equal or RA is ing and such as indicated above for R2, R3, R9accordingly, R10or mean temporary aminosidine group, such as tert-butoxycarbonyl, and

PG2means a temporary carboxylate group, such as tert-butyl,

then remove, if necessary, present protective groups,

and the compounds of formula (I) with the appropriate (i) solvents and/or (ii) acids or bases, if necessary, transferred to their solvate, salt and/or solvate salts.

Thus, the transformation (A)→(I) in accordance with option [A] is performed by the serial combination of individual, if necessary, adequately protected component (carboxylic acid, amine respectively) or in accordance with the variant [In] by direct acylation adequately protected dipeptide derivative. The reaction mix (formation of ester, amide respectively) implement known from the chemistry of peptides methods [see, for example, .Bodanszky, Principles of Peptide Synthesis, Springer, Berlin, 1993; H.-D.Jakubke, H.Jeschkeit, Aminosauren, Peptide, Proteine, publisher Chemie, Weinheim, 1982].

As inert solvents for the implementation of the reactions of the combination use, for example, ethers such as diethyl ether, tert-butylmethylamine EF the R, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated Uglevodorody, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents, such as acetone, ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N,N'-dimethylpropyleneurea, N is an organic or acetonitrile. Along with this, you can use a mixture of these solvents. Preferred solvents are dichloromethane, dimethylformamide or mixtures thereof.

As a means of condensation for the implementation of the reactions of the combination use, for example, carbodiimide, such as N,N'-diethylcarbamoyl, N,N'-dipropylacetamide, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide or N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride, phosgene derivatives such as N,N'-carbonyldiimidazole, the compounds 1,2-oxazole, such as 2-ethyl-5-phenyl-1,2-oxazole-3-sulfate or perchlorate 2-tert-butyl-5-methylisoxazole, acylaminoacyl, such as 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, or isobutylparaben, anhydride papapostolou acid, diethyl ether cianferoni acid, bis(2-oxo-3-oxazolidinyl)phosphorylchloride, exagerrated benzotriazol-1-yloxytris-(dimethylamino)phosphonium, hexaphosphate benzotriazol-1-yloxytris-(pyrrolidino)of phosphonium, tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea, hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea, tetrafluoroborate 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium, hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea or tetrafluoroborate O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium, optionally in combination with other excipients, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide and used as grounds carbonates of alkali metals, for example sodium carbonate or potassium carbonate, or organic bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine or 4-N,N-dimethylaminopyridine. For the formation of ether is preferably used N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride in combination with 4-N,N-dimethylaminopyridine. For the formation of amide preferably using N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride in combination with 1-hydroxybenzotriazole or N-hydroxysuccinimide and, if necessary, a base such as N,N-diisopropylethylamine.

The reaction combinations in General performed in the temperature range from 0 to +60°C, preferably from +20 to +40°C. They can him who under normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). The reaction combinations in General carried out at normal pressure.

The compounds of formula (I) can be obtained by the above methods directly in the form of salts. Such salts by performed in an inert solvent processing base, respectively acid, chromatographic methods or by ion-exchange resins, if necessary, can be converted into the corresponding free base, acid respectively. Other salts proposed in the invention compounds, if necessary, can be obtained by replacing the counterions by ion-exchange chromatography, for example, involving the use of resins Amberlite®.

When implementing the above-described reaction sequences are optionally present in the residues R4, R6L3and/or L4functional groups, especially amino groups, guanidinium, hydroxyl group, mercaptopropyl and carboxyl groups, if appropriate or necessary, can be also in temporarily protected form. However, the imposition and removal of the respective protective groups carry out the usual, well-known from the chemistry of peptides methods [see, for example, T.W.Greene, P.G.M.Wuts, Protective Groups in Organic Synthesis, from ateljstva Wiley, New York, 1999; M.Bodanszky, A.Bodanszky, The Practice of Peptide Synthesis, Springer, Berlin, 1984].

As groups intended to protect the amino and guanidino, preferably using tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z). As groups intended to protect a hydroxyl or carboxyl functional groups, preferably using tert-butyl or benzyl. These protective groups otscheplaut conventional methods, preferably implemented in an inert solvent, such as dioxane, dichloromethane or acetic acid, the interaction of a secure connection with a strong acid, such as Bogorodchany, vodorodnoe or triperoxonane acid; removal if necessary, can also be performed without the use of an inert solvent. If as a protective group using benzyl and benzyloxycarbonyl, it can also be removed by hydrogenolysis in the presence of palladium catalyst. Cleavage of these protective groups can optionally be performed simultaneously or in separate reaction stages.

Compounds of formula (II), (III), (IV), (VIII), (IX), (X), (XI), (XII) and (XIII) are commercially available, known from the literature or can be obtained by known literature methods. So, for example, compounds of formulas (II) and (VIII)in which L1according to the state L 2means CH2group, can be obtained from corresponding compounds in which L1accordingly L2means of communication, known methods of lengthening chains of carboxylic acids, for example, by the reaction of the Arndt-Eistert [Eistert and others, Ber. Dtsch. Chem. Ges., 60, 1364-1370 (1927); and Ye other, Chem. Rev., 94, 1091-1160 (1994); Cesar and others, Tetrahedron Lett., 42, 7099-7102 (2001)] or interaction with N-hydroxy-2-dipyridine [see Barton and others, Tetrahedron Lett., 32, 3309-3312 (1991)].

Obtaining the compounds of formula (A) (2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]-methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile) described in example 6 of the international application WO 03/053441.

Getting proposed in the invention compounds represented by the following diagrams (abbreviations see below).

Proposed in the invention compounds and their salts are optimal prodrugs of the compounds of formula (A) as active substance. They have a high stability, for example, at different values of pH and at the same time undergo efficient conversion into the compound of the formula (A) at physiological pH and especially in vivo. In addition, we offer in the invention compounds have high solubility in water or other is physiologically compatible environments what determines their suitability for therapeutic, especially intravenous administration. In addition, if oral use, there povyshenna bioavailability compared to the reference compound of formula (A).

The compounds of formula (I), alone or in combination with one or more other active substances that are suitable for the prophylaxis and/or treatment of various diseases, especially, for example, diseases of the cardiovascular system, for cardiotoxic after heart disease, and metabolic diseases.

In accordance with the present invention under the diseases of the cardiovascular system implies, for example, hypertension (high blood pressure), peripheral and cardiac vascular diseases, ischemic heart disease, coronary restenosis, for example restenosis after balloon dilation of peripheral blood vessels, myocardial infarction, acute coronary syndrome, acute coronary syndrome with ST-segment elevation acute coronary syndrome without ST-segment elevation, stable and unstable angina, cardiac weakness, angina Prinzmetala, persistent ischemic dysfunction ("hibernating myocardium"), a transient postischemic dysfunction ("stunned myocardium"), heart failure, tachycardia, atrial tachycardia, arrhythmia,atrial fibrillation, ventricular fibrillation, persistent atrial fibrillation, persistent atrial fibrillation, atrial fibrillation with normal left ventricular function, atrial fibrillation with restriction of left ventricular function, symptoms of premature ventricular stimulation, peripheral circulatory disorders, increased levels of fibrinogen and low-density lipoprotein, as well as the increased concentration of inhibitor 1, plasminogen activator (R-1), primarily hypertension, ischemic heart disease, acute coronary syndrome, angina, heart failure, myocardial infarction and atrial fibrillation.

In accordance with the present invention, the term "heart failure" is used to refer to both acute and chronic forms of heart failure, as well as specific or similar paintings of this disease, such as acute decompensated heart failure, failure of the right ventricle, the failure of the left ventricle, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart disease, valvular disease, heart failure in valvular disease, narrowing of the mitral valve, mitral valve insufficiency, stenosis of the aortic valve, failure of the valve and the mouths the narrowing of the tricuspid valve insufficiency tricuspid valve stenosis pulmonary valve stenosis, the valve insufficiency pulmonary artery, combined valvular disease of the heart, inflammation of the heart muscle (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, cardiomyopathy, caused by alcoholism, heart tourismos, and diastolic and systolic heart failure.

In addition, the proposed in the invention compounds can be used primarily for the recovery of affected due to infarct region of the myocardium, and also to prevent repeat heart attacks.

In addition, the proposed in the invention compounds are especially suitable for the prevention and/or treatment of thromboembolic diseases, reperfusion lesions after ischemia, microvascular and macrovascular lesions (vasculitis), arterial and venous thrombosis, edema, ischemia such as myocardial infarction, cerebral haemorrhage and transient ischemic attacks, to protect the heart during coronary artery bypass surgery, primary percutaneous transluminal coronary angioplasty, percutaneous transluminal coronary angioplasty after thrombolyse, emergency percutaneous transluminal coronary angioplasty heart transplant and open-heart surgery, and to protect organs during transplantation and grafting, when the surveys with the use of a catheter and other operating procedures.

Other indications for a possible application of the proposed invention compounds include, for example, for the prophylaxis and/or treatment of urological diseases, such as acute renal failure, hyperesthesia bladder, urinary incontinence, erectile dysfunction and female sexual dysfunction, as well as to the prevention and/or treatment of inflammatory diseases such as inflammatory dermatitis and arthritis, especially rheumatoid arthritis, diseases of the Central nervous system and neurodegenerative disorders (status after stroke, Alzheimer's disease, Parkinson's disease, dementia, horii's disease, epilepsy, depression, multiple sclerosis), pain syndromes and migraine headaches, liver fibrosis, cancer, nausea and vomiting in cancer treatment and healing of wounds.

Other indications for a possible application of the proposed invention compounds include, for example, for the prophylaxis and/or treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic Fi the roses (fibrosis) and pulmonary hypertension, first and foremost pulmonary hypertension.

Proposed in the invention compounds can also be used for the prevention and/or treatment of metabolic diseases such as diabetes, especially diabetes mellitus, gestational diabetes, insulin-dependent diabetes and non-insulin-dependent diabetes, diabetic complications such as retinopathy, nephropathy and neuropathy, metabolic diseases such as metabolic syndrome, hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance and obesity (disease Percuma), as well as atherosclerosis and dyslipidemia (hypercholesterolemia, hypertriglyceridemia, elevated concentrations of postprandial triglycerides in plasma, hypoalphalipoproteinemia, combined hyperlipidemia), first just for the prophylaxis and/or treatment of diabetes, metabolic syndrome and dyslipidemia.

Another object of the present invention is the application of the proposed invention compounds for the treatment and/or prophylaxis of diseases, especially of the aforementioned diseases.

Another object of the present invention is the application of the proposed invention compounds for the manufacture of a medicinal product intended for the treatment and/or prevention of diseases, primarily indicated the s above diseases.

Another object of the present invention is a method of treatment and/or prophylaxis of diseases, especially of the aforementioned diseases, involving the application of an effective amount of at least one of the proposed invention compounds.

Proposed in the invention compounds can be used individually or, if necessary, in combination with other active substances. Another object of the present invention is a medicinal product intended for the treatment and/or prophylaxis of the aforementioned diseases, which contain at least one proposed in the invention compounds and one or more other active ingredients.

Preferred additional active substances are, for example, active substances that alter lipid metabolism, anti-diabetic agents; agents used to reduce blood pressure, an agent stimulating blood flow, and/or antithrombotic agents, antiarrhythmic agent, antioxidants, receptor antagonists of chemokine inhibitors R-kinase, agonists of neuropeptidergic, agonists orexin, tools, suppress the appetite, inhibitors acetylhydrolase of platelet activating factor, anti-inflammatory drugs (Cox inhibitors, antagonists Retz is ptor leukotriene B4), as well as analgesic agents, such as aspirin.

The object of the present invention are primarily a combination of at least one of the proposed invention in connection with at least one altering fat metabolism active ingredient, an anti-diabetic agent, active ingredient to reduce blood pressure, anti-arrhythmic agent and/or antithrombotic agent.

