UA77551C2 - Substituted thiophene derivatives, method of production, their use as drugs or diagnostic reagents, pharmaceutical compositions - Google Patents

Abstract

The invention relates to substituted thiophene derivatives of formula (I), wherein: R1 to R8 have the meanings as cited in the claims. Medicaments containing compounds of this type are useful in preventing or treating various diseases. Thus, these compounds can be used, among other things, for treating breathing disturbances and snoring, for improving the breathing drive, for treating acute and chronic diseases, diseases triggered by ischemic and/or reperfusion events as well as by proliferative or fibrotic events, for the treatment or prophylaxis of diseases of the central nervous system, lipid metabolism and diabetes, blood clotting and parasitic infection.

Description

Description of the invention

The invention relates to compounds of the substituted thiophene derivatives of formula (I). Medicinal products containing 2 compounds of this type are useful in the prevention or treatment of various diseases. Thus, the compounds can be used, in particular, for the treatment of breathing disorders and snoring, as well as for the improvement of the respiratory impulse, for the treatment of acute and chronic diseases, for the treatment of diseases caused by ischemic and/or reperfusion phenomena, as well as proliferative or fibrotic phenomena, for treatment or prevention of diseases of the central nervous system, fat metabolism and diabetes, blood coagulation and damage by parasites.

The invention relates to the compounds of formula (1): where

КИ and К2, independently of each other, mean Н, РЕ, СИ, Вг, И, СМ, МО", "(X)p-СаНзд-2, cycloalkyl with 3, 4, 5 or 6 carbon atoms, alkenyl with 2 , C or 4 carbon atoms, alkenylalkyl with C or 4 carbon atoms, ethynyl or alkylalkynyl with C or 4 carbon atoms; n means zero or 1; Gee!

X means an oxygen atom, MH, M-CH3, (OK; o

Kk means zero, 1 or 2; d means zero, 1, 2, Z, 4, 5 or 6; 27 means a hydrogen or Spot atom; t means zero, 1, 2, C or 4; h

KZ means a hydrogen atom, methyl, PE, SI, Vg, I, CM, B(O)2СНвз, -МО», -ОО-СН»у;

Kk means zero, 1 or 2; what

K4 means a hydrogen atom, cycloalkyl with 3, 4, 5 or b carbon atoms, alkenyl with 2, 3 or 4 carbon atoms, alkenylalkyl with 3 or 4 carbon atoms, ethynyl or alkylalkynyl with 3 or 4 carbon atoms, -C/Nog -IN; r means zero, 1, 2, C or 4; -

U means a hydrogen atom or trifluoromethyl; -

K5 and Kb mean a hydrogen atom or together mean a bond;

K7 and kK8, independently of each other, mean (C3-Cv)-alkyl, (Co-Cv)-alkenyl, (Co-Cv)-alkynyl, (C5-Cv)-cycloalkyl or (C./-Cv)- cycloalkenyl; " or

K?7 and K8 together mean an alkylene chain consisting of 3-8 carbon atoms, and the hydrogen atoms in the chain may be unsubstituted, partially or completely replaced by fluorine atoms; ц or "» К?7 and К8 together mean the residue овго пи, and К5 and КбЕ together form a bond; 1 КИ10 and К11, independently of each other, mean an atom of hydrogen, fluorine, chlorine, bromine, methyl, СМ, ОН, -0О-SN»U, shk MO», Mne or -SEz;

KU and K12 mean a hydrogen atom or E; or one of the substituents КУ and К12 means a hydrogen atom, and the other means ЕК, СИ, Вг, И, СМ, МО», СООН, СО-МК1ЗК14, , и и ; 5ОО-МК1З3К14, alkenyl with 2, 3 or 4 carbon atoms, alkenylalkyl with 3 or 4 carbon atoms, ethynyl, (F) alkylalkynyl with 3 or 4 carbon atoms or -(X)5-СаНза-2; r КИЗ and К14, the same or different, mean a hydrogen atom or an alkyl with 1, 2, 3 or 4 carbon atoms; or in KIZ and K14, together with the nitrogen atom to which they are connected, form a saturated 5-, 6-, or 7-ene ring; n means zero or 1;

X means an oxygen atom, MH, M-CH3, (OK;

Kk means zero, 1 or 2; ve d means zero, 1, 2, Z, 4, 5 or 6; and

27 means a hydrogen or Spot atom; t means zero, 1, 2, C or 4; and to their pharmaceutically acceptable salts, as well as to their trifluoroacetic acid salts.

One embodiment relates to compounds of formula (I), where

КИ and К2, independently of each other, mean Н, РЕ, СИ, Вг, И, СМ, МО", "(X)p-СаНзд-2, cycloalkyl with 3, 4, 5 or 6 carbon atoms, alkenyl with 2 , C or 4 carbon atoms, alkenylalkyl with C or 4 carbon atoms, ethynyl or alkylalkynyl with C or 4 carbon atoms; n means zero or 1; 70 X means an oxygen atom, МН, М-СН3, (OK;

Kk means zero, 1 or 2; d means zero, 1, 2, Z, 4, 5 or 6; 27 means a hydrogen or Spot atom; t means zero, 1, 2, C or 4;

KZ means a hydrogen atom, methyl, PE, SI, Vg, I, CM, B(O)2СНвз, -МО», -ОО-СН»у;

K4 means a hydrogen atom, cycloalkyl with 3, 4, 5 or b carbon atoms, alkenyl with 2, 3 or 4 carbon atoms, alkenylalkyl with 3 or 4 carbon atoms, ethynyl or alkylalkynyl with 3 or 4 carbon atoms, -СаНод-2; d means zero, 1, 2, C or 4; 7 means a hydrogen atom or trifluoromethyl;

K5 and Kb mean a hydrogen atom or together mean a bond;

K7 and kK8, independently of each other, mean (C5-C5)-alkyl-, (Co-Cv)-alkenyl, (Co-Cv5)-alkynyl, (C5-Cv)-cycloalkyl or (C./-Cv) -cycloalkenyl; or

K?7 and K8 together mean an alkylene chain consisting of 3-8 carbon atoms, and hydrogen atoms may be unsubstituted, partially or completely substituted by fluorine atoms; or about

K?7 and K8 together mean the remainder 30 4 | and the Jew

Che yu and - and K5 and KbE together form a connection; 35 КУ, К10 и К11, independently of each other, mean hydrogen, fluorine, chlorine, bromine, methyl, СМ, ОН, - -0-СНу, МО», Мне or -СЕз;

KU and K12 mean a hydrogen atom; or "one of the substituents КУ and К12 means a hydrogen atom, and the other means ЕК, СИ, Вг, И, СМ, МО", СООН, СО-МК1ЗК14, 40 5ОО-МК1З3К14, alkenyl with 2, 3 or 4 carbon atoms, alkenylalkyl with 3 or 4 carbon atoms, ethynyl, - with alkylalkynyl with 3 or 4 carbon atoms or -(X)y-CaHza-2; h КИЗ and К14, the same or different, mean a hydrogen atom or an alkyl with 1, 2, 3 or 4 carbon atoms; -» n means zero or 1;

X means an oxygen atom, MH, M-CH3, (OK; 45 Kk means zero, 1 or 2; - and d means zero, 1, 2, З, 4, 5 or 6; -1 and 27 means a hydrogen atom or Spot ; 1 t means zero, 1, 2, C or 4; s 20 as well as their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts.

Preferred compounds of formula (I), where -. КИ and К2, independently of each other, mean Н, РЕ, СИ, Вг, СН3, СЕз, ЗОСН»3, 5О2МН», however, at most one of the substituents КИ and К2 means a hydrogen atom;

KZ means a hydrogen atom, E or SI;

KA means a hydrogen atom, an alkyl with 1, 2, 3 or 4 carbon atoms or cyclopropyl;

Gee! K5 and Kb mean a hydrogen atom or together mean a bond;

K?7 and K8 together mean an alkylene chain consisting of 3, 4, 5, 6, 7 or 8 carbon atoms; name) or

K?7 and K8 together mean the remainder of va yan 65 i, and K5 and KbE together form a connection;

KO and K11, independently of each other, mean a hydrogen atom, OH, a fluorine or chlorine atom;

KU and K12 mean a hydrogen atom; or one of the substituents КО and К12 means a hydrogen atom, and the other means Е, СИ, Вг, СМ, СООН, СО-МК13К14, 502-МК1З3К14 or -(X)y-СаНод-2;

КИЗ and К14, the same or different, mean a hydrogen atom or methyl; n means zero or 1;

X means an oxygen atom, MH, M-CH»3 or B(O)K; 70 Kk means zero, 1 or 2; d means zero, 1, 2, C or 4; 7 means a hydrogen atom or CE"; and their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts.

Compounds of formula (I) are especially preferred, where

КИ kg, independently of each other, mean Р, СИ, Вг, СНз or СЕ";

KZ means a hydrogen atom;

K4 means a hydrogen atom, methyl, ethyl;

K5 and Kb mean a hydrogen atom or together mean a bond;

K?7 and K8 together mean an alkylene chain consisting of 3, 4, 5, 6, 7 or 8 carbon atoms; or K?7 and

The K8s together represent the remainder

Ве в У, о and К5 and КбЕ together form a bond;

KO and K11, independently of each other, mean a hydrogen atom, OH or a fluorine atom;

KU and K12 mean a hydrogen atom; or -- one of the substituents КО and К12 means a hydrogen atom, and the other means БЕ, СИ, Вг or "(Х)а-СаНга- 2; y n means zero or 1;

X means an oxygen atom, MH, M-CH»3 or B(O)K; Io)

Kk means zero, 1 or 2; ich- 4 means zero or 1; 7 means a hydrogen atom or CE"; and their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts.

