Derived 5-(2-imidazolidinone)benzimidazole, the pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of 5-(2-imidazolidinone)benzimidazole of General formula I, where R1is methyl, ethyl, cyclopropyl, R2is hydrogen, C1-C3-alkyl, halogen, R3is hydrogen, methyl, hydroxy, cyano, R4is hydrogen, methyl, R5is hydrogen, methyl, amino, halogen, cyano, provided that at least one of R2, R3, R4, R5different from hydrogen or fluorine, provided that when R1is methyl and both R2and R5- hydrogens, R3may not be the stands, provided that when R3is cyano, R1is stands, and any tautomer above structure or a pharmaceutically acceptable salt, or biohydrology ester, amide or imide this connection. The compounds are agonists alpha-2 adrenergic receptors. Also described pharmaceutical composition, agonistic respect to alpha-2 adrenergic receptors containing a safe and effective amount of the compounds of formula I and a pharmaceutically acceptable carrier. 2 C. and 7 C.p. f-crystals, 4 PL.

This invention relates to certain substituted benzimidazole compounds, which have Olufsen is anoreceptive, and they can be used to treat disorders associated with agonists of alpha-receptors.

Alpha-adrenergic receptors, agonists, antagonists, and compounds related in structure to the compounds of the present invention, are described in the following literature references;

Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, "12.1-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol. 3, Membranes &Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. & P. A. van Zwieten, "-Adrenoceptor Agonists and Antagonists", Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters & C. J. E. Niemegeers, "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the1and2-Selectivity values of Test Compounds: (2) -Adrenoceptor Agonists", European Journal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink & P. A. van Zwieten, "Quantitative Relationships between-Adrenergic Activity and Binding Affinity of-Adrenoceptor Agonists and Antagonists", Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van the meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & P. A. van Zwieten, "selectivity values of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat", The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. C. , J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith & M. R. Stillings, "Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard-Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C. C., R. C. M. Butler. D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I:F. Tulloch, " 2-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in. Human Platelets", Br. J. Pharmac. Vol. 82 (1984), pp. 467-476; U. S. Patent No. 3,890,319 issued to Danielewicz, Snarey & Thomas on June 17, 1975; and U. S. Patent No. 5,091,528 issued to Gluchowski on February 25, 1992.

Agonists alpha-2 adrenergic receptors are used to treat a variety of disorders and diseases, including respiratory diseases (e.g. asthma, nasal congestion (nasal congestion), chronic obstructive pulmonary disease (COPD), cough, cystic fibrosis), gastrointestinal disorders (e.g., diarrhea, irritable bowel syndrome), eye diseases (such as glaucoma), cardiovascular disease (e.g. myocardial ischemia, shock, arrhythmia, angina, congestive heart failure), benign prostate tumors and migraines. However, many of the compounds described in the literature, as well as structural analogs of this invention are not selective for the alpha-2 adrenergic receptors (for example, they interact with other alpha receptors, such as alpha-1 adrenergic receptors). The selectivity to alpha-2 adrenergic receptors are desirable in the treatment of disorders associated with alpha-2 adrenergic receptors, or disorders, where the alpha-2 adrenergic receptors are prom is positive for alpha-1 adrenergic effect, cause cardiovascular side effects such as hypertension. In addition, many of the compounds described in the literature and structural analogs of compounds of this invention have significant activity against Central nervous system (CNS), which can lead to undesirable side effects such as a strong sedative effect.

In addition, it was observed that some agonists alpha-adrenergic receptors are exposed to intense metabolic transformations in the body of primates. This metabolic transformation leads to inactivation of the parent compound or to the formation of the active metabolite with a different pharmacological profile than the parent compound. Of particular importance for the present invention has a metabolic transformation that occurs in some alpha-adrenergic benzimidazole, which are selective agonists of the peripheral actions of alpha-2 adrenergic receptors. Metabolic N-methylation in the benzimidazole ring allows you to get a connection that

1) are inactive.

2) are antagonists of the alpha-2 adrenoreceptors;

3) have a high activity attributed the al for action on the Central nervous system.

Therefore, there is a constant need for selective alpha-2 adrenergic compounds peripheral actions, which have less impact on the Central nervous system and which are resistant to metabolic transformation in unwanted connections.

The present invention relates to compounds having a structure corresponding to the following formula:

< / BR>
in which (a) R1 represents alkyl;

(b) R2 is chosen from the group consisting of hydrogen, alkyl, metoxygroup, ceanography and halogen;

(C) R3 is selected from the group consisting of hydrogen, methyl, hydroxyl, ceanography and halogen;

(g) R4 is chosen from the group consisting of hydrogen, methyl, ethyl and isopropyl;

(d) R5 is chosen from the group consisting of hydrogen, methyl, amino, metoxygroup, hydroxyl, ceanography and halogen;

(e) provided that at least one of the substituents R2, R3, R4 or R5 is not hydrogen or fluorine;

(g) provided that when R1 represents methyl, and R2 and R5 are hydrogen, then R5 is not stands or halogen;

(C) provided that when R3 represents ceanography, R1 represents methyl; and

any tautomer the above structure is soedineniya of the present invention are used to treat many medical conditions, including, for example, respiratory diseases, ophthalmic diseases, gastrointestinal disorders, disorders associated with the activity of the sympathetic nervous system, migraine, peripheral pain and disorder, in which the narrowing of the vessels may have a beneficial effect. Accordingly, the invention also relates to pharmaceutical compositions containing these compounds. This invention also provides methods of treatment using these compounds or compositions containing them.

Terms and definitions.

"Alkyl" means unsubstituted saturated or unsaturated hydrocarbon chain having from 1 to 3 carbon atoms. The alkyl chain may be straight, branched or cyklinowanie. Preferred alkyl groups are methyl, ethyl or cyclopropyl.

"Biohydrology amide" refers to amide compounds according to the invention, which is easily converted in vivo into the active compound according to the invention.

"Biohydrology ester" means an ester compounds according to the invention, which is easily converted into the active compound of this invention.

"Halo", "halogen" or "halogen" means the Halogens are chlorine and bromine.

"Pharmaceutically acceptable salt" means a cationic salt formed with any acidic (e.g., carboxyl) group, or an anionic salt formed with any basic (e.g., amino) group. Many such salts are known in the art, as described in the international application 87/05297, Jonston et A1. published September 11, 1987, incorporated here by reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium), salts of alkaline earth metals (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides, sulfonates, carboxylates, phosphates, etc., Obviously we can assume that among such salts are salts of adhesion, which can give optically active center where it is. For example, chiral salt of tartaric acid can be obtained from the compounds according to the invention, and this definition includes such chiral salt.

The term "primacy" includes people.

Connection

The present invention relates to compounds having the following structure:

< / BR>
In the above structure, R1 is an alkyl. Preferably R1 is a methyl, ethyl or qi is a group or halogen. Preferably R2 represents hydrogen, alkyl or cyano. More preferably R2 represents methyl or halogen.

In the above structure, R3 represents hydrogen, methyl, hydroxyl, cyano or halogen. Preferably R3 represents a cyano or hydroxide, when R1 represents methyl. Most preferably R3 represents cyano, when R1 represents methyl. Preferably R3 represents methyl or halogen when R1 is not the stands.

In the above structure, R4 represents hydrogen, methyl, ethyl or isopropyl. Preferably R4 represents hydrogen or methyl, more preferably hydrogen.

In the above structure, R5 represents hydrogen, methyl, amino group, methoxy group, hydroxyl, cyano or halogen. Preferably R5 represents hydrogen, methyl or halogen.

In the above structure, at least one of the substituents R2, R3, R4 and R5 is different from hydrogen or fluorine. In addition, when R1 represents methyl, and R2 and R5 are hydrogen, R3 is other than methyl or halogen. Finally, when R3 represents ceanannas above structure. For example, when shown tautomeric form D molecules (see below), it should be understood that there is also a tautomeric form that is Thus an indication of one tautomeric form means the indication of each tautomer and all tautomers.

< / BR>
This invention also relates to pharmaceutically acceptable salts, formed by attaching acid ("salt accession acid"), biohydrology esters, amides and imides of the above patterns.

Compounds of the present invention are sufficiently basic to form a salt accession acid. These compounds can be used in free base form and in salt form attach with acid, and both forms are included in the scope of the invention. Salt accession acid in some cases are more convenient form for use. In practice, the salt form is essentially equivalent to the use of active substances in the form of a Foundation. The acid used to obtain the salts of accession, preferably include those acids which when connected with the free base gives salt acceptable for medical use. The anions of the salts are relatively harmless to the body W is basis, not removed by any of the side effects attributed to the acid anions.

Examples of suitable salts of joining with acids include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, hydrosulfate, acetate, triptorelin, nitrate, maleate, citrate, fumarate, formate, stearate, succinate, Mallat, malonate, adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, triftorbyenzola, p-toluensulfonate, dodecyl sulphate, cyclohexanesulfamic, etc., However, other suitable, acceptable for pharmaceutical use salt in the scope of the invention receive from other mineral acids and organic acids. Salt accession major compounds with acids get several ways. For example, the free base can be dissolved in a water-alcohol solution containing the appropriate acid and excrete salt through evaporation of the solution. An alternative can be obtained by reaction of the free base with an acid in an organic solvent so as to directly allocate Sol. In cases where the selection of salt is difficult, it can precipitate a second organic solvent or can be obtained by concentrating the sustained fashion, all salts joining with acids included in the scope of the present invention. All salts joining with acids used as sources of the free base, even if these salts by themselves, it is desirable to use only as an intermediate product. For example, when salt only get to clean or identification, or when it is used as an intermediate product upon receipt of salt, acceptable from a medical point of view, methods of ion exchange, it is obvious that these salts are considered as part of this invention.

The compounds of this invention are applicable for the treatment of various diseases, disorders and conditions, which vary under the action of alpha-1 adrenergic receptors and alpha-2 adrenergic receptors. Used herein, the terms "disease", "disorder" and "condition" are used as interchangeable terms. Here the disorder, described by the terms "modulated by alpha-2 adrenoreceptors or modulated under the action of alpha-2 adrenergic receptors" means a disorder, condition or disease for which the effect of alpha-2 receptors is an effective means of mitigating this disorder, or one or more biological projetada, which leads to the disorder or is the cause of the underlying disorder, or it mitigates one or more symptoms of the disorder. Thus, for disorders at "modulation" refers to those disorders for which:

- the absence of alpha-2 activity is the cause of the disorder or one or more of its biological manifestations, regardless of any changes to the activity of genetically, by infection, irritation, internal stimulus, or for any other reason;

- the disease or disorder, or an observable manifestation or manifestations of a disease or disorder softened by the action of alpha-2 activity. The absence of alpha-2 activity is not necessarily associated with a disease or disorder or their observable manifestations;

alpha-2 activity prevents part of the biochemical or cellular cascade of reactions that leads to the disease or disorder, or is associated with them. In this regard, alpha-2 activity changes the cascade and thus eliminate the disease, condition or disorder.

Compounds of the present invention are perifericheskie selective agonists alpha-2 adrenergic receptors. Alf which shows a higher degree of activity against Central nervous system, preferably, but not limited to, use for indications related to the Central nervous system, such as cardio-vascular disorders (eg, hypertension), pain, abuse and/or abandonment of the use of medicinal substances. The Central action means that they have some effect on alpha-2 adrenergic receptors in the Central nervous system, in addition to their action on peripheral alpha-2 adrenergic receptors.

Perifericheskie active compounds are preferred, but is not limited to the treatment of respiratory diseases, eye diseases, migraine, some cardiovascular diseases and certain gastrointestinal disorders. Peripheral action means that these compounds are not easily overcome the blood-brain barrier and therefore the first to act on the alpha-2 adrenergic receptors in the periphery. In addition, greater specificity of action of these compounds can be achieved by delivery of the drug in the place where it is desirable action (for example, local application with eyes, mucous membranes of the nose, or respiratory tract), and thereby reduce systemic exposure. Still is and sedative action. In engineering there are ways to determine which compounds are less Central actors than others.

The compounds of this invention do not have or have only weak activity as agonists of alpha-1 receptors and have no or almost no effect on the Central nervous system, even at the regular dosage.

Thus, the compounds of the present invention is particularly applicable for the treatment of respiratory diseases, including nasal congestion associated with allergies, colds, and other nasal disorders (as well as the consequences of swelling of the mucous membranes, such as sinusitis or otitis of the middle ear), cough, chronic obstructive pulmonary disease and asthma. It was found that the effective dose possible to avoid unwanted side effects.

Compounds of the invention are also applicable to the treatment of eye diseases, such as increased eye pressure, glaucoma, hyperemia, conjunctivitis, and uveitis.

The compounds of this invention are also applicable to combat gastrointestinal diseases such as diarrhea, irritable bowel syndrome, hyperchlorhydria and peptic of szablewski and disorders, associated with sympathetic nervous system activity, including hypertension, myocardial ischemia, cardiac blood flow, angina, heart failure and benign tumor of the prostate.

Compounds of the invention are also applicable to the prevention or emergency treatment of migraine.

Compounds of the invention are also applicable for the treatment of peripheral pain conditions associated with various diseases (for example, peripheral neuralgia).

Compounds of the invention are also applicable to other diseases and disorders that can be useful narrowing of blood vessels, particularly veins, including septic or cardiogenic shock, increased intracranial pressure, hemorrhoids, venous insufficiency, varicose veins and hot flashes during menopause.

The pharmacological activity and selectivity of these compounds can be identified using published test methods. The selectivity of these compounds relative to the alpha-2 adrenergic receptors was determined by measuring the ability to bind to receptors and functional activity in various tissues known that they are the alpha-2 and/or alpha-1 Retz is rodents or other objects. The activity of the Central nervous system were determined by measuring locomotor activity as indicator of sedation. (See for example, Spyraki, C. & N. Fibiger, "Clonidine-induced Sedation in Rats: Evidence for Mediation by Postsynaptic Alpha-2 Adrenoreceptors", Journal of Neural Transmission, Vol. 54 (1982), pp. 153-163). Activity to eliminate nasal congestion measured using rhinomanometry to assess the resistance to airflow through the nose. (See for example, Salem, S. & E. Clemente, "A New Experimental Method for Evaluating Drugs in the Nasal Cavity", Archives of Otolarvngology, Vol. 96 (1972), pp. 524-529).

Antiglaucoma activity was determined by measuring intraocular pressure. (See for example, Potter, D., "Adrenergic Pharmacology of Aqueous Human Dynamics", Pharmacological Reviews, Vol. 13 (1981), pp. 133-153).

Antidiarrheal activity was determined by measuring the ability of test compounds to inhibit diarrhea caused by prostaglandins. (See, for example, Thollander, M., R. Hellstrom & T. Svensson, "Suppression of Castor Oil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists", Alimentary Pharmacology and Therapeutics, Vol. 5 (1991), pp. 255-262).

The effectiveness of the treatment of irritable bowel syndrome was determined by measuring the ability of test compounds to reduce stress-induced increase in the output of faeces. (See, for example, Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro & N. Ormsbee III, "a Cold-restraint str the power reduction hyperchlorhydria was determined by measuring the reduction of gastric secretion of acid, which give these compounds. (See, for example, Tazi-Saad, K., J, Chariot, M. Del TASS & C. Roze, "Effect of2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat", British Journal of Pharmacology, Vol. 106 (1992), pp. 790-796).

Anti-asthma activity was determined by measuring the actions of the test compounds on bronchostenosis (narrowing of the lumen of the bronchus), associated with the introduction in light of substances such as inhaled antigens. (See, for example, Chang, J. J. Musser & J. Hand, "Effects of a Novel Leukotriene D4Antagonist with 5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, on Leukotriene-D4- and Antigen-Induced Bronchoconstriction in Guinea Pig", International Archives of Allergy and Applied Immunology, Vol. 86 (1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger, B. Marchette, J. Stevenson & W. Abraham, "The Role of Slow-Reacting Substance of Anaphylaxis in the Late Bronchial Response After Antigen Challenge in Allergic Sheep", American Reviews of Respiratory Disease, Vol. 130 (1984), pp. 748-754).

Activity against cough was determined by measuring the number and duration of latent period cough reactions to the introduction of substances that affect breathing, such as inhaled citric acid. (See, for example, Callaway, J. & R. King, "Effects of Inhaled2-Adrenoceptor and GABA Receptor Agonists on Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs", European Journal of Pharmacology, Vol. 220 (1992), pp. 187-195).

Sympathetic activity of these compounds was determined by measuring the decrease in the concentration of CA is ne, rilmenidine and UK 14,304", European Journal of Pharmacology, Vol. 282 (1995), pp. 29-37) or reducing the activity of renal sympathetic nerve (see, for example, Feng, Q., S. Carlsson, P. Thoeren & T. Hedner, "Effects of clonidine on renal sympathetic nerveactivity, natriuresis and diuresis in chronic congestive heart failure rats". Journal of Pharmacology and Experimental Therapeutics, Vol. 261 (1992), pp. 1129-1135), giving the basis for their beneficial action on the heart failure and benign tumor of the prostate. Hypotensive effect of these compounds was measured directly as a decrease in the average blood pressure. (See for example, Timmermans, R. & R. Van. Zwieten, "Central and peripheral a-adrenergic effects of some imidazolidines", European Journal of Pharmacology, Vol. 45 (1977), pp. 229-236).

Clinical studies have shown the positive effects of agonists alpha-2 receptors to prevent myocardial ischemia during surgery (see, for example, Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D. Mangano, "Effects of Perioperative Dexmedetomidine Infusion in Patients Undergoing Vascular Surgery, Anesthesiology, Vol. 82 (1995), pp. 620-633) and to prevent strokes. (See, for example, Wrighf, R. A., P. Decroly, So Kharkevitch & M. Oliver, "Exercise Tolerance in Angina is Improved by Mivazerol an2-Adrenoceptor Agonist", Cardiovascular Drugs and Therapy, Vol. 7 (1993), pp. 929-934).

The effectiveness of these compounds in the cardiac circulation was demonstrated by measuring the decrease perfusion Injury After Myocardia Ischemia in the Cat", Circulation. Vol. 86 (1992), pp. 279-288).