Proposed in the invention compounds preferably can be combined with one or more of the following active substances:

- altering fat metabolism active substances, for example, preferably selected from the group comprising inhibitors of HMG-CoA-reductase inhibitors of the expression of HMG-CoA-reductase inhibitors of the synthesis of squalene, ACAT inhibitors, inducers of receptor low density lipoprotein inhibitors absorption of cholesterol, polymeric bile acid absorbers, inhibitors of bile acid reabsorption, MTP inhibitors, lipase inhibitors, activators lipoprotein lipase, fibrates, nicotinic acid, inhibitors SER, α-agonists, PPAR γ agonists of PPAR, and/or δ-agonists of PPAR, RXR modulators, FXR modulators, modulators LXR, thyroid hormones and/or thyroid simulators, inhibitors of ATP-citrate lyase, antagonists of Lp(a), 1-receptor antagonists cannabinoid, agonists recipe is RA leptin, agonists of receptor bombezin, agonists of the histamine receptor and antioxidants/acceptors radicals;

- antidiabetic agents that are listed in the Roten Liste 2004/11, Chapter 12, and also, for example, preferably selected from the group comprising sulfanilamide, biguanides, derived meglitinides, glucosidase inhibitors, inhibitors of dipeptidyl-peptidases IV (DPP-IV-inhibitors), oxadiazolidine preparations, thiazolidinediones, agonists of the GLP-1 receptor, glucagon antagonists, insulin sensitizers, CCK agonists 1-receptor agonists, leptin receptor, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, as well as the means to open potassium channel, for example, described in international applications WO 97/26265 and WO 99/03861;

- blood pressure-lowering active ingredients, for example, preferably selected from the group including calcium antagonists, antagonists of angiotensin AII, ACE inhibitors, renin inhibitors, antagonists beta-adrenoceptor antagonists alpha adrenoceptor, diuretics, aldosterone antagonists, antagonists of the receptor mineralocorticoid hormone, ECE inhibitors, and inhibitors of vasopeptidase;

- means having anticoagulant effect, for example, preferably selected from the group comprising inhibitors of AGR the delegation of the platelet and antithrombotic agents;

- antiarrhythmic agent, primarily intended for the treatment of supraventricular arrhythmias and tachycardia;

- substances for the prevention and treatment of ischemic and reperfusion disorders;

- receptor antagonists vasopressin;

organic nitrates and NO donors;

connection with the positive inotropic effect;

- compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (camp), such as inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and/or 5, especially PDE inhibitors 5, such as sildenafil, vardenafil and tadalafil, and PDE inhibitors 3, such as milrinone;

- natriuretic peptides such as atrial natriuretic peptides (ANP, anaritide), natriuretic peptides B-type or brain natriuretic peptides (BNP, nesiritide), natriuretic peptide C-type (CNP), as well as urodilatin;

the agonist of the prostacyclin receptor (IP receptor), such as iloprost, beraprost and cicaprost;

calcium sensitizers, for example, preferably such as " levosimendan";

potassium biologically active additives;

- NO - and gamesanime activators of guanylate cyclase, primarily compounds described in international applications W0 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

- O-independent, however wasawesome stimulators of guanylate cyclase, primarily compounds described in international applications WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

inhibitors of human neurotrophines elastase (HNE), such as sivelestat and DX-890 (deltran);

- compounds that inhibit the cascade of signal transduction such as inhibitors of tyrosine kinase, primarily sorafenib, imatinib, gefitinib and erlotinib;

connections that have an impact on the energy metabolism of the heart, such as etomoxir, dichloroacetate, ranolazine and Trimetazidine;

- analgesic funds; and/or

- substances for the prevention and treatment of nausea and vomiting.

Under modify fat metabolism active ingredients preferably include compounds selected from the group comprising inhibitors of HMG-CoA-reductase inhibitors of the synthesis of squalene, ACAT inhibitors, inhibitors of the absorption of cholesterol, MTP inhibitors, lipase inhibitors, thyroid hormones and/or thyroid simulators, agonists of the Niacin receptor, inhibitors SER, α-agonists, PPAR γ agonists of PPAR, and/or δ-PPAR agonists, polymeric bile acid absorbers, inhibitors of bile acid reabsorption antagonists Lp(a), 1-receptor antagonists cannabinoid, antioxidants/acceptors radicals, and 1-receptor antagonists cannabinoid.

In p edocfile embodiment of the invention proposed in the invention compounds are used in combination with an inhibitor of HMG-CoA reductase inhibitor from the class of statins, for example, preferably by lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, tseriwastatina or pitavastatin.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an inhibitor of the synthesis of squalene, for example, preferably such as BMS-188494 or SO-475.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an ACAT inhibitor, such as, preferably such as avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an inhibitor of the absorption of cholesterol, for example, preferably such as ezetimibe, tiqueside or plaquenil.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an MTP inhibitor, for example, preferably such as implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a lipase inhibitor, for example, preferably such as orlistat.

In a preferred embodiment of the invention proposed in ISO is reenie compounds used in combination with thyroid hormone and/or thyroid imitators, for example, preferably such as D-thyroxine or 3,5,3'-triiodothyronine (TK).

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an agonist of the receptor of Niacin, for example, preferably such as nicotinic acid, acipimox, acifran or radical.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an inhibitor SETR, for example, preferably such as torcetrapib, JTT-705, BAY 60-5521, BAY 78-7499 or vaccine SETR (avant).

In a preferred embodiment of the invention proposed in the invention compounds used in combination with γ-agonist PPAR, for example, preferably such as pioglitazone or rosiglitazone.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with δ-agonist PPAR, for example, preferably such as GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with a polymer absorber bile acids, for example, preferably such as cholestyramine, colestipol, kresolver, cholestagel or colestimide.

In a preferred embodiment of the invention proposed in the image is the situation compounds used in combination with an inhibitor of bile acid reabsorption, for example, preferably such as the ASBT inhibitor (respectively IBAT), for example, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with the antioxidant/acceptor radicals, for example, preferably such as probucol, AGI-1067, 653 or AEOL-10150.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with 1-receptor antagonist cannabinoid, for example, preferably such as rimonabant or SR-147778.

Under antidiabetic agents preferably involve insulin and derivatives of insulin used and also oral hypoglycemic active ingredients. Under the insulin derivatives of the mean insulin insulin animal, human or biotechnological origin, and their mixtures. Under the orally applied hypoglycemic active ingredients preferably involve sulfanilamide, biguanides, derived meglitinides, glucosidase inhibitors, inhibitors of DPP-IV and γ agonists of PPAR.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with insulin.

In a preferred embodiment of the invention offers is proposed in the invention compounds are used in combination with sulfanilamides, for example, preferably such as tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with biguanides, for example, preferably such as Metformin.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with derivative meglitinide, for example, preferably such as Repaglinide or nateglinide.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a glucosidase inhibitor, for example, preferably such as miglitol or acarbose.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with an inhibitor of DPP-IV, for example, preferably such as sitagliptin or vildagliptin.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with a PPAR agonist, for example, from the class of preparations of thiazolidinediones, such as, preferably such as pioglitazone or rosiglitazone.

Under reducing blood pressure means preferably include compounds selected from the group including calcium antagonists, and tagonist of angiotensin AII, the ACE inhibitors, renin inhibitors, antagonists beta-adrenoceptor antagonists alpha adrenoceptor and diuretics.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a calcium antagonist, for example, preferably such as nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an antagonist of angiotensin AII, for example, preferably such as losartan, valsartan, candesartan, ambulanten, olmesartan or telmisartan.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an ACE inhibitor, for example, preferably such as enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril, perindopril or trancopal.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a renin inhibitor, for example, preferably such as aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an antagonist of beta-adrenoceptor, for example, preferably such as propranolol, at olol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, daprela, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an antagonist of alpha-adrenoceptor, for example, preferably such as prazosin.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a diuretic, for example, preferably such as furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerin, isosorbide, mannitol, amiloride or triamterene.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a receptor antagonist of aldosterone or mineralocorticoid, for example, preferably such as spironolactone or eplerenone.

In a preferred embodiment of the invention proposed in the invention compounds used in comb the nation with an antagonist of the vasopressin receptor, for example, preferably such as conivaptan, tolvaptan, lixivaptan or SR-121463.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with donor organic nitrate or NO, for example, preferably such as sodium nitroprusside, nitroglycerin, isosorbidemononitrate, isosorbidedinitrate, molsidomine or SIN-1, or in combination with inhaled NO.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a compound which has a positive inotropic action, for example, preferably such as cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists, in particular isoproterenol, adrenaline, noradrenaline, dopamine or dobutamine.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with antisimmetricheskikh means, such as reserpine, clonidine or alpha methyldiethanolamine or in combination with potassium channel agonists, such as Minoxidil, diazoxide, dihydralazine or hydralazine.

Under tools, which have anti-clotting effect, preferably mean compounds selected from the group including inhibitors aggregated what I platelet and antithrombotic agents.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an inhibitor of the aggregation of platelets, for example, preferably such as aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with a thrombin inhibitor, for example, preferably such as ximelagatran, melagatran, bivalirudin or therapy.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an antagonist of GPIIb/IIIa, for example, preferably such as tirofiban or abciximab.

In a preferred embodiment of the invention proposed in the invention compounds used in combination with an inhibitor of factor XA, for example, preferably such as rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fedexcan, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention proposed in the invention compounds are used in combination with heparin or low-molecular weight derivative of heparin.

In a preferred embodiment of the invention proposed in ISO is reenie compounds used in combination with vitamin K antagonists, for example, preferably such as coumarin.

Under reducing arrhythmia means preferably include substances of class Ia antiarrhythmics (eg, quinidine), class Ic antiarrhythmics (eg, flecainide, propafenone); class II antiarrhythmics (e.g., metoprolol, atenolol, sotalol, oxprenolol and other inhibitors of beta-receptors), class III antiarrhythmic drugs (e.g. sotalol, amiodarone) and class IV antiarrhythmic drugs (e.g. digoxin, and verapamil, diltiazem and other calcium antagonists).

In accordance with the present invention particularly preferred are combinations containing at least one proposed in the invention compounds and one or more other active compounds, selected from the group comprising inhibitors of HMG-CoA reductase inhibitor (statin), diuretics, antagonists beta-adrenoceptor antagonists alpha adrenoceptor, donors, organic nitrates and NO, calcium antagonists, ACE inhibitors, antagonists of angiotensin AII antagonists of the receptor for aldosterone and mineralocorticoid, receptor antagonists vasopressin, platelet aggregation inhibitors, anti-coagulants agents and antiarrhythmic agent, as well as their use for the treatment and/or prevention of the above diseases.

Other about who the subject of the present invention are drugs, containing at least one proposed in the invention, the connection usually together with one or more inert, nontoxic, pharmaceutically suitable excipients and their use for the above purposes.

Proposed in the invention compounds can have systemic and/or local action. In line with this, they can be used, for example, orally, parenterally, pulmonale, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, through the ear canal or in the form of the implant, respectively, of the stent. Proposed in the invention compounds can be used in forms that match the specified options of the application.

For oral administration suitable operating in accordance with the prior art form of application that can quickly and/or modificirovana to release proposed in the invention compounds and containing proposed in the invention compounds in the crystal, amalfitano and/or dissolved, such as tablets (tablets are uncoated or provided with, for example, are resistant to gastric juice or slowly soluble or insoluble coating for controlled release proposed in the invention compounds), tablets or films/whether felisati, quickly disintegrating in the oral cavity, films/wafers, capsules (for example, provided with a shell of hard or soft gelatin), pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral application is possible in the absence of resorption (e.g., intravenous, intraarterial, intracardiac, vnutripolostnoe or vnutribolnychnoy application) or resorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal application). Suitable for parenteral administration forms, in particular, are drugs for injection and infusion in the form of solutions, suspensions, emulsions, liofilizatow or sterile powders.

For other uses suitable, for example, inhalation dosage forms (including powder inhalers, aerosol sprays), naselenie drops, solutions or sprays, tablets for lingual, sublingual or buccal use, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, potions like "mash"), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), drugs in the form of milk, as well as pastes, foams, powders, implants or stents.

Preferred is oraln the e or parenteral application, first of all oral administration.

Proposed in the invention compounds can be converted in the above applications. The corresponding transformation can be performed by the known methods of mixing proposed in the invention compounds with inert, non-toxic, pharmaceutically suitable excipients. Suitable excipients are, in particular, include substances-carriers (for example microcrystalline cellulose, lactose or mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulphate or polychiorinated), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (in particular antioxidants, such as ascorbic acid), colorants (in particular inorganic pigments such as iron oxides), as well as the substances intended for the adjustment of taste and/or smell.

In General, the amount proposed in the invention of the compounds necessary to achieve the desired effect, when parenteral administration is preferably in the approximate range of 0.001 to 1 mg, mostly from 0.01 to 0.5 mg per kilogram of body weight. For oral use according to the proper dosage is about 0.01 to 100 mg/kg, preferably from 0.01 to 20 mg/kg and even more preferably from 0.1 to 10 mg/kg of body weight.

Despite this, if necessary, may need to be adjusted to the above dosages, which is determined by body weight, use of medication, individual attitude to the current matter, the type of drug and the time of its application (periodicity). For example, in some cases, may be sufficient doses lower than the above minimum limit values, whereas in other cases may require a dosage in excess of the above maximum values. In the latter case, it is recommended to distribute the dosage for a few applied within days of the doses.