Particularly preferred are the following compounds of formula (I), selected from the group including transo-K,K-2-chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4 -methyl-3-thienylamine; trans-K,K-2-bromo-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine; 2-chloro-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine; t c 2-bromo-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine; h 2-chloro-3M-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine; » 2-chloro-3M-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine; 2-chloro-3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene; 2-bromo-3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene; - 2-bromo-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene; - 2-chloro-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene; 2-chloro-3M-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene; o (1H-benzimidazol-2-yl)-(2-chloro-4-methylthiophen-3-yl)methylamine; c 20 (2-bromo-4-methylthiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)amine; 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene; -. 2,4-dichloro-3M-(2-benzimidazolylamino)thiophene; 2-bromo-4-chloro-3M-(2-benzimidazolylamino)thiophene; 2,4-dichloro-3M-(4-methyl-2-benzimidazolylamino)thiophene; 25 transo-K,K-2,4-dichloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine; or

Gee! 2,4-dichloro-3M-(4-chloro-2-benzimidazolylamino)thiophene; and their pharmaceutically acceptable salts, for example, the hydrochloride or hydrobromide or methanesulfonate of each of the compounds.

The compounds of formula (I) can be in the form of salts. As additive salts of acids, it is possible to use salts of all pharmacologically acceptable acids, for example, halides, especially hydrochlorides, hydrobromides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, benzenesulfonates, p-toluenesulfonates, adipinates, fumarates, gluconates, glutamates, glycerol phosphates, maleinates, benzoates, oxalates and pamoates. This group also corresponds to physiologically acceptable anions; however, also to trifluoroacetates.

If the compounds contain an acid group, they can form salts with bases, for example, they can be in the form of alkali metal salts, preferably sodium or potassium salts, or in the form of ammonium salts, for example, in the form of salts with ammonia or organic amines or amino acids. They can also be in the form of a zwitterion.

If the compounds of formula (I) contain one or more centers of asymmetry, then, independently of each other, they can be in both the 5- and the K-configuration. The compounds can be in the form of optical isomers, diastereomers, racemates or in the form of their mixtures.

Compounds of formula (I), further, can be in the form of tautomers or in the form of a mixture of tautomeric structures. At the same time, for example, the following tautomers are meant: no, but 6 not I in shi:

M yan - as in so on

Alkyl residues can be linear or branched. This also applies to those cases when they do not contain substituents or are in the form of substitutes for other residues, for example, in fluoroalkyl or alkyl residues. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl (- 1-methylethyl), n-butyl, isobutyl (- 2-methylpropyl), sec-butyl (- 1-methylpropyl), tert-butyl (- 1,1 -dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl or hexyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl. In alkyl residues, one or more, for example, 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen atoms can be replaced by fluorine atoms. Examples of such fluoroalkyl residues are trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, heptafluoroisopropyl. Substituted alkyl residues can be substituted in any position.

Alkenyl residues can be linear or branched. This also applies to those cases when they are found as substituents, for example, in alkenylalkylenes. Alkenyl residues can be unsaturated in different positions. Examples of alkenyl residues are ethenyl, propenyl or butenyl. at

Alkynyl residues can be linear or branched. This also applies to those cases, if they are found as substituents, for example, in alkynylalkylenes. Alkynyl residues can be unsaturated in various positions. Examples of alkynyl residues are ethynyl, propynyl or butynyl.

Examples of cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Substituted -- 3o cycloalkyl residues can be substituted in any position. Cycloalkyl residues can also be C o) branched, such as alkylcycloalkyl or cycloalkylalkyl.

Also described are methods of obtaining the compounds proposed according to the invention. Thus, compounds of the formula (I) can be obtained by a method known to a specialist from the starting isothiocyanates of the formula (II) and the corresponding diamines (II) of the formula (PI). m zh ek no v s y More. "» Intermediate derivative of thiourea, which is formed in this case, with the help of methyl iodide | Zupipevziv, 41-42 " (1974))| or carbodiimide (Zupipeziz, 864-865 (1977) or with the help of anhydride, p-toluenesulfonic acids are cyclized to obtain the corresponding compound of formula (I). The isothiocyanates of formula (II) used in this case, if they are not commercially available, can be obtained by a method known from the literature from the corresponding aminothiophene derivatives by methods known to those skilled in the art, for example, by treatment with thiophosgene (U. Med. Spet., -I 18, 90-99 (1975)) or thiocarbonyldiimidazole Yuziiz Ieridv App, Spet., 657, 104 (19623) .

Along with the above-mentioned isothiocyanates of the formula (II), also isocyanates of the formula (II) o shk - Vodvy and o can be successfully introduced into interaction with amines of the amine type of formula (III), obtaining compounds of the formula (I). In this case, the resulting intermediate urea derivative is cyclized with the help of phosphorus oxychloride with

HF) by obtaining the corresponding compounds of formula (1). 7 According to the present invention, it was unexpectedly shown that the described compounds are effective inhibitors of sodium/proton exchange (NPE), especially sodium/proton exchange of subtype C (NPE).

Known so far MNEZ inhibitors are derivatives of compounds of the acylguanidine type (European patent 8251781), norbornylamine type 60 (Federal patent 19960204, 2-guanidinequinazoline type | MO application 0179186) or benzamidine type, UMO application 0121582, MO 0172742). Also described as an inhibitor of MNEZ, squalamine M. Oopom/i et al., At. ..

RPuzio!.,, 276 (Seiyi Ryuzioi. 45): C136-C144), according to the state of the art, does not act directly, like the compound of formula (I), but through a mediated mechanism and, thus, reaches its maximum activity only after an hour . Such MNEZ inhibitors acting on a different mechanism are therefore suitable as a component of the combination with 65 compounds presented according to the invention.

Similar to the compounds described in this context, clonidine is known as a weak MNE inhibitor. True, its effect on the MNEZ of the rat at the half-maximal inhibitory concentration (IS0), which is 6b20μmol, is too mediocre. Instead, it has a known selectivity for MNE2 |U. OgpiomuzKi and others, U. Vioi.

Spet., 268, 25-36). Therefore, it should rather be called an MNE2 inhibitor. Along with a weak effect on MNE, clonidine has a high affinity for adrenergic alpha2-receptor and imidazoline-I1-receptor, due to which there is a strong effect that lowers blood pressure (Egpzbregdeg et al., Eig. U. Rnagtasoi., 134, 1 (1987).

Compounds similar to clonidine with a thiophene ring instead of a phenyl ring are known from (FRG patent 19417611.

These known compounds differ from the structures of formula (I) described in this context by significantly smaller K7 and КВ residues and especially by the fact that К?7 and КВ cannot form any common cycle.

Due to this difference in the K7 and K8 substituents, it is possible to exclude the above-described undesirable cardiovascular effects of these thiophene derivatives similar to clonidine, mediated by alpha-adrenoceptor influence.

At the same time, as a result of this difference in substitution, the MNE inhibitory properties of the compounds described in this context are enhanced up to the micromolar and submicromolar range, while the compounds known from (Federal patent 19417611) /5 bpoluks do not show or only show very weak MNE inhibitory effects. Thus, the main representative according to German Patent No. 1941761, selected as a developed drug for lowering blood pressure, thiamendin, in the amount, respectively, ZOOμmole, does not have any inhibitory effects on the investigated subtypes

MNE: MNE, MNE2, MNEZ and MNE5.

Compounds of formula (I) are distinguished by inhibition of sodium-proton exchange and especially inhibitory action of MNEZ.

MNEZ in the body of various species occurs in the bile, intestines and kidneys (I agu Riiedei! and others, Viosnet.

That's it. Vioi., 76, 735-741 (1998)), but it can also be found in the brain (E. Ma et al., Mepyigozsiepse, 79, 591-603).

Due to MNE-inhibiting properties, the compounds of formula (I) are suitable for the prevention and treatment of diseases that are provoked by MNE activation or, accordingly, activated MNE, as well as recurring diseases caused by MNE disorders.

Since MNE inhibitors mainly act through the regulation of the pH value in cells, they can be advantageously combined with other compounds that also regulate the intracellular pH value, and as a component of the combination, inhibitors of the enzyme group of carbonic anhydratase, inhibitors of bicarbonate-ion transport systems, as a common sodium- of bicarbonate transport (MVS) or sodium-dependent "- zo Xhporide-bicarbonate exchange (MSVE), as well as inhibitors of MNE with an inhibitory effect on other subtypes of MNE, since due to them it is possible to strengthen or modulate pharmacologically relevant, regulating pH values, the effects described in this context MNE inhibitors. yu

The use of the compounds proposed according to the invention refers to the prevention and treatment of acute and chronic diseases in human and animal medicine. uh-

The pharmacological effect of the compounds of formula (I) differs in that they lead to an improvement of the respiratory impulse. Therefore, they can be used to treat respiratory disorders that may occur, for example, in the case of the following clinical conditions and diseases: disturbed central respiratory impulse (for example, central sleep apnea, sudden death of a child, postoperative hypoxia), muscle-related disorders breathing, breathing disorders after long-term artificial ventilation, breathing disorders during adaptation to high altitudes, obstructive or mixed form of sleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia. In addition, compounds increase the muscle tone of the upper

And the respiratory tract, so that snoring is suppressed. These compounds are therefore mainly used for the production of a medicinal product for the prevention and treatment of sleep apnea and muscle-related breathing disorders, for the production of a medicinal product for the prevention and treatment of snoring.