Antiarrhythmic effect of these compounds was demonstrated by measuring the inhibition of arrhythmia caused by wabana. (See, for example, Thomas, G. & Stephen R., "Effects of Two Imidazolines (ST-91 and ST-93) on the Cardiac Arrhythmias and Lethality Induced by Ouabain in Guinea-Pig", Asia Pacific Journal of Pharmacology, Vol. 8 (19-93), pp. 109-113; and Samson, R. , J. Cai, E. Shibata, J. Martins & H. Lee, "Electrophysiological effects of2-adrenergic stimulation in canine cardiac Purkinje fibers", American Journal of discrimination. Vol. 268 (1995), pp. H2024-H2035).

The vasoconstrictor action of these compounds is shown by measuring the contraction of isolated arteries and veins in vitro (see, for example, Flavahan, N. T. Rimele, J. Cooke & M. Vanhoutte, "Characterization of Postjunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenous or Nerve-Released Norepinephrine in the Canine Saphenous Vein", Journal of Pharmacology and Experimental Therapeutics, Vol. 230 (1984), pp. 699-705).

The effectiveness of these compounds to reduce intracranial pressure was shown by measuring this property; in a dog model of subarachnoid hemorrhage. (See, for example, McCormick, J., P. McCormick, J. Zabramski & R Spetzer, "Intracranial pressure reduction by a central alpha-2 adrenoreceptor agonist after subarachnoid hemorrhage", Neurosurgery, Vol. 32 (1993), pp. 974-979).

Inhibition of tides" at the climax demonstrated by measuring the reduction of facial blood flow in rats (see, for example, Escott, K., D. Beattie, H. Connor & s Brain, "sterowane for agonists alpha-2 adrenergic receptors on cutaneous blood flow in the tail in rats. (See for example, Redfem, W., M. MacLean, R. Clague & J. McGrath, "The role of alpha-2 adrenoceptors in the vasculafure of the rat tail", British Journal of Pharmacology, Vol. 114 (1995), pp. 1724-1730). Caused the action of these compounds is shown by measuring the decrease in neurogenic inflammation of the meninges, caused by stimulation of the ganglion of the trigeminal nerve in rats. (See, for example, Matsubara, T., M. Moskowitz and Z. Huang, "UK-14, 304, R(-)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakage within dura mater by predjunctional mechanisms", European Journal of Pharmacology, Vol. 224 (1992), pp. 145-150).

Metabolic stability

It was observed that some benzimidazole, which perifericheskie acting alpha-2-selective agonists adrenergic receptors, which are metabolic stability in vitro and in vivo in the body of rodents undergo metabolic transformations in the body of primates (i.e., monkeys and humans) via N-methylation in the benzimidazole ring. It has been shown that metabolic transformation changes the profile of these benzimidazole so that they can in the process of metabolism to turn into compounds that (1) are inactive; (2) are antagonists of the alpha-2 adrenergic receptors; (3) have increased activity relative to other unwanted receptibility of the present invention are perifericheskie acting alpha-2-selective adrenergic compounds, which have low activity against Central nervous system and which are resistant to metabolic transformation in such unwanted connections.

The metabolic stability of the compounds described above, is evaluated in vitro using high-precision analysis of a thin slice of liver precision-cut liver slice assay) and in vivo by pharmacokinetic studies in primates. Precision analysis of a thin slice of the liver is a well - known recognized model for studying the in vitro xenobiotics metabolism in animals and man. (See Ekins, S. "Past, present and future applications of precision-cut liver slices for in vitro xenobiotic metabolism", (Department of Medicine and Therapeutics, University of Aberdeen, UK.) Drug-metab-Rev. (November, 1996) Vol. 28, 4, pp. 591-625). This analysis is used to assess the metabolic activity of agonists alpha-2 adrenergic receptors. The result of this analysis, get information about the biotransformation occurring within the intact liver cell biological objects of interest. Thus, in this case, there is a complete set of metabolic enzymes of phase I and phase II for implementation of the metabolism of drugs, as is the case in vivo.

For pharmacokinetic studies, the compounds were administered orally tobaccogrowing monkeys in isolation of metabolites, using aliquot parts of 100 ál of urine collected over different time intervals after administration of the dose. In a typical case, to each sample was added chemical homologue or containing stable isotope internal standard and then a 100-fold diluted with water. Ten µl of the prepared sample is then analyzed by the method of gradient HPLC with detection using the dual-mass spectrometry. Used schema reaction monitoring a single ion battery for selective detection of the test compounds, N-methylated metabolite (if it was present) and the internal standard.

According to the results of these analyses in relation to the compounds of the present invention has been shown that metabolic N-methylation slightly or completely absent. In contrast, the N-methylated metabolites were detected for other selective with respect to alpha-2 adrenergic receptors benzimidazole compounds such as 5-(2-imidazolidinyl)-4-methylbenzimidazole and 4-ethyl-5-(2-imidazolidinone) benzimidazole. 5-(2-Imidazolidinyl)-4-methylbenzimidazole gives pharmacological profile very similar to the profile 7-cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole (see pargachevsky receptors with very low activity against Central nervous system. In the precision analysis of thin slice liver no data has been received about the presence of methylated metabolite 7-cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole. However, 5-(2-imidazolidinyl)-4-methylbenzimidazole quickly metabolisable during this test, and it was found that its metabolite is an agonist of the alpha-2 adrenergic receptor with a much higher potential activity against CNS than the original compound. 4-Ethyl-5-(2-imidazolidinone)benzimidazole, another selective agonist of the alpha-2 adrenergic receptors, quickly and heavily N-metiliruetsa in the body of primates. Its metabolite is a very strong alpha-2 antagonist, but not alpha-2 agonist.

These results indicate that metabolic transformation of benzimidazole via N-methylation can lead to the rapid formation of undesirable metabolites that give other pharmacological effects compared to the reference compound, and that these effects are difficult to predict. Not connecting it with theory, we can assume that the factor has a positive effect on the metabolic stability of the benzimidazole compounds of this invention are serices is idazole.

Compounds of the present invention can be obtained using conventional organic syntheses. Particularly preferred synthesis is done using the following General scheme (scheme 1-5). In the following schemes of reactions R1, R2, R3, R4 and R5 are as defined above. For clarity, denote Rl, R2, R3, R4 and/or R5 are not shown on the intermediate products in this particular scheme, if they are not received or are not required in this scheme. Preferably, Rl is part of the original substance (see scheme 1). R2 may be part of the original substance or entered by amination or synthesized, with consequent impacts on the functional group (see scheme 2). R3 may be part of the original substance (see diagram 1) or can be obtained by the action of the carboxylic acid (see scheme 3). R4 is administered by amination of aniline substrate before forming the benzimidazole rings (see scheme 1). R5 or the immediate predecessor R5 is injected during the formation of the benzimidazole ring (see scheme 4). Finally, 5-(2-imidazolidinone)group conveniently be obtained from aminobenzimidazole obtained according to schemes 1-4 (see scheme 5).

The source of the substance shown in the diagrams, issued by the industry, or is in this area. An experienced specialist can change the temperature, pressure, atmosphere, solvents or order of the reactions, if appropriate. In addition, an experienced specialist can use a protective group, to block adverse reactions or increase the output if necessary. All such modifications can easily make a specialist in the field of organic chemistry, and therefore they are within the scope of the invention.

The following not limiting the invention examples illustrate the compounds of the present invention.

Example 1

< / BR>
7-Cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole 2,6-dinitro-p-tolarova acid. In a round bottom flask 500 ml) was added 120 ml of concentrated sulfuric acid. The flask with the acid was cooled to 0oWith and was added p-Truelove acid (90 g, 0.22 mol). To this mixture was slowly added to a mixture of fuming nitric acid (25 ml) and concentrated sulfuric acid (100 ml) via addition funnel. The resulting mixture was then stirred at 0oWith 10 minutes was slowly heated, first to room temperature, then 90oWith 1.5 hours. The mixture was cooled to room temperature and poured into water with ice. The obtained solid is then filtered and the-toluyl carboxamid. A mixture of 2,6-dinitro-p-Truelove acid (15,14 g of 66.9 mmol) and sulphonamide (14,79 g, 153,8 mmol) in anhydrous pyridine (80 ml) was stirred in argon atmosphere at 100oWith 3 hours. The mixture was poured into ice water and the precipitate was filtered and washed with water; obtained 2,6-dinitro-p-toluyl carboxamide in the form of a whitish solid.

3-Amino-2,6-dinitro-p-toluyl carboxamid. In a three-neck round bottom flask of 1 l, equipped with a mechanical stirrer, was placed 2,6-dinitro-p-toluyl carboxamide (4.0 g, 18 mmol) and hydroxylamine hydrochloride (3.3 g, 48 mmol) in ethanol (550 ml) and water (24 ml). The mixture was cooled to 0oC and treated dropwise with a saturated solution of potassium hydroxide in methanol (80 ml) for 1.5 hours. The resulting mixture was licked in a round bottom flask 2 l and diluted with 400 ml of water. The methanol and the ethanol was then removed by evaporation in a rotary evaporator, formed a yellow precipitate, which was filtered and obtained 3-amino-2,6-dinitro-p-toluyl carboxamide in the form of yellow needles.

2,3-Diamino-6-nitro-p-toluyl carboxamid. To a mixture of 3-amino-2,6-dinitro-p-toluamide (2.2 g, 9.2 mmol) in ethanol (200 ml) at 80oC was added dropwise a solution of sodium sulfide (2.2 g, 28 mmol) in water (80 ml) for one hour. Smashes were extracted with ethyl acetate (5300 ml). The combined extracts were dried over magnesium sulfate and evaporated in a rotary evaporator; obtained 2,3-diamino-6-nitro-p-toluyl carboxamide in the form of a red-brown solid. This compound was used in the next stage without further purification.

7-(4-Methyl-5-nitrobenzimidazole)carboxamide. A solution of 2,5-diamino-6-nitro-p-toluyl carboxamide (1,49 g, 7.1 mmol) in formic acid (10 ml) was stirred at 100oWith two hours. The solution was cooled to room temperature and poured into ice and podslushivaet to pH 10 with concentrated ammonium hydroxide solution. Formed brown precipitate, which was filtered; received 7-(4-methyl-5-nitrobenzimidazole)carboxamide in the form of a yellowish-brown solid.

7-Cyano-4-methyl-5-nitrobenzimidazole. A mixture of 7-(4-methyl-5-nitrobenzimidazole)carboxamide (1.5 g, 7.0 mmol) in phosphorus oxychloride (20 ml) and toluene (20 ml) was heated to boiling under reflux in an argon atmosphere for two hours. The mixture was cooled to room temperature, poured into ice and podslushivaet to pH 10 with concentrated ammonium hydroxide solution. The resulting mixture was extracted with a mixture of methylene chloride and isopropyl alcohol 3:1 (6100 ml) and the combined extralegal with elution with a mixture of chloroform: methanol: ammonium hydroxide in the ratio of 9: 1:0,1; received 7-cyano-4-methyl-5-nitrobenzimidazole in the form of a yellow solid.

5-Amino-7-cyano-4-methylbenzimidazole. A mixture of 7-cyano-4-methyl-5-nitrobenzimidazole (0,91 g, 4.5 mmol) and 10% palladium on coal (100 mg) in methanol (200 ml) was treated with hydrogen (1 at, from a cylinder) 14 hours. The resulting mixture was filtered through celite and evaporated in a rotary evaporator. The residue after evaporation was purified flash chromatography (silica gel, ethyl acetate: methanol 95:5); received 5-amino-7-cyano-4-methylbenzimidazole.

7-Cyano-5-isothiocyanato-4-methylbenzimidazole. To a solution of di-2-pyridylmethylamine (1,02 g, 3.1 mmol) and 4-dimethylaminopyridine (25 mg, 0.21 mmol) in tetrahydrofuran (350 ml) was added dropwise a solution of 5-amino-7-cyano-4-methylbenzimidazole (0.36 g, 2.1 mmol) in tetrahydrofuran (50 ml). The solution was stirred one hour at room temperature. The reaction mixture is evaporated in a rotary evaporator and the residue after evaporation was purified by flash chromatography (silica gel, 100% ethyl acetate); received 7-cyano-5-isothiocyanato-4-methylbenzimidazole in the form of a whitish solid.

N-5-(7-Cyano-4-methylbenzimidazolyl)-N'-2-aminoethylamino. A solution of 7-cyano-5-isothiocyanato-4-methylbenzimidazole (0.29 grams, 1,35 mm ml). After stirring the solution at room temperature for 15 minutes, the white precipitate appeared. The reaction mixture is evaporated in a rotary evaporator; received N-5-(7-cyano-4-methylbenzimidazolyl)-N'-2-aminoethylthiomethyl in the form of a whitish solid.

7-Cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole. In a round bottom flask of 500 ml was added methanol (150 ml) and N-5-(7-cyano-4-methylbenzimidazolyl)-N'-aminoethylthiomethyl (0.31 g, 1.1 mmol). The mixture was gently heated by a flow of warm air from a hair dryer, to obtain a homogeneous mixture. To this mixture was added a acetate mercury (0.39 g, 1.2 mmol). The resulting mixture was stirred at room temperature for 4 hours, then filtered through celite and concentrated; received 7-cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole in the form of a white foam.

2,6-Dinitro-p-tolarova acid1H-NMR (DMSO-d6): 8.50 (s, 2H), 2.52 (s, 3H);13C-NMR (DSO-d6): 163.97, 151.45, 131.03, 130.82, 127.51, 13.83; CIMS (NH3CH4) m/z 227 (M+H).

Carboxamid 2,6-dinitro-p-Truelove acid so pl. 188.4-191.0oC 1H-NMR (DMSO-d6): 8.8 (c, 2H), 2.4 (c, 3H);13C-NMR (DSO-d6): 163.6, 150.8, 133.9, 129.9, 126.4, 14.8; CIMS (NH3CH4) m/z 226 (M+H).

Carboxamide 3-amino-2,6-dinitro-p-Truelove to the ): 168.8, 145.7, 139.5, 136.1, 131.5, 128.9, 114.0, 15.8; IS (NH3CH4) m/z 241 (M+H).

Carboxamid 2,3-diamino-6-nitro-p-Truelove acid1H-NMR (DMSO-d6): 7.8 (s, 1H), 7.2 (s, 3H, NH2), 4.9 (s, 2H, NH2), 2.2 (s, 3H); 13C-NMR (DSO-d6): d 170,5, 142.1, 138.6, 134,0, 118.2, 116,4, 115.9, 109.2, 14,0; CIMS (NH3CH4) m/z 211(M+H).

7-(4-Methyl-5-nitrobenzimidazole)carboxamid so pl. 249,8oC (with decomp).1H-NMR (DMSO-d6): 8.7 (W.c. 1H, NH), 8.5 (s, 1H), and 8.4 (c, 1H), 7.8 (sh.S., 1H, NH), 2.8 (s, 3H);13C-NMR (DSO-d6): 165.7, 147.0, 143.2, 119,4, 118.9, 118,2, 15.2; CIMS (NH3CH4) m/z 221 (M+H).

7-Cyano-4-methyl-5-nitrobenzimidazole so pl. 209,4oC (with decomp)1H-NMR (DMSO-d6): 8.7 (s, 1H), 8.4 (c, 1H), 2.8 (s, 3H);13C-NMR (DSO-d6): 148.6, 142.9, 123.8, 115.5, 15.1; CIMS (NH3CH4) m/z 203 (M+H); IR (captivity): 2105.6 cm-1(CN).

5-Amino-7-cyano-4-methylbenzimidazole1H-NMR (DMSO-d6): 8.1 (s, 1H), 7.0 (s, 1H), 5.1 (sh.s, 2H, NH2), 2.2 (s, 3H);13C-NMR (DSO-d6): 142.4, 141.8, 135.9, 134.9, 118.0, 114.6 112.4, 97.7, 12.2; CIMS (NH3CH4) m/z 173 (M+H).

7-Cyano-5-isothiocyanato-4-methylbenzimidazole 1H-NMR (CD3D): 8.5 (1H), 7.8 (s, 1H), 2,4 (c, 3H); CIMS (NH3CH4) m/z 215 (M+H); IR (captivity): 2214 cm-1(CN), 2033,5 cm-1(NCS).

N-5-(7-Cyano-4-methylbenzimidazolyl)-N'-2-and the 3 CH4) m/z 275 (M+H), 173 (M+H-C3H6N2S).

Acetate 7-cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole so pl. 261-262oC,1H-NMR (D2O): 8.4 (s, 1H), 7.7 (c, 1H), 3.8 (s, 4H), and 2.6 (s, 3H), 1.9 (s, 3H). CIMS (NH3CH4) m/z 241 (M+H);

calculated: C14H16O2N61/4 H2O: C, 55.16; H, 5,46; N, 27.57.

found: C, 54.76; H, 5.33; N, 27.82.

Example 2

< / BR>
4-Ethyl-5-(2-imidazolidinone)-7-methylbenzimidazole

3-(1-Hydroxyethyl)-6-methylaniline. It chilled with ice to a solution of 4-methyl-3-nitroacetophenone (25 g, 139 mmol) in methanol (200 ml) was added sodium borohydride (6.2 g, 163 mmol) for 15 minutes. The mixture was stirred at room temperature for 1 hour, then switched off the reaction water. The mixture is evaporated in a rotary evaporator and the residue after evaporation was distributed between water and ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated in a rotary evaporator, receiving light brown viscous oil. This oil was diluted with ethyl acetate (200 ml) was added 5% palladium on coal (5 g) and the mixture was treated with hydrogen at a pressure of 40 pounds per square inch (0,28 MPa) 18 hours. The mixture is then filtered on celite, and the filtrate is evaporated in a rotary evaporator; received 3-(1-hydroxyethyl)-6-methylaniline)-6-methylaniline (21,3 g, 139 mmol), acetic anhydride (28 ml, 296 mmol), triethylamine (41 ml, 296 mmol) and 4-dimethylaminopyridine (0.5 g, 4 mmol) in methylene chloride (200 ml) was stirred at room temperature for 3 hours. Was added methanol (50 ml) and the mixture is evaporated in a rotary evaporator. The residue after evaporation was distributed between water and ethyl acetate. The organic layer was washed with water, 1 N. hydrochloric acid, water and brine, then dried (magnesium sulfate) and evaporated in a rotary evaporator. The residue after evaporation was diluted triperoxonane acid (100 ml) and cooled in an ice bath. Added diethylsilane (35 ml, 270 mmol) and the resulting mixture was stirred at room temperature for 2 hours. This mixture is evaporated in a rotary evaporator, and the residue after evaporation was purified by flash chromatography on silica gel (hexane: ethyl acetate 3: 1); received 3-ethyl-6-methylacetanilide in the form similar to a white foam solid.