The following examples serve to illustrate the present invention. The examples do not limit the scope of the invention.

In the absence of specific instructions, the percentage data in the following experiments and examples are given in weight percents, part of the mass parts. The quantitative relationships between the components of solvents, dilution and concentration of liquid components in the fluids specified in the corresponding volumetric units.

A. Examples

Abbreviations and acronyms

Boctert-butoxycarbonyl
DIEAN,N-diisopropylethylamine
DMAP4-N,N-dimethylaminopyridine
DMF (DMF)N,N-dimethylformamide
DMSOthe sulfoxide
d. Th.the output from theoretical
EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
ESIelectrospray ionization (mass spectrometry)
hwatch
HOBt1-hydroxybenzotriazole
HPLChigh-performance liquid chromatography (chromatography under high pressure)
LC-MScombined liquid chromatography-mass spectrometry
minminutes
MSmass spectrometry
NMR nuclear magnetic resonance
Ppair
Pd/Cpalladium on charcoal
Phphenyl
quant.quantitative (output)
RTroom temperature
Rtthe retention time (in HPLC)
terttertiary
TFAtriperoxonane acid
THFtetrahydrofuran
UVultravioleta spectrometry
v/vthe volumetric ratio of the components (in solution)
Zbenzyloxycarbonyl

Methods LC-MS and HPLC

Method 1 (LC-MS). The type of mass spectrometer: Micromass ZQ; instrument type for HPLC: Waters Alliance 2795; column Phenomenex Synergi, 2 μm Hydro-RP Mercury 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% And is a 2.5 min 30% A→a 3.0 min 5% A→4.5 min 5% A; consumption: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven temperature 50°C; UV detection of 210 nm.

Method 2 (LC-MS). Instrument: Micromass Quattro LCZ with HPLC Agilent Serie 1100; column: Phenomenex Synergi, 2 μm Hydro-RP Mercury 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% And 2.5 min 30% A→a 3.0 min 5% A→4.5 min 5% A; flow rate: 0,0 min 1 ml/min to 2.5 min/min 3,0/4,5 min 2 ml/min; oven temperature 50°C; UV detection 208-400 nm.

Method 3 (LC-MS). The type of mass spectrometer: Micromass ZQ; instrument type for HPLC: HP 1100 Series; UV DAD detector; column Phenomenex Synergi, 2 μm Hydro-RP Mercury 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A→a 2.5 min 30% A→a 3.0 min 5% A→4.5 min 5% A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min /4.5 min 2 ml/min; oven temperature 50°C; UV detection of 210 nm.

Method 4 (LC-MS). The type of mass spectrometer: Micromass ZQ; instrument type for HPLC: HP 1100 Series; UV DAD detector; column Phenomenex Gemini, 3 μm, 30 mm × 3.00 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A→a 2.5 min 30% A→a 3.0 min 5% A→4.5 min 5% A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min /4.5 min 2 ml/min; oven temperature 50°C; UV detection of 210 nm.

Method 5 (preparative HPLC). The device type for VE is X: pump Abimed/Gilson 305/306; gauge node 806; UV-site: Knauer Variable Wavelength Monitor; column: Gromsil C18, 10 nm, 250 mm × 30 mm; eluent A: 1 l water + 0.5 ml of 99% triperoxonane acid, eluent B: 1 l acetonitrile; gradient: 0,0 min 2% B→10 min 2% B→50 min 90% B; flow rate 20 ml/min; volume: 628 ml and 372 ml Century.

Method 6A (preparative HPLC). Column VP 250/21 Nukleodur 100-5 C18 ec, Macherey &Nagel Nr. 762002; eluent A: water/0.01% of triperoxonane acid, eluent b: acetonitrile/0.01% of triperoxonane acid; gradient: 0 min 0% B→20 min 20% B→40 min 20% B→60 min 30% B→80 min 30% B→90 min 100% B→132 min 100% B; flow rate 5 ml/min; room temperature; UV detection of 210 nm.

Method 6b (preparative HPLC). Column VP 250/21 Nukleodur 100-5 C18 EC, Macherey &Nagel Nr. 762002; eluent A: 1 l water/1 ml 99% triperoxonane acid, eluent B: 1 l of acetonitrile/1 ml 99% triperoxonane acid; gradient: 0 min 30% B→20 min 50%→40 min 80% B→60 min 100% B; flow rate 5 ml/min; room temperature; UV detection of 210 nm.

Method 7 (analytical HPLC). Column XTerra WAT 186000478, 3.9 mm × 150 mm; eluent A: 10 ml of 70% perchloro acid in 2.5 l of water, eluent b: acetonitrile; gradient: 0,0 min 20% B→1 min 20% B→4 min 90% B→9 min 90% B; room temperature; flow rate 1 ml/min

Method 8 (LC-MS). Mass spectrometer Micromass Quattro LCZ with HPLC Agilent series 1100; column Phenomenex Onyx Monolithic C18, 100 mm × 3 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l acetonic the La + 0.5 ml 50% formic acid; the gradient of 0.0 min 90% A→2 min 65% A→4.5 min 5% A→6 min 5% A; flow rate: 2 ml/min; oven temperature 40°C.; UV detection 208-400 nm.

Method 9 (LC-MS). Instrument: Micromass Platform LCZ with HPLC Agilent Serie 1100; column Thermo Hypersil GOLD, 3 μm, 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 100% A→0.2 to min 100% A→a 2.9 min 30% A→a 3.1 min 10% A→a 5.5 min 10% A; oven temperature 50°C; flow rate: 0.8 ml/min; UV detection of 210 nm.

Method 10 (LC-MS). The type of mass spectrometer: Micromass ZQ; instrument type HPLC: HP 1100 series; UV DAD detector; column Phenomenex Gemini, 3 μm, 30 mm × 3.00 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A→a 2.5 min 30% A→a 3.0 min 5% A→4.5 min 5% A; flow rate of 0.0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven temperature 50°C; UV detection of 210 nm.

Method 11 (LC-MS). The type of mass spectrometer: Micromass ZQ; instrument type HPLC: Waters Alliance 2795; column Phenomenex Synergi, 2.5 μm MAX-RP 100A Mercury 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A→a 0.1 min 90% A→a 3.0 min 5% A→4,0 min 5% A→4,01 min 90% A; flow rate 2 ml/min; oven temperature 50°C; UV detection of 210 nm.

Method 12 (LC-MS). Instrument: Micromass Quattro LCZ with HPLC Agilent Serie 1100; column: Phenomenex Synergi, 2.5 μm MAX-RP 100A Mercury 20 m is × 4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A→a 0.1 min 90% A→a 3.0 min 5% A→4,0 min 5% A→4,1 min 90% A; oven temperature 50°C; UV detection 208-400 nm.

Method 13 (LC-MS). The type of mass spectrometer: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD, 1,9 μm, 50 mm × 1 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A→a 0.1 min 90% A→1.5 min 10% A→a 2.2 min 10% A; oven temperature 50°C; flow rate of 0.33 ml/min; UV detection of 210 nm.

The initial compounds and intermediate products

Example 1A

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-valinnat triptorelin

1 g (1.92 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile [according to example 6 of the international application WO 03/053441], 0,460 g (2,11 mmol) N-Boc-L-valine, 0,442 g (2,31 mmol) 1-(3-dimethylaminopropyl)-3-Amilcar-bodiimide hydrochloride, and is 0.023 g (0,19 mmol) of 4-dimethylaminopyridine combine in a mixture of 40 ml of dichloromethane with 10 ml DMF and during the night stirred at room temperature. Formed a clear solution. The products of the reaction is poured into a mixture Polynesians solution of ammonium chloride with d is chlormethine. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified flash chromatography on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (gradient 10:1→7:1→5:1). The appropriate fractions are combined, the solvent is removed by distillation in vacuum. In the drying of the residue in high vacuum gain of 0.85 g of the BOC-protected intermediate product (output from theoretical 62%).

The residue is introduced into a mixture of 5 ml dichloromethane and 5 ml of anhydrous triperoxonane acid, and the obtained solution is stirred for two hours at room temperature. It is then concentrated to a dry residue that was mixed with ethyl acetate. The resulting precipitates are filtered, washed with diethyl ether and dried in high vacuum. Receive 935 mg of the target compound as colorless crystals (quantitative yield).

HPLC (method 7): Rt=5,5 minutes

LC-MS (method 10): Rt=to 2.06 min; MS (ESIpos): m/z=619 (M+N)+.

Example 2A

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-alaninate triptorelin

1.5 g (2,88 mmol) 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-thio)-4-[4-2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 1.64 g (8,66 mmol) N-Boc-L-alanine, 0,719 g (3.75 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0,176 g (1.44 mmol) of 4-dimethylaminopyridine combine in a mixture of 25 ml of dichloromethane containing 25 ml of DMF and stirred for two hours at room temperature. The reaction products was concentrated in vacuo, the residue is introduced into the ethyl acetate. The mixture is extracted twice with 5% citric acid and twice with a solution of sodium bicarbonate. The organic phase is concentrated, the residue is mixed with 50 ml of diethyl ether and 50 ml of pentane. The rest sucked off on a vacuum filter and washed with pentane. In the drying of the residue in high vacuum gain of 1.23 g of the BOC-protected intermediate product (output from theoretical 62%).

The residue is introduced into a mixture of 18 ml of dichloromethane and 2 ml of anhydrous triperoxonane acid, and the solution for one hour process at room temperature in an ultrasonic bath. It is then concentrated, and the residue is mixed with diethyl ether. The resulting precipitates are filtered, washed with diethyl ether and dried in high vacuum. Get 1200 mg of target compound as colorless crystals (yield from theoretical 96%).

HPLC (method 7): Rt=5,3 minutes

LC-MS (method 12): Rt=1,73 min; MS (ESIpos): m/z=591 (M+N)+.

Example 3A

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio-3,5-dicyanodiamide-4-yl]phenoxy}ethyl-O-tert-butyl-L-serinate

1 g (1.92 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 0,612 g (2,12 mmol) of N-(tert-butoxycarbonyl)-0-tert-butyl-L-serine, 0,442 g (2,31 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, as well as 0,024 g (0,192 mmol) of 4-dimethylaminopyridine combine in a mixture of 40 ml of dichloromethane with 10 ml DMF and during the night stirred at room temperature. Then the reaction products are poured into the mixture Polynesians solution of ammonium chloride with dichloromethane. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is introduced into dichloromethane and mixed with diethyl ether. The formed precipitate is sucked off on a vacuum filter and washed with diethyl ether. In the sludge drying in high vacuum earn 1.25 g of the protected intermediate product (output from theoretical 85%).

The residue is introduced into a mixture of 100 ml of dichloromethane, 10 ml of anhydrous triperoxonane acid, and the solution within the hour, stirred at room temperature. Then the reaction products are poured into the mixture Polynesians solution of sodium bicarbonate with dichloromethane. The organic phase is separated, dried over sulfa what Ohm magnesium, filter and concentrate. In the drying of the residue under high vacuum, get 1020 mg of the target compound as colorless powder (yield from theoretical 95%).

HPLC (method 7): Rt=5,4 minutes

LC-MS (method 11): Rt=of 1.65 min; MS (ESIpos): m/z=663 (M+N)+.

Example 4A

N2-(tert-butoxycarbonyl)-N-{2-[(tert-butoxycarbonyl)amino]ethyl}-L-α-glutamine

1.5 g (of 4.45 mmol) of (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid, 783 mg (4,89 mmol) of tert-butyl(2-amino-ethyl)-carbamate, 938 mg (4,89 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 749 mg (0,489 mmol) 1-hydroxy-1H-benzotriazole hydrate combine in 140 ml of DMF and during the night stirred at room temperature. Then the reaction products are poured into the mixture Polynesians solution of ammonium chloride with ethyl acetate. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is mixed with diethyl ether. The formed precipitate is sucked off on a vacuum filter, washed with diethyl ether and dried in high vacuum. Get 1.9 grams protected intermediate product (output from theoretical 89%).

LC-MS (method 12): Rt=2,19 min;

MS (ESIpos): m/z=480 (M+is) +.

1.9 grams (3,96 mmol) obtained intermediate product is dissolved in 125 ml of methanol and after adding 250 mg of 10% palladium on charcoal for two hours hydronaut at room temperature and normal pressure. Then the catalyst is separated by filtration, and the solvent is removed by distillation in vacuum. Receive 1500 mg of target compound as a colourless foam (yield from theoretical 97%).

LC-MS (method 10): Rt=1,94 min; MS (ESIpos): m/z=390 (M+N)+.