A combination of the MNE inhibitor of the formula (I) with a carbonic anhydrase inhibitor (such as -I, for example, acetazolamide) may be useful, and the latter causes metabolic acidosis and, thanks to this, already increases respiratory activity, so that an enhanced effect can be achieved with a reduced introduction of a biologically active substance. - The compounds proposed according to the invention, as a result of their inhibitory MNEZ action, preserve cellular energy resources, which are quickly depleted in toxic and pathogenic phenomena and, thus, lead to up to 5 years of damage or death of the cell. At the same time, energy-intensive ATP consuming sodium resorption in the proximal tubule under the influence of compounds of formula (I) temporarily does not occur and the cell, thus, can survive as an acute pathogenic, ischemic or toxic situation. The compounds are therefore suitable, for example, as drugs for the treatment of ischemic pathogenic factors, for example, acute renal failure.

Further, the compounds are also suitable for the treatment of all chronic kidney diseases and forms of nephritis, which due to increased protein excretion lead to chronic kidney failure. Accordingly, the compounds of formula (I) are suitable for obtaining a medicinal product for the treatment of diabetic late lesions, diabetic

F) nephropathy and chronic kidney diseases, especially all inflammations of the kidneys (nephritis) that are associated with increased excretion of protein/albumin.

It was found that the compounds used according to the invention have a moderate laxative effect and, as a result, can also be preferably used as a laxative or in case of threatening intestinal obstruction.

Further, the compounds proposed according to the invention can be used primarily for the prevention and treatment of acute and chronic intestinal diseases, for example, provoked by ischemic conditions in the intestinal area and/or subsequent reperfusion or inflammatory conditions and phenomena. Such complications are possible, 65 for example, due to insufficient intestinal peristalsis, which, for example, can often be observed after surgical interventions, with intestinal obstruction or with greatly reduced intestinal activity.

With the help of the compounds proposed according to the invention, there is a possibility of preventing the formation of gallstones.

MNE inhibitors offered according to the invention are suitable, in general, for the treatment of diseases provoked by ischemia and reperfusion.

Due to their pharmacological properties, the compounds proposed according to the invention are suitable as antiarrhythmic drugs.

Due to their cardioprotective component, MNE inhibitors of the formula (I) are perfectly suitable for the prevention of heart attack and the treatment of heart attack, as well as for the treatment of angina pectoris, and they also prophylactically inhibit 7/0 or strongly reduce pathophysiological processes when ischemic-induced injuries occur, especially when ischemic-induced heart arrhythmia. Due to their protective effect against pathological hypoxic and ischemic situations, the compounds of formula (I) used according to the invention, due to the inhibition of the cellular Mo"/H"-exchange mechanism, can be used as medicinal products for the treatment of all acute or chronic ischemia-induced injuries or primary or recurrent diseases induced due to this. This 75 refers to their use as medicines during surgical interventions. Thus, the compounds proposed according to the invention can be used in organ transplants, and the compounds can be used both to protect organs in the donor before and during extraction, to protect the extracted organs, for example, during treatment with physiological solutions of electrolytes or during their storage in physiological solutions of electrolytes, as well as when transferred into the body of the recipient pretreated with compounds of formula (I).

The compounds are also valuable, protective drugs during angioplasty operations, for example, in the case of the heart, as well as in the case of peripheral organs and vessels.

Since MNE inhibitors not only effectively protect human tissue and organs from damage caused by ischemia and reperfusion, but also from the cytotoxic effect of drugs that are used, especially, in the treatment of cancer and autoimmune diseases, combined administration together with compounds of the formula (I) to reduce or suppress the cytotoxic effects of therapy By reducing the cytotoxic effects, especially cardiotoxicity, due to concomitant drug therapy with MNE inhibitors, it is also possible to increase the dose of the cytotoxic therapeutic agent and/or continue the drug therapy with such drugs . The therapeutic effectiveness of such cytotoxic therapy can be significantly increased due to the combination with MNE inhibitors. The compounds of formula (I) are especially suitable for improving therapy with drugs that have an undesirable cardiotoxic component. i am

According to their protective action against ischemia-induced damage, the compounds according to the invention are also (3) suitable as medicinal agents for the treatment of ischemia of the nervous system, especially of the central nervous system, and they are suitable, for example, for the treatment of stroke or brain edema. -

Compounds of formula (I) are also suitable for the treatment and prevention of diseases and disorders arising due to increased excitability of the central nervous system, especially for the treatment of diseases of the group of epileptic nosological forms, centrally provoked clonic and tonic spasms, mental depressive states associated with fear of diseases and psychoses. At the same time, the MNE inhibitors offered according to the invention can be used individually or in combination with other antiepileptic substances or antipsychotic biologically active substances or carbonic anhydratase inhibitors, for example, with acetazolamide, as well as with other inhibitors of MNE or sodium-dependent chloride-bicarbonate and exchange (MSVE). Moreover, the compounds of formula (I) proposed according to the invention are also suitable for the treatment of forms of shock, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shock.

Compounds of formula (I) can also be used for the prevention and treatment of thrombotic-I diseases, since they, as MNE inhibitors, can even inhibit platelet aggregation. Moreover, they can inhibit, respectively, prevent what happens after ischemia and reperfusion release

She mediators of inflammation, deviating from the established value and coagulation, especially Willebrand factor and c thrombogenic selectin proteins. Thus, it is possible to reduce or exclude the pathogenic influence of thrombogenic and essential factors in the case of inflammation. MNE inhibitors according to this invention are therefore combined with other anticoagulant and/or thrombolytic biologically active substances, such as, for example, with recombinant or natural tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, fibrinolytic drugs substances, thromboxane receptor antagonists, phosphodiesterase inhibitors, Miia factor antagonists, clopidogrel, ticlopidine, etc. The combined use of these MNE inhibitors with MUVE inhibitors and/or with carbonic anhydratase inhibitors, such as, for example, with acetazolamides, is especially favorable.

F. Moreover, the compounds of formula (I) proposed according to the invention are distinguished by a strong inhibitory effect on cell proliferation, for example, the proliferation of fibroblasts or the proliferation of smooth muscle vascular cells. Therefore, the compounds of formula (I) are considered as valuable therapeutic agents for diseases, because the primary or secondary cause of which is cell proliferation, and as a result, they can be used as antiatherosclerotic agents, agents against chronic renal failure, and oncological diseases. Thus, they can be used to treat hypertrophy and hyperplasia of organs, for example, the heart and prostate.

The compounds of formula (I) are therefore suitable for the prevention and treatment of heart failure (congestive heart failure - SNE), as well as for the treatment and prevention of hyperplasia, respectively, prostate hypertrophy. 65 The compounds of formula (I) are further distinguished by retardation or prevention of fibrotic diseases. Thus, they are suitable as means for the treatment of fibrosis of the heart, as well as fibrosis of the lungs, liver, kidneys and other fibrotic diseases.

Since MNE is significantly increased in essential hypertensives, the compounds of formula (I) are suitable for the prevention and treatment of high blood pressure and cardiovascular diseases.

At the same time, they can be used individually or together with a suitable component of combinations and preparative forms for the treatment of high blood pressure and cardiovascular diseases. For example, one or more thiazide-like diuretics, bypass diuretics, aldosterone and pseudoaldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerone, can be combined with compounds of formula (1) . Further, the 70 MNE inhibitors according to the invention can be used in combination with calcium antagonists such as verapamil, diltiazem, amlodipine or nifedipine, as well as with ACE inhibitors such as, for example, ramipril, enalapril, lisinopril, fosinopril or captopril. Other favorable components of combinations are also p-blockers, such as metoprolol, albuterol, etc., antagonists of the angiotensin receptor and its receptor subtypes, such as losartan, irbesartan, valsartan, omapatrilat, hematopatrilat, endothelin antagonists, renin inhibitors, 7/5 receptor agonists adenosine, inhibitors and activators of potassium channels, such as glibenclamide, glimepiride, diazoxide, cromokalim, minoxidil and its derivatives, activators of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of other potassium channels, such as Kmi.5, etc. d.

Due to their anti-inflammatory effect, MNE inhibitors can be used as anti-inflammatory agents. From the point of view of the mechanism, the inhibition of the release of inflammatory mediators is distinguished. The compounds can thus be used individually or in combination with an anti-inflammatory agent to prevent or treat chronic and acute inflammatory diseases. Steroid and non-steroidal anti-inflammatory drugs are mainly used as components of the combination.

In addition, it has been shown that the compounds of formula (I) have a beneficial effect on serum lipoproteins.

Therefore, they can be used for the prevention and regression of atherosclerotic changes, since they exclude ("su

Causal risk factor, which includes not only primary hyperlipidemias, but also known secondary hyperlipidemias, which are, for example, in diabetes. Moreover, the compounds of formula (I) lead to a marked reduction in infarct-induced metabolic abnormalities and, in particular, to a significant reduction in the size of the induced infarct and its severity.