2,4-Dinitro-3-ethyl-6-methylacetanilide. To ice a mixture of 3-ethyl-6-methylacetanilide (11,5 g, 64.8 mmol) and concentrated sulfuric acid (90 ml) was slowly added fuming nitric acid (7 ml). The mixture was stirred for 30 minutes in an ice bath, then for 1 hour at room temperature. The mixture was poured into ice, and the tro-3-ethyl-6-methylacetanilide and 4,5-dinitro-3-ethyl-6-methylacetanilide were separated by flash chromatography on silica gel (hexane:ethyl acetate, the gradient of the composition of from 4:1 to 2:3).

2,4-Dinitro-3-ethyl-6-methylaniline. A mixture of 2,4-dinitro-3-ethyl-6-methylacetanilide (4.0 g, 14.9 mmol), potassium carbonate (2.6 g, 19 mmol) and 6 N. hydrochloric acid (40 ml) in methanol (100 ml) was heated under reflux for 2 hours. The mixture was cooled to room temperature, brought to pH 9 with ammonium hydroxide and evaporated in a rotary evaporator. The residue after evaporation was purified by flash chromatography on silica gel (chloroform:methanol 9:1); received 2,4-dinitro-3-ethyl-6-methylaniline as a yellow solid.

4-Ethyl-5-formamido-7-methylbenzimidazole. A mixture of 2,4-dinitro-3-ethyl-6-methylaniline (2.0 g, 6,9 mmol) and iron powder (5.0 g, 90 mmol) in 90% formic acid (36 ml) was heated to boiling reflux for 18 hours. The mixture was cooled to room temperature, diluted with methanol (75 ml) and filtered through celite. The filtrate is evaporated in a rotary evaporator and the residue after evaporation was purified by flash chromatography on silica gel (chloroform: methanol 9:1); received 4-ethyl-5-formamido-7-methylbenzimidazole in the form of a yellow-brown solid.

5-Amino-4-ethyl-7-methylbenzimidazole. A mixture of 4-ethyl-5-formamido-7-methylbenzimidazole (1.7 g, at 8.36 mmol), carbon is mesh was cooled to room temperature, brought to pH 9 with ammonium hydroxide solution and evaporated in a rotary evaporator. The residue after evaporation was purified by flash chromatography on silica gel (chloroform: methanol 9:1); received 5-amino-4-ethyl-7-methylbenzimidazole in the form of a yellow-brown solid.

4-Ethyl-5-isothiocyanato-7-methylbenzimidazole. To a mixture of di-2-pyridylmethylamine (0,72 g, 3.11 mmol) and 4-dimethylaminopyridine (0.02 g) in ethyl acetate (50 ml) was added dropwise a solution of 5-amino-4-ethyl-7-methylbenzimidazole (0,42 g, 2,39 mmol) in ethyl acetate (20 ml) and methanol (5 ml). The mixture was stirred at room temperature for 3 hours, then evaporated in a rotary evaporator. The residue after evaporation was purified by filtration through a small nozzle layer of silica gel and elution with ethyl acetate; obtained 4-ethyl-5-isothiocyanato-7-methylbenzimidazole in the form of a yellow-brown solid.

4-Ethyl-5-(2-imidazolidinone)-7-methylbenzimidazole, salt with triperoxonane acid. To a mixture of Ethylenediamine (0,65 ml, to 9.66 mmol) in methylene chloride (50 ml) was added a suspension of 4-ethyl-5-isothiocyanato-7-methylbenzimidazole (0,42 g of 1.93 mmol) in methylene chloride (50 ml). The mixture was stirred 1 hour at room temperature, then evaporated on a rotary ispar remedial at room temperature for 2 hours. The mixture was filtered on celite and the solid precipitate was washed with methanol. The filtrate is evaporated in a rotary evaporator and the residue after evaporation was purified by the method of preparative liquid chromatography high pressure (ghvd) (C18 column; flow rate 45 ml/min; gradient composition solvent: 0.1% solution triperoxonane acid (in water): acetonitrile, the composition changes from the initial ratio of 95: 5 to 0:100 for 45 minutes); obtained 4-ethyl-5-(2-imidazolidinone)-7-methylbenzimidazole in the form of a salt with triperoxonane acid.

5-Amino-4-ethyl-7-methylbenzimidazole 1H-NMR (300 MHz, CD3D); 8,42 (s, 1H), 6,72 (s, 1H), 2,86 (kV, J=7.5 Hz, 2H, 2,49 (s, 3H), 1,24 (t, J=7.5 Hz, 3H). MS (APCI) m/z 176 (M+H)+.

4-Ethyl-5-isothiocyante-7-methylbenzimidazole1H-NMR (300 MHz, Dl3): of 8.27 (s, 1H), 7,65 (Shir.s, 1H),? 7.04 baby mortality (s, 1H), 3,05 (kV, J=7.5 Hz, 2H), 2,65 (s, 3H), 1,32 (t, J=7.5 Hz, 3H). MS (APCI) m/z 218 (M+H)+.

Monohydrate salt triperoxonane acid 4-ethyl-5-(2-imidazolidinone)-7-methylbenzimidazole.1H-NMR (300 MHz, DMSO-d6): 10,42 (s, 1H), 9,31 (s, 1H), 8,24 (s, 2H), 7,18 (s, 1H), to 3.64 (s, 4H), 2,88 (kV, J=7.5 Hz, 2H), by 2.55 (s, 3H), of 1.55 (t, J=7.5 Hz, 3H).13C-NMR (DMSO-d6): 160,09, 159,71, (kV, JCF= 34 Hz), 142,21, 131,66, 131,33, 130,86, 126,65, 126,54, 123,94, 117,10 (kVJCF=293 Hz), 43,38, 20,14, 16,67, 14,91, MS (APCI) m/z 244 (M+H)+2ABOUT: WITH 639.96, N.: A 4.03, N: TO 13.09. Found: C: 39,80, N: 3,90, N: 13,06.

4-Ethyl-5-formamido-7-methylbenzimidazole 1NMR (300 MHz, Dl3) (mixture of rotamers) (main) 8,32 (s, 1H), 8,16 (s, 1H), 7,19 (s, 1H), 2,93 (sq, J= 7.5 Hz, 2H), 2,54 (s, 3H), 1,24 (t, J=7.5 Hz, 3H); (minor) of 8.33 (s, 1H), 8,18 (s, 1H), 6,94 (s, 1H), 2,99 (kV, J=7.5 Hz, 2H), 2.57 m (s, 3H), 1,24 (t, J=7.5 Hz, 3H), MS (APCI) m/z 204 (M+N)+, 407 (2M+N)+.

3-(1-Hydroxyethyl)-6-methylaniline 1H-NMR (300 MHz, Dl3): 6.97 (d, J=7.8 Hz, 1H), 6.68 (c, 1H), 6.67 (d, J=7.8 Hz, 1H), 4.73 (q, J=6.6 Hz, 1H), 3.45 (sh. s, 3H), 2.12 (s, 3H), 1.42 (t, J=6.6 Hz, 3H).13C-NMR (Dl3); 150.17, 149.42, 135.32, 126.35, 120.64, 117.04, 74.88, 30.10, 22.02, MS (APCI) m/z 152 (M+N)+, 487 (2M-N2O+N)+.

3-Ethyl-6-methylacetanilide 1H-NMR (300 MHz, Dl3): 7.57 (c, 1H), 7.28 (bs, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 2.63 (q, J=7.5 Hz, 2H), 2.27 (s, 3H), 2.20 (s, 3H), 1.23 (t, J=7.5 Hz, 3H).13C-NMR (Dl3): 168.82, 143.09, 135.65, 130.57, 127.67, 127.14, 125.24, 123.42, 28.69, 24.36, 17.63, 15.79. MS (APCI) m/z 178 (M+N)+, 355 (2M+N)+.

2,4-Dinitro-3-ethyl-6-methylacetanilide1H-NMR (300 MHz, Dl3): 9.16 (bs, 1H), 7.82 (c, 1H), 2.70 (q, J=7.5 Hz, 2H), 2.28 (c, 3H), 2.09 (c, 3H), 1.21 (t, J=7,5 Hz, 3H).13C-NMR (Dl3): 169.78, 147.78, 138.52, 132.65, 128.87, 40.18, 22.18, 21.88, 18.48, 14,96, MS (APCI, AP-scan) m/z 266 (M-N).

2,4-Dinitro-3-ethyl-6-methylaniline 1H-NMR (300 MHz, Dl3): 7.75 (c, 1H), 5.38 (b, 2H) m/z 224 (M-N).

Example 3

< / BR>
4-Cyclopropyl-5-(2-imidazolidinone)-7-methylbenzimidazole

Commercially available 1-(4-were)-1-cyclopropanecarbonyl acid was treated with tetrafluoroborate nitronium in sulfolane, and obtained 1-(4-methyl-3-nitrophenyl)-1-cyclopropanecarbonyl acid. This compound was converted to 1-(4-methyl-3-nitrophenyl)-1-bromocyclopropane treatment with mercuric oxide and bromine in methylene chloride. By restoring the zinc dust in the presence of calcium chloride in aqueous ethanol received a 5-cyclopropyl-2-methylaniline. The transformation of 4-cyclopropyl-5-(2-imidazolidinone)-7-methylbenzimidazole completed in the same way as in the case of 4-ethyl-5-(2-imidazolidinone)-7-methylbenzimidazole (see example 2).

Example 3': Salt Hydrobromic acid 4-cyclopropyl-5-(2-imidazolidinone)-7-methylbenzimidazole

6 Brom-2'-methylacetanilide Mixture of 4-bromo-2-nitrotoluene (10.8 g, 50 mmol), iron powder (12,6 g, 225 mmol) and glacial acetic acid (100 ml) was stirred and heated at 105oC (oil bath) for 18 hours. After cooling to room temperature the reaction mixture was treated with acetic anhydride (2.55 g, 2.35 ml, 25 mmol) and stirred at room temperature for 1.5 hours.ELISA and neorganicheskoi salts. The obtained filtrate was evaporated in a rotary evaporator to obtain 6'-bromo-2'-methylacetanilide in the form of a light brown solid (11 g, yield 96%) which was used in the next stage without additional purification. MS (c.i.): m/z 229 [M+H]+.

6'-Bromo-4', 7'-dinitro-2'-methylacetanilide. To a mixture of 6'-bromo-2'-methylacetanilide (10.8 g, of 47.3 mmol) and glacial acetic acid (8 ml) was added sulfuric acid (55 ml, 98%). Under stirring in a mixture of sulfuric acid was added dropwise fuming HNO3(7.5 g, 4.8 ml, 119 mmol) while the reaction temperature below 5oC. After the addition, the reaction mixture was stirred for 30 minutes at a temperature below the 5oC, 1.5 hours at room temperature and then poured into ice. After filtration the precipitate was washed with 10% NaHCO3(28 ml) and water (420 ml) and then dried in vacuum for 24 hours to obtain 6'-bromo-4', 7'-dinitro-2'-methylacetanilide in a solid yellow color (to 13.6 g, yield 90%) which was used in the next stage without additional purification.1H-NMR (Meon); of 2.08 (s, 3H, CH3); of 2.28 (s, 3H, CH3); of 7.97 (s, 1H, Ar). MS: m/z 336 [M+H]+.

6'-Cyclopropyl-4', 7'-dinitro-2'-methylacetanilide. A mixture of 6'-bromo-4',7'-dinitro-2'-methylacetanilide (0,364 g to 1.14 mmol), calaminariae at 115oC for 1.5 hours and then was added silver nitrate (0.2 g, 1.2 mmol). The reaction mixture is boiled under reflux (115oC) for 7 hours. Added additional amount of Pd(PPh3)4(0.15 g) and the reaction mixture was stirred at 115oC for 1 hour, after which was added another portion of silver nitrate (0.12 g). The mixture was boiled under reflux at a temperature of 115oWith over 7 hours. Cycle added Pd(PPh3)4and silver nitrate and boiling under reflux was repeated two more times, after which HPLC and TLC showed that the starting material was consumed. The reaction mixture was filtered through celite, washed with ethyl acetate and then evaporated in a rotary evaporator. The obtained residue was dissolved in acetonitrile and separated by means of preparative HPLC. Removing the solvent from fractions containing product gave 6'-cyclopropyl-4',7'-dinitro-2'-methylacetanilide as a pale yellow solid (0.1 g, 30% yield).1H-NMR (Dl3): 0,36 (m, 2H, CH2); to 1.70 (m, 1H, CH); 2,17(s, 3H, CH3); 7,30 (s, 1H, NH); of 7.69 (s, 1H, Ar); MS: m/z 280 [M+H]+.

2-Amino-3,5-dinitro-4-cyclopropylethanol 6'-cyclopropyl-4', 7'-dinitro-2'-methylacetanilide (0,23 g 0,82 is I) within 17 hours. Added an additional amount of sodium methoxide (2.5 ml, 0.5 M, 1.25 mmol) and the reaction proceeded for 18 hours at 100oC. removing the solvent on a rotary evaporator gave a brown residue, which was dissolved in triperoxonane acid (0.5 ml) and a minimum amount of methanol and then purified preparative HPLC. Removing the solvent from fractions containing product gave 2-amino-3,5-dinitro-4-cyclopropylethanol in a solid yellow color (has 0.168 g, yield 86%).13C-NMR (Dl3): 7,04, 13,04, 17,81, 123,20, 128,67, 134,27, 142,61, 145,21, 149,32.

4-Cyclopropyl-7-methyl-5-formallynominated. A mixture of 2-amino-3,5-dinitro-4-cyclopropylethanol (0,165 g, 0.7 mmol), iron powder (0.34 g, 6.1 mmol) and formic acid (9 ml, 90%) was stirred at 120oC (oil bath) for 17 hours. The mixture was filtered through a syringe filter (PVDF 0.45 mm, Whatman), washed with formic acid, evaporated to dryness on a rotary evaporator. The obtained residue together evaporated with methanol/triperoxonane acid (20: 1) three times, then was purified preparative HPLC. Removal of solvent gave 4-cyclopropyl-7-methyl-5-formallynominated as not quite white solid (0.14 g, yield 93%). MS: m/z 216 [M+H]+Azolla (0.14 g, of 0.65 mmol) and sodium methoxide (2,6 ml, 0.5 M, 1.3 mmol) in methanol (8 ml) was stirred at 100oC (oil bath) for 12 hours. Removal of solvent on a rotary evaporator gave the crude product, which was dissolved in triperoxonane acid (0.5 ml) and a minimum amount of methanol and then purified preparative HPLC. Removing the solvent from fractions containing product gave 5-amino-4-cyclopropyl-7-methylbenzimidazole in a solid yellow color (0,116 g, yield 95%).1H-NMR (CD3OD): 0,75 (m, 2H, CH2); to 1.23 (m, 2H, CH2); 2,00 (m, 1H, CH3); of 5.53 (s, 2H, NH2); 7,21 (s, 1H, Ar); 9,39 (s, 1H, NH);13C-NMR (CD3D): 7,30, 7,94, 16,85, 117,42, 121,43, 126,49, 129,98, 133,46, 136,58, 141,70. MS: m/z 188 [MN]+.

4-Cyclopropyl-5-isothiocyanato-7-methylbenzimidazole 5-amino-4-cyclopropyl-7-methylbenzimidazole (0.16 g, 0.86 mmol), DPTs (0,204 g of 0.878 mmol), D is 0.019 g, 0,155 mmol) and methylene chloride (15 ml) were combined and stirred at room temperature for 4 hours. The reaction mixture was filtered and the residue was washed with methylene chloride, receiving 4-cyclopropyl-5-isothiocyanato-7-methylbenzimidazole in the form of a solid, sufficiently pure for use in the next stage. The filtrate was purified preparative HPLC with getting established exit 63% (0,122 g).1H-NMR (Dl3): 0,83 (m, 2H, CH2); of 1.20(m, 2H, CH2); 2,00 (m, 1H, CH); of 2.56 (s, 3H, CH3); 7,07 (s, 1H, Ar); of 8.90 (s, 1H, Ar);13C-NMR (Dl3): 7,10, 8,88, 16,45, 124,01, 124,45, 125,10 129,50, 131,64, 132,66, 137,01, 140,68. MS: m/z 230 [MN]+.

4-Cyclopropyl-5-(2-imidazolidinone)-7-methylbenzimidazole. To a solution of Ethylenediamine (0,144 g, 0.16 ml, 2.4 mmol) in methylene chloride (2 ml) was added a solution of 4-cyclopropyl-5-isothiocyanato-7-methylbenzimidazole (0,122 g of 0.53 mmol) in methylene chloride (10 ml). The reaction mixture was stirred for 4 hours at room temperature and then evaporated on a rotary evaporator. The residue was mixed with methanol (10 ml) and acetate mercury (0.17 g, of 0.53 mmol). The color of the mixture rapidly changed from light yellow to black. The reaction mixture was stirred over night at room temperature, was treated with a solution of Na2S9H2O (0,128 g of 0.53 mmol) in N2About (2 ml), filtered through a syringe filter (PVDF 0.45 mm, Whatman), and then evaporated on a rotary evaporator. The obtained residue together evaporated with methanol/triperoxonane acid (10: 1) three times, then was purified preparative HPLC. Removing the solvent from fractions containing product gave salt triperoxonane acid, which was dissolved in the minimum quantity is the Aquum obtaining salts of Hydrobromic acid 4-cyclopropyl-5-(2-imidazolidinone)-7-methylbenzimidazole (0,166 g, yield 67%) as a solid yellow color.1H-NMR (CD3OD): 0,71 (m, 2H, CH2); to 1.23 (m, 2H, CH2); 2,07 (m, 1H, CH); of 2.66 (s, 3H, CH3); a 3.83 (s, 4H, CH2CH2), was 7.36 (s, 1H, Ar); a 9.60 (s, 1H, Ar);13C-NMR (CD3D): 7,55, 9,31, 17,03, 44,79, 125,50, 126,53, 127,87, 13,67, 133,62, 135,10, 142,54, 160,95. MS: m/z 256 [MN]+.