Example 5A

N2-(tert-butoxycarbonyl)-N-{2-[(tert-butoxycarbonyl)amino]ethyl}-L-glutamine

1.5 g (of 4.45 mmol) of (4S)-5-(benzyloxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid, 783 mg (4,89 mmol) of tert-butyl(2-amino-ethyl)-carbamate, 938 mg (4,89 mmol) 1-(3-dimethylaminopropyl)-3-tilcara-diimide hydrochloride, and 749 mg (4,89 mmol) 1-hydroxy-1H-benzotriazole hydrate combine in 140 ml of DMF and during the night stirred at room temperature. Then the reaction products are poured into the mixture Polynesians solution of ammonium chloride with ethyl acetate. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is mixed with diethyl ether. The resulting precipitate is daywalt on a vacuum filter, washed with diethyl ether and dried in high vacuum. Obtain 2.1 g of the protected intermediate product (output from theoretical 98%).

LC-MS (method 10): Rt=2,47 min; MS (ESIpos): m/z=480 (M+N)+.

2.1 g (of 4.38 mmol) obtained intermediate product is dissolved in 140 ml of methanol and after adding 250 mg of 10% palladium on charcoal for two hours hydronaut at room temperature and normal pressure. Then the catalyst is separated by filtration, and the solvent is removed by distillation in vacuum. Receive 1540 mg of target compound as a colourless foam (yield from theoretical 90%).

LC-MS (method 11): Rt=to 1.35 min; MS (ESIpos): m/z=390 (M+N)+.

Example 6A

N2-(tert-butoxycarbonyl)-N-{2-[(tert-butoxycarbonyl)amino]ethyl}-L-asparagine

1.5 g (with 4.64 mmol) of (3S)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-4-oxomalonate acid, 818 mg (5.1 mmol) of tert-butyl(2-amino-ethyl)-carbamate, 978 mg (5.1 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 781 mg (5.1 mmol) of 1-hydroxy-1H-benzotriazole hydrate combined in 75 ml DMF and during the night stirred at room temperature. Then the reaction products are poured into the mixture Polynesians solution of ammonium chloride with ethyl acetate. The organic phase is separated, washed sequentially with water, saturated dissolve the ohms of sodium bicarbonate and a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue is mixed with diethyl ether. The formed precipitate is sucked off on a vacuum filter, washed with diethyl ether and dried in high vacuum. Obtain 2.1 g of the protected intermediate product (output from theoretical 81%).

LC-MS (method 10): Rt=2,47 min; MS (ESIpos): m/z=466 (M+N)+.

2.1 g (4,51 mmol) obtained intermediate product is dissolved in 140 ml of methanol and after adding 250 mg of 10% palladium on charcoal for two hours hydronaut at room temperature and normal pressure. Then the catalyst is separated by filtration, and the solvent is removed by distillation in vacuum. Get 1690 mg of target compound as a colourless foam (yield from theoretical 99%).

LC-MS (method 11): Rt=to 1.35 min; MS (ESIpos): m/z=376 (M+N)+.

Example 7A

5-(2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl)-1-tert-butyl-L-glutamate

3,117 g (6 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 2 g (6,59 mmol) of (4S)-5-tert-butoxy-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoate, 1,38 g (7.19 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0,073 g (0.6 mmol) of 4-dimethylaminopyridine combine in a mixture of 80 ml of dichloromethane with 20ml DMF) and during the night stirred at room temperature. Then the reaction products are poured into the mixture Polynesians solution of ammonium chloride with dichloromethane. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The remainder allocate deposition from a mixture of dichloromethane with petroleum ether. The product is sucked off on a vacuum filter, washed with diethyl ether and dried in high vacuum. Get 4.44 g of the protected intermediate product (output from theoretical 92%).

LC-MS (method 10): Rt=3,38 min; MS (ESIpos): m/z=805 (M+N)+.

57 mg (0.07 mmol) of the obtained intermediate product is introduced into a mixture of 6 ml of dichloromethane with 0.6 ml of anhydrous triperoxonane acid, and the solution is stirred for 2.5 hours at room temperature. Then the reaction products are poured into the mixture Polynesians solution of sodium bicarbonate with dichloromethane. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated. The result of drying in high vacuum, receive 50 mg of the target compound as colorless powder (quantitative yield).

HPLC (method 7): Rt=5,4 minutes

LC-MS (method 11): Rt=1,72 min; MS (ESIpos): m/z=705 (M+N)+.

Example 8A

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-and the]phenoxy}ethyl-L-Latinate triptorelin

The target connection receive analogously to example 1A from 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]-pyridine-3,5-dicarbonitrile and Boc-L-leucine.

HPLC (method 7): Rt=5,5 minutes

LC-MS (method 12): Rt=1,75 min; MS (ESIpos): m/z=633 (M+H)+.

Example 9A

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-D-alaninate triptorelin

The target connection receive analogously to example 2A from 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]-pyridine-3,5-dicarbonitrile and Boc-D-alanine.

HPLC (method 7): Rt=5,2 minutes

LC-MS (method 13): Rt=1,15 min; MS (ESIpos): m/z=591 (M+N)+.

Example 10A

N2-(tert-butoxycarbonyl)-N-{2-[(tert-butoxycarbonyl)amino]ethyl}-D-α-glutamine

The target connection receive analogously to example 4A from (2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid.

HPLC (method 7): Rt=4,4 minutes

LC-MS (method 11): Rt=1,37 min; MS (ESIpos): m/z=390 (M+N)+.

Example 11A

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethylglycine triptorelin

The target connection receive analogously to example 2A from 2-amino-6-({[2-(4-shall lorgeril)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]-pyridine-3,5-dicarbonitrile and BOC-glycine.

HPLC (method 7): Rt=5,1 minutes

LC-MS (method 13): Rt=1,13 min; MS (ESIpos): m/z=577 (M+N)+.

Example 12A

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-phenylalanine triptorelin

The target connection receive analogously to example 2A from 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]-pyridine-3,5-dicarbonitrile and Boc-L-phenylalanine.

HPLC (method 7): Rt=5,1 minutes

LC-MS (method 13): Rt=1,13 min; MS (ESIpos): m/z=577 (M+N)+.

Examples of carrying out the invention

Example 1

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-lysyl-L-valinnat the dihydrochloride

1.5 g (1.77 mmol) of the compound from example 1A, a 2.36 g (5,31 mmol) of 2,5-dioxopiperidin-1-yl-N2N6bis(tert-butoxycarbonyl)-L-lysinate and 1.5 ml of N,N-diisopropylethylamine combined in 20 ml of DMF and during the night stirred at room temperature. Then the solvent is removed by distillation in vacuo, and the residue purified flash chromatography on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (gradient 3:1→2:1). The appropriate fractions are combined and the solvent is removed by distillation in vacuum. In the drying of the residue under high vacuum, get 1,2 gashishnogo intermediate product (output from theoretical 66%).

HPLC (method 7): Rt=6,7 minutes

1.2 g (1,27 mmol) obtained intermediate product is introduced into 3 ml of dichloromethane and mixed with 50 ml of saturated solution of podorozhaniya in dichloromethane. Reagents for 30 minutes, stirred at room temperature, and the target product precipitates. The solvent is removed by evaporation, the residue is mixed with 70 ml of diethyl ether. The mixture is filtered, the filter residue washed with diethyl ether and dried in high vacuum. Receive 893 mg of the target compound as colorless crystals (yield from theoretical 86%).

HPLC (method 7): Rt=5,1 minutes

LC-MS (method 12): Rt=1,47 min; MS (ESIpos): m/z=747 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=0,94 and 0.95 (2d, 6N), 1,4 (m, 2H), 1.55V (m, 2H), of 1.75 (m, 2H), and 2.14 (m, 1H), 2,7-2,8 (m, 2H), 3,95 (m, 1H), a 4.3 to 4.5 (m, 2H)and 4.65 (s, 2H), 7,12 (d, 2H), 7,51 (d, 2H), 7,58 (d, 2H), 7,95 (d, 2H), of 7.97 (s, 1H), 8.0 a (m, 2H), 8,3 (m, 2H), and 8.8 (d, 1H).

Example 2

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-β-alanyl-L-valinnat hydrochloride

0.1 g (0.12 mmol) of the compound from example 1A, 0,051 g (0.18 mmol) of 2,5-dioxopiperidin-1-yl-N-(tert-butoxycarbonyl)-β-alaninate and 82 μl of N,N-diisopropylethylamine combined in 6 ml of DMF and during the night stirred at room temperature. Then the solvent is removed by distillation in vacuo, and the residue purified flash what cromatografia on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (gradient 4:1→3:1→2:1). The appropriate fractions are combined and the solvent is removed by distillation in vacuum. In the drying of the residue under high vacuum, get 0,052 g protected intermediate product (output from theoretical 56%).

HPLC (method 7): Rt=6,3 minutes

0.05 g (0,063 mmol) obtained intermediate product is injected in 1 ml dichloromethane and mixed with 15 ml of saturated solution of podorozhaniya in dichloromethane. The reagents are stirred for three hours at room temperature, and the target compound precipitates. The solvent is removed by evaporation, the residue is mixed with 10 ml of diethyl ether. The mixture is filtered, the filter residue washed with diethyl ether and dried in high vacuum. Obtain 41 mg of the target compound as colorless crystals (yield of theoretical, 85%).

HPLC (method 7): Rt=5,2 minutes

LC-MS (method 12): Rt=2,1 min; MS (ESIpos): m/z=690 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=0,89 and 0.9 (2d, 6N), 2,04 (m, 2H), 2,5 (m, 2H), of 2.9-3.0 (m, 2H), 4,2 (m, 1H), 4,25 (m, 2H), 4,35 to 4.5 (m, 2H), 4,67 (s, 2H), 7,12 (d, 2H), and 7.5 (d, 2H), EUR 7.57 (d, 2H), and 7.8 (m, 2H), 7,94 (s, 1H), to 7.95 (d, 2H), and 8.5 (d, 1H).

Example 3

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-1-arginyl-L-valinnat the dihydrochloride

2.24 g (4,72 mmol) of N2 N5bis(tert-butoxycarbonyl)-N5-{[(tert-butoxy-carbonyl)amino](imino)methyl}-L-ornithine, 0.96 g (7,08 mmol) 1-hydroxy-1H-benzotriazole hydrate and 1.09 g (to 5.66 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is combined in 200 ml of DMF. After 30 minutes of stirring, 2 g (2.36 mmol) of the compound from example 1A, and 1.65 ml of N,N-diisopropylethylamine, and components during the night stirred at room temperature. Then the reaction mixture was concentrated, the residue is mixed with water. The mixture is sucked off on a vacuum filter, and the residue purified flash chromatography on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (gradient 4:1→3:1). The appropriate fractions are combined and the solvent is removed by distillation in vacuum. In the drying of the residue in high vacuum to obtain 1.12 g of the protected intermediate product (output from theoretical 44%).

HPLC (method 7): Rt=6,1 minutes

1.12 g (1.04 mmol) of the intermediate product is introduced into 10 ml of dichloromethane, mixed with 10 ml of anhydrous triperoxonane acid and during the night stirred at room temperature. Then the reaction products are concentrated, and the residue is twice washed with THF. The mixture is filtered, the filter residue is introduced into a mixture of 25 ml of THF and 5 ml of methanol. With stirring, add 20 ml of a 2M solution of podorozhaniya at diet the fishing ether. Formed after a short additional stirring the precipitate is sucked off on a vacuum filter and washed with diethyl ether. The result of drying in high vacuum to obtain 920 mg of the target compound as colorless crystals (yield from theoretical 99%).

HPLC (method 7): Rt=5,1 minutes

LC-MS (method 10): Rt=1,7 min; MS (ESIpos): m/z=775 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=of 0.95 and 0.97 (2d, 6N), and 1.6 (m, 2H), of 1.75 (m, 2H), and 2.14 (m, 1H), 3,25 (m, 2H), of 4.05 (m, 1H), 4,25 (t, 1H), 4,3 (m, 2H), 4.4 to 4.5 (2m, 2N)and 4.65 (s, 2H), 7,12 (d, 2H), of 7.48 (d, 2H), 7,58 (d, 2H), 7.95 is (m, 3H), and 8.4 (m, 2H), 8,9 (d, 1H).

Example 4

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-lysyl-L-alaninate the dihydrochloride

1.2 g (1.7 mmol) of the compound from example 2A, 1.13 g (2.55 mmol) of 2,5-dioxopiperidin-1-yl-N2N6bis(tert-butoxycarbonyl)-L-lysinate and 1.5 ml of N,N-diisopropylethylamine combined in 40 ml of DMF and during the night stirred at room temperature. Then the reaction products are concentrated, and the residue distributed between ethyl acetate and water. The organic phase is separated and sequentially extracted twice with 5% citric acid and twice with 5% sodium hydrogen carbonate solution. The organic phase is concentrated, and the residue purified flash chromatography on silica gel, using as ale the NTA mixture of dichloromethane with ethyl acetate (gradient 3:1 → 2:1). The appropriate fractions are combined and the solvent is removed by distillation in vacuum. The residue is mixed with 50 ml of diethyl ether and 50 ml of pentane, and sucked off on a vacuum filter. In the drying of the residue under high vacuum, get to 1.14 g of the protected intermediate product (output from theoretical 73%).