These compounds are therefore mainly used to obtain a medicinal product for the treatment of "-- Hypercholesterolemia; to prevent atherogenesis; for the prevention and treatment of atherosclerosis; for the prevention and treatment of diseases caused by high cholesterol levels; for the prevention and treatment of diseases caused by endothelial dysfunction; for the prevention and treatment of hypertension induced by atherosclerosis; for the prevention and treatment of thrombosis induced by atherosclerosis; for the prevention and treatment of ischemic injuries and postischemic reperfusion injuries induced by hypercholesterolemia and endothelial dysfunction; for the prevention and treatment of cardiac hypertrophies and cardiomyopathies and congestive heart failure (CHF); for the prevention and treatment of coronary spasms and myocardial infarctions induced by hypercholesterolemia and endothelial dysfunction; for the prevention and treatment of these diseases in combination with blood pressure-lowering substances, mainly with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. The combination of the MNE inhibitor of the formula (I) with a biologically active substance that lowers blood pressure, preferably with an inhibitor of NMO-CoA reductase (for example, as lovastatin or pravastatin), and the latter has a hypolipidemic effect and, thanks to this, improves the hypolipidemic properties of the MNE inhibitor formula (I), turns out to be a favorable "" combination with enhanced action and reduced use of the biologically active substance.

Thus, compounds of formula (I) lead to effective protection against endothelial damage of various genesis. Due to the protection of blood vessels against the syndrome of endothelial dysfunction, the compounds of formula (I) are valuable drugs for the prevention and treatment of coronary spasms of blood vessels, peripheral vascular diseases, especially Charcot syndrome, atherogenesis and atherosclerosis, left ventricular hypertrophy and - dilated cardiomyopathy, and thrombotic diseases. c In addition, MNE inhibitors of formula (I) are suitable for the treatment of non-insulin-dependent diabetes (MIOM), whereby, for example, insulin resistance is suppressed. In order to enhance the antidiabetic effectiveness and otherwise improve the quality of action of the compounds proposed according to the invention, it may be beneficial to combine them - with a biguanide, such as metformin, with an antidiabetic sulfonylurea, such as glyburide, glimepiride, tolbutamide, etc., with a glucosidase inhibitor, an agonist PRAK, such as rosiglitazone, pioglitazone, etc., with an insulin drug of various forms of administration, with an OVA4 inhibitor, with an insulin-sensitizing agent, or with meglitinide.

Along with direct antidiabetic effects, the compounds of formula (I) counteract the occurrence of diabetic late complications and therefore they can be used as medicinal products for the prevention and (F) treatment of diabetic late damage, such as diabetic nephropathy, diabetic neuropathy, diabetic choretinopathy, diabetic cardiomyopathy and other diseases , which occur as a result of diabetes. At the same time, they can preferably be combined with the following antidiabetic drugs in the treatment of MIOM, because combinations with a favorable form of insulin administration are of particular importance.

The MNE inhibitors of formula (I) proposed according to the invention, in addition to protective effects against acute ischemic events and subsequent acute aggravating events of reperfusion, also exhibit further direct therapeutically useful actions against diseases and disorders in the case of the whole mammalian organism, which are associated with the phenomena of the chronic aging process and which are also independent of acute ischemic conditions and may also occur in normal non-ischemic conditions. In the case of these pathological, long-term aging and aging-related phenomena such as disease, debilitating disease and death, which have recently become available for treatment with MNE inhibitors, we are talking about diseases and disorders that are largely caused by aging changes vital organs and their functions in the aging organism acquire increasing importance. Diseases that are associated with aging-related dysfunction, with aging-related phenomena of "wear and tear" of organs, are, for example, insufficient sensitivity and responsiveness of blood vessels in relation to contractions and relaxation reactions. This aging-induced deterioration of the vascular response to constrictive and relaxing stimuli, which is an essential process of the cardiovascular system and, thus, the deterioration of the quality of life and health, can be significantly inhibited or reduced with the help of MNE inhibitors. An important function and measure of 7/0 in maintaining vascular responsiveness is blockade, respectively, retardation of progressive endothelial dysfunction caused by aging, which can be largely eliminated with the help of MNE inhibitors. The compounds of formula (I), thus, are suitable for the treatment and prevention of age-related progressive endothelial dysfunction, especially Charcot syndrome. In addition, the compounds of formula (I) are thus suitable for the treatment and prevention of heart failure, congestive heart failure (CHF), as well as for 7/5 treatment and, especially, for the prevention of age-related forms of cancer.

In addition, it is possible to use a combination with drugs that lower blood pressure, such as ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca antagonists, etc., or with drugs that normalize metabolism, such as cholesterol-lowering agents. formulas (I) are thus suitable for the prevention of tissue changes caused by aging and for prolongation

Life while achieving a high quality of life.

The compounds proposed according to the invention are effective inhibitors of the cellular sodium-proton antiport (Ma/H exchange), which in the case of numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) is increased also in such cells that are easily available for measurement, such as in erythrocytes, platelets or leukocytes. The compounds used according to the invention are therefore suitable as excellent and simple scientific means, for example, when they are used as diagnostic means for the determination and recognition of certain forms of hypertension, however, also atherosclerosis, diabetes and diabetic late complications, proliferative and9) diseases, etc. .d.

Further, MNEZ inhibitors are suitable for the treatment of diseases caused by bacteria, as well as protozoa (in humans and animals). In the case of diseases caused by protozoa, especially human malaria and chicken coccidiosis should be mentioned.

In addition, the compounds are suitable as means to combat mammalian parasites in human and animal medicine, and also in plant protection. At the same time, in medicine and veterinary medicine, it is mainly used as a means against blood-sucking parasites.

Compounds of formula (I), along with their high indicators of inhibition of MNE, their - pharmacological properties and the absence of unwanted biological effects, also differ in favorable - pharmacokinetic properties, which allow them to be especially favorably used as medicinal products.

Thus, the invention relates to a medicinal product for use in human medicine, veterinary medicine or for phytoprotective use, containing an effective amount of the compound of formula (I) and/or its pharmaceutically acceptable salts individually or in combination with other pharmacological biologically active substances with or medicinal means Medicinal products containing compounds of formula (I) can be administered, for example, orally, parenterally, intramuscularly, intravenously, rectally, nasally, by inhalation, subcutaneously, or by a suitable transdermal route of administration, the preferred administration depending on the appropriate pictures of the disease.

Compounds of formula (I) can be used individually or together with galenic auxiliary substances -I, namely in veterinary medicine, in human medicine and in plant protection.

What excipients are suitable for the desired finished dosage form is known to the person skilled in the art based on his special knowledge. Along with solvents, gelling agents, suppository bases, auxiliary substances for tablets and other carriers of biologically active substances, for example, antioxidants, dispersants, emulsifiers, antifoams, taste-improving substances, preservatives, substances promoting dissolution or dyes can be used. - M For the oral form of administration, the active compounds are mixed with suitable admixtures for this purpose, such as carriers, stabilizers or inert diluents, and reduced by conventional methods to suitable forms of administration, such as tablets, dragees, detachable capsules, aqueous, alcoholic or oily solutions As inert carriers can

Use, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch. At the same time, preparation is carried out both in the form of dry granules,

F, as well as in the form of wet granules. As oil carriers or as solvents, for example, vegetable oils or animal oils such as sunflower oil or fish oil are used.

For subcutaneous, transdermal or intravenous administration, a solution, suspension or emulsion is prepared from the active compounds used, if desired, together with substances usual for this purpose, such as solubilizing substances, emulsifiers or other auxiliary substances. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol, glycerol, as well as sugar solutions, such as glucose and mannitol solutions, or a mixture of the various solvents indicated. 65 As a pharmaceutical composition for administration in the form of aerosols or sprays, for example, solutions, suspensions or emulsions of the biologically active substance of formula (I) in a pharmaceutically safe solvent are suitable,

such as, in particular, ethanol or water, or mixtures of such solvents. If necessary, the composition may also contain other pharmaceutical excipients, such as surfactants, emulsifiers and stabilizers, as well as propellant. Such a preparation usually contains a biologically active substance in a concentration from about 0.19 mass. to 1095 mass., especially from about 0.395 mass. to Zuomas.

The dosage of the biologically active substance of formula (I), which is administered, and the frequency of administration depend on the strength and duration of action of the compounds used; in addition, from the type and intensity of the disease being treated, as well as from the sex, age, weight and individual sensitivity of the mammal being treated.

On average, the daily dose of the compound of formula (I) in the case of a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.1 mg/kg, up to a maximum of 30 mg/kg, preferably mg/kg of body weight. In acute situations, for example, immediately after transferring states of respiratory arrest in the highlands, even higher doses may also be required. Especially with intravenous administration, for example, in the case of a patient with a heart attack in the intensive care unit, up to 200 mg/kg per day may be required. The daily dose can be divided into one or more, for example, up to 4 single doses.

If we are talking about enantiomeric compounds, then the configuration and/or sign of the optical rotation is indicated. If these data are missing, then we are talking about racemates or optically inactive compounds.