Example 4

< / BR>
7-Hydroxy-5-(2-imidazolidinyl)-4-methylbenzimidazole

4,6-Dimethyl-5-isothiocyanatobenzene. A mixture of 5-amino-4,6-dimethylbenzimidazole (265 mg, of 1.64 mmol), tetrahydrofuran (20 ml), di-2-pyridylmethylamine (584 mg, is 1.81 mmol) and 4-dimethylaminopyridine (20 mg, to 0.016 mmol) was stirred at room temperature for 2 hours. The mixture is evaporated in a rotary evaporator, and the residue after evaporation was purified by chromatography on silica gel (hexane: ethyl acetate 50:50); received 4,6-dimethyl-5-isothiocyanatobenzene in the form of a whitish solid.

4,6-Dimethyl-5-(2-imidazolidinone)benzimidazole. A solution of 4,6-dimethyl-5-isothiocyanatobenzene (250 mg, of 1.23 mmol) in methylene chloride (5 ml) was added dropwise to a solution of Ethylenediamine (370 mg, 6.2 mmol) in methylene chloride (5 ml). The resulting solution was stirred at room temperature for 15 minutes, then evaporated in a rotary evaporator. The residue after vipasyana the mixture was stirred at room temperature for 1 hour, was filtered through a layer of silica gel and evaporated in a rotary evaporator. The residue after evaporation was purified by chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide 70:50:0,5); received 4,6-dimethyl-5-(2-imidazolidinone)benzimidazole as a white solid.

Example 4': Salt triperoxonane acid 7-hydroxy-5-(2-imidazolidinyl)-4-methylbenzimidazole.

N-Acetyl-2-methoxy-5-methyl-4-nitroaniline: a Solution of 5-methyl-2-methoxyaniline (13,72 g, 100 mmol) in a mixture of acetic acid (30 ml) and water (21,7 ml) was cooled to 0-5oWith the help of ice (35 g) and immediately with rapid stirring, was added acetic anhydride (10.3 ml). Within a few seconds the reaction mixture was hardened with the formation of a crystalline mass, and the temperature rose to about 20oC. Then the flask was heated in a water bath at 80oWith to dissolve the solid mass. After cooling to 45oWith stirring, the crystals began to separate from the mixture. The reaction flask was again cooled in an ice bath was added 70% nitric acid (10 ml, 158 mmol) the entire quantity immediately. The temperature of the mixture was rapidly increased up to 75oS, after which the flask was cooled to 60-65oC. the Mixture was left at this temperature amywali ice water and dried in vacuum to obtain 14,02 g (62.5%) and N-acetyl-2-methoxy-5-methyl-4-nitroaniline, which, as shown by HPLC analysis (Tg=min 11,4), had >96% purity and was used in the next stage without additional purification: 1H-NMR (Dl3) 8,43 (s, 1H), 7,93 (Shir. s, 1H), 7.62mm (s, 1H), 3,95 (s, 3H), 2.63 in (s, 3H), of 2.25 (s, 3H);13C-NMR (Dl3) 168,84, 145,71, 132,64, 129,05, 122,25, 106,80, 56,52, 25,31, 21,29.

N-Acetyl-4,6-dinitro-2-methoxy-5-methylaniline.

Tetrafluoroborate nitronium (200 ml, 0.5 M in sulfolane, 100 mmol) for 2.5 hours was added dropwise to a stirred solution of N-acetyl-2-methoxy-5-methyl-4-nitroaniline (14,02 g, 62.5 mmol) in dichloromethane (500 ml) at -78oC. After addition the mixture was stirred for 10 minutes at -78oC and then maintained at 0oC for 1 hour. Volatiles were removed on a rotary evaporator and to the residue was added to 1.8 l of ice water, and the mixture was stirred over night. The yellow precipitate was collected, washed with water and dried in vacuum to obtain 15,97 g regioisomeric mixture dinitroanilines. After fractional crystallization of this mixture from methanol and the mixture was washed with a simple ether with getting 9,79 g (58.2 per cent) N-acetyl-4,6-dinitro-2-methoxy-5-methylaniline with <1% N-acetyl-3,4-dinitro-2-methoxy-5-methylaniline according to HPLC (Tto= 10,1 12,8 min versus min):1H-NMR (Dl3) a 7.62 (s, 1H), 7,19 (sho-d6) 168,50, 153,57, 149,55, 148,37, 123,86, 116,60, 110,34, 56,55, 21,73, 13,84. MS (DCI) m/z=287,1 (M+NH4)+.

4,6-dinitro-2-methoxy-5-methylaniline. The alkaline solution of Clausena (Claisen) (obtained by dissolving 8.8 g of KOH in 6.3 ml of water and diluting a mixture of 25 ml of methanol, 13 ml, 82 mmol) was added to a solution of N-acetyl-4,6-dinitro-2-methoxy-5-methylaniline (5,385 g, 20 mmol) in methanol (50 ml). The resulting mixture was boiled under reflux in an argon atmosphere for 5 hours, and the solvent was then removed using a rotary evaporator. The residue was combined with 700 ml of ice water and allowed to stand over night. Red-orange crystals were collected, washed with water and dried in vacuum to obtain 4,01 g (88%) of 4,6-dinitro-2-methoxy-5-methylaniline, which according to HPLC analysis (Tr= 13,3 min) had a purity >99%: 1H NMR (Dl3) of 7.75 (s, 1H), 5,61 (Shir.s, 2H), 4,01 (s, 3H), of 2.56 (s, 3H); MS (DCI) m/z=245,0 (M+NH4)+.

5-Formylamino-7-methoxy-4-methylbenzimidazole. Iron powder (-325 mesh, 5,682 g, 102 mmol), 4,6-dinitro-2-methoxy-5-methylaniline (2,271 g, 10.0 mmol) and formic acid (99%, 70 ml) were combined and heated under reflux in an argon atmosphere with stirring for 18 hours. After adding to the warm fluid mixture of concentrated Hcl (5,4 mW mass continued to heat up at 100-125oC for 2.5 hours. After cooling to room temperature, the solid was extracted with methanol (~300 ml) and the extracts were filtered through celite. The filtrate was concentrated and purified flash chromatography on silica gel using as eluents first 1: 10: 190, and then 1:10:90 ammonium hydroxide/methanol/chloroform. After combining the fractions containing the product were obtained 1.20 g (58,5%) of compound 6 in a solid beige and 1.27 g of a mixture of 5-formylamino-7-methoxy-4-methylbenzimidazole and the product of hydrolysis of 5-amino-7-methoxy-4-methylbenzimidazole; 1H-NMR (CD3D) of 8.33 (s, 1H), 8,08 (s, 1H), 7,00 (s, 1H), 4,89 (Shir.C ~6N), of 3.97 (s, 3H), 2,42 (s, 3H); MS (APCI) m/z=206,1 (M+N)+.

5-Amino-7-methoxy-4-methylbenzimidazole a Mixture of 5-formylamino-7-methoxy-4-methylbenzimidazole (258,6 mg of 1.26 mmol), anhydrous potassium carbonate (251,4 mg, 1.82 mmol) and 6 N. hydrochloric acid (4.0 ml, 24 mmol) was boiled under reflux in methanol (15 ml) for 3 hours and the solvent was removed using a rotary evaporator. To solid substance pale lilac with a bronze tint color was added water (10 ml), the mixture was podslushivaet to pH 11 and the solution was extracted with ethyl acetate (520 ml) and chloroform (20 ml). The combined organic SL is ukta 5-amino-7-methoxy-4-methylbenzimidazole in the form of a solid brownish-beige color:1H-NMR (CD3D) 7,83 (s, 1H), 6,38 (s, 1H), 4.95 points (Shir.s, 1H), 3,92 (s, 3H), of 2.28 (s, 3H); MS (APCI) m/z=178,3 (M+N)+.

5-Isothiocyanato-7-methoxy-4-methylbenzimidazole. Di-2-peridition (138,1 mg to 0.60 mmol) and 4-dimethylaminopyridine (17.5 mg, 0.14 mmol) was combined with 5-amino-7-methoxy-4-methylbenzimidazole (93.4 in mg, of 0.53 mmol) in anhydrous methylene chloride (20 ml) and this suspension was stirred for 4 hours at room temperature. The reaction mixture was concentrated on silica gel and purified flash chromatography on silica gel using as eluents 1: 1 ethyl acetate/hexane 1:9 methanol/chloroform to obtain 73 mg (63%) 5-isothiocyanato-7-methoxy-4-methylbenzimidazole in a solid yellow color:1H-NMR (CD3D) 8,17 (s, 1H), 6,72 (s, 1H), 3,98 (s, 3H), of 2.54 (s, 3H); MS(APCI) m/z=to 220.1 (M+N)+.

1-(2-amino-ethyl)-3-(7-methoxy-4-methyl-1H-benzoimidazol-5-yl)-thiourea. To a stirred solution of Ethylenediamine (0.3 ml, 4.5 mmol) in benzene (75 ml) at room temperature was added a solution of 5-isothiocyanato-7-methoxy-4-methylbenzimidazole (73 mg, 0.33 mmol) in tetrahydrofuran (12 ml). The resulting mixture was stirred at room temperature for 2 hours and concentrated in vacuo to about 20 ml of the sediment somesimilar-5-yl)-thiourea, which as shown by HPLC analysis (Tr=was 2.76 min), had >99.7% of purity; MS(DCI) m/z= 280,1 (M+N)+.

5-(2-Imidazolidinone)-7-methoxy-4-methylbenzimidazole. To a stirring solution of 1-(2-amino-ethyl)-3-(7-methoxy-4-methyl-1H-benzimidazole-5-yl)-thiourea (93 mg, 0.33 mmol) in methanol (10 ml) was added acetate mercury (111,5 mg, 0.35 mmol) and the resulting bright yellow mixture was heated under reflux for 1 hour. After cooling the mixture of black color was filtered through a short column with silica gel, which was then washed with chloroform/methanol/ammonium hydroxide (70:30:1). The fractions containing the product were combined and concentrated in vacuo to obtain a syrup, which was dissolved in methanol and treated triperoxonane acid. After precipitation of the product by a simple broadcast received 46 mg (29%) 5-(2-imidazolidinone)-7-methoxy-4-methylbenzimidazole(2,0 TN)(0.6 N2(O):1H-NMR (CD3D) 9,19 (s, 1H), 7,03 (s, 1H), 4,90 (s, 5H), 4,07 (s, 3H), 3,81 (s, 4H), of 2.50 (s, 3H);13WITH NMR (CD3D) 159,78, 146,69, 140,56 (NOE), 134,50, 131,07, 123,00, 114,94, 105,70 (NOE), 57,65, 43,10, 10,51;19F-NMR (CD3D) 89,68; MS (DCI) m/z= 246,1 (M+N)+. Anal. (C, H, N): Expect. for C12H15N5O(2,0 CF3CO2N)(0,6)H2O (MW 484,14)=39,69%, 3,789% H, of 14.46% N, found = 39,93% mmol) and 5-(2-imidazolidinone)-7-methoxy-4-methylbenzimidazole (2,0 HOAc) (210,1 mg, 575 μmol) were combined in a sealed flask and was heated at 210-215oWith stirring for 1.5 hours. After cooling to room temperature, to a hardened mass was added water (11 ml), the pH of the obtained brown solution was brought to 8 by using 10 N. aqueous solution of sodium hydroxide (~3,1 ml) and the volatiles removed in vacuum. The residue containing the product were extracted in methanol, and treated with TN and was purified preparative HPLC. The fractions containing the product was additionally purified flash chromatography on silica gel using as eluent methanol/acetic acid (60:40). After processing the vitreous product in methanol 30% Nug in acetic acid and precipitation by a simple broadcast received untreated sample hydrobromide salt, which was purified preparative HPLC. The final crystallization from methanol/simple ether gave 46.4 mg (18%) 7-hydroxy-5-(2-imidazolidinyl)-4-methylbenzimidazole(2,0 TN) as white solids:1H-NMR (CD3D) 9,23 (s, 1H), 6,83 (s, 1H), 4.92 in (lat.s, 8H), 3,86 (s, 4H), 2,47 (s, 3H); 13C-NMR (CD3D) 161,32, 146,27, 141,83 (NOE), 135,54, 132,93, 123,94, 114,51, 110,73 (NOE), 44,65, 11,99; MS (APCI) m/z= 232,2 (M+H)+. Anal. (C, H, N): Expect. for C11H13N5O (2,0 CF3COis ylamino) benzimidazole

5-Chloro-2,4-dinitro-m-xylene1H-NMR (Dl3) 7,33 (s, 1H), 2,34 (s, 3H), of 2.33 (s, 3H);13C-NMR 150,43, 146,43, 132,89, 130,37, 126,42, 124,20, 17,25, 12,95; CIMS (NH3CH4) m/z=231 (M+H).

5-Azido-2,4-dinitro-m-xylene1H-NMR (Dl3) 7,05 (s, 1H), 2.40 a (s, 3H), of 2.23 (s, 3H);13C-NMR 133,95, 133,46, 124,72, 118,98, 17,73, 12,77; CIMS (NH3CH4) m/z=255 (M+NH4), 238 (M+H).

4,6-Dimethyl-5-nitrobenzimidazole.1H-NMR (CD3D) 8,23 (s, 1H), 7,34 (s, 1H), 2.49 USD (c, 3H), of 2.36 (s, 3H); IS (NH3CH4) m/z=192 (M+H), 162 (M+H-NO).

5-Amino-4,6-dimethylbenzimidazole. 1H-NMR (CD3D) 7,89 (s, 1H), 7,14 (s, 1H), a 2.36 (s, 3H), and 2.27 (s, 3H);13C-NMR (CD3D) 140,31, 139,83, 137,14, 121,64, 114,68, 108,24, 18,69, 11,58; CIMS (NH3CH4) m/z=162 (M+H).

4,6-Dimethyl-5-(2-imidazolidinone)benzimidazole, salt luxusni acid. So pl. 180-185oC (decomp. );1H-NMR (CD3D): 8,1 (s, 1H), and 7.4 (s, 1H), 3,9-3,6 (m, 4H), of 2.5 (s, 3H), of 2.35 (s, 3H), and 1.9 (C, 6N); CIMS (NH3CH4) m/z=230 (M+H); Anal. Calculated for C16H23N5O4:: 55,00, R.: 6,64, N: 20,04. Found: C: 55,21, N: 6,82, N: 20,27.

Example 6: Salt triperoxonane acid 6-bromo-5-(2-imidazolidinyl)-4-methylbenzimidazole

N-Acetyl-3,6-dinitro-2-methylaniline. To a chilled (ice bath) of concentrated sulfuric acid drop is the rate, in order to maintain the internal temperature within 4-7oC. At the end of the addition the temperature slowly gave rise to the 15oSince, at this point, the mixture was poured on crushed ice (750 ml). After the ice melted, the precipitate was filtered, washed several times with water and dried in vacuum to obtain 34.4 g (93%) 1/1 mixture of N-acetyl-3,6-dinitro-2-methylaniline and N-acetyl-3,4-dinitro-2-methylaniline. These two isomers were not separated. MS (Cl/NH4) m/z 257 (M+NH4)+. N-acetyl-3,6-dinitro-2-methylaniline: 1P-NMR (Dl3) 9,58 (Shir. s, 1H), 7,74 (d, J=9,2 Hz, 1H), 7,66 (d, J=9,2 Hz, 1H), and 2.27 (s, 3H), 2.06 to (c, 3H). N-acetyl-3,4-dinitro-2-methylaniline: 1H-NMR (Dl3) of 9.30 (broad s, 1H), 8,01 (d, J=9,2 Hz, 1H), 7,87 (d, J=9,2 Hz, 1H), 2,03 (C, 6N).

3,4-Dinitro-2-methylaniline. Suspension 1/1 mixture of N-acetyl-3,6-dinitro-2-methylaniline and N-acetyl-3,4-dinitro-2-methylaniline (16,14 g, 67 mmol) in 50% sulfuric acid (100 ml) was heated to 85-90oC for 3 hours. The mixture was poured into water (200 ml) and after 30 minutes the precipitate was filtered and washed with water. The solid was purified flash chromatography on silica gel with elution with a gradient from 30% to 70% ethyl acetate in hexane to obtain 7,52 g (56%) of 3,4-dinitro-2-methylaniline in a solid yellow color. So pl. 220oC ( 1/1 solution of acetic acid/methylene chloride (100 ml) was added dropwise bromine (0,52 ml, 10,14 mmol). The mixture was stirred at room temperature and the reaction was monitored using HPLC. Aliquots of bromine (0.2 ml) was added after 3 and 6 hours, and the mixture was stirred in General within 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, neutralized with ammonium hydroxide and was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and was evaporated on a rotary evaporator to obtain 1.66 g (59%) of 5-bromo-3,4-dinitro-2-methylaniline in the form of a solid substance.1H-NMR (CD3D) 8,32 (s, 1H), to 4.87 (s, 2H), 2.13 and (s, 3H). MS (Cl/NH4) m/z 293 (M+NH4)+.

6-Bromo-5-formamido-4-methylbenzimidazole. A mixture of 5-bromo-2-methylaniline (2.66 g, 9,63 mmol), iron powder (5,38 g, 96.3 mmol) and 90% formic acid (100 ml) was boiled under reflux for 24 hours. The mixture is then filtered on celite with washing solids with methanol. The filtrate was evaporated on a rotary evaporator, and the residue was purified flash chromatography on silica gel, elwira chloroform/methanol 9/1 with obtaining 1.5 g (61%) of 6-bromo-5-formamido-4-methylbenzimidazole in the form of solids. MS(APCI) m/z 254 (M+N)+.