HPLC (method 7): Rt=6,4 minutes

LC-MS (method 11): Rt=2,64 min; MS (ESIpos): m/z=919 (M+N)+.

1,14 g (1,24 mmol) of the intermediate product is introduced into 10 ml dichloromethane and mixed with 60 ml of saturated solution of podorozhaniya in dichloromethane. The reaction products during the night stirred at room temperature, and the target compound precipitates. The solvent is concentrated to one-third of the original volume, and the resulting suspension is mixed with 200 ml of diethyl ether. The mixture is filtered, the filter residue washed with diethyl ether and dried in high vacuum. Obtain 1.0 g of the target compound as colorless crystals (quantitative yield).

HPLC (method 7): Rt=5,0 minutes

LC-MS (method 10): Rt=rate of 1.67 min; MS (ESIpos): m/z=719 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=1,35 (d, 3H), 1,4 (m, 2H), 1,6 (m, 2H), of 1.75 (m, 2H), 2,75 (m, 2H), and 3.8 (m, 1H), 4,25 (m, 2H), a 4.3 to 4.5 (m, 3H), 4,63 (s, 2H), 7,12 (d, 2H), of 7.48 (d, 2H), 7,58 (d, 2H), from 7.9 to 8.0 (m, 5H), 8,3 (m, 2H), 9,05 (d, 1H).

Example 5

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]what enocsi}ethyl-L-lysyl-L-serinate the dihydrochloride

of 0.58 g (1,675 mmol) of N2N6bis(tert-butoxycarbonyl)-L-lysine, 0.28 g (1,83 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0.35 g (1,83 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is combined in 40 ml of DMF and mixed with 1.01 g (of 1.52 mmol) of the compound from example 3A. Reagents during the night stirred at room temperature and poured into a mixture of Polynesians solution of ammonium chloride with dichloromethane. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified flash chromatography on silica gel, using as eluent first mixture with dichloromethane-ethyl acetate (gradient 3:1→2:1), and then a mixture of dichloromethane/ethyl acetate/methanol (150:50:5). The appropriate fractions are combined and concentrated. In the drying of the residue in high vacuum gain of 1.23 g of the protected intermediate product (output from theoretical 81%).

HPLC (method 7): Rt=6,5 minutes

LC-MS (method 12): Rt=2,99 min; MS (ESIpos): m/z=991 (M+N)+.

1,216 g (1.48 mmol) of the intermediate product is introduced into 6 ml of dichloromethane, mixed with 6 ml of anhydrous triperoxonane acid, and reagents during the night stirred at room temperature. Reactio the by-products are concentrated, the residue is again mixed with dichloromethane. The mixture is filtered, and the filter residue is introduced into a mixture of 25 ml of dichloromethane with 25 ml of ethyl acetate. With stirring, add 20 ml of a 2M solution of podorozhaniya in diethyl ether. Formed after a short additional stirring the precipitate is sucked off on a vacuum filter, washed with diethyl ether and dried in high vacuum. The residue is subjected to recrystallization from a mixture of 20 ml of methanol with 20 ml of ethyl acetate. The precipitate is again sucked off on a vacuum filter, washed with ethyl acetate and dried in high vacuum. Receive 845 mg of the target compound as colorless crystals (yield from theoretical 70%).

HPLC (method 7): Rt=4,9 minutes

LC-MS (method 10): Rt=of 1.62 min; MS (ESIpos): m/z=735 (M+N)+.

Example 6

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-N-(2-amino-ethyl)-L-α-glutaminate the dihydrochloride

1 g (1.92 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 0,824 g (2,11 mmol) of the compound from example 4A, 0,442 g (2,31 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, as well as 0,024 g (0,19 mmol) of 4-dimethylaminopyridine combine in a mixture of 40 ml of dichloromethane with 10 ml DMF and during the night stirred at room temperature. Then the reaction product is poured into a mixture of Polynesians solution of ammonium chloride with dichloromethane. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified flash chromatography on silica gel, using as eluent first with a mixture of dichloromethane with ethyl acetate (3:1), and then a mixture of dichloromethane/ethyl acetate/methanol (gradient 300:100:5→300:100:10). The appropriate fractions are combined, the solvent is removed by distillation in vacuum. In the drying of the residue in high vacuum to obtain 1.52 g of the protected intermediate product (output from theoretical 89%).

HPLC (method 7): Rt=6,0 minutes

LC-MS (method 11): Rt=2,54 min; MS (ESIpos): m/z=891 (M+N)+.

1,518 g (1.7 mmol) of the intermediate product is introduced into 5 ml of dichloromethane, mixed with 5 ml of anhydrous triperoxonane acid, and reagents for hours and stirred at room temperature. The reaction products are concentrated, the residue was washed with dichloromethane. Then the residue is dissolved in 20 ml of ethyl acetate. With stirring, add 20 ml of a 2M solution of podorozhaniya in diethyl ether. After a short additional mixing, the mixture is sucked off on a vacuum filter, the filter residue washed with diethyl ether and dried. Get 1,300 mg of target compound (yield from theoretical 99%). The product p will gorhaut recrystallization from a mixture of 25 ml of methanol with 25 ml of ethyl acetate. The precipitate is again sucked off on a vacuum filter, washed with ethyl acetate and dried in high vacuum. Get 1080 mg of target compound (yield from theoretical 83%).

HPLC (method 7): Rt=4,9 minutes

LC-MS (method 10): Rt=to 1.59 min; MS (ESIpos): m/z=691 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=2,05 (m, 2H), 2,45 (m, 2H), to 2.85 and 2.95 (2m, 2H), 3.25 and 3.5 to (2m, 2N), and 3.7 (m, 1H), 4,3 (m, 2H), 4,4 (m, 2H)and 4.65 (s, 2H), 7,12 (d, 2H), of 7.48 (d, 2H), 7,58 (d, 2H), to 7.93 (s, 1H), 7,94 (d, 2H), 8,1 (m, 3H), 8,45 (m, 3H), of 8.95 (t, 1H).

Example 7

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-N-(2-amino-ethyl)-L-glutaminate the dihydrochloride

1 g (1.92 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 0,824 g (2,11 mmol) of the compound from example 5A, 0,442 g (2,31 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, as well as 0,024 g (0,192 mmol) of 4-dimethylaminopyridine combine in a mixture of 40 ml of dichloromethane with 10 ml DMF and during the night stirred at room temperature. The products of the reaction is poured into a mixture Polynesians solution of ammonium chloride with dichloromethane. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue isolated from the dichloromethane OSA is based diethyl ether. The precipitate was separated by filtration, washed with diethyl ether and dried in high vacuum. Obtain 1.5 g of the protected intermediate product (output from theoretical 87%).

HPLC (method 7): Rt=6,0 minutes

LC-MS (method 10): Rt=3,12 min; MS (ESIpos): m/z=891 (M+N)+.

1.5 g (1.7 mmol) of the intermediate product is introduced into 20 ml of dichloromethane, mixed with 5 ml of anhydrous triperoxonane acid, and reagents for hours and stirred at room temperature. The reaction products are concentrated, the residue is washed several times with toluene. Then the residue is introduced into a mixture of 15 ml of dichloromethane, 5 ml of ethyl acetate and 1 ml of methanol. With stirring, add 20 ml of a 2M solution of podorozhaniya in diethyl ether. After a short additional mixing, the mixture is sucked off on a vacuum filter, the filter residue washed twice with diethyl ether and dried. Then the residue is dissolved in 50 ml of diluted hydrochloric acid (pH 3) and lyophilized. Get 1265 mg of target compound (yield from theoretical 98%).

HPLC (method 7): Rt=4,9 minutes

LC-MS (method 11): Rt=1,19 min; MS (ESIpos): m/z=691 (M+N)+.

Example 8

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-N-(2-amino-ethyl)-L-Asparaginate the dihydrochloride

1 g (1.92 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}t is about)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 0,794 g (2,12 mmol) of the compound from example 6A, 0,442 g (2,31 mmol) 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, as well as 0,024 g (0,192 mmol) of 4-dimethylaminopyridine combine in a mixture of 40 ml of dichloromethane with 10 ml DMF and during the night stirred at room temperature. Then the reaction products is then poured into a mixture of Polynesians solution of ammonium chloride with dichloromethane. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is precipitated from dichloromethane diethyl ether. Precipitates are filtered, washed with diethyl ether and dried in high vacuum. Obtain 1.28 g of the protected intermediate product (output from theoretical 74%).

HPLC (method 7): Rt=6,0 minutes

LC-MS (method 10): Rt=3,13 min; MS (ESIpos): m/z=877 (M+N)+.

1.28 g (of 1.46 mmol) of the intermediate product is introduced into 20 ml of dichloromethane, mixed with 5 ml of anhydrous triperoxonane acid, and reagents for hours and stirred at room temperature. The reaction products are concentrated, and the residue is washed several times with toluene. Then the residue is introduced into a mixture of 15 ml of dichloromethane, 5 ml of ethyl acetate and 1 ml of methanol. With stirring, add 5 ml of 2M solution of podorozhaniya in diethyl ether. After KRA is sovremennogo additional mixing, the mixture is sucked off on a vacuum filter, the residue on the filter is washed twice with diethyl ether and dried. Get 1096 mg of target compound (quantitative yield).

HPLC (method 7): Rt=4,9 minutes

LC-MS (method 10): Rt=1,58 min; MS (ESIpos): m/z=677 (M+N)+.

Example 9

(2S)-5-(2-{4-[2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethoxy)-2-[(3-carboxypropanoyl)amino]-5-oxopentanoic acid

0,432 g (2.48 mmol) of 4-tert-butoxy-4-oxomalonate acid value (0.475) g (2.48 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0,380 g (2.48 mmol) of 1-hydroxy-1H-benzotriazole hydrate, as well as of 1.59 g (2,254 mmol) of the compound from example 7A is combined in 70 ml of DMF and during the night stirred at room temperature. The products of the reaction is poured into a mixture Polynesians solution of ammonium chloride with ethyl acetate. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified flash chromatography on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (gradient 10:1→5:1→3:1). The appropriate fractions are combined and the solvent is removed by distillation in vacuum. Then the rest in individual portions again purified using the preparation is effective HPLC (method 6b). The appropriate fractions are combined and the solvent is removed by distillation in vacuum. In the drying of the residue in high vacuum to obtain 1.63 g of the protected intermediate product (output from theoretical 84%).

HPLC (method 7): Rt=6,3 minutes

LC-MS (method 11): Rt=2,71 minutes

MS (ESIpos): m/z=861 (M+N)+.

1,285 g (1,49 mmol) of the intermediate product is introduced into 10 ml of dichloromethane, mixed with 10 ml of anhydrous triperoxonane acid, and reagents for hours and stirred at room temperature. The reaction products are concentrated, the residue is washed several times with toluene. Then the residue is mixed with diethyl ether, the resulting solid is sucked off on a vacuum filter and washed with diethyl ether. In the drying of the residue in high vacuum to obtain 1.06 g of target compound (yield from theoretical 95%).

HPLC (method 7): Rt=5,4 minutes

LC-MS (method 10): Rt=2,23 min; MS (ESIpos): m/z=749 (M+N)+.

Example 10

Disodium salt of (2S)-5-(2-{4-[2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)for 3,5-dicyanodiamide-4-yl]phenoxy}ethoxy)-2-[(3-carboxy-propanol)amino]-5-oxopentanoic acid

0.5 g (0,667 mmol) of the compound from example 9 are dissolved in a mixture of 12.5 ml of acetonitrile with 62.5 ml of water and mixed with 13 ml of 0.1 N sodium hydroxide solution. After a short mixing components lio is result. The result of drying in high vacuum gain of 0.53 g of target compound (quantitative yield).

HPLC (method 7): Rt=5,4 minutes

LC-MS (method 11): Rt=to 2.06 min; MS (ESIpos): m/z=749 (M+N)+.