The retention times (CO) indicated below refer to measurements by mass spectrometry with liquid chromatography (I CM5) with the following parameters:

Analytical methods:

A stationary phase: Megsk RygozrNeg, Z micron, 2x55mMmM mobile phase: 9595 Ng2O (0.195 HCOOH) 9595 acetonitrile (0.195 HCOOH); 5 min. -» 9595 acetonitrile (0.195 NCOOH); 2 min. -» 9595 Ng2O (0.190

NSOOH); Ikhv.; Oh, 45 ml/min. c in o stationary phase: UM in vrpege HVO, approximately 4 microns, 2.1x3Z3mmM mobile phase: 9595 Hg2O (0.195 HCOOH) 9595 acetonitrile (0.0895 HCOOH); 2.5 min. -» 9595 acetonitrile (0.08956 NCOOH); Oh, 5 Bhv. -» 9595 HO (0.195 NCOOH); About 5 minutes; 1, ml/min. c "- stationary phase: UM in vrpege NVO, 4 microns, 2.1x20mm and mobile phase: 9095 Ng2O (0.0595 TFOK) 9595 acetonitrile; 1.9 min.; -» 9595 acetonitrile; Oh, 5 min.; ml/min o iv) stationary phase: Megsk RygozrNeg, Z micron, 2x55mMmM in mobile phase: 9595 Ng2O (0.195 HCOOH) 9595 acetonitrile (0.195 HCOOH); 3.4 min. -» 9595 acetonitrile (0.195 NCOOH); their -» 9595 Нг2О (0.195 325 НеООН); 0.2 min; 0.7 Bml/min. -

E stationary phase: Megsk RygozrNeg, Z micron, 2x55mMmM mobile phase: 9595 Ng2O (0.0595 SEZSOOH) -» 9595 acetonitrile (0.0595 SEZSOOH); 3h, 4 min. -» 9595 acetonitrile (0.05956 SEZSOOH); 1xV.; "

About 75 ml/min. c - s stationary phase: UM in vrpege HBO, 4 microns, 2.1x20mm with mobile phase: 9695 Ng2O (0.0595 SEZSOOH) -» 9595 acetonitrile; 2 min.; 29595 acetonitrile; 0.4 min.; Tml/min

Preparative high-performance liquid chromatography (HPLC) is performed under the following conditions:

Stationary phase: Megsk Rygozrpeg KR18 (10μM) 250хХ25mM - 75 mobile phase: 9095 Нг2О (0.0595 TFOK) 9095 acetonitrile; 4 Covering; 25 ml/min. -I Example 1 sl ZN-(5-Fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

Names a) 4-Methyl-3-thienyl isothiocyanate 99 4-Methyl-3-thienyl isothiocyanate is obtained by the interaction of equimolar amounts of 3-amino-4-methylthiophene and

HF) of M,M'-thiocarbonyldiimidazole in anhydrous tetrahydrofuran (THF) by stirring the reaction mixture for 5 hours at room temperature and then keeping it overnight at room temperature.

Isolation of 4-methyl-3-thienyl isothiocyanate is carried out by distillation of the solvent under reduced pressure in a rotary evaporator, dissolution of the residue in ethyl acetate and repeated washing of the organic phase with water. 60 After drying the organic phase over sodium sulfate, the organic solvent is distilled off in a rotary evaporator under reduced pressure and 4-methyl-3-thienyl isothiocyanate is obtained as a brown oily residue. Further use of 4-methyl-3-thienyl isothiocyanate can be carried out without further purification. c) M-(2-Amino-5-fluorophenyl)-M'-(4-methyl-3-thienyl)thiourea bo To a solution of 0.02 mol of 4-methyl-3-thienyl isothiocyanate in bOml of anhydrous tetrahydrofuran, add 0.02 mmol

4-fluoro-1,2-diaminobenzene. After stirring the reaction mixture for 2 hours at room temperature and standing overnight, the solvent is distilled off in a rotary evaporator under reduced pressure and the oily residue is purified on a silica gel column using a mixture of equal parts of toluene and ethyl acetate.

Brown colored crystalline solid: mp: 180960, c) 3M-(5-Fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 1.5g (0.005С3mol) M-(2-amino- 5-fluorophenyl)-M'-(4-methyl-3-thienyl)thiourea in 5 mL of anhydrous ethanol is mixed with a multiple molar amount (approximately 1.5-4 mol) of methyl iodide and refluxed for 5 hours. After standing overnight at room temperature, ethanol 70 is distilled off in a rotary evaporator under reduced pressure, the residue is mixed with water, and with the help of a saturated aqueous solution of sodium hydrogencarbonate, the pH value is set from 8 to 9. Extracted many times with ethyl acetate, the organic phase is washed with water, dried over sulfate of sodium, the solvent is distilled off under reduced pressure in a rotary evaporator and the residue is purified by column chromatography on silica gel using a mixture of solvents with equal volume fractions of ethyl acetate and toluene (hereinafter referred to as "mixture 75 2") as an eluent. The oily product obtained after distillation of the organic solvent is dissolved in ethyl acetate, strongly acidified with a saturated solution of hydrogen chloride in anhydrous diethyl ether, and the precipitate that crystallizes after prolonged exposure is filtered off. Crystalline solid; t.pl.: 1922-2960,

Example 2 2-Chloro-3M-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and 2,5-dichloro-3M-(5-fluoro-2-benzimidazolyl)4-methyl-3-thienylamine hydrochloride

Ysla IC and GE. ryk ZHE vna u shi a sch t shi y: SHY o

A solution of 0.24 g (0.0018 mol) of M- of chlorosuccinimide in 15 ml of glacial acetic acid, the reaction mixture is stirred for about 2-3 hours at room temperature, and the solvent is distilled off under reduced pressure in a rotary evaporator. After mixing the residue with water, it is basified with a 2N MasonN solution, extracted with ethyl acetate, the organic phase is washed with water, M is dried over sodium sulfate, and the solvent is distilled off in a rotary evaporator under reduced pressure. The oily residue obtained in this way is separated on a column by means of medium pressure chromatography and using a solvent mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid (hereinafter referred to as "mixture 17") as an eluent, and after treatment with a solution of gaseous hydrogen chloride in diethyl ether yields: 2-chloro-3M-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride from fractions 1 and 2: colorless to slightly yellow crystalline product; t.pl.: 200-202; 2,5-dichloro-ZM-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride from fraction C: colorless up to 70% yellow crystalline product; t.pl.: 286-28826. -o s Example 3 and ZIM-(5,6-Dichloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride "" zhNk ry as shk. en ch ce. a) M-(2-Amino-4,5 -dichlorophenyl)-M'-(4-methyl-3-thienyl)thiourea "sl Obtained similarly to the reaction indicated in example 15) from 4-methyl-3-thienyl isothiocyanate (4,5-dichloro-1,2-diaminobenzene. Crystalline solid substance; mp: 310-32090. i-th 5). 3M-(5,6-Dichloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride - M Obtained similarly to the method indicated in example 1c) with

M-(2-amino-4,5-dichlorophenyl)-M'-(4-methyl-3-thienyl)thiourea and methyl iodide. Crystalline solid; t.pl.: 290-294960,

Example 4

3M-(2-Benzimidazolyl)-4-methyl-3-thienylamine hydrochloride o "vin de) i, Y vada di bo o a) M-(2-Aminophenyl)-M'-(4-methyl-3-thienyl)thiourea

It is obtained similarly to the reaction indicated in example 15) from 4-methyl-Z-thienyl isothiocyanate (1,2-diaminobenzene. Crystalline solid from (1) m.p.: 177-1822C, after recrystallization from bB (2) m.p. pl.: 285-29096. c) 3M-(2-Benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

Obtained similarly to the method indicated in example 1c) from M-(2-aminophenyl)-M'-(4-methyl-3-thienyl)thiourea and methyl iodide. Crystalline solid after recrystallization from ethyl acetate/ethanol/m.p.: 194-20026.

Example 5

3M-(4-Fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and in 4 and a) 3-Fluoro-1,2-diaminobenzene

Obtained in the form of an oily amorphous product by hydrogenation of 3-fluoro-2-nitrophenylhydrazine (obtained by the reaction of 2,6-difluoronitrobenzene with hydrazine hydrate) with the help of hydrogen and a catalyst of 10905 and 75 palladium-on-carbon in methanol at room temperature and normal pressure. 65) M-(2-Amino-3-fluorophenyl)-M'-(4-methyl-3-thienyl')thiourea

Obtained similarly to the reaction specified in example 15) from 4-methyl-Z-thienyl isothiocyanate (

Z-fluoro-1,2-diaminobenzene. Crystalline solid; decomposition temperature 224096. c) ZM-(4-Fluoro-2-benzimidazolyl)-4-methyl-3-thienyl amine hydrochloride

It is obtained similarly to the method specified in example 1c).

M-(2-amino-3-fluorophenyl)-M'-(4-methyl-3-thienyl)thiourea and methyl iodide. An amorphous precipitate that is crystallized from acetone. Crystalline solid; t.pl.: 220-23026.

Example 6

3-(4,6-Difluoro-2-benzimidazolyl)-4-methyl-3-thienyl amine hydrochloride (C)

Would

That "- a) M-(2-Amino-3,5-difluorophenyl)-M'-(4-methyl-3-thienyl)thiourea IF)

It is obtained similarly to the reaction indicated in example 15) from 4-methyl-3-thienyl isothiocyanate (and 3,5-difluoro-1,2-diaminobenzene. A crystalline solid from (1) mp: 178-1822С, after again of crystallization from (2) mp: 299-30190, - c). 3M-(4,6-Difluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride im-

It is obtained similarly to the method specified in example 1c).

M-(2-amino-3,5-difluorophenyl)-M'-(4-methyl-3-thienylthiourea and methyl iodide. Amorphous precipitate that is crystallized from ethyl acetate. Crystalline solid; mp: 232-23496.

Example 7 "

3ICH-(3,4,5,6-Tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride shsch y -i a) M-(2-Amino-3,4,5,6-tetrafluorophenyl)-M -(4-methyl-3-thienyl)thiourea - Obtained similarly to the reaction indicated in example 15) from 4-methyl-3-thienyl isothiocyanate (3,4,5,6-tetrafluoro-1,2-diaminobenzene. Crystalline solid; m.p.: 286-290. o 5) 3M-(3,4,5,6-Tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride sl 50 Obtained similarly to the method specified in example 1c) Kk)

M-(2-amino-3,4,5,6-tetrafluorophenyl)-M'-(4-methyl-3-thienyl)thiourea and methyl iodide. An amorphous precipitate, which is crystallized from ethyl acetate. Crystalline solid; t.pl.: 225-22896.