5-Amino-6-bromo-4-methylbenzimidazole. A mixture of 6-bromo-5-formamido-4-methylbenzimidazole (1.5 g, 5,Tim refrigerator for 3 hours. The mixture was evaporated on a rotary evaporator, and the residue was diluted with water, podslushivaet with ammonium hydroxide and was extracted with ethyl acetate. The extracts were dried (magnesium sulfate) and was evaporated on a rotary evaporator to obtain 1 g (75%) of 5-amino-6-bromo-4-methylbenzimidazole in the form of a solid substance.1H-NMR (300 MHz, CD3D): 9,77 (s, 1H), EUR 7.57 (s, 1H), 4.91 (Shir.s, 3H), of 2.44 (s, 3H). MS (APCI) m/z 226 (M+N)+.

6-Bromo-5-isothiocyanato-4-methylbenzimidazole. To a heated (45o(C) suspension of 5-amino-6-bromo-4-methylbenzimidazole (1 g, was 4.42 mmol) in ethyl acetate (150 ml) was added di-2-parititioning (2.15 g, 9.28 are mmol). After stirring for 1 hour at 45oWith the suspension turned into a clear solution, and heating bath was removed. Added an aliquot of di-2-pyridylmethylamine (1 g) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated on a rotary evaporator, and the residue was purified flash chromatography (hexane/ethyl acetate) to give 6-bromo-5-isothiocyanato-4-methylbenzimidazole. NMR (300 MHz, CD3D): 8,84 (s, 1H), 8,31 (s, 1H), 2,75 (s, 3H).

Salt triperoxonane acid 4-bromo-5-(2-imidazolidinyl)-1-methylbenzimidazole. To a mixture of Ethylenediamine (1.3 ml, 19 mmol) in methylenechloride was stirred for 3 hours at room temperature, then evaporated on a rotary evaporator. The residue was diluted with methanol (100 ml) was added acetate mercury (1.27 g, 4 mmol). The mixture was stirred at room temperature for 3 hours. The mixture of black color filters on celite with methanol wash of the solids. The filtrate was evaporated on a rotary evaporator, and the residue was diluted with methanol (10 ml), treated triperoxonane acid (2 ml) and evaporated on a rotary evaporator. The residue was purified preparative HPLC (C18 column; flow rate 45 ml/min; gradient of solvent a: 0.1% of triperoxonane acid (in water)/acetonitrile, starting with 95/5 and to 0/100 over 45 minutes) to obtain 4-bromo-5-(2-imidazolidinone)-benzimidazole in the form of a salt triperoxonane acid (0,225 g). MS (APCI) m/z 329 (M+N)+. NMR (300 MHz, DMSO): (mixture of rotamers) the 10.40 (s, 1H), 8,63 and of 8.27 (s, 1H), 8,10 and 7.94 (s, 1H), 6,00 (Shir. s, 2H, NH), 3.72 points and 3,61 (Shir.s, 4H), of 2.51 and 2,49 (s, 3H). Anal. Calculated for C15H14N5O4BrF6C : 34,50, H: 2,70, N: 13,40. Found: C: 34,44, H: 2,70, N: 12,98.

Example 9

< / BR>
2,4-Dimethyl-5-(2-imidazolidinone)benzimidazole

2,3-Diamino-6-nitrotoluene. To a solution of 3-methyl-2,4-dinitroaniline (30 g) in boiling ethanol (750 ml) was added dropwise within 90 minutes the solution nonahydrate of sodium sulfide (109,6) - Rev. ed (2000) and left to stand until until all the ice has not melted. The mixture was then extracted with methylene chloride, and the organic layer was dried over magnesium sulfate and evaporated in a rotary evaporator. The residue after evaporation was purified flash chromatography on silica gel with elution with methylene chloride; obtained 2,3-diamino-6-nitrotoluene as an orange solid.

2,4-Dimethyl-5-nitrobenzimidazole. A mixture of 2,3-diamino-6-nitrotoluene (0,945 g, the 5.65 mmol), concentrated hydrochloric acid (5 ml) and glacial acetic acid (30 ml) was heated under reflux for 2 hours. The mixture was cooled to room temperature, then was poured into a mixture of crushed ice (100 ml) and ammonium hydroxide (100 ml) and was extracted with a solution of 20% methanol in chloroform (2400 ml). The combined extracts were dried over potassium carbonate and evaporated in a rotary evaporator; received 2,4-dimethyl-5-nitrobenzimidazole in the form of a brown solid. This product is used in the next stage without further purification.

1-tert-Butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole. A mixture of 2,4-dimethyl-5-nitrobenzimidazole (0,63 g, 4.3 mmol), di-tert-butyl-dicarbonate (0.24 g, the 10.8 mmol), triethylamine (0,725 ml, 5.2 mmol) and 4-dimethylaminopyridine (0.05 g) in ethyl acetate (45 ml) was stirred the Oia was purified flash chromatography on silica gel with elution with a solution of 10% ethyl acetate in hexane; received 1-tert-butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole in the form of a white solid.

5-Amino-1-tert-butoxycarbonyl-2,4-dimethylbenzimidazole. To a solution of 1-tert-butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole (1.26 g, 4,32 mmol) in methanol (15 ml) and ethyl acetate (100 ml) was added 10% palladium on coal (0.1 g) and ammonium formate (1,09 g, 17.3 mmol). The mixture was stirred at room temperature for 3 hours, then filtered on celite with leaching solid residue with methanol. The filtrate is evaporated in a rotary evaporator, and the residue after evaporation was purified flash chromatography on silica gel with elution 20% solution of ethyl acetate in hexane; received 5-amino-1-tert-butoxycarbonyl-2,4-dimethylbenzimidazole in the form of a white solid.

1-tert-Butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzene. A solution of 5-amino-1-tert-butoxycarbonyl-2,4-dimethylbenzimidazole (1.1 g, 4.2 mmol) in methylene chloride (60 ml) was added dropwise during 30 minutes to a solution of di-2-pyridylmethylamine (1,9 g, 8.2 mmol) and 4-dimethylaminopyridine (0.1 g) in methylene chloride (150 ml). The mixture was stirred 2 hours at room temperature and then evaporated in a rotary evaporator. The residue after evaporation was purified flash chromatography n is-5-isothiocyanatobenzene in the form of a white solid.

N-(1-tert-Butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiomethyl. A solution of 1-tert-butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzene (1,15 g, 3.8 mmol) in methylene chloride (100 ml) was added dropwise within 15 minutes to 1,2-Ethylenediamine (1,26 ml of 18.9 mmol) in solution in methylene chloride (200 ml). The mixture was stirred 2 hours at room temperature. The mixture is evaporated in a rotary evaporator and the residue after evaporation was washed with ether (150 ml) for 1 hour at room temperature. The solid was filtered and dried in a vacuum; received N-(1-tert-butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiomethyl in the form of a white solid.

2,4-Dimethyl-5-(2-imidazolidinone)benzimidazole. A mixture of N-(1-tert-butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl-N'-2-aminoethylthiomethyl (1,33 g, 3,66 mmol) and acetate mercury (1.45 g, of 4.54 mmol) in methanol (150 ml) was stirred at room temperature for 1 hour. Received the black mixture was filtered on celite, washing the solid residue on the filter with methanol. The filtrate is evaporated in a rotary evaporator, and the residue after evaporation was purified flash chromatography on thin layer silica gel with elution with a mixture of 10% methanol in chloroform containing 1% hydroxy shall imethyl-5-(2-imidazolidinone)-benzimidazole in the form of a white solid.

2,3-Diamino-6-nitrotoluene1H-NMR (Dl3) 7,37 (d, J=9,2 Hz, 1H), 6,50 (d, J= 9,2 Hz, 1H), 2,87 (broad s, 4H), of 2.33 (s, 3H). MS (C1/CH4) m/z 168 (M+N)+.

2,4-Dimethyl-5-nitrobenzimidazole 1H-NMR (CD3D) 7,87 (d, J=8,8 Hz, 1H), 7,33 (d, J=8,8 Hz, 1H), 4,90 (broad s, 1H), has 2.56 (s, 3H). MS (Cl/CH4) m/z 192 (M+N)+.

1-tert-Butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole1H-NMR (Dl3) 7,98 (d, J=8,8 Hz, 1H), 7,80 (d, J=8,8 Hz, 1H), 2,88 (s, 3H), 2,85 (s, 3H), 1,72 (s, N).13C-NMR (Dl3) 154,70, 148,06, 145,16, 141,93, 126,74, 120,91, 112,16, 88,59, 27,97, 18,50, 13,98. MS(C1/CH4+NH4) m/z 292 (M+N)+, 192 (M+H-BOC)+.

5-Amino-1-tert-butoxycarbonyl-2,4-dimethylbenzimidazole1H-NMR (Dl3) 7,53 (d, J=8,8 Hz, 1H), 6,69 (d, J=8,8 Hz, 1H), 3,51 (broad s, 2H), 2,77 (s, 3H), 2,42 (s, 3H), 1,67 (s, N).13C-NMR (Dl3) 152,58, 149,06, 141,93, 140,84, 125,80, 112,69, 112,31, 112,15, 84,75, 28,02, 18,40, 10,69. MS (Cl/CH4+NH4) m/z 262 (M+N)+.

1-tert-Butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzene 1H-NMR (Dl3) of 7.70 (d, J=8,8 Hz, 1H), 7,14 (d, J=8,8 Hz, 1H), 2,82 (s, 3H), of 2.64 (s, 3H), 1.70 to (C, N).13C-NMR (Dl3) 153,99, 148,70, 141,61, 134,83, 131,16, 126,77, 126,13, 122,06, 112,72, 85,99, 27,99, 18,43, 12,57. MS (Cl/CH4+NH4) m/z 304 (M+N)+.

N-(1-tert-Butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N'-2-aminoet who 2H), of 2.30 (s, 3H), 1,60 (s, N).13C-NMR (Dl3) 181,41, 152,36, 148,32, 141,38, 130,68, 126,08, 124,19, 111,66, 85,28, 47,04, 40,68, 27,47, 18,03, 11,82. MS (Cl/CH4+NH4) m/z 364 (M+N)+.

2,4-Dimethyl-5-(2-imidazolidinone)benzimidazole dihydrobromide So pl. : 316-320oC (decomp.)1H-NMR (DMSO-d6) 10,24 (s, 1H), 8,14 (s, 2H), 7,63 (d, J= 8,8 Hz, 1H), 7,33 (d, J=8,8 Hz, 1H), 3,60 (s, 4H), 2,80 (s, 3H), 2,42 (s, 3H).13C-NMR (DMSO-d6) 158,63, 152,39, 131,61, 130,75, 130,03, 125,02, 121,61, 111,73, 42,65, 12,53, 12,48. MS (Cl/CH4+NH4) m/z 230 (M+N)+. Elemental analysis. Calculated for C12H15N5Nug: C, Eur36, 85; N, To 4.38; N, 17,91. Found: C, 36,93; N, 4,32; N, 17,72.

Example 10

< / BR>
7-Cyano-2,4-dimethyl-5-(2-imidazolidinone)benzimidazole

This compound was synthesized according to scheme 4 from 3-amino-2,6-dinitro-p-toluamide, obtained in example 1.

Example 11

< / BR>
2-Amino-4,6-dimethyl-5-(2-imidazolidinone)benzimidazole

N-Acetyl-3,5-dimethylaniline. A mixture of 3,5-dimethylaniline (20 g, 165 mmol), acetic anhydride (24 ml, 247 mmol) and triethylamine (70 ml, 495 mmol) in methylene chloride (300 ml) was stirred at room temperature for 16 hours. The mixture was washed with water and dried (magnesium sulfate) and evaporated in a rotary evaporator. The residue after evaporation triturated in hexane and filtered; received N-ACET the-3,5-dimethylaniline (25 g, 153 mmol) in concentrated sulfuric acid (500 ml) was added potassium nitrate (48 g, 474 mmol). The mixture was stirred 45 minutes at 0oC, then for 15 hours at room temperature. The mixture was poured into a mixture of ice water and was extracted with chloroform. The extract was dried (magnesium sulfate) and evaporated in a rotary evaporator. The residue after evaporation was purified flash chromatography on silica gel (mixture of 30% ethyl acetate and hexane); received N-acetyl-3,5-dimethyl-2,4-dinitroaniline (14.6 g).

3,5-Dimethyl-2,4-dinitroaniline. A mixture of N-acetyl-3,5-dimethyl-2,4-dinitroaniline (14.6 g, 57 mmol) and sodium methoxide (25% by weight solution in methanol) (26 ml) and methanol (200 ml) was heated under reflux for 90 minutes. The mixture is evaporated in a rotary evaporator and the residue after evaporation was distributed between water and chloroform. The organic layer was dried (magnesium sulfate) and evaporated in a rotary evaporator. The residue was purified flash chromatography on silica gel (25% ethyl acetate in hexane); received 3,5-dimethyl-2,4-dinitroaniline (8.0 g) as an orange solid.

1,2-Diamino-3,5-dimethyl-4-nitrobenzene. A solution of 3,5-dimethyl-2,4-dinitroaniline (1.5 g, 7 mmol) in ethyl acetate (100 ml) was treated with hydrogen at atmospheric pressure for 2 hours. The mixture Phi is(1.25 g) as a red solid.

2-Amino-4,6-dimethyl-5-nitrobenzimidazole. A mixture of 1,2-diamino-3,5-dimethyl-4-nitrobenzene (0.87 g, a 4.83 mmol) and cyanogenmod (0.87 g, 7,73 mmol) in methanol (50 ml) was stirred at room temperature for 16 hours. The mixture is evaporated in a rotary evaporator; obtained 2-amino-4,6-dimethyl-5-nitrobenzimidazole. This product is used in the next stage without further purification.

2-(tert-Butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole. A mixture of 2-amino-4,6-dimethyl-5-nitrobenzimidazole (1.3 g, of 6.31 mmol), di-tert-BUTYLCARBAMATE (2.5 ml 1M solution in tetrahydrofuran, 7.56 mmol), triethylamine (2.6 ml, of 18.9 mmol) and dimethylaminopyridine (0.1 g) in a mixture of 20% methanol and ethyl acetate (60 ml) was stirred at room temperature for 16 hours. The mixture is evaporated in a rotary evaporator. The residue after evaporation was distributed between chloroform and 3% aqueous solution of sodium carbonate. The organic layer was dried (magnesium sulfate) and evaporated in a rotary evaporator. The residue after evaporation was purified flash chromatography on silica gel (30% ethyl acetate hexane); obtained 2-(tert-butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole.

5-Amino-2-(tert-butoxycarbonyl)amino-4,6-dimethylbenzimidazole. A suspension of 2-(tert-butoxycarbonyl)-NT/sq. inch (0.31 MPa) for 15 hours. The mixture was filtered on celite and the filtrate is evaporated in a rotary evaporator; received 5-amino-2-(tert-butoxycarbonyl)amino-4,6-dimethylbenzimidazole (0.5 g).

2-Amino-4,6-dimethyl-5-(2-imidazolidinone)benzimidazole. A mixture of 5-amino-2-(tert-butoxycarbonyl)amino-4,6-dimethylbenzimidazole (0.4 g, 1.44 mmol), di-2-pyridylketone (1.0 g, 4,32 mmol) and dimethylaminopyridine (0.1 g) in methylene chloride (40 ml) and methanol (2 ml) was stirred at room temperature for 15 hours. This mixture is then slowly added to a solution of 1,2-Ethylenediamine (0.6 ml, 8,97 mmol) in methylene chloride (10 ml). The resulting mixture was stirred at room temperature for 1 hour. The mixture is evaporated in a rotary evaporator, and the residue after evaporation was washed with ethyl acetate and filtered. The solid is suspended in methanol (300 ml), was added acetate mercury (0.56 g of 1.75 mmol) and the resulting mixture was stirred at room temperature for 15 hours. The mixture was filtered through celite, and the filtrate is evaporated in a rotary evaporator. The residue after evaporation was purified preparative liquid chromatography high pressure (ghvd) (C4 column, gradient solvent composition: 0.1% solution triperoxonane acid in water: acetonitrile, original autosole with triperoxonane acid.

1,2-Diamino-3,5-dimethyl-4-nitrobenzene. 1H-NMR (DMSO) of 1.85 (s, 3H), of 1.95 (s, 3H), of 4.45 (s, 2H), 5,10 (s, 2H), of 6.20 (s, 1H).13C-NMR (DMSO) 13,47, 17,87, 112,68, 113,90, 116,24, 119,15, 130,94, 132,73, 137,92, 142,66.

2-Amino-4,6-dimethyl-5-nitrobenzimidazole. 1H-NMR (DMSO) of 2.30 (s, 3H), 2.40 a (s, 3H), 3,50 (broad s, 2H), 7,20 (s, 2H), and 8.50 (s, 1H).13C-NMR (DMSO) 10,83, 15,81, 109,33, 112,72, 123,34, 126,26, 129,26, 134,52, 150,56.

2-(tert-Butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole. 1H-NMR (Dl3) to 1.70 (s, N), to 2.35 (s, 3H), 2,42 (s, 3H), 6,60 (broad s, 1H), 7,30 (s, 1H). MS (APCl) 307 (M+N)+, 207 (M+N+-VOS).

5-Amino-2-(tert-butoxycarbonyl)amino-4,6-dimethylbenzimidazole 1H-NMR (Dl3) of 1.65 (s, N), 2,10 (s, 3H), of 2.18 (s, 3H), 4,25 (broad s, 2H), 6.90 to (s, 1H), 7,10 (s, 1H).13C-NMR 11,46, 19,04, 84,85, 108,47, 112,68, 113,74, 121,14, 140,68, 141,20, 150,49, 152,84.

2-Amino-4,6-dimethyl-5-(2-imidazolidinone)benzimidazole triptorelin1H-NMR (CD3OD) of 2.36 (s, 3H), 2.40 a (s, 3H), 3,60 to 4.0 (m, 4H), 7,21 (s, 1H). MS (ESI) 245 (M+N)+. Elemental analysis. Calculated for C12H16N6THAN2O: C, 39,19; N, 4,11; N, 17,14. Found: C, 39,12; N, 4,11; N, 17,14.