Example 11

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-lysyl-L-lacint the dihydrochloride

0,928 g (2.68 mmol) of N2N6bis(tert-butoxycarbonyl)-L-lysine, 0,362 g (2.68 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 0,411 g (2,144 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is combined in 200 ml of DMF. Add 1,335 g (1,787 mmol) of the compound from example 8A and 935 μl of N,N-diisopropylethylamine, and components during the night stirred at room temperature. Then the reaction mixture was concentrated in vacuo, the residue is introduced into the ethyl acetate and sequentially extracted with water, 5% citric acid and twice with 5% sodium hydrogen carbonate solution. The organic phase is concentrated, and the residue purified flash chromatography on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (gradient 3:1→2:1). The appropriate fractions are combined, the solvent is removed by distillation in vacuum. In the drying of the residue in high vacuum to obtain 1.39 g of the protected intermediate product (from in theory the CSOs 81%).

HPLC (method 7): Rt=6,8 minutes

1,385 g (1.44 mmol) of the obtained intermediate product is introduced into 20 ml of dichloromethane and mixed with 50 ml of saturated solution of podorozhaniya in dichloromethane. The reaction products within hours and stirred at room temperature, and the target product precipitates. The solvent is removed by evaporation, the residue is mixed with 70 ml of pentane, briefly stirred and sucked off on a vacuum filter. In the drying of the residue under high vacuum, get 1,17 g of target compound (yield from theoretical 97%).

HPLC (method 7): Rt=5,17 minutes

LC-MS (method 10): Rt=1,76 min; MS (ESIpos): m/z=761 (M+N)+.

Example 12

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-lysyl-D-alaninate the dihydrochloride

0,59 g (1,702 mmol) of N2N6bis(tert-butoxycarbonyl)-L-lysine, 0,345 g (2,553 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0,391 g (2,042 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride combine in 24 ml of DMF. 5 minutes after mixing the reagents at room temperature add 1.2 g (1,702 mmol) of the compound from example 9A and 1.5 ml N,N-diisopropylethylamine, and continue stirring over night at room temperature. Then the reaction mixture was concentrated, and the residue is distributed is between 500 ml of ethyl acetate and 500 ml of water. The organic phase is separated and successively extracted three times with 5% citric acid and three times with 10% sodium hydrogen carbonate solution. Then the organic phase is concentrated, and the residue purified flash chromatography on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (gradient 2:1→1:1). The appropriate fractions are combined, the solvent is removed by distillation in vacuum. The residue is mixed with 30 ml of ethyl acetate, and then with 100 ml of diethyl ether. The mixture is sucked off on a vacuum filter, the filter residue washed with diethyl ether. In the drying of the residue under high vacuum, get 0,773 g protected intermediate product (output from theoretical 49%).

HPLC (method 7): Rt=6,1 minutes

0.74 g (0,805 mmol) obtained intermediate product is introduced into 200 ml of dichloromethane. Through the resulting solution under stirring miss gaseous Bogorodchany. At the same time deprived of the protection target compound precipitates. Continue stirring at room temperature, and after an hour of stop the reaction. The products of the reaction was concentrated in vacuo to half the original volume and the precipitate are filtered. The filter residue is washed with diethyl ether and dried in high vacuum at 100°C. Receive 539 mg of the target compound as colorless crystals(yield of theoretical, 85%).

HPLC (method 7): Rt=5,0 minutes

LC-MS (method 13): Rt=1,04 min; MS (ESIpos): m/z=719 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=1,3 (d, 3H), of 1.35 (m, 2H), of 1.52 (m, 2H), of 1.75 (m, 2H), 2,75 (m, 2H), and 3.8 (m, 1H), 4,3 (m, 2H), a 4.3 to 4.5 (m, 3H), 4,63 (s, 2H), 7,12 (d, 2H), of 7.48 (d, 2H), 7,58 (d, 2H), 7,8-8,0 (m, 5H), 8,25 (m, 2H), and 9.0 (d, 1H).

Example 13

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-N-(2-amino-ethyl)-D-α-glutaminate the dihydrochloride

0,522 g (1.0 mmol) 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 0,430 g (1,104 mmol) of the compound from example 10A, 0,231 g (1,204 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and a 0.012 g (0.1 mmol) of 4-dimethylaminopyridine combine in a mixture of 20 ml dichloromethane and 5 ml of DMF and during the night stirred at room temperature. The products of the reaction is poured into a mixture Polynesians solution of ammonium chloride with dichloromethane. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified flash chromatography on silica gel, using as eluent first with a mixture of dichloromethane with ethyl acetate (3:1), and then a mixture of dichloromethane/ethyl acetate/methanol (gradient 300:100:5→300:100:10). �sootvetstvuyushie factions unite, the solvent is removed by distillation in vacuum. In the drying of the residue under high vacuum, get 0,711 g protected intermediate product (output from theoretical 79%).

HPLC (method 7): Rt=6,0 minutes

LC-MS (method 13): Rt=1,54 min; MS (ESIpos): m/z=891 (M+N)+.

0,711 g (0,798 mmol) obtained intermediate product is introduced into 4 ml of dichloromethane, mixed with 4 ml of anhydrous triperoxonane acid, and reagents for hours and stirred at room temperature. The reaction products are concentrated, the residue was washed with dichloromethane. Then the residue is dissolved in 50 ml of ethyl acetate. With stirring, add 20 ml of a 2M solution of podorozhaniya in diethyl ether. After a short additional mixing, the mixture is sucked off on a vacuum filter, the filter residue washed with diethyl ether and dried. Obtain 590 mg of target compound (yield from theoretical 97%).

HPLC (method 7): Rt=4,9 minutes

LC-MS (method 11): Rt=1,22 min; MS (ESIpos): m/z=691 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=2,05 (m, 2H), 2,45 (m, 2H), to 2.85 and 2.95 (2m, 2H), 3.25 and 3.5 to (2m, 2N), and 3.7 (m, 1H), 4,3 (m, 2H), 4,4 (m, 2H)and 4.65 (s, 2H), 7,12 (d, 2H), of 7.48 (d, 2H), 7,58 (d, 2H), to 7.93 (s, 1H), 7,94 (d, 2H), 8,1 (m, 3H), 8,45 (m, 3H), 8,93 (t, 1H).

Example 14

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-arginyl-L-alaninate the dihydrochloride

0,269 g (0,567 mmol) of N5-[N,N'-bis(tert-butoxycarbonyl)carbamimidoyl]-N2-(tert-butoxycarbonyl)-L-ornithine, 0,115 g (0,851 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0,131 g (0,681 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is combined in 20 ml of DMF. After 30-minute stirring, 0.2 g (0,284 mmol) of the compound from example 2A, and 200 μl of N,N-diisopropylethylamine, and components during the night stirred at room temperature. The mixture is then concentrated in vacuo, the residue is introduced into dichloromethane and successively extracted with 5% citric acid, 5% sodium hydrogen carbonate solution and water. The organic phase is concentrated, and the residue purified flash chromatography on silica gel, using as eluent a mixture of dichloromethane with ethyl acetate (3:1). The appropriate fractions are combined, the solvent is removed by distillation in vacuum. In the drying of the residue under high vacuum, get 0,179 g protected intermediate product (output from theoretical 60%).

HPLC (method 7): Rt=5,8 minutes

0,178 g (0,17 mmol) obtained intermediate product is introduced into 30 ml of saturated solution of podorozhaniya in dichloromethane and during the night stirred at room temperature. The products of the reaction was concentrated in vacuo to half the original volume, and obrazovalis the precipitate are filtered. The filter residue is washed with diethyl ether and dried in high vacuum. Obtain 119 mg of the target compound as colorless crystals (yield of theoretical, 82%).

HPLC (method 7): Rt=4,9 minutes

LC-MS (method 10): Rt=1,58 min; MS (ESIpos): m/z=747 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=1,35 (d, 3H), of 1.55 (m, 2H), of 1.75 (m, 2H), 3,25 (m, 2H), 3,85 (m, 1H), 4,25 (m, 2H), a 4.3 to 4.5 (m, 3H)and 4.65 (s, 2H), 7,12 (d, 2H), of 7.48 (d, 2H), 7,58 (d, 2H), of 7.75 (t, 1H), to 7.93 (s, 1H), 7,94 (d 2N), and 8.3 (m, 3H), and 9.1 (d, 1H).

Example 15

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-histidyl-L-alaninate the dihydrochloride

0,145 g (0,567 mmol) of N-(tert-butoxycarbonyl)-L-histidine, 0,115 g (0,851 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0,131 g (0,681 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is combined in 20 ml of DMF. After 30-minute stirring, 0.2 g (0,284 mmol) of the compound from example 2A, and 200 μl of N,N-diisopropylethylamine, and components during the night stirred at room temperature. The mixture is then concentrated in vacuo, the residue is introduced into dichloromethane and successively extracted with 5% citric acid, 5% sodium hydrogen carbonate solution and water. The organic phase is concentrated, and the residue purified flash chromatography on silica gel, using as eluent to shift the ü toluene with ethanol (3:1). The appropriate fractions are combined, the solvent is removed by distillation in vacuum. In the drying of the residue under high vacuum, get 0,206 g protected intermediate product (output from theoretical 88%).

HPLC (method 7): Rt=5,3 minutes

0,206 g (0,249 mmol) obtained intermediate product is introduced into 30 ml of saturated solution of podorozhaniya in dichloromethane and stirred for two hours at room temperature. The products of the reaction was concentrated in vacuo to half the original volume, and the resulting precipitates are filtered. The filter residue is washed with diethyl ether and dried in high vacuum. Obtain 171 mg of the target compound as colorless crystals (yield from theoretical 90%).

HPLC (method 7): Rt=4,8 minutes

LC-MS (method 10): Rt=to 1.59 min; MS (ESIpos): m/z=728 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=1,35 (d, 3H), 3.15 and 3.25 (2dd, 2H), 4,25 (m, 3H), of 4.3 to 4.5 (m, 3H)and 4.65 (s, 2H), 7,12 (d, 2H), and 7.4 (s, 1H), of 7.48 (d, 2H), 7,58 (d, 2H), to 7.93 (s, 1H), 7,94 (d, 2H), 8,5 (m, 3H), 9,05 (s, 1H), 9,2 (d, 1H).

Example 16

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-N-[(2S)-2,4-diaminobutane]-L-alaninate the dihydrochloride

0,181 g (0,567 mmol) (2S)-2,4-bis[(tert-butoxycarbonyl)amino]-butyric acid, 0,115 g (0,851 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0,131 g (0,681 mmol) of N-(3-dim is calaminaris)-N'-ethylcarbodiimide hydrochloride is combined in 20 ml of DMF. After 30 minutes stirring at room temperature, add 0.2 g (0,284 mmol) of the compound from example 2A, and 200 μl of N,N-diisopropylethylamine, and components during the night stirred at room temperature. The mixture is then concentrated in vacuo, the residue is introduced into dichloromethane and successively extracted with 5% citric acid, 5% sodium hydrogen carbonate solution and water. The organic phase is concentrated and the residue purified flash chromatography on silica gel, using as eluent a mixture of toluene with ethanol (10:1). The appropriate fractions are combined, the solvent is removed by distillation in vacuum. In the drying of the residue under high vacuum, get 0,217 g protected intermediate product (output from theoretical 86%).

HPLC (method 7): Rt=6,3 minutes

0,212 g (0,238 mmol) obtained intermediate product is introduced into 25 ml of saturated solution of podorozhaniya in dichloromethane and stirred for 1.5 hours at room temperature. The products of the reaction was concentrated in vacuo to half the original volume, and the resulting precipitates are filtered. The filter residue is washed with diethyl ether and dried in high vacuum. Obtain 171 mg of the target compound as colorless crystals (yield of theoretical, 94%).

HPLC (method 7): Rt=4,8 minutes

LC-MS (method 10): Rt=1,56 min; MS (ESIpos): m/z=691 (M+N)+.

Example 17

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-laserpoint the dihydrochloride

0,185 g (0,535 mmol) of N2N6bis(tert-butoxycarbonyl)-L-lysine, to 0.108 g (0,803 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0,123 g (0,642 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is combined in 15 ml of DMF and within 5 minutes was stirred at room temperature. Then add 0,37 g (0,535 mmol) of the compound from example 11A and 466 μl of N,N-diisopropylethylamine, and components during the night stirred at room temperature. The reaction products was concentrated in vacuo, the residue partitioned between 500 ml of ethyl acetate and 200 ml of water. The organic phase is separated, sequentially extracted three times with 5% citric acid and three times with 5% sodium hydrogen carbonate solution and dried over magnesium sulfate. The organic phase is concentrated and the residue within 10 min mix with 50 ml of ethyl acetate. Then slowly add 100 ml of diethyl ether, and the formed precipitate is sucked off on a vacuum filter. The result of drying in high vacuum, get 0,303 g protected intermediate product (output from theoretical 63%).