Example 8

3M-(4-Methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride my 60 a) M-(2-Amino-3-methylphenyl)-M'-(4-methyl-3-thienyl)thiourea

Obtained similarly to the reaction specified in example 15) from 4-methyl-Z-thienyl isothiocyanate (

Z-methyl-1,2-diaminobenzene. Crystalline solid; t.pl.: 184-18620. c) 3M-(4-Methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

Obtained similarly to the method indicated in example 1c) from 65 /M-(2-amino-3-methylphenyl)-M'-(4-methyl-3-thienyl)thiourea and methyl iodide. An amorphous precipitate that is crystallized from acetone. Crystalline solid; decomposition temperature: 32026.

Example 9 trans-3M-(Za,4,5,6,7,7a-Hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate) and a) trans-M-(2-Aminocyclohexyl) -M'-(4-methyl-3-thienyl)thiourea (racemate)

Obtained similarly to the reaction specified in example 15) from 4-methyl-Z-thienyl isothiocyanate and racemic 70. trans-1,2-diaminocyclohexane. Crystalline solid; t.pl.: 205-2102S.

B) trans-3M-(Za,4,5,6,7,7a-Hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate)

O,bg of racemic trans-M-(2-aminocyclohexyl)-M'-(4-methyl-3-thienyl)thiourea is suspended in bOml of toluene and dissolved by heating to a temperature of 90 C. Leave to cool to a temperature of 709 C, add the solution dropwise 0.37 bg of dicyclohexylcarbodiimide in 5 ml of anhydrous toluene, stir for a total of 15 for about 10 hours at a temperature of 70 9C and for 2-3 days at room temperature.

The crystalline precipitate is filtered off, the solvent is removed in a rotary evaporator under reduced pressure, and the thus obtained oily residue is dissolved in a small amount of ethyl acetate. After adding an anhydrous solution of hydrogen chloride in diethyl ether, a viscous precipitate is formed, which crystallizes after adding a small amount of ethanol. Crystalline solid; t.pl.: 261-26496. 20 Example 10

Trans-kK,kK-3M-(Za,4,5,6,7,7a-Hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride from a) Trans-k,K-M-(2 -Aminocyclohexyl)-M'-(4-methyl-3-thienyl)thiourea

It is obtained similarly to the reaction indicated in example 15) from 4-methyl-Z-thienyl isothiocyanate (trans-K,K-1,2-diaminocyclohexane by separation using column chromatography on silica gel with - 30 elution with a mixture of solvents consisting of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part of 2695th aqueous ammonia solution (hereinafter referred to as "mixture 4") in the form of an amorphous oily product along with a higher molecular weight crystalline product with a melting point of 94 -1002 C. The amorphous product is subjected to further transformation without further purification

B). trans-K,K-3M-(Za,4,5,6,7,7a-Hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

Zo Obtained similarly to the method specified in example 1c) by introducing into the interaction -

K,k-M-(2-aminothiohexyl)-M'-(4-methyl-3-thienyl)thiourea and methyl iodide in anhydrous methanol as a solvent and reaction medium. The amorphous precipitate is chromatographed on silica gel using mixture 4 as an eluent and crystallized from acetone. Crystalline solid; t.pl.: 235-23820. "

Example 11 7 trans-5,5-3M-(Za,4,5,6,7,7a-Hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride sh a i ; and 45 and Ш - a)trans-5,5-3М-(2-Aminocyclohexyl)-М'-(4-methyl-3-thienyl)thiourea -I Obtained similarly to the reactions indicated in example 15) with 4-methyl-3- thienyl isothiocyanate (trans-5,5-1,2-diaminocyclohexane by separation using column chromatography on silica gel using mixture 4 as an eluent in the form of an amorphous oily product along with more than 20 high molecular weight products with a melting point of 94-1022С. The amorphous product is subjected to further transformation without further purification. thienylamine hydrochloride

It is obtained similarly to the method specified in example 1c) by introducing into the interaction 5,8-M-(2-aminotsxhohexyl)-M'-(4-methyl-3-thienyl)thiourea and methyl iodide in anhydrous ethanol as a solvent and reaction medium. Amorphous precipitate, which is subjected to chromatography on silica gel using mixture 4 as

HF) of the eluent and crystallized from acetone. Crystalline solid; t.pl.: 225-23096.

Example 12 o 2-Chloro-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and 2,5-dichloro-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 60; ех ой вх пн и 65 Met io S shcha

Obtained similarly to the method indicated in example 2 with

3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and M-chlorosuccinimide in glacial acetic acid.

Column chromatography on silica gel using mixture 17 as eluant separated 2,5-dichloro-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (colorless crystalline compound; mp: 29120) from 2- chloro-3M-(2-benzimidazolyl)-4-methyl-33-thienylamine hydrochloride (colorless crystalline compound; m.p.: 257-25920).

Example 13 2-Chloro-3M-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 70 dvven

It is obtained similarly to the method specified in example 2 with 3M-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and M-chlorosuccinimide in glacial acetic acid. After column chromatography on silica gel using mixture 17 as an eluent, 2-chloro-3M-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained as a colorless to slightly yellowish crystalline product, t.pl.: 255-25926.

Example 14 2-Chloro-3M-(4,5,6,7-tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

Obtained similarly to the method indicated in example 2 with

3M-(4,5,6,7-tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and M-chlorosuccinimide in glacial acetic acid. Crystalline product; t.pl.: 233-235960. "-

Example 15 trans-2-Chloro-ZM-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate)

That's "in yet another"

Obtained similarly to the method indicated in example 2 with

ZM-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate) and "

of M-chlorosuccinimide in glacial acetic acid. Crystalline product; t.pl.: 258-26026.

Example 16 - with Trans-K,K-2-Chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride with trans-K ,K-2,5-dichloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

Obtained similarly to the method specified in example 2 with o Trans-kK,kK-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and c 20 M -chlorosuccinimide in glacial acetic acid after chromatographic separation of both crystalline products in the following sequence: - a)

Trans-K,kK-2,5-dichloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride; decomposition during foaming, starting at a temperature of 802C;

B). trans-K,K-2-chloro-3M-(Za,4,5,6,1,7a-hexahydro-THN-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride;

HF) crystalline product; t.pl.: 260-26226.

Example 17 about mn pori H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride bo "dec oi. au g

Obtained similarly to the method specified in example 2 from 65 Transo-5,5-Z3M-(Za,4,5,6,1,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-Z-thienylamine hydrochloride and

of M-chlorosuccinimide in glacial acetic acid after chromatographic separation. Colorless crystalline product; t.pl.: 258-26090.

Example 18 2-Bromo-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and 2,5-dibromo-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride pi: KI soni same What 70 r: g ie From a dream

Obtained similarly to the method indicated in example 2 with

3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and M-bromosuccinimide (instead of M-chlorosuccinimide) in glacial acetic acid. After column chromatography on silica gel using a mixture of 5 parts of dichloromethane, 3 parts of n-heptane, 1 part of glacial acetic acid and 1 part of ethanol (hereafter referred to as "mixture 1") as an eluent and treatment with a solution of gaseous hydrogen chloride in diethyl ether obtain, by fractional crystallization from ethyl acetate, 2-bromo-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, a crystalline product with mp: 228-23190, and 2,5-dibromo-3M-( 2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, crystalline product with m.p. 208-21096.

Example 19 transo-K,K-2-bromo-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and transo-K,K -2,5-dibromo-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride » via Fr

Obtained similarly to the method specified in example 18 from trans-K,K-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and

of M-bromosuccinimide in glacial acetic acid. After column chromatography on silica gel using -- mixture 1 as an eluent and treatment with a solution of gaseous hydrogen chloride in diethyl ether, after fractional crystallization from ethyl acetate, the following is obtained: o transo-K,K-2-bromo-3M-(Za,4,5 ,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride; yuyu crystalline product; t.pl.: 215-2189С; and trans-K,K-2,5-dibromo-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride; - crystalline product; t.pl.: 218-22026. -

Example 20

3M-(4-Chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride n " xz a B " a) M-(2-Amino-3-chlorophenyl)-M'-(4-methyl-3-thienyl)thiourea

Obtained similarly to the reaction specified in example 15) from 4-methyl-Z-thienyl isothiocyanate (

Z-chloro-1,2-diaminobenzene (obtained by catalytic hydrogenation of Z-chloro-2-nitroaniline with the help of platinum on activated carbon at normal pressure and at room temperature). Crystalline solid; - First floor: 298-30596. in). 3M-(4-Chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride i-th Obtained similarly to the method specified in example 1c) with c 50 M-(2-amino-3-chlorophenyl)-M'-(4-methyl-Z3 -thienyl)thiourea and methyl iodide. An amorphous precipitate that is crystallized from ethyl acetate. Crystalline solid; decomposition temperature: 240-24596.

Example 21 2-Chloro-3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride o ССО 60 Obtained similarly to the method specified in example 2 C

3M-(4-chloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and M-chlorosuccinimide in glacial acetic acid.

After column chromatography on silica gel using a mixture of 10 parts of dichloromethane and 1 part of methanol as an eluent, 2-chloro-3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride is obtained in the form of colorless to slightly yellowish color solid after crystallization from b5 ethyl acetate; t.pl.: 270-27296,

Example 22

2-Bromo-3M-(4-chloro-2-beneimidazolylamino)-4-methylthiophene hydrochloride is also available.