Example: 7-Cyano-4,6-dimethyl-5-(2-imidazolidinone)-benzimidazole

6-Cyano-2,4-dinitro-m-xylene. A mixture of 4-cyano-m-xylene (0.8 g, 6.1 mmol), and NO2BF4(32 ml, 0.5 M in sulfolane, 1 the Wali and washed with 10% Panso3(28 ml) and water (425 ml) and then dried in vacuum for 24 hours to obtain 6-cyano-2,4-dinitro-m-xylene in a solid yellow color (1,14 g, yield 85%) which was sufficiently pure for use in the next stage.1H-NMR (Dl3) to 2.46 (s, 3H, CH3), of 2.51 (s, 3H, CH3), 8,23 (s, 1H, Ar).13C-NMR (Dl3) 15,30, 17,04, 114,21, 114,79, 129,74, 130,75, 138,59, 148,56, 154,01. MS (c.i.): m/z 222 [M+H]+.

6-Cyano-3,5-dimethyl-2,4-dinitroaniline. A solution of 6-cyano-2,4-dinitro-m-xylene (of 2.21 g, 10 mmol) and aminotriazole (2.8 g, 33 mmol) in DMSO (55 ml) was added dropwise in DMSO solution (100 ml) of t-BuOK (5 g, to 44.6 mmol) under stirring with a magnetic stirrer. During the addition the temperature of the reaction mixture was maintained below 10oC. After removal of the cold bath, the reaction mixture was stirred at room temperature for 4 hours, then poured into a mixture of ice and acetic acid (3 ml). After filtration the crude product was purified flash chromatography on a column of silica gel (dry loading, elution with 10-20% EtOAc in hexane) to give 6-cyano-3,5-dimethyl-2,4-dinitroaniline (1.1 g, yield 47%) as a solid yellow color.1H-NMR (Dl3) to 2.40 (s, 3H, CH3), of 2.50 (s, 3H, CH3), 5,94 (s, 2H, NH2), 7,28 (s, 1H, Ar).o
C (oil bath) for 30 hours. The mixture was filtered through a plug of silica/celite, washed with formic acid, MeOH/EtOAc (1:1), then evaporated on a rotary evaporator to dryness. The resulting residue is evaporated together with the methanol/triperoxonane acid (20:1) four times, then was purified preparative HPLC to obtain 7-cyano-4,6-dimethyl-5-formylanhalonidine in a solid yellow color (0,44 g, yield 93%). MS: m/z 215 [M+H] +.

5-Amino-7-cyano-4,6-dimethylbenzimidazole. 7-Cyano-4,6-dimethyl-5-formallynominated (0.71 g, 3.3 mmol), potassium carbonate (0,688 g, 5 mmol), hydrochloric acid (15 ml, 45 mmol, 3H), methanol (8 ml) and water (10 ml) were combined and stirred at 65oC (oil bath) for 30 hours. The reaction mixture was concentrated to dryness, evaporated together with H2O/Meon/TN (5:5:1, 415 ml), was dissolved in H2O/MeOH and was purified preparative HPLC to obtain 5-amino-7-cyano-4,6-dimethylbenzimidazole in the form of solids (0,59 g, yield 96%).1H-NMR (CD3D) 2,47 (s, 3H, CH3), 2,52 (s, 3H, CH3), a 9.25 (s, 1H, Ar).131H-NMR (DMSO) of 2.58 (s, 3H, CH3), 2,61 (s, 3H, CH3), 8,51 (s, 1H, Ar). MS: m/z 229 [MN]+.

7-Cyano-4,6-dimethyl-5-(2-imidazolidinone)benzimidazole. To a solution of Ethylenediamine (0,49 g of 0.65 ml, 8.2 mmol) in methylene chloride (10 ml) was added a mixture of 7-cyano-4,6-dimethyl-5-isothiocyanatobenzene (0.39 g, 1,71 mmol) in methylene chloride (10 ml). The reaction mixture was stirred for 5 hours at room temperature and then evaporated on a rotary evaporator. The residue was mixed with methanol (12 ml) and acetate mercury (0.54 g, 1.7 mmol). The color of the mixture was rapidly changing from yellow to black. The reaction mixture was stirred at room temperature for 4 hours, then treated with a mixture of PA2S92On (0,49 g) and H2O (0.5 ml). The mixture was stirred at room temperature during the spritely. The obtained residue was evaporated together with methanol/triperoxonane acid (10:1, 38 ml) and was purified preparative HPLC to obtain salt triperoxonane acid, 7-cyano-4,6-dimethyl-5-(2-imidazolidinone)benzimidazole as a white solid (0,185 g, 22%).1H-NMR (CD3OD) at 2.59 (s, 3H, CH3), and 3.72 (m, 2H, CH3), a 3.87 (m, 2H, CH2), 8,48 (s, 1H, Ar).13C-NMR (CD3D) 13,69, 17,47, 44,55, 44,85, 99,99, 116,56, 129,42, 132,16, 137,21, 138,41, 140,58, 146,07, 161,44. MS m/z 255 [M+H]+. Elemental analysis. Calculated for C13H14N6C4O4F6H2: C, 42,33; N, TO 3.34; N, 17,42. Found: C, 42,26; N, At 3.35; N, 17,14.

Example b: 2-Amino-4-methyl-5-(2-imidazolidinone)benzimidazole dihydrobromide

2,4-Dinitro-3-methylaniline. Hydroxylamine hydrochloride (49,6 g, 0,713 mol) was dissolved in water (60 ml). Added ethanol (1100 ml) and 2,6-dinitrotoluene (50 g, 0,274 mol) and the mixture was cooled in a bath with ice. Then was added dropwise for 2 hours, a saturated solution of potassium hydroxide in methanol (500 ml). Bath ice was removed and the mixture was stirred for 2 hours at room temperature. Then the mixture was poured into ice water (4000 ml) and the resulting suspension was allowed to stand at room temperature until the ice melted. The suspension was filtered logo color.1H-NMR (Dl3) to 7.95 (d, J=9,2 Hz, 1H), 6,72 (d, J=9,2 Hz, 1H), and 5.2 (broad s, 2H), has 2.56 (s, 3H).13C-NMR (Dl3) 144,5, 140,6, 137,4, 129,1, 127,7, 114,5. MS (CI/CH4) m/z 198 (M+N)+.

2,3-Diamino-6-nitrotoluene. The solution nonahydrate of sodium sulfide (109,6 g, 0,456 mol) in water (750 ml) was added dropwise over 90 minutes to a boiling solution of 2,4-dinitro-3-methylaniline (30 g, 0,152 mol) in ethanol (750 ml). At the end of the addition the mixture was heated under reflux for 30 minutes, then poured into ice (2000 g) and allowed to stand until the ice breaks up. Then the mixture was extracted with methylene chloride and the organic layer was dried over magnesium sulfate and evaporated on a rotary evaporator. The residue was purified flash chromatography on silica gel, elwira with methylene chloride, to obtain 11.8 g (46%) of 2,3-diamino-6-nitrotoluene in a solid orange color.1H-NMR (Dl3) 7,37 (d, J=9,2 Hz, 1H), 6,50 (d, J=9,2 Hz, 1H), 2,87 (broad s, 4H), of 2.33 (s, 3H). MS (CI/CH4) m/z 168(M+N)+.

2-Amino-4-methyl-5-nitrobenzimidazole. Bromide CYANOGEN (6.9 ml, 34.5 mmol) was added in 3 portions at intervals of 30 minutes to a suspension of 2-amino-3-methyl-4-nitroaniline (1.92 g, 11.5 ml) in water (50 ml). The mixture was stirred at room temperature for 15 hours. The mixture was filtered, and filtrovala, washed with water, then was purified flash chromatography on silica gel, elwira 5% methanol in ethyl acetate containing 0.1% ammonium hydroxide, with the receipt of 1.94 g (87%) of 2-amino-4-methyl-5-nitrobenzimidazole in a solid yellow color.1H-NMR (DMSO-d6) 7,66 (d, J=8,8 Hz, 1H), 7,01 (d, J=8,8 Hz, 1H), 6,60 (s, 2H), has 2.56 (s, 3H). MS (CI/CH4+NH4) m/z 193 (M+N)+.

2-tert-Butoxycarbonylamino-4-methyl-5-nitrobenzimidazole. A mixture of 2-amino-4-methyl-5-nitrobenzimidazole (0.87 g, to 4.52 mmol), di-tert-BUTYLCARBAMATE (1,38 g, 6,33 mmol), triethylamine (0.75 ml, 5.43 mmol) and 4-dimethylaminopyridine (0.02 g) in a mixture of methanol (30 ml) and ethyl acetate (150 ml) was stirred at room temperature for 5 hours. Added another portion of di-tert-BUTYLCARBAMATE (1,38 g, 6,33 mmol) and the mixture was stirred at room temperature overnight. The mixture was evaporated on a rotary evaporator and the residue was purified flash chromatography on silica gel, elwira first 50% ethyl acetate in hexane, then ethyl acetate, to obtain 1.07 g (81%) of 2-tert-butoxycarbonylamino-4-methyl-5-nitrobenzimidazole in the form of a solid pale yellow color.1H-NMR (DMSO-d6) (mixture of rotamers 3/1) basic: of 7.69 (d, J=8,8 Hz, 1H), 7,51 (d, J=8,8 Hz, 1H), 7,45 (broad s, 1H), 2,54 (s, 3H), 1.61 of (s, N). UP>+
.

5-Amino-2-tert-butoxycarbonylamino-4-methylbenzimidazole. To a suspension of 2-tert-butoxycarbonylamino-4-methyl-5-nitrobenzimidazole (1.07 g, 3,66 mmol) in methanol (25 ml)/ethyl acetate (60 ml) was added palladium on carbon (10%, 0.1 g) and ammonium formate (0,92 g, 14.6 mmol). The mixture was stirred at room temperature for 3 hours, then filtered on celite with methanol wash of the solids. The filtrate is evaporated on a rotary evaporator, and the residue was distributed between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were dried over magnesium sulfate and evaporated on a rotary evaporator with the receipt of 0.91 g (94%) of 5-amino-2-tert-butoxycarbonylamino-4-methylbenzimidazole in the form of a white solid.1H-NMR (Dl3) of 7.24 (d, J=8,8 Hz, 1H), 6,60 (broad s, 1H), 6,45 (d, J=8,8 Hz, 1H), up 3.22 (broad, 2H), and 2.27 (s, 3H), of 1.66 (s, N). MS (CI/CH4+NH4) m/z 263 (M+N)+.

2-tert-Butoxycarbonylamino-4-methyl-5-benzimidazole isothiocyanate. A solution of 5-amino-2-tert-butoxycarbonylamino-4-methylbenzimidazole (0,91 g, 3.46 mmol) in methylene chloride (50 ml)/ethyl acetate (50 ml) for 30 minutes was added dropwise to a solution of di-2-pyridylketone (1,57 g of 6.75 mmol) and 4-dimethylaminopyridine and on a rotary evaporator. The residue was purified flash chromatography on silica gel, elwira 25% ethyl acetate in hexane, to obtain 0,72 g (68%) of 2-tert-butoxycarbonylamino-4-methyl-5-benzimidazolyl isothiocyanate in the form of a white solid.1H-NMR (Dl3) was 7.08 (d, J=8,8 Hz, 1H), 6,98 (broad s, 2H), 6,60 (d, J=8,8 Hz, 1H), and 2.14 (s, 3H), of 1.37 (s, N). MS (CI/CH4+NH4) m/z 305 (M+H)+.

2-tert-Butoxycarbonylamino-5-(2-imidazolidinyl)-4-methylbenzimidazole. A suspension of 2-tert-butoxycarbonylamino-4-methyl-5-benzimidazolyl isothiocyanate (0,70 g to 2.29 mmol) in methylene chloride (70 ml) was added dropwise within 15 minutes to 1,2-Ethylenediamine (of 0.77 ml, 11,49 mmol) dissolved in methylene chloride (150 ml). The mixture was stirred for 12 hours at room temperature. To the suspension was added a simple ether (100 ml) and the mixture was stirred at room temperature for 10 minutes. The solid was filtered and dried in vacuum to obtain 0,78 g of a white solid. The solid was dissolved in methanol (250 ml), was added acetate mercury (0.88 g, a 2.75 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture of black color filters on celite with methanol wash of the solids, and the filtrate was evaporated on a rotary Ipari Rasim 1% ammonium hydroxide. The fractions containing the product were collected and evaporated on a rotary evaporator to obtain 0,80 g (89%) of the acetate salt of 2-tert-butoxycarbonylamino-5-(2-imidazolidine)-4-methylbenzimidazole in the form of a white solid.1H-NMR (DMSO-d6) to 7.35 (d, J= 8,8 Hz, 1H), 7,24 (broad s, 2H), 6.75 in (d, J=8,8 Hz, 1H), 3,50 (s, 4H), are 2.19 (s, 3H), of 1.66 (s, Asón), 1,60 (s, N).13C-NMR (DMSO-d6) 175,48 (Asón), 159,56, 153,78, 149,72, 142,27, 132,29, 127,57, 120,86, 117,40, 111,21, 85,49, 42,36, 27,52, 23,87 (Asón), To 11.56. MS (CI/CH4+NH4) m/z 231 (M+H-BOC)+.

2-Amino-5-(2-imidazolidinyl)-4-methylbenzimidazole dihydrobromide. To a solution of the acetate salt of 2-tert-butoxycarbonylamino-5-(2-imidazolidinyl)-4-methylbenzimidazole (0,76 g, 1.94 mmol) in glacial acetic acid (12 ml) was added a solution of Hydrobromic acid in glacial acetic acid (30%, 1.1 ml). The mixture was stirred at room temperature and followed by evolution of gas. After the evolution of gas (approximately 4 hours) the mixture was diluted simple ether (50 ml) and the precipitate was filtered and washed with simple ether. The solid is recrystallized from ethanol/simple ether and dried in vacuum to obtain 0,41 g (54%) monohydrate dihydrobromide salt 2-amino-5-(2-imidazolidinyl)-4-methylbenzimidazole in the form of a white 2 (l, J=8,8 Hz, 1H), 7,05 (d, J=8,8 Hz, 1H), to 3.58 (s, 4H), of 2.25 (s, 3H).13C-NMR (DMSO-d6) 158,81, 151,11, 129,64, 128,97, 128,86, 122,64, 119,35, 109,49, 42,62, 12,16. MS (CI/CH4+NH4) m/z 231 (M+N)+. Elemental analysis. Calculated for C11H14N62HBrH2O: C, 32,22; H, WAS 4.42; N, 20,49. Found: C, 32,28; N, 4,56; N, 20,61.

Example 12

< / BR>
2-Amino-6-bromo-5-(2-imidazolidinyl)-4-methylbenzimidazole

This compound was obtained by combining figures 1 and 4. Commercially available 2,6-dinitrotoluene was converted into 2,3-diamino-6-nitrotoluene according to scheme 2. Reaction with cyanogenmod got 2-amino-4-methyl-5-nitrobenzimidazole. After protection of the amino group, tert-butoxycarbonyl group connection was restored by hydrogenation (in the presence of palladium on coal) and bromisovali bromide, sodium acetate, acetic acid) to give 5-amino-6-bromo-2-tert-butoxycarbonylamino-4-methylbenzimidazole. The formation of 5-(2-imidazolidinone)group finished in the usual way, and tert-butoxycarbonyl group tsalala treatment with hydrochloric acid; received 2-amino-6-bromo-5-(2-imidazolidinyl)-4-methylbenzimidazole.

Example 13

< / BR>
2-Cyano-4,6-dimethyl-5-(2-imidazolidinone)benzimidazole

2-Amino-4,6-dimethyl-5-nitrobenzimidazole (polutrilliona acid and subsequent reaction with copper cyanide. Then the synthesis of 2-cyano-4,6-dimethyl-5-(2-imidazolidinone)-benzimidazole was completed according to the scheme 5.

Example 14

< / BR>
6-Bromo-2-cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole

2-Amino-4-methyl-5-nitrobenzimidazole (see example 12) was converted into 2-cyano-4-methyl-5-nitrobenzimidazole by processing the first, sodium nitrate and terraforming acid and subsequent reaction with copper cyanide. In the recovery of the 5-nitro group and subsequent synthesized (bromine, acetic acid) was obtained 5-amino-6-bromo-2-cyano-4-methylbenzimidazole. The synthesis was then completed according to the scheme 5.

Example 15

< / BR>
2-Fluoro-7-cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole

3-Amino-2,6-dinitro-p-toluene carboxamid turned into 7 carboxamido-2-diazo-4-methyl-5-nitrobenzimidazole tetrafluoroborate according to scheme 4. The conversion of 7-carboxamido-2-fluoro-4-methyl-5-nitrobenzimidazole was carried out by thermal decomposition of diazonium salts. Then the synthesis was completed in the same manner as in example 1.

Example 16

< / BR>
4-ethyl-2-fluoro-5-(2-imidazolidinone)benzimidazole

2,4-Dinitro-3-ethyl-6-methylaniline (see example 2) was treated with sodium sulfate and received 1,2-diamino-3-ethyl-6-methyl-4-nitrobenzene. Treatment-4-ethyl-7-methyl-5-nitrobenzimidazole tetrafluoroborate the action of sodium nitrite and terraforming acid. By thermal decomposition of the diazonium salts obtained 4-ethyl-2-fluoro-7-methyl-5-nitrobenzimidazole. The transformation of 4-ethyl-2-fluoro-5-(2-imidazolidinone)benzimidazole completed according to the scheme 5.

Examples 17-49

The compounds of formula

< / BR>
in which R1, R2, R3, R4 and R5 are listed in table 1. Connection examples 17-39 synthesized using the methods described and shown in the examples above.