HPLC (method 7): Rt=6,1 minutes

0,279 g (0,308 mm is l) obtained intermediate product is introduced into 120 ml of dichloromethane. Through the resulting solution under stirring miss gaseous Bogorodchany, at the same time deprived of the protection target compound precipitates. The reaction products within the next hour and stirred at room temperature. The mixture is then concentrated in vacuo to half the original volume and slowly add 30 ml of absolute THF. The mixture is stirred for a further 15 minutes, the resulting precipitate are filtered. The filter residue is washed with diethyl ether and dried in high vacuum. Obtain 212 mg of the target compound as colorless crystals (yield of theoretical, 88%).

HPLC (method 7): Rt=4,8 minutes

LC-MS (method 10): Rt=1,52 min; MS (ESIpos): m/z=705 (M+H)+.

Example 18

2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)for 3,5-dicyanodiamide-4-yl]phenoxy}ethyl-L-lysyl-L-phenylalanine the dihydrochloride

0,166 g (0.48 mmol) of N2N6bis(tert-butoxycarbonyl)-L-lysine, 0,097 g (to 0.72 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0,110 g (0,576 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is combined in 7 ml DMF and within 5 minutes was stirred at room temperature. Then add 0.375 g (0.48 mmol) of the compound from example 12A and 418 μl of N,N-diisopropylethylamine, and components during the night stirred at room te is the temperature. The reaction products was concentrated in vacuo, the residue is introduced into 200 ml of ethyl acetate, sequentially extracted twice with a 10% citric acid and twice with a 10% solution of sodium bicarbonate and dried over magnesium sulfate. The organic phase is concentrated, the residue is introduced into 10 ml of ethyl acetate, and the target product is precipitated by adding diethyl ether. The precipitate is sucked off on a vacuum filter and dried in high vacuum. Get 0,338 g protected intermediate product (output from theoretical 71%).

HPLC (method 7): Rt=6,7 minutes

0.32 g (0,321 mmol) obtained intermediate product is introduced into 100 ml of dichloromethane. Through the resulting solution under stirring miss gaseous Bogorodchany, at the same time deprived of the protection target compound precipitates. The reaction products within the next hour and stirred at room temperature, concentrated in vacuo to half the original volume and slowly add 10 ml of absolute THF. The mixture is stirred for a further 15 minutes, the resulting precipitate are filtered. The filter residue is washed with diethyl ether and dried in high vacuum. Obtain 188 mg of the target compound as colorless crystals (yield of theoretical, 67%).

HPLC (method 7): Rt=5,0 minutes

LC-MS (method 11): Rt=1,33 min; MS (ESIpos): m/z=795 (+H) +.

C. Determination of solubility, stability and the ability to release

a) Determination of solubility

The test compound suspended in 5% aqueous solution of dextrose. The resulting suspension within 24 hours of shaking at room temperature. After a 30-min ultracentrifugation with acceleration 224000g the supernatant was diluted with DMSO and analyzed by HPLC. Quantitative evaluation of the results of the analysis carried out on the basis of two-point calibration curve of the test compound in DMSO.

The analysis of acids by HPLC

The instrument Agilent 1100 with DAD detector (G1315A), four-way pump (G1311A), an automatic pipette (CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: Phenomenex Gemini C18, 5 μm, 50 mm × 2 mm; temperature 40°C.; eluent A: water/phosphoric acid pH 2, eluent b: acetonitrile; flow rate 0.7 ml/min; gradient: 0-0,5 min 85% A, 15% B; linear 0.5 to 3 min 10% A, 90%; of 3-3 .5 min 10% A, 90% B; linear 3.5 to 4 min 85% A, 15% B; 4-5 min 85% A, 15% Century

Analysis of the bases by HPLC

The instrument Agilent 1100 with DAD detector (G1315A), four-way pump (G1311A), an automatic pipette (CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: VDSoptilab Kromasil 100 C18, 3.5 µm, 60 mm × 2.1 mm; temperature 30°C; eluent A: water + 5 ml perchloro acid per liter, eluent b: acetonitrile; flow rate: 0.75 ml/min; gradient: 0-0,5 min 98% a, 2 B; linearly to 0.5-4.5 min 10% A, 90% B; 4,5-6 min 10% A, 90% B; linear 6,5-6,7 min 98% a, 2% B; 6,7-7,5 min 98% a, 2% C.

Table 1 shows the solubility of compounds from the representative embodiments of the invention in a 5% aqueous solution of dextrose

Table 1
ExampleSolubility [mg/l]
1>500
3450
4>500
5>500
6>500
7100
10390
11>500
12>500
13>500
14>500
15450
17>500
18450

Destru the tion of the compounds in the specified solution is missing.

Solubility underlying the tested compounds active ingredient [compound of formula (A)] in 5% aqueous solution of dextrose is less than 0.1 mg/liter.

b) Stability in buffer solutions at various pH values

In the test tube for HPLC volume of 2 ml take a sample of the test compound (0.3 mg) and mix it with 0.5 ml of a mixture acetonitrile/DMSO (9:1). With the aim of dissolving the test compound tube for approximately 10 seconds and placed in an ultrasonic bath. Then add 0.5 ml of appropriate buffer solution, and the sample is again subjected to ultrasonic processing.

Used buffer solutions

pH 2:0.03 mol of citric acid, 0.061 mol of sodium chloride and 0,0082 mol of hydrochloric acid; dilute with water to 1 liter.
pH 4:1 l passed through the ultra filter water with a pH of 4.0, established by 1N hydrochloric acid.
pH 5:0,096 mol of citric acid and 0.2 mol of sodium hydroxide; dilution with water to 1 liter.
pH 6:0.06 mol of citric acid and 0.16 mol of sodium hydroxide, dilute with water to 1 liter.
pH 7,4:90.0 g of sodium chloride, 13,61 g of potassium dihydrophosphate, 83,35 g of 1N sodium hydroxide solution, dilute with water to 1 liter; this solution further diluted with missing through ultra-thin filter with water in the ratio 1:10.
pH 8:0,013 mol Borax and 0,021 mol of hydrochloric acid; dilute with water to 1 liter.

Within 24 hours at 25°C. the hourly perform HPLC analysis of a sample solution volume of 5 μl on the content remains without changes of the test compounds, respectively formed educt of the formula (A). Quantitative evaluation of the results of the analysis carried out on the basis of the percentages of the areas of the corresponding peaks.

Method HPLC

The instrument Agilent 1100 with DAD detector (G1314A), binary pump (G1312A), automatic pipette (G1329A), oven (G1316A) and thermostat (G1330A); column Kromasil 100 C18, 125 mm × 4 mm, 5 μm; column temperature 30°C.; eluent A: water + 5 ml perchloro acid per liter, eluent b: acetonitrile; gradient: 0-2,0 min 90% A, 10% B; a 2.0 to 18.0 min 64% And 36%; 18,0-20,0 min 64% A, 36%; 20,0-21,0 min 10% A, 90% B; 21,0-23,0 min 90% A, 10% B; 23,0-26,0 min 90% A, 10% B; flow rate 2.0 ml/min; UV detection 294 nm.

Table 2 shows the content of the tested compounds obtained in representative embodiments of the invention, a particular is certain as ratios of peak areas (F) in the time (t) to their space in the initial moment of time.

25
Table 2
ExamplepHThe content of the test compounds after 4 h, % [F(t=4 h) × 100/F (t=0 h)]The content of the test compounds after 24 h, % [F(t=24 h) × 100/F (t=0 h)]
14100100
16100100
17,49996
189990
24100100
27,4100100
34100100
37,499 55
44100100
4510098
469784
47,4482
54100100
5510098
569570
62100100
64100100
659680
6678
67,480
7410098
77,4512
94100100
97,4100100
10410099
107,410099
114100100
117,49055
1249998
127,4 2
13410099
137,4240
144100100
147,4688

In terms of this test simultaneously with the decrease in the content of the test connection state the increase in the content of active ingredient [compound of formula (A)].

(C) Stability in rat and human plasma in vitro

In the test tube for HPLC volume of 2 ml take a sample of the test compound (1 mg) and mix it with 1.5 ml of DMSO and 1 ml of water. With the aim of dissolving the test compound tube for approximately 10 seconds and placed in an ultrasonic bath. To 0.5 ml of the appropriate solution add 0.5 ml of rat, respectively, in human plasma with a temperature of 37°C. the Tube is shaken and taken for an analysis of the first sample volume of about 10 μl (time t0). During the period of time after the start of incubation, up to 2 hours, selected from 4 to 6 are designed is to quantify the additional aliquot samples. Samples during testing maintained at a temperature of 37°C. the characterization and quantification performed by HPLC method.

Method HPLC

The instrument Agilent 1100 with DAD detector (G1314A), binary pump (G1312A), automatic pipette (G1329A), oven (G1316A) and column thermostat (G1330A); column Kromasil 100 C18, 250 mm × 4 mm, 5 μm; column temperature 30°C.; eluent A: water + 5 ml perchloro acid per liter, eluent b: acetonitrile; gradient: 0-8,0 min 53% And 47%; 8,0-18,0 min 53% And 47%; 18,0-20,0 min 90% A, 10% B; 20,0-21,0 min 90% A, 10% B; 21,0-22,5 min 98% a, 2% B; 22,5-25,0 min 98% a, 2% B; flow rate 2 ml/min; UV detection 294 nm.

Table 3 shows the values of time (t50%A), in which after co-incubation obtained in representative examples of the tested compounds with rat plasma is formed 50% of the maximum possible amount of active ingredient [compound of formula (A)]. Quantitative assessment perform relative peak areas in the appropriate time and at the initial incubation.

Table 3
Examplet50%A[min] for rat Plaza
160
230
355
41,7
58,0
61,1
70,5
9>120
10>120
122
130,5
140,5

d) pharmacokinetic studies on Wistar rats by intravenous injection of the tested compounds

On the day of application of the tested compounds in the jugular vein of anesthetized by Isofluran®experimental animals (male Wistar rats weighing 200-250 g) are implanted used in subsequent blood withdrawal catheter.

On the day of the experiment into the tail vein of rats glass Hamilton syringe®enter a specific dose of the test compound in the form of an appropriate solution (duration of less than 10 seconds). In the next 24 hours via catheter sequentially selected from 8 to 12 blood samples. The purpose of separation of plasma samples centrifuged in heparinbinding Trubach the Ah. The purpose of deposition of protein a specific volume of plasma at the appropriate time mixed with acetonitrile. After centrifugation, using the appropriate method LC/MS-MS, quantitatively determine the content of the test compounds and, if necessary, well-known products of its destruction in the supernatant.

On the basis of measured concentrations in plasma calculate the pharmacokinetic characteristics of the test compounds, respectively, the compounds of formula (A)released from the tested compounds as the active substance, such as AUC, CmaxT1/2(the period of providentia) and CL (coefficient of cleansing the blood).

After intravenous administration of the compounds of examples 4, 5, 6 and 7 of them were not observed in plasma at the first blood test. During the entire test period (24 hours) in plasma was detected only active substance of the formula (A).

e) pharmacokinetic studies on Wistar rats for oral use of the tested compounds

On the day of application of the tested compounds in the jugular vein of anesthetized by Isofluran®experimental animals (male Wistar rats weighing 200-250 g) are implanted used in subsequent blood withdrawal catheter.

On the day of the experiment in the stomach of the animal via a stomach tube impose opredelennuyu of the test compounds in the form of an appropriate solution. In the next 24 hours via catheter sequentially selected from 8 to 12 blood samples. The purpose of separation of plasma samples centrifuged in heparinbinding tubes. The purpose of deposition of protein a specific volume of plasma at the appropriate time mixed with acetonitrile. After centrifugation, using the appropriate method LC/MS-MS, quantitatively determine the content of the test compounds and, if necessary, well-known products of its destruction in the supernatant.

On the basis of measured concentrations in plasma calculate the pharmacokinetic characteristics of the test compounds, respectively, the compounds of formula (A)released from the tested compounds as the active substance, such as AUC, CmaxT1/2(the period of providentia) and CL (coefficient of cleansing the blood).

After oral administration of the compounds of examples 4, 5 and 6 of them were not observed in plasma at the first blood test. During the entire test period (24 hours) in plasma was detected only active substance of the formula (A).

f) the Effect of the tested compounds on the heart rate under anesthesia in rats

Using male Wistar rats with body weight of more than 250, the night before the experiment the animals do not provide food, but they have free access is to drinking water. Animals prepare and investigate under General anesthesia performed by Trapanal®(100 mg/kg body weight). Injection and infusion is performed via a catheter in the jugular vein, blood pressure registering through a catheter in the femoral Vienna (transducer firm Braun, Melsungen). To compensate for the loss of fluid after preparation perform continuous intravenous infusion of physiological saline. The test compound or placebo solution applied intravenously after the time of equilibration (about 1 hour) as a loading dose. Heart rate and arterial blood pressure during equilibration and after at least 30 minutes after the shock injection recording using digital analysis software.