Obtained similarly to the method indicated in example 2 with

3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride and M-bromosuccinimide (instead of M-chlorosuccinimide) in 70 glacial acetic acid. After column chromatography on silica gel using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid as an eluent and treatment with a solution of gaseous hydrogen chloride in diethyl ether, by fractional crystallization from ethyl acetate in the presence of diethyl ether saturated with hydrogen chloride, 2 is obtained -bromo-3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride. Crystalline product with m.p. 278-28026.

Example 23 (2-Bromo-4-methylthiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)amine hydrochloride

And so and so and so

ZbOmg of (5-Fluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)ioamine (example 1) is dissolved in B5Oml of glacial acetic acid. At room temperature and with intensive stirring, a solution of 207 mg of M-bromosuccinimide in 1 Oml of glacial acetic acid is slowly added dropwise. At the end of the addition, it is stirred for 10 minutes, then the glacial acetic acid is distilled off under vacuum, the residue is dissolved in ethyl acetate and washed with a saturated solution of potassium carbonate. After drying over magnesium sulfate, it is filtered and concentrated. The residue is purified by preparative chromatography, fractions containing the product are combined, acetonitrile is removed, alkalized and extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered. After removing the solvent, the residue is mixed with water with PE and 2N hydrochloric acid and freeze-dried. Get 245mg of the target product. HOM, KI (B): 0.95 min.; mass spectrometry (MS) (electron spray ionization with the formation of positive ions (EB "7, o

MAINE): 326.09. iv)

Example 24 M 2-Bromo-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride and 2,5-dibromo-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride -

Sleep for 8 s. To a solution of 0.214 g of 3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride in 1 ml of glacial acetic acid, add a solution of 0.161 g of M-bromosuccinimide in 1 ml of glacial acetic acid, and the mixture is stirred for

30 minutes at room temperature. After distillation of the solvent, the residue is mixed with water, alkalized with a 2N solution of NaOH and extracted with ethyl acetate. The organic phases are dried, the solvent is distilled off and the residue is separated by column chromatography on silica gel using a mixture of 20 parts of ethyl acetate,

10 parts of n-heptane and 3 parts of glacial acetic acid. Hydrochlorides of both compounds are obtained by distilling -I solvents from fractionated solutions, dissolving in ethyl acetate and precipitation by adding diethyl ether saturated with hydrogen chloride. At the same time, crystallization is accelerated due to the heating. o Example 24a: c 20 2-bromo-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride: colorless crystals; heating capacity: 21296 shk (decomposition).

Example 246: 2,5-dibromo-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride: colorless crystals; t.pl.: 242-244 (decomposition).

Example 25 (F) 3M-(5-Methoxy-2-benzimidazolylamino)-4-methylthiophene and 3M. hey in with w what a) M-(2-Amino-4-methoxyphenyl)-M'-(4-methyl-3-thienyl)thiourea

A mixture of 5.89 g of 4-methylthiophene-3-isothiocyanate and 5 g of 4-methoxy-1,2-diaminobenzene in bOml of anhydrous tetrahydrofuran is stirred for 2 hours at room temperature and the solvent is distilled off. The residue is mixed with water, extracted with ethyl acetate, the dark solution is treated with activated carbon and the organic solvent is evaporated again. The residue is treated several times with slightly heated diisopropyl ether and the solid is filtered off. Brown colored crystalline solid; t.pl.: 143-146.

B) A mixture of 2.83 g of M-(2-amino-4-methoxyphenyl)-M'-(4-methyl-3-thienyl)thiourea, 8.5 g of methyl iodide and 100 Oml of anhydrous ethanol is refluxed for 5 hours , then the solvent is distilled off and the residue is mixed with water. It is basified with a 2N sodium hydroxide solution, extracted with ethyl acetate, the organic phase is treated with water and then with activated carbon and purified by column chromatography on silica gel using an eluent mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and

From pieces of glacial acetic acid. ZM-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene is obtained as a 7/0 amorphous product.

Example 26

3M-(5-Methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

Obtained by precipitation from a solution of 0.2 g of ZM-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene (example 25) in 1 Oml of ethyl acetate using a saturated solution of gaseous hydrogen chloride in diethyl ether in the form of a crystalline precipitate; t.pl.: 222-22596.

Example 27 2-Chloro-3M-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

BUT separate from. schi o se eV,

A mixture of 0.519 g. 3M-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride, 0.046 g of M-chlorosuccinimide and 10-15 ml of glacial acetic acid are heated at a temperature of 459 for approximately 2-2.5 hours. Then glacial acetic acid is distilled off, water is added to the residue and the pH value is set to 9-10 with the help of a 2N solution of MaOH. It is extracted with ethyl acetate, the solvent is evaporated and the residue is chromatographed on silica gel using a medium pressure column using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The base obtained after distillation of the solvent in ethyl acetate is converted into the hydrochloride with the help of a saturated solution of hydrogen chloride in diethyl ether and crystallized from

From ethyl acetate. Crystalline solid; t.pl.: 182-1862S. -

Example 28 2,5-Dichloro-3M-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride "on"

In a similar treatment of the reaction mixture with

3M-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride, M-chlorosuccinimide and glacial acetic acid -1 but for about 2-2.5 hours at a temperature of 55 °C which: 2,5-dichloro-3M-(5 -methoxy-2-benzimidazolylamino)-4-methylthiophene. Crystalline solid; t.pl.: 278-28226. - Example 29 with ZM-(4-Methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

Ne e c 20 sho o zhnok oo a) 3-Methoxy-1,2-diaminobenzene

GF! Obtained in the form of a brown oil by hydrogenation of 2-methoxy-6-nitroaniline with gaseous hydrogen and nickel Raney as a catalyst at room temperature and pressure Zbar. The product is converted into thiourea without further purification. c) M-(2-Amino-3-methoxyphenyl)-M'-(4-methyl-3-thienyl)thiourea is obtained similarly to the method described in example 25ba) from 3-methoxy-1,2-diaminobenzene, 4-methyl -3-thienyl isothiocyanate in anhydrous tetrahydrofuran and by subsequent medium pressure chromatography on silica gel using a mixture of 1 part toluene and 1 part ethyl acetate. Crystalline solid; t.pl.: 148-1532S. Approval of the melt and the nearest hot water tank. at 26020. c). 3ZM-(4-Methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride b5 Obtained similarly to the methods described in examples 25 and 26 with

M-(2-amino-3-methoxyphenyl)-M'-(4-methyl-Z-thienyl)uthiourea by heating with methyl iodide in tetrahydrofuran, similar treatment and treatment of benzimidazole using NS! in diethyl ether.

Crystalline solid; t.pl.: 230-23590.

Example 30 2-Chloro-3M-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride ve. I "in vne 70 - also 5 nya de ov v

A mixture of 01 g of 3M-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride, 0.046 mg of M-chlorosuccinimide and 10-15 ml of glacial acetic acid is heated at a temperature of 409C for approximately 2-2.5 hours. Then the glacial acetic acid is distilled off, water is added to the residue, and with the help of 2N MasonN solution, the pH value is set to 75 at the level of 9-10. It is extracted with ethyl acetate, the solvent is evaporated and the residue is chromatographed on silica gel using a medium pressure column using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The thus obtained base in ethyl acetate is converted into hydrochloride using a saturated solution of hydrogen chloride in diethyl ether. Colorless to pale yellow crystalline solid; t.pl.: 248-25096.

Example 31

3M-(4-Chloro-6-trifluoromethyl-2-benzimidazolylamino)-4-methylthiophene hydrochloride with I c: a B a). M-(2-Amino-3-chloro-5-trifluoromethylphenyl)-M'-(4-methyl-3-thienyl)thiourea

It is obtained similarly to the method described in example 25a) by the reaction of 3-chloro-5-trifluoromethyl-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous tetrahydrofuran for 3 days at room temperature. After distilling off the solvent and adding water to the residue, it is extracted with ethyl acetate, the solvent is distilled off again, and the amorphous residue is crystallized from diisopropyl ether; yu t.pl.: 231096, c). 3M-(4-Chloro-b6-trifluoromethyl-2-benzimidazolylamino)-4-methylthiophene hydrochloride -

They are obtained similarly to the methods described in examples 25 and 26 with them

M-(2-amino-3-chloro-5-trifluoromethylphenyl)-M'-(4-methyl-3-thienyl)thiourea by refluxing for 5 hours with methyl iodide in tetrahydrofuran, similar treatment and purification by column chromatography medium pressure on silica gel using a mixture of equal parts by volume of ethyl acetate and toluene. After evaporation of the solvent, the residue is dissolved in ethyl acetate, and by adding a saturated solution of hydrogen chloride in diethyl ether, it is obtained - with ZM-(4-chloro-b6-trifluoromethyl-2-benzimidazolylamino)-4-methylthiophene hydrochloride in the form of a crystalline precipitate; and a solid substance; t.pl.: 210-21396,. "» Example 32 2-Chloro-3M-(4-chloro-b6-trifluoromethyl-2-benzimidazolylamino)-4-methylthiophene hydrochloride -2-benzimidazolylamino)-4-methylthiophene hydrochloride, 0.151 g of M-chlorosuccinimide and 20 ml of glacial acetic acid are kept for 0.5 hours at room temperature and heated for 6 hours at a temperature of 6°C. Then the glacial acetic acid is distilled off, water is added to the residue, and with the help of a 2N solution of MasoN, the pH value is set at the level of 9-10. It is extracted with ethyl acetate, the solvent is evaporated and the residue is chromatographed on silica gel using a medium pressure column using a mixture of equal parts of toluene and ethyl acetate. In this way, the basis obtained after distillation of the solvent in

Ge) ethyl acetate with the help of a saturated solution of hydrogen chloride in diethyl ether is converted into hydrochloride.