Songs

Another aspect of this invention are compositions that contain a safe and effective amount of the compounds according to the invention or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier. Used herein, the phrase "safe and effective amount" means an amount of compound of the present invention sufficient to induce a positive modification in the condition that is being treated, but low enough to avoid serious side effects (at a reasonable acceptable ratio of benefits and risks), within medical indications. Safe and effective amount of the compounds of the present invention may vary depending on age and physical condition of the patient is FIPA, used concrete pharmaceutically acceptable carrier and other like factors within the knowledge and experience of the treating physician.

Compositions according to the invention preferably contain from about 0,0001% to about 99% by weight of compounds of the present invention, more preferably from about 0.01% to about 90%, also preferably from about 10% to about 50%, also preferably from about 5% to 10%, also preferably from 1% to about 5%, also preferably from about 0.1% to about 1%.

In addition to the compounds of the present invention, the composition according to the invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used here, means one or more compatible solid or liquid fillers-thinners or kapsulirujushchej substances, which are suitable for administration to a human or lower animal. The term "compatible", as used here, means that the components of the composition is able to be mixed with the compound of this invention and with each other so that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary conditions p is of low toxicity, so they were suitable for administration to a human or lower animal being treated.

Some examples of substances which can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and methyl cellulose; powdered tragakant; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols, such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Tween; moisturizing agents, such as sodium lauryl sulfate; coloring additives; tabletiruemye agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of pharmaceutically acceptable carrier, which should be used in a mixture with the compound of this invention, the plants must be given by injection, preferred pharmaceutically acceptable carrier is sterile, physiological saline solution containing compatible with blood suspendisse tool, which establish the pH is approximately equal to 7.4.

The preferred method of administration of the compounds of the invention is oral administration. Therefore, the preferred form of the standard doses are tablets, capsules, cakes, chews, etc. Such forms of standard doses contain a safe and effective amount of the compounds of the invention, which preferably is in the range from about 0.01 mg to about 200 mg, more preferably from about 0.1 mg to about 50 mg, more preferably from about 0.5 mg to about 25 mg, also preferably from about 1 mg to about 10 mg of Pharmaceutically acceptable carriers suitable for the preparation of standard forms doses for oral administration are well known in pharmacology. Tablets typically contain commonly used pharmaceutically compatible auxiliary substances, representing an inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, e); lubricants such as magnesium stearate, stearic acid and talc. Substances that improve slip, such as silicon dioxide, can be used to improve the flowability of the powder mixture. Coloring additives, such as dyes, FD and C, can be added to improve appearance. Sweeteners and flavorings, such as aspartame, saccharin, menthol, peppermint and fruit flavors are useful excipients used for chewable tablets. Capsules typically contain one or more solid diluents described above. The selection of carrier components depends on secondary considerations like taste, cost, and storage stability, which are crucial for the purposes of this invention, and this choice can easily be done by the specialist in this field.

Compositions for oral administration include liquid solutions, emulsions, suspensions, etc., Pharmaceutically acceptable carriers suitable for the preparation of such compositions is well known in medicine. Such liquid oral compositions preferably contain from about 0,001% to about 5% of the compound of this invention, more preferably from about 0.01% to about 0.5%. Titanpoker, a polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions typical suspendresume agents are methyl cellulose, sodium carboxymethyl cellulose Avicel RC-591, tragakant and sodium alginate; typical wetting agents include lecithin and Polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweeteners, flavoring and coloring agents discussed above.

Other routes of administration used to achieve systemic distribution in the body of the compounds of this invention include dosage forms for subcutaneous, intravenous, sublingual, and transbukkalno (buccal) administration. Such compositions typically contain one or more substances which are soluble fillers, such as sucrose, sorbitol and mannitol; binders, such as, Arabian gum, microcrystalline cellulose, carboxymethyl cellulose and hypromellose. Additives that improve slip, lubricants, sweeteners, coloring additives, described above, can also be included in the composition.

The preferred method of introduction is inane: the dose in the nose (intranasally) with nasal congestion, inhalation in asthma, eye drops, gels and creams with eye disorders.

Preferred compositions of the present invention for insertion into the nose include aqueous solutions containing a safe and effective amount of the compounds according to the invention. Such compositions preferably contain from about 0,001% to about 5% of the compound of this invention, more preferably from about 0.01% to about 0.5%. Such compositions also typically contain a safe and effective amount of preservatives, such as benzylaniline and thimerosal; buffer substances, such as phosphate and acetate; substances for isotonic solution, such as sodium chloride; antioxidants, such as ascorbic acid; flavouring substances; and acids and bases to establish the necessary pH of these aqueous compositions.

Preferred compositions of this invention for inhalation and spray include aqueous solutions, suspensions and dry powders containing a safe and effective amount of a compound of the invention. Such compositions preferably contain from about 0.1% to about 50% of the compound of the present invention, more preferably from primer. These compositions usually contain propellants, as well as chlorofluorocarbons 12/11 and 12/114; solvents such as water, glycerol and ethanol; stabilizers such as ascorbic acid, sodium metabisulfite; preservatives, such as cetylpyridinium and benzylaniline; substances for regulating the concentration (toychest), such as sodium chloride; and flavoring agents such as sodium salt of saccharin.

Preferred intranasal compositions according to the invention include aqueous solutions containing a safe and effective amount of the compounds of the present invention. Such compositions preferably contain from about 0,0001% to about 5% of the compound of the invention, more preferably from about 0.01% to about 0.5%. Such compositions usually also contain one or more preservatives, such as benzylaniline, thimerosal, acetate finalstate; fillers such as poloxamer, modified cellulose, povidone, purified water; substances for regulation of concentration, such as sodium chloride, mannitol and glycerin; buffer substances, such as acetate, citrate, phosphate and borate; antioxidants such as sodium metabisulfite, bottled hydroxytoluene and acetylate the CLASS="ptx2">

Additional active pharmaceutical substances

Compositions of the present invention can, optionally, contain other active medicinal substances. Limitiruyuschie examples of active medicinal substances that may enter into the composition of these songs below.

Antihistamines: Hydroxyzine, preferably in the range of doses from about 25 to about 400 mg; doxylamine, preferably in the range of doses from about 6,25 to about 200 mg; chlorpheniramine, preferably in the range of doses from about 1 to about 24 mg; phenindamine, preferably in the range of doses from about 6,25 to about 150 mg; dexchlorpheniramine, preferably in the range of doses from about 0.5 to about 12 mg; dexbrompheniramine, preferably in the range of doses from about 0.5 to about 12 mg; clematis, preferably in the range of doses from about 1 to about 9 mg; diphenylhydramine, preferably in the range of doses from about 6,25 to about 300 mg; azelastin, preferably in the range of doses from about 140 to about 1680 μg (at a dose of nose); from 1 to about 8 mg (a dose oral); acrivastine, preferably in the range of doses from about 1 to about 24 mg; levocabastine (which can be what Erno 100 to about 800 mcg; mequitazine, preferably in the range of doses from about 5 to about 20 mg; astemizole, preferably in the range of doses from about 5 to about 20 mg; elastin; loratadine, preferably in the range of doses from about 5 to about 40 mg; cetirizine, preferably in the range of doses from about 5 to about 20 mg; terfenadine, preferably in the range of doses from about 30 to about 480 mg; metabolite of terfenadine; promethazine, preferably in the range of doses from about 6,25 to about 50 mg dimenhydrinate, preferably in the range of doses from about 12.5 to about 400 mg; meclizine, preferably in the range of doses from about 6,25 to about 50 mg; tripelennamine, preferably in the range of doses from about 6,25 to about 300 mg; carbinoxamine, preferably in the range of doses from about 0.5 to about 16 mg; cyproheptadin, preferably in the range of doses from about 2 to about 20 mg; azatadine, preferably in the range of doses from about from about 0.25 to 2 mg; brompheniramine, preferably in the range of doses from about 1 to about 24 mg; triprolidine, preferably in the range of doses from about 0.25 to about 10 mg; cyclized, preferably in the range of doses from about 12.5 to about 200 mg; thonzylamine, prefer is up to about 75 mg; cyclized, preferably in the range of doses from about 12.5 to about 200 mg, and others.

Antitussives: codeine, preferably in the range of doses from about 2.5 to about 120 mg; hydrocodone preferably in the range of doses from about 2.5 to about 40 mg; dextromethorphan, preferably in the range of doses from about 2.5 to about 120 mg; noscapine, preferably in the range of doses from about 3 to about 180 mg; benzonatate, preferably in the range of doses from about 100 to about 600 mg; diphenhydramine, preferably in the range of doses from about 12.5 to about 150 mg; chlophedianol, preferably in the range of doses from about 12.5 to about 100 mg; clobutinol, preferably in the range of doses from about 20 to about 240 mg; Foinaven, preferably in the range of doses from about 80 to about 480 mg; glaucine; Volodin, preferably in the range of doses from about 1 to about 40 mg; zipeprol, preferably in the range of doses from about 75 to about 300 mg; hydromorphone, preferably in the range of doses from about 0.5 to about 8 mg; carbetapentane, preferably in the range of doses from about 15 to about 240 mg; caramiphen, levopropoxyphene, preferably in the range of doses from about 25 to Priceline tools: ibuprofen, preferably in the range of doses from about 50 to about 3200 mg; naproxen, preferably in the range of doses from about 62,5 to about 1500 mg; sodium naproxen, preferably in the range of doses from about 110 to about 1650 mg; Ketoprofen, preferably in the range of doses from about 25 to about 300 mg; indoprofen, indomethacin, preferably in the range of doses from about 25 to about 200 mg; sulindac, preferably in the range of doses from about 75 to about 400 mg; diflunisal, preferably in the range of doses from about 125 to about 1500 mg; Ketorolac, preferably in the range of doses from about 10 to about 120 mg; piroxicam, preferably in the range of doses from about 10 to about 40 mg; aspirin, preferably in the range of doses from about 80 to about 4000 mg; meclofenamate, preferably in the range of doses from about 25 to about 400 mg; benzydamine, preferably in the range of doses from about 25 to about 200 mg; carprofen, preferably in the range of doses from about 75 to about 300 mg; diclofenac, preferably in the range of doses from about 25 to about 200 mg; etodolac, preferably in doses ranging from about 200 to about 1200 mg; fenbufen, preferably in the range of doses from about 300 on edocfile in doses ranging from about 50 to about 300 mg; mefenamovaya acid, preferably in the range of doses from about 250 to about 1500 mg; nabumeton, preferably in the range of doses from about 250 to about 2000 mg; phenylbutazone, preferably in the range of doses from about 100 to about 400 mg; pirprofen, preferably in the range of doses from about 10 to about 800 mg; tolmetin, preferably in the range of doses from about 200 to about 1800 mg, and others.

Analgesics: acetaminophen, preferably in the range of doses from about 80 to about 4000 mg; and others, including narcotic and non-narcotic analgesics.

Expectorants/Mucolytics: guaifenesin preferably in the range of doses from about 50 to about 2400 mg; N-acetylcysteine, preferably in the range of doses from about 100 to about 600 mg; Ambroxol, preferably in the range of doses from about 15 to about 120 mg, Bromhexine, preferably in the range of doses from about 4 to about 64 mg; terpyridyl, preferably in the range of doses from about 100 to about 1,200 mg; potassium iodide, preferably in the range of doses from about 50 to about 250 mg, and others.

Atropine, preferably atropine introduced into the nasal or oral: ipratroprium (preferably WEO oral), preferably in doses ranging from about 10 to about 1000 μg; belladonna (preferably in the form of extract), preferably in doses ranging from about 15 to about 45 mg-equivalents; scopolamine, preferably in the range of doses from about 400 to about 3200 mcg; scopolamine methobromide, preferably in the range of doses from about 2.5 to about 20 mg; gomatropin methobromide, preferably in the range of doses from about 2.5 to about 40 mg; giostsiamin (preferably oral), preferably in doses ranging from about 125 to about 1000 μg; isopropamide (preferably oral), preferably in doses ranging from about 5 to about 20 mg; orphenadrine (preferably oral), preferably in doses ranging from about 50 to about 400 mg; benzalconi chloride (preferably an introduction to the nose), preferably a solution with a concentration of 0.005 to about 0.1%, and others.

Stabilizers mast cells (mast cells), preferably the stabilizers of the fat cells, are introduced into the nasal or oral: Cromalin, preferably in the range of doses from about 10 to about 60 mg; nedocromil, preferably in doses ranging from about 10 to about 60 mg; oxatomide, preferably in the interval is g; lodoxamide, preferably in the range of doses from about 100 to about 3000 μg, and others.

Antagonists of leukotrienes (LT): zileuton and others.

Methylxanthines: caffeine, preferably in the range of doses from about 65 to about 600 mg; theophylline, preferably in the range of doses from about 25 to about 1,200 mg; enprofylline; pentoxifylline, preferably in the range of doses from about 400 to about 3600 mg; aminophylline, preferably in the range of doses from about 50 to about 800 mg; Tefillin, preferably in the range of doses from about 200 to about 1600 mg, and others.

Antioxidants or radical inhibitors: ascorbic acid, preferably in the range of doses from about 50 to about 1000 mg; tocopherol, preferably in the range of doses from about 50 to about 2000 mg; ethanol, preferably in the range of doses from about 500 to about 10,000 mg, and others.

Steroids, it is preferable steroids for insertion into the nose: beclomethasone, preferably in the range of doses from about 84 to about 336 mcg; fluticasone, preferably in the range of doses from about 50 to about 400 mcg; budesonide, preferably in the range of doses from about 64 to about 256 mcg; mometazon; triaminotoluene, the oz from about 168 to about 1008 mcg; flunisolide, preferably in the range of doses from about 50 to about 300 mg; prednisone (preferably oral), preferably in doses ranging from about 5 to about 60 mg; hydrocortisone (preferably oral), preferably in doses ranging from about 20 to about 300 mg, and others.

Bronchodilators, preferably inhalation: albuterol, preferably in the range of doses from about 90 to about 1080 μg, about 2 to about 16 mg (when ingested); epinephrine, preferably in the range of doses from about 220 to about 1320 μg; ephedrine, preferably in the range of doses from about 15 to about 240 mg (when ingested); from 250 to about 1000 µg (with the introduction of the nose); metaproterenol, preferably in the range of doses from about 65 to about 780 μg or from about 10 to about 80 mg when ingested; terbutaline, preferably in the range of doses from about 200 to about 2400 ug; 2.5 to about 20 mg when ingested; isoetharine, preferably in the range of doses from about 200 to about 2400 ug; bitolterol, preferably in the range of doses from about 370 to about 2220 mcg; fenoterol, preferably in the range of doses from about 100 to about 1200 μg; otmaro 1600 mcg; ipratroprium, preferably in the range of doses from about 18 to about 216 mcg (inhalation) and others.

Antiviral drug: amantadine, preferably in the range of doses from about 50 to about 200 mg; rimantadine, preferably in the range of doses from about 50 to about 200 mg; enviroxime; nonoxinol, preferably in the range of doses from about 2 to about 20 mg (preferably in the form for introduction into the nose); acyclovir, preferably in the range of doses from about 200 to about 2000 mg (oral); from 1 to about 10 mg, preferably in the form for introduction into the nose); alpha-interferon, preferably in the range of doses from about 3 to about 36 units (MIU); beta-interferon, preferably in the range of doses from about 3 to about 36 units (MIU) and others.

The main drugs: acetylcholinesterase inhibitors, for example, echothiophate at a concentration of from about 0.03% to about 0.25% in the solution for local use, and others; and

Gastrointestinal drugs: Antidiarrheals such as loperamide, from about 0.1 mg to about 1.0 mg per dose, and substituted salicylate of bismuth, from about 25 mg to about 300 mg per dose, and others.

Active is also referred to. This overlap is known in medicine, and experienced practitioner will easily pick up the necessary dosage.

Applications

Compounds of the present invention can be used for treatment of many diseases, including, for example, respiratory diseases, ophthalmic diseases, gastrointestinal disorders, disorders associated with the activity of the sympathetic nervous system, migraine, peripheral pain and disorders, where the narrowing of blood vessels can have a positive effect.

Preferred methods of using these compounds are oral application; introduction to the nose; parenteral, subcutaneous; and a local application.

Another aspect of this invention includes methods of preventing or treating nasal congestion by introducing safe and effective amount of the compounds being considered human or lower animal that is experiencing or at risk of experiencing nasal congestion. This nasal congestion may be associated with diseases or disorders, which include, but are not limited or seasonal allergic rhinitis, acute viral infection of the upper respiratory tract, sinusitis, chronica who raised the dose of a compound in the range from about 0.001 mg/kg to about 10 mg/kg, more preferably from about 0.01 mg/kg to about 5 mg/kg, more preferably 0.1 mg/kg to about 1 mg/kg of the Introduction of such oral doses or in the nose is preferred. Reception frequency of the considered compounds according to the present invention is preferably from about one to about six times per day, more preferably from about 2 times to about 4 times a day. Such a dose and frequency of administration are preferred for the treatment of other respiratory conditions, such as inflammation of the middle ear, cough, chronic obstructive pulmonary disease and asthma.

Another aspect of this invention includes methods of preventing or treating glaucoma by introducing safe and effective amount of the compounds being considered a mammal suffering from or at risk for glaucoma. When the reception is systematic, with each dose of the considered compounds are preferably administered a dose of a compound in the range from about of 0.0001 mg/kg to about 5 mg/kg, more preferably from about 0.001 mg/kg to about 0.5 mg/kg If used intraocular introduction, it is preferably introduced a certain amount (for example 1 or occhialino from about 0.01 to about 0.5% of the compound. Determining the exact dosage and regimen of medicines is the responsibility of a specialist in this field. Intraocular introduction of such doses is preferred. The frequency of introduction of the compounds according to this invention is preferably from about one to about six times per day, more preferably from about one to about 4 times a day.

Another aspect of this invention includes methods of preventing or treating migraine, through the introduction of safe and effective amount of the compounds being considered human or lower animal suffering from or at risk of suffering from migraine. Each dose of the considered compounds are preferably administered a dose of a compound in the range from about 0.001 mg/kg to about 10 mg/kg, more preferably from about 0.01 mg/kg to about 5 mg/kg, even more preferably from about 0.1 mg/kg to about 1 mg/kg Oral administration or introduction into the nose of such doses is preferred. Frequency of use of the compounds according to this invention is preferably from about one to about six times per day, more preferably from about 2 times to about 4 times a day.