Table 4 shows the decrease in maximum heart rate in the first 30 minutes after shock intravenous injection (100 µg/kg) of the active substance of the formula (A), respectively, equivalent dosage of the compounds of the representative embodiments of the invention.

Table 4
ExampleThe decrease in heart rate, [%]
And24
110
419
512
617
715

C. Examples of the manufacture of pharmaceutical preparations

Proposed in the invention compounds can be converted, for example, in the following pharmaceutical products.

Tablets

The composition of

100 mg offered in the invention compounds, 50 mg of lactose in the form of a monohydrate, 50 mg natural corn starch, 10 mg

polyvinylpyrrolidone (PVP 25 BASF (Ludwigshafen, Germany) and 2 mg of strata magnesium.

Weight pills 212 mg. a Diameter of 8 mm, the radius of curvature of 12 mm

Manufacturing

The mixture proposed in the invention compounds, lactose and starch granularit using a solution of polyvinylpyrrolidone in water concentration of 5% wt. The granules after drying, mix for 5 minutes with Starata magnesium. The resulting mixture is subjected to extrusion in a conventional tablet press (settings tablets listed above). Normalized pressing force of 15 kN.

Orally applied suspension

The composition of

1000 mg offered in the invention compounds, 1000 mg of ethanol (96%), 400 mg xanthan resin is Rhodigel ®company FMC (USA, Pennsylvania) and 99 g of water.

A single dose containing 100 mg of the proposed invention in connection corresponds to 10 ml of oral suspension applied.

Manufacturing

Resin Rhodigel®suspended in ethanol and to the resulting suspension type proposed in the invention the connection. With stirring, add water. The components are stirred for about 6 hours until the completion of the swelling resin Rhodigel®.

Orally applied solution

The composition of

500 mg offered in the invention compound, 2.5 g of Polysorbate and 97 g of polyethylene glycol is PEG 400. A single dose containing 100 mg of the proposed invention in connection corresponds to 20 ml orally applied solution.

Manufacturing

The proposed invention in connection with stirring suspended in a mixture of polyethylene glycol with a Polysorbate. Stirring is continued until complete dissolution of the proposed invention the connection.

Solution for intravenous injection

Proposed in the invention of the compound at a concentration below the saturation limit is dissolved in a physiologically compatible solvent (e.g., isotonic sodium chloride, 5% glucose solution and/or a 30% solution of polyethylene glycol PEG 400, the pH of which is set in the range from 3 to 5). The solution is filter the Ute if necessary under sterile conditions and/or Packed in sterilized and free from pyrogenic impurities vessels for injection.

1. The compound of formula (I)

in which RAmeans a group of the formula

or
where * indicates the place of attachment to the oxygen atom,
L1and L2independently from each other mean a bond or-CH2group
R1, R2and R3mean hydrogen,
R4and R6the same or different and independently of one another denote hydrogen or methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methylpropan-1-yl, butane-1-yl, tert-butyl, phenyl, benzyl, n-hydroxybenzyl, indole-3-ylmethyl, imidazol-4-ylmethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, mercaptomethyl, methylthiomethyl, 2-mercapto-ethyl, 2-methylthioethyl, carbarnoyl-methyl, 2-carbamoylethyl, carboxymethyl, 2-carboxyethyl, 4-aminobutane-1-yl, 4-amino-3-hydroxybutane-1-yl, 3-aminopropan-1-yl, 2-amino-ethyl, aminomethyl, 3-guanidinopropionic-1-yl, 3-ureidopropionic-1-Il,
R5and R7mean hydrogen,
L3denotes unbranched or branched alcander with 2-4 carbon atoms, which is substituted by an amino group,
R8, R9and R10mean hydrogen,
m means 2, 3, 4, 5 or 6,
L4denotes unbranched or branched alcander with 2-4 carbon atoms, which, in addition, substituted carboxyl group,
R1 means hydrogen or methyl,
and
n denotes 1, 2, 3,or 4
as well as its physiologically acceptable salt.

2. The compound of formula (I) according to claim 1, in which
RAmeans a group of the formula

or
where * indicates the place of attachment to the oxygen atom,
L1means of communication,
L2means bond or-CH2group
R1and R3mean hydrogen,
R4means hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methylpropan-1-yl, butane-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl,
R6means hydrogen, imidazol-4-ylmethyl, 4-aminobutane-1-yl, 3-aminopropan-1-yl, 2-amino-ethyl, aminomethyl or 3-guanidinopropionic-1-Il,
L3means unbranched alcander with 2-4 carbon atoms, which is substituted by an amino group,
R8and R10mean hydrogen,
m means 2, 3,or 4
L4means unbranched alcander with 2-4 carbon atoms, which is substituted by a carboxyl group,
R11means hydrogen or methyl,
and
n represents 2, 3 or 4, as well as its physiologically acceptable salt.

3. The compound of formula (I) according to claim 1, in which
RAmeans a group of the formula

or
where * indicates the place of attachment to the oxygen atom,
L1and L2each mean a relationship,
R4means hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methylpropan-1-yl, butane-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl,
R6means imidazol-4-ylmethyl, 4-aminobutane-1-yl, 3-amino-propane-1-yl, 2-amino-ethyl, aminomethyl or 3-guanidinopropionic-1-Il,
L3means a group of the formula-CH(NH2)-CH2-, -CH2-CH(NH2)-,
-CH2-CH(NH2)-CH2, -CH(NH2)-CH2-CH2or
-CH2-CH2-CH(NH2)-,
m means 2, 3,or 4
L means a group of the formula **-CH2-CH(COOH)- or
**-CH2-CH2-CH(COOH)-, where
** means the place of connection to the adjacent carbonyl group,
and n represents 2 or 3,
as well as its physiologically acceptable salt.

4. The compound of formula (I) according to claim 1, in which
RAmeans a group of the formula

where * indicates the place of attachment to the oxygen atom,
L1and L2each mean a relationship,
R4means hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, hydroxymethyl or 1-hydroxyethyl,
and
R6means imidazol-4-ylmethyl, 4-aminobutane-1-yl, 3-amino-propane-1-yl, 2-am is noetic, aminomethyl or 3-guanidinopropionic-1-yl, as well as its physiologically acceptable salt.

5. The compound of formula (I) according to one of claims 1 to 3, in which
RAmeans a group of the formula

where * indicates the place of attachment to the oxygen atom,
L3means a group of the formula-CH(NH2)-CH2-, -CH2-CH(NH2)-, -CH(NH2)-CH2-CH2or-CH2-CH2-CH(NH2)-,
and m represents 2 or 3,
as well as its physiologically acceptable salt.

6. The method of obtaining compounds of formula (I) as defined in claims 1 to 5, characterized in that the compound of formula (A)

in an inert solvent in the presence of means of condensation atrificial carboxylic acid of formula (II), (III) or (IV)

in which L1L3L4, R1, R4, R5and R11are specified in claims 1 to 5 values,
PG1means a temporary aminosidine group, and
PG2means a temporary carboxylato group,
obtaining the compounds of formula (V), (VI) or (VII)


in which L1L3L4, R1, R4, R5, R11, PG1and PG2have indicated to enter the values,
then otscheplaut protective group PG1or PG2and then in an inert solvent in the presence of means of condensation combine in the case of compound (V) with the compound of the formula (VIII)in the case of compound (VI) with the compound of the formula (IX) in the case of compound (VII) with the compound of the formula (X)

in which L2, R6, R7, R8, PG2, m and n are specified in claims 1 to 5 values,
and
R2aand R3aand R9aand R10aeach the same or different and are specified in claims 1 to 5 for R2, R3, R9and R10values or mean temporary aminosidine group,
then, if necessary, remove present protective groups,
and the compounds of formula (I), if necessary, using the appropriate (i) solvents and/or (ii) acids or bases transferred to their physiologically acceptable salts.

7. The use of compounds as defined in one of claims 1 to 5 for the manufacture of a medicinal product intended for the treatment and/or prevention of cardiovascular diseases.

8. Medicinal product for the treatment and/or prevention of cardiovascular diseases, containing 0.01 to 100 mg of the compounds of formula (I) as defined in one of claims 1 to 5, optionally in combination : the tion with one or more inert, non-toxic, pharmaceutically suitable excipients.



 

Same patents:

FIELD: chemistry.

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51 cl, 14 ex, 8 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new 3,8-diaminotetrahydroquinoline derivatives of formula (1a) or to their pharmaceutically acceptable salts wherein X represents CH2, C=O or CH-OR; m is 1 or 2; Ar represents a phenyl group or a 5-merous or 6-merous aromatic heterocyclic group having one element specified in S and N, (wherein the phenyl group may be substituted by 1-2 halogen atoms); each R1 and R2 represents a hydrogen atom; R3 represents a C1-C6 alkyl group or indolyl-C1-4 alkyl group (the indolyl group is optionally substituted by a C1-C6 alkyl group or a halogen atom), n is 0; R4 and R5 which may be identical or different, each represents a hydrogen atom or a C1-C6 linear or branched alkyl group; each R6 and R7 represents a hydrogen atom; and R represents a hydrogen atom. Also, the present invention refers to a drug preparation and a pharmaceutical composition of the basis of the compound of formula (1a), to the compound of formula (F1), to a method for preparing an intermediate compound (e).

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10 cl, 1 tbl, 124 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to crystalline modifications: 1 (polymorphous form F), 2 (polymorphous form I) and 3 (polymorphous form X) of monosodium salt of D-isoglytamyl-D-tryptophan (1:1) characterised by powder X-ray pattern peaks presented in the application materials, as well as to pharmaceutical compositions containing them. The invention describes their use for treating various diseases and body conditions of at least one autoimmune diseases specified in a group consisting of psoriasis, atopic dermatitis and rheumatoid arthritis.

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42 cl, 4 ex, 9 dwg

FIELD: chemistry.

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3 ex

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9 cl, 8 ex, 3 tbl, 3 dwg

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FIELD: medicine, pharmaceutics.

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30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I

and pharmaceutical compositions containing them and used for IAP-function modulation by inhibiting the binding of BIR-binding protein and BIR domain of IAP and for treating proliferative diseases such as cancer. What is also disclosed is a compound of formula I marked by a detectable tag and an affinity tag which is applicable as a probe for identifying the compounds bound with BIR domain of IAP.

EFFECT: preparing the compounds used for IAP-function modulation.

33 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods for synthesis of nonapeptide ethylamide, having strong LH-RH/FSH-RH activity, of formula pGlu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·2AcOH (I), and intermediate compounds for synthesis thereof. The nonapeptide ethylamide is obtained via condensation of a C-terminal tetrapeptide of formula H-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (II) with a dipeptide of formula: X-Ser-Tyr-OH (IV), where X is a protective group. The obtained N-substituted hexapeptide ethylamide of formula X-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (III) is treated with an unblocking agent to remove the N-protective group, and then condensed with a tripeptide of formula pGlu-His-Trp-OH·HCl (V) and the end product is purified through chromatography and extracted in form of a monoacetate salt.

EFFECT: high output.

4 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: synthesis is carried out using a liquid-phase technique via condensation of pentafluorophenyl ether of Nα-benzloxycarbonyl-Nε-tert-butoxycarbonyl-L-lysine with methyl ether of O-tert-butyl-L-threonine in the presence of N-methylmorpholine in ethyl acetate medium and followed by hydrogenation of the obtained compound with hydrogen in methyl alcohol using palladium hydroxide as a catalyst. Purification of the desired protected dipeptide is carried out using a salt with oxalic acid. The initial pentafluorophenyl ether is obtained from reaction of Nα-benzyloxycarbonyl-Nε-tert-butoxycarbonyl-L-lysine with pentafluorophenol and is then used without extraction. The disclosed method enables to obtain the desired product with output of over 96% and high degree of purity.

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2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

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EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

wherein the cycle A represents a carbocyclic group or a heterocyclic group; R1 means (i) lower alkyl optionally substituted by halogen, (ii) lower alkenyl, (iii) lower alkynyl or (iv) a carbocyclic group; each of R3a, R3b, R3c and R3d independently means hydrogen, halogen, lower alkyl optionally substituted by halogen, lower alkenyl, carbocyclyl - lower alkoxy or a carbocyclic group, or R3a and R3b or R3c and R3d can form C3-C10 cycloalkane ring together with an adjoining carbon atoms and can form oxo; a pharmaceutically acceptable salt or solvate of said compound effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

EFFECT: preparing the pharmaceutically acceptable salt or solvate effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

18 cl, 139 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

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