The dosage may vary depending on the patient being treated, the condition that is being treated, the severity of this condition, from the method of drug administration, etc. to achieve the desired effect.

2) Data confirming the activity of the compounds as nasal decongestants funds

In the following table 2 D40 NAR (nasal resistance to airflow in Guinea-pig) is a measure of effectiveness (as naseleniya in the nasal cavity; thus, the smaller the score the better the connection. For comparative purposes are included efficacy data (NAR model of the present applicant) for pseudoephedrine and phenylpropanolamine, which are widely used anti-edema in the nasal cavity, intended for oral administration.

3) Data confirming the usefulness of the compounds for other indications, where of disorders modulated alpha-2 adrenergic receptors.

In the following table 3 shows an affinity for binding and response agonist at alpha-2 adrenergic receptor. Nasal turbinates Guinea pigs were used as source of alpha-2 receptors to analyze the binding. Values of Kireported represent the number of connections required to displace 50% of the known radioligand (labeled with tritium of rauwolscine or RX-821002). For the response of the agonist was measured by the ability of compounds to inhibit the induced action of electric current contraction of the ileum of Guinea pigs. The value of EC50represents the concentration required to produce 50% of maximum response.

Examples of compositions and methods of using

Semeneya do not limit the invention, but provide guidance in this area, in order to obtain and use the compounds, compositions and methods of this invention. In each case, other compounds in this invention can replace, for example, the connection shown below, with similar results. An experienced specialist can appreciate that the examples serve as a guide and can change depending on the condition being treated and the patient.

An example of a

Composition of tablets for oral administration

The ingredient Quantity per tablet (mg)

Connection example 1 - 20,0

Microcrystalline cellulose (Avicel pH 102) - 80,0

Disubstituted calcium phosphate (San RHO4) - 96,0

Colloidal silicon dioxide (Cab-O-Sil) - 1,0

Magnesium stearate - 3,0

All 200,0

The patient with nasal congestion swallowed one pill. The congestion has decreased significantly.

Example B

Composition chewable tablets

The ingredient Quantity per tablet (mg)

Connection example 2 - 15,0

Mannitol - 255,6

Microcrystalline cellulose (Avicel pH 101) - 100,8

Dextrinization sucrose (Di-Pac) - 199,5

The flavor mimics the orange - 4.2V

Sodium saccharin - 1,2

Stearine (Cab-O-Sil) - 2,7

All of 600.0

The patient with nasal congestion chewed and swallowed one pill; stuffy significantly decreased.

The example IN

Composition of tablets for reception under language

The ingredient Quantity per tablet (mg)

Connection example 3 - 2,00

Mannitol - 2,00

Microcrystalline cellulose (Avicel pH 101) - 29,00

Mint flavors - 0,25

Sodium saccharin - 0,08

Just - 33,33

One tablet placed under the tongue of the patient with nasal congestion and allowed to dissolve. Stuffy quickly and significantly decreased.

Example D

Composition of solution for injection in nose

Ingredient Composition (% weight/vol.)

The compound of example 4 - 0,20

Benzalconi chloride - 0.02

Thimerosal - 0,002

d-Sorbitol - 5,00

Glycine - 0,35

Aromatic additives - 0,075

Purified water, a sufficient quantity (q.s.)

Just 100,00

One-tenth ml of the composition was sprayed from the injection device into each nostril of the patient with nasal congestion. The congestion was significantly decreased.

Example D

The gel composition for introduction into the nose

Ingredient Composition (% weight/vol.)

The compound of example 5 - 0,10

Benzalconi chloride - 0.02

Timezoneid sodium (0,65%) - a sufficient amount of

Just 100,00

One-fifth ml of the composition was introduced dropwise from a pipette into each nostril of the patient with nasal congestion. The congestion was significantly decreased.

Example E

Aerosol composition for inhalation

Ingredient Composition (% weight/volume)

Connection example 1 - 5,0

Alcohol - 33,0

Ascorbic acid - 0,1

Menthol - 0,1

Sodium saccharin - 0,2

Propellant (F 12, F 114) - a sufficient amount of

Just 100,0

Sprayed twice aerosol composition from the inhaler with measured doses of inhaled asthma patient. Asthmatic condition effectively facilitated.

Example G

Composition for topical application in the eye diseases

Ingredient Composition (% weight/vol.)

The compound of example 7 - 0,10

Benzalconi chloride - 0,01

EDTA - 0,05

Hydroxyethylcellulose (Natrosol M) - 0,50

Metabisulphite sodium - 0,10

A solution of sodium chloride (0.9 percent) is enough

Just 100,0

One-tenth ml of the composition was injected directly into each eye of the patient with glaucoma. Intraocular pressure was significantly reduced.

Example C

Liquid composition for oral administration

Ingregient - 1.8 g

Ethanol (95%) - 1.5 ml

Methanol - 12.5 mg

Eucalyptus oil - 7.55 mg

Flavors - 0.05 ml

Sucrose - of 7.65 g

Carboxymethylcellulose (CMC) - 7.5 mg

Microcrystalline cellulose and sodium salt of CMC (Avicel RC 591) - 187.5 mg

Polysorbate 80 - 3.0 mg

Glycerin is 300 mg

Sorbitol 300 mg

Dye red 40 (FD and C) - 3 mg

Sodium saccharin - 22,5 mg

Monobasic sodium phosphate - 44 mg

Sodium citrate, monohydrate - 28 mg

Purified water, a sufficient quantity of

Only 15 ml

A single dose of 15 ml liquid composition swallowed the patient with nasal congestion, over from the nose (rhinorrhea) and chihanie caused by allergic rhinitis. Stuffiness, rhinorrhea, and sneezing effectively decreased.

Example

Liquid composition for oral administration

Ingredient - the Number in the dose of 15 ml

The compound of example 7 to 30 mg

Sucrose - 8,16 g

Glycerin is 300 mg

Sorbitol 300 mg

Methylparaben - 19.5 mg

Propylparaben - 4.5 mg

Menthol - 22,5 mg

Eucalyptus oil - 7.5 mg

Flavors of 0.07 ml

Dye red 40 (FD & C) - 3.0 mg

Sodium saccharin 30 mg

Purified water, a sufficient quantity of

Only 15 ml

Od is m The congestion was significantly decreased.

Example TO

Composition of tablets for oral administration

The ingredient Quantity per tablet (mg)

Chlorpheniramine maleate, USP (USP) - 4,0

The compound of example 8 - 4,0

Microcrystalline cellulose, State Pharmacopoeia (NF) - 130,0

Starch 1500, NF - 100,0

Magnesium stearate - 2,0

Just - 240,0

To ease nasal congestion due to common cold, hay fever (pollinosis) or other allergic diseases of the upper respiratory tract, or associated with sinusitis; weakens rhinorrhea, sneezing, and itchy and watery eyes, which can occur in allergic rhinitis. Restores freer breathing through the nose. Adults 12 years and older take one tablet every four hours.

Example L

Composition of tablets for oral administration

The ingredient Quantity per tablet (mg)

Loratadine - 5,0

The compound of example 9 to 12.0

The hypromellose to 12.0

Magnesium stearate, USP - 2,0

Anhydrous lactose, USP - 200,0

All 231,0

To alleviate symptoms associated with allergic rhinitis, such as sneezing,P> Example M

The composition is encapsulated tablets for oral administration

The ingredient Quantity per tablet (mg)

Naproxen sodium, anhydrous, USP - 220,0

The compound of example 10 - 6,0

The hypromellose, USP - 6,0

Magnesium stearate, USP - 2,0

Povidone K-30, USP - 10,0

Talc, USP to 12.0

Microcrystalline cellulose, NF - 44,0

All 300,0

To alleviate symptoms associated with common cold, sinusitis or flu including nasal congestion, headache, fever, aches and pains. Adults 12 years and older take two capillarian tablets every twelve hours.

Example N

Composition of tablets for oral administration

Ingredient mg/tablet

Acetaminophen, USP - 500,0

Connection example 1 - 6,0

The hypromellose, USP - 6,0

Silicon dioxide, colloidal, NF - 30,0

Gelatinizing starch, NF - 50,0

Magnesium stearate, USP - 4,0

All 596,0

For the relief of stuffiness and sdavlennoy of the nose and sinuses, headaches associated with sinusitis, hay fever, allergies of the upper respiratory tract or a common cold. Adults 12 years and older take one tablet is of

The ingredient Quantity per tablet (mg)

Naproxen sodium, anhydrous, USP - 220,0

Loratadine - 2,5

The compound of example 5 - 6,0

The hypromellose, USP - 6,0

Magnesium stearate, USP - 2,0

Povidone K-30, USP - 10,5

Talc, USP to 12.0

Microcrystalline cellulose, NF - 44,0

All 303,0

To alleviate symptoms associated with allergic rhinitis, such as sneezing, rhinorrhea, nasal congestion, pain in the sinuses and headache. Adults 12 years and older take two encapsulated tablets every twelve hours.

Example PARAGRAPH

Composition of tablets for oral administration

The ingredient Quantity per tablet (mg)

Naproxen sodium, anhydrous, USP - 220,0

Chlorpheniramine maleate, USP - 6,0

Connection example 2 - 6,0

The hypromellose, USP to 12.0

Magnesium stearate, USP - 2,0

Povidone K-30, USP - 10,0

Talc, USP to 12.0

Microcrystalline cellulose, NF - 44,0

All 312,0

To alleviate symptoms due to common cold, flu, hay fever or other allergic diseases of the upper respiratory tract, or associated with sinusitis; weakens rhinorrhea, sneezing, and itching and tears from his eyes, kotoroe freer breathing through the nose. Adults 12 years and older take two tablets every twelve hours.

Example R

Composition of tablets for oral administration

The ingredient Quantity per tablet(mg)

Acetaminophen, USP - 500,0

Loratadine - 1,3

The compound of example 4 - 3,0

Hydroxypropylmethylcellulose, USP - 3,0

Silicon dioxide, colloidal, NF - 30,0

Gelatinizing starch, NF - 50,0

Magnesium stearate, USP - 2,7

All 590,0

To alleviate symptoms associated with allergic rhinitis, such as sneezing, rhinorrhea, nasal congestion, pain in the sinuses and headache. Adults 12 years and older take 2 tablets every 6 hours.

Example WITH

Composition in tablet form for oral administration

The ingredient Quantity per tablet (mg)

Connection example 1 - 20,0

Microcrystalline cellulose (Avicel pH 102) - 80,0

Disubstituted calcium phosphate - 96,0

Colloidal silicon dioxide (Cab-O-Sil) - 1,0

Magnesium stearate - 3,0

All 200,0

The patient with migraine swallow one pill. The pain and symptoms that precede a migraine significantly reduced.

Example T

Composition of tablets for oral administration
is for (Avicel pH 102) - 80,0

Disubstituted calcium phosphate - 96,0

Colloidal silicon dioxide (Cab-O-Sil) - 1,0

Magnesium stearate - 3,0

All 200,0

The patient suffering from diarrhea swallow one pill. Diarrhea is significantly reduced.

You can look at other examples of combinations of active ingredients. Examples of medications that can be combined with the main active ingredient that is included in U.S. patent 4552899 issued by Sunshine et al., which is included here as a reference. All other links related to the entire description is included as a reference.

Although there have been described particular embodiments of the present invention, the experts in this field it is obvious that various alterations and modifications of the present invention, without departing from the scope of invention. I.e., appended claims will cover all modifications that are included in the scope of the present invention.

Metabolic stability of the claimed compounds

I found that some of perifericheskie selective benzimidazole, which is the alpha-selective adrenergic agonists, was metabolically stable in rodents in vitro and in vivo exposed to meta the price. It has been shown that metabolic transformation changes the profile of these benzimidazole so that they can be converted into compounds which (1) are not active; (2) are antagonists of the alpha-2 adrenergic receptors; (3) have increased activity on other unwanted receptors such as alpha-1 adrenergic receptors; and/or (4) have a high potential in relation to actions on the Central nervous system.

Metabolic stability of these benzimidazole compounds was evaluated in vitro investigation of ultrathin sections of samples of the liver. Method of examination of ultrathin sections of samples of the liver is a recognized, approved in vitro model for the study xenobiotics metabolism in animals and humans. (See Ekins, S. Past, present and future applications of precision-cut liver slices for in vitro xenobiotic metabolism (Department of Medicine and Therapeuticcs, University of Aberdeen, UK) Drug-Metab-Rev. (November, 1996) Vol. 28, N. 4: pp. 591-623). This method was used to assess the metabolic activity of alpha-2 adrenergic agonists. Using this method get data on the biotransformation occurring in intact hepatocytes studied species.

For this study, sections of liver samples were obtained from the liver tissue of rats Sprague-Da relative scope of their education using HPLC/MOH profiling and scanning experiments M3/M5. The results are presented in table 4.

1. Derived 5-(2-imidazolidinone)benzimidazole having the following structural formula:

< / BR>
where R1represents methyl, ethyl and cyclopropyl;

R2represents hydrogen, C1-3alkyl, halogen;

R3represents hydrogen, methyl, hydroxy, cyano;

R4represents hydrogen or methyl;

R5represents hydrogen, methyl, amino, halogen, cyano;

provided that at least one of R2, R3, R4, R5different from hydrogen or fluorine;

provided that when R1is the stands and both R2and R5are hydrogen, R3may not be the stands;

provided that when R3is cyano, R1is stands;

and any tautomer above patterns, or a pharmaceutically acceptable salt, or biohydrology ester, amide or imide this connection.

2. Connection on p. 1, wherein R2and R5independently selected from the group consisting of hydrogen, methyl and halogen.

3. Connection PP. 1 and 2, characterized in that R1is sobees fact, what R1represents ethyl or cyclopropyl and R3selected from the group consisting of methyl, hydroxyl.

5. Connection on p. 1, wherein the connection is selected from the group consisting of:

7-cyano-5-(2-imidazolidinyl)-4-methylbenzimidazole,

7-hydroxy-5-(2-imidazolidinyl)-4-methylbenzimidazole,

4-ethyl-5-(2-imidazolidinone)-7-methylbenzimidazole and

4-cyclopropyl-5-(2-imidazolidinone)-7-methylbenzimidazole.

6. The pharmaceutical composition of agonistic respect to alpha-2 adrenergic receptors containing a safe and effective amount of a compound according to any one of the preceding paragraphs and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to p. 6, additionally containing one or more active ingredients selected from the group consisting of an antihistamine, antioxidant or a radical inhibitor, a bronchodilator, antiviral agents, analgesics, anti-inflammatory agents, gastro-intestinal funds and eye means.

8. Connection PP. 1-5 as an agonist, alpha-2 adrenergic receptors.

9. Connection PP. 1-5, suitable for the production of pharmaceutical preparations is riznica:

24.11.1997 under item 1 (compounds in which R1- all values of R2- N, R3- CN, R4- N, R5(H) p. 2 (compound where R2- N), p. 3 (compound where R3- CN), p. 5, 8, 9;

25.11.1997 under item 1 (compounds in which R1- all values of R2- H, C1-C3-alkyl, R3- SP, R4- H, CH3, R5- H, CH3), p. 2 (compound where R2- H, CH3), p. 4, 5, 6, 7, 8, 9.

 

Same patents:

The invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt

The invention relates to an improved process for the preparation of 8-methyl-8-azabicyclo[3,2,1]Oct-3-silt ester of indole-3-carboxylic acid hydrochloride which is a substance tropisetrona and is used as an antiemetic, effective for vomiting caused by anticancer chemotherapy drugs

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to medicine, specifically to pharmacology

The invention relates to medicine and can be used for the treatment and prevention of allergies and reactions psevdoallergicakie

The invention relates to medicine, in particular to the technology of drugs based on chloropyramine hydrochloride used in allergic dermatitis, allergic rhinitis

The invention relates to medicine and can be used as a preventive AIDS in allergic diseases

The invention relates to a new benzimidazole derivative of the formula (I), where a represents a single bond or C1-2-alkylenes group; R6is a hydrogen atom or a C1-4is an alkyl group; b - C2-3-alkylenes group; X represents an oxygen atom, each of R1and R2is a hydrogen atom; E is C1-2-alkylenes group; R3is a phenyl group (this phenyl group may be optionally substituted by halogen atom), each of R4and R5that are independent from each other, represents a hydrogen atom or a C1-4is an alkyl group; D - C1-2-alkylenes group and Ar is a phenyl group (this phenyl group may be optionally substituted by a halogen atom, a C1-4is an alkyl group, a C1-4-alkoxygroup or triptorelin group)

The invention relates to a new antileukotriene, antihistaminic, anti-allergic and anti-inflammatory compositions of non-steroidal anti-inflammatory sulfonanilide and its salts with antihistamine drugs of the second generation (receptor blockers H1)

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt

Anti-allergic drug // 2184544
The invention relates to the field of medicine and relates to a drug for treatment of allergic diseases

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, СООR34,4-dimethyl-2-oxazoline

The invention relates to new derivatives of 2-renominate General formula (I), where R1and R2represent hydrogen, C1-C6-alkyl, deformity, trifluoromethyl, C3-C6-cycloalkyl, saturated 5-membered heterocycle containing one oxygen atom, indanyl, 6,7-dihydro-5H-cyclopentadienyl or1-C6-alkyl, substituted phenyl, indayla or3-C6-cycloalkyl, R3is hydrogen, R4represents hydrogen, halogen, C1-C6-alkyl, trifluoromethyl, or R4represents a radical of the formula-O-R7where R7is hydrogen, R5represents hydrogen or R4and R5taken together may form a bivalent radical of formula-CH2-CH2-O-CH2-CH2-, R6represents hydrogen or C1-C6-alkyl, -a-b - represents a bivalent radical of the formula- (CR10= CR11or СНR10-СНR11where each R10and R11independently represents hydrogen or C1-C6-alkyl, L represents hydrogen, C1-C6-alkyl, C1-C6-allyloxycarbonyl,1-C6-alkyl, substituted by one or two penilai

The invention relates to medicine, namely, venereology, and is intended for outpatient treatment of patients with subclinical genital herpes infection (GVI)
Up!