Colorless to pale yellow crystalline solid; t.pl.: 247-25096. where Example 33

ZM-(4-Carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride bo BO vno 65 sov, juices This is a)-M-(2-Amino-3-carboxyphenyl)-M'-(4-methyl-3-thienyl) uthiourea

Obtained similarly to the method described in example 25a) from 3-carboxy-1,2-diaminobenzene, 4-methyl-3-thienyl isothiocyanate in anhydrous tetrahydrofuran and by further medium pressure chromatography on silica gel using a mixture of 12 parts of dichloromethane and 1 part of methanol. Amorphous product. in). 3M-(4-Carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

Obtained by refluxing a solution from 112g

M-(2-amino-3-carboxyphenyl)-M'-(4-methyl-3-thienyl)thiourea and 3.1 g of methyl iodide in bOml of ethanol. The solvent is evaporated, the residue is mixed with water, with the help of 2N hydrochloric acid, the pH value is set to 5 and the precipitate is filtered. Crystalline solid; decomposition temperature: 265-28590. 70 Example 34 2-Chloro-3M-(4-carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride was prepared from

It is obtained similarly to the method described in example 32 with 0.2 g

3M-(4-carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride and 0.103 g of M-chlorosuccinimide in 20-25 ml of glacial acetic acid and precipitation of the corresponding hydrochloride in ethyl acetate using saturated HCl 20 diethyl ether and subsequent crystallization from diisopropyl ether and ethyl acetate . Decomposition temperature: 17026.

Example 35

ZICH-I(I4-«1-Piperidinecarbonyl)-2-benzimidazolylamino|-4-methylthiophene hydrochloride 25 | what

She che (o) binrya NN ; 30 she and oyu

0.215 g of M,M'-carbonyldiimidazole is added to a mixture of 0.330 g of 3M-(4-carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride, 30 ml of anhydrous tetrahydrofuran and 5 ml of anhydrous dimethylacetamide. M) is stirred for about 4 hours at room temperature, and the release of carbon dioxide ends, and the solution is then mixed with 0.411 g of piperidine. The solution is stirred for 2 hours at room temperature and

After further retention overnight, the solvent is distilled off under reduced pressure. The residue is mixed with water, the solid substance is filtered off, dissolved in ethyl acetate, the insoluble part is removed by filtration and the solvent is distilled off under reduced pressure. Foamy amorphous product.

Example 36 "2-Chloro-4-methyl-3M-I4-(1-piperidinocarbonyl)-2-benzimidazolylamino|hyophene hydrochloride 40 units. - with them, Shk: ke ek de

She and I Y KZ U, -I B o» 5 -I Mixture of 0.2g. 3M-(4-(1-piperidinocarbonyl)-2-benzimidazolylamino|-4-methylthiophene hydrochloride and 0.086g

M-chlorosuccinimide in about 20 ml of glacial acetic acid is stirred for 1.5 hours at room temperature and for about 30 minutes at a temperature of 352C, the solvent is distilled off and the residue after adding 20 g of water is alkalized with a 2N solution of MAOOH. After extraction with ethyl acetate, the solvent is evaporated and the residue is purified by medium pressure chromatography on a silica gel column using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The solvent is distilled off, the residue is dissolved in ethyl acetate and acidified with saturated hydrogen chloride diethyl ether.

The amorphous residue is crystallized from a mixture of ethyl acetate with a small amount of acetone and a small amount of ethanol. Amorphous solid; decomposition temperature starting from 1002C.

F! Example 37 2-Chloro-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride 0.234 g of 3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride in approximately 20 ml of glacial acetic acid is mixed with 0.132 g of M -chlorosuccinimide, stir for 30 minutes at room temperature and 65 during the next 1.5 hours at a temperature of 50-6020. After distillation of acetic acid under reduced pressure, the residue is mixed with water and with the help of a 2N solution of MaOH, the pH value is set to approximately 10-11, extracted with ethyl acetate, which is then distilled off. The residue is chromatographed on silica gel using a column under medium pressure using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. After concentration, the residue is dissolved in a small amount of ethyl acetate and the hydrochloride is precipitated by adding diethyl ether saturated with hydrogen chloride. Colorless to pale yellow crystalline solid; t.pl.: 268-27026.

Example 38 2-Chloro-3M-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride and. ! then o zna is sv I: sn sv v

A suspension of 0.13 g of 2-chloro-3M-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride in approximately 20 ml of anhydrous dichloromethane is added to a suspension of 0.29 g of active anhydrous aluminum chloride in 1 ml of anhydrous dichloromethane, and the reaction mixture is stirred for 2 hours at at a temperature of 55 20. After cooling, the reaction mixture is poured into ice water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is distilled off. The residue is chromatographed on a silica gel column under medium pressure using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid, and the eluate is evaporated under reduced pressure. The residue is dissolved in ethyl acetate and the hydrochloride is precipitated by adding diethyl ether saturated with hydrogen chloride. Crystalline solid; t.pl.: 246-24826.

Example 39 2-Chloro-3M-(2-benzimidazolylamino)-4-methylthiophene: more

By SHE Kok and :- I and Z "-

It is obtained by adding a 2N solution of maon to a solution of 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene hydrochloride in 200 ml of water, setting the pH value up to 10. The crystals are filtered and additionally washed many times with water. Output: 2.52 g. Colorless crystalline powder; t.pl.: 182-185960.

Example 40 - 2-Chloro-3M-(2-benzimidazolylamino)-4-methylthiophene hydrobromide - ste -

Roche for KNe still pact 5 « 20 0.25g of 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene is dissolved in 1Oml of ethanol, then mixed with O.Tml with c 48906 Ng and briefly stirred at room temperature. The solvent is distilled off and the residue is subjected to crystallization from ethyl acetate. Output: 0.29g. Colorless crystals; decomposition temperature: 252-25426. . and" Example 41

Adipic acid salt of 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene 7 АХ and about p.

2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene with 50 one equivalent of adipic acid is obtained similarly to the method described in example 40. Colorless crystals; t. pl.: 155-15726.

Example 42 - M Oxalic acid salt of 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene (B in ana voyun

Mshe Zha (F. Obtained similarly to the method described in example 40 by introducing into the interaction 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene with one equivalent of oxalic acid in ethyl acetate.

Colorless crystals; t.pl.: 220-22296. 60 Example 43

Phosphoric acid salt of 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene. I and sei dv ves ii Ma b5 y . y and s. and and and

Obtained similarly to the method described in example 40 from 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene with one equivalent of phosphoric acid. Colorless crystals; decomposition temperature: 113-17596.

Example 44 (1nH-Benzimidazol-2-yl)-(2-chloro-4-methylthiophen-3-yl)umethylamine'

To a solution of 125 mg of 2-chloro-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine (from example 39) and 20 ml of anhydrous 70 methanol, add bbmg of powdered dry potassium carbonate. Then, in the absence of moisture and with intensive stirring, 74 ml of methyl iodide is added dropwise and the mixture is refluxed for three days. After removing the solvent, the residue is partitioned between ethyl acetate and water, the ethyl acetate phase is dried over magnesium sulfate, the magnesium sulfate is filtered off, and the filtrate is evaporated to dryness. After that, it is purified using HPLC. Fractions containing the product are combined and, after 75% removal of acetonitrile, subjected to freeze-drying. For further processing, it is then chromatographed on silica gel using a mixture of ethyl acetate and heptane (in a ratio of 1:4). After combining the fractions containing the product, they are concentrated to dryness, treated with NOSI and freeze-dried. 5 mg of solid substance is obtained.

YSM5, KI (A): 2.04 min.; MS (EB", MAN"): 278.05.

Example 45

Salt of trifluoroacetic acid (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine a

That's about it

A solution of 1.08 g of 3-isothiocyanate-4-methylthiophene in 30 ml of absolute tetrahydrofuran is added dropwise to a solution of 1 g of 1,2-diamino-4,5-difluorobenzene in 20 ml of absolute tetrahydrofuran. Then stir for 2 hours at room temperature and leave to stand overnight. After adding 0.44 ml of methyl iodide, it is stirred for 8 hours and left to stand overnight. After that, the tetrahydrofuran is removed, the residue is partitioned between ethyl acetate and water, the phases are separated and the ethyl acetate phase is dried over magnesium sulfate. The residue is applied to silica gel and chromatographed by eluting with a 1:11 mixture of n-heptane and ethyl acetate. 229 mg of the target compound are obtained as a free base. them-

The contaminated fraction obtained as a result of the above-mentioned chromatography is purified using

From preparative HPLC. At the same time, after freeze-drying, 42.2 mg of the target compound is isolated in the form of a salt of trifluoroacetic acid.

YSM5, KI (A): 1.98 min.; MS (EB", MAN"): 266.13.

Example 46 "(2-Chloro-4-methylthiophen-3-yl)-(5,6-difluoro-1H-benzimidazol-2-yl) amine hydrochloride Z і schi s B sho s B і ; and KO:. Shy and -

In p

To a solution of 225 mg of (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine in bml of glacial acetic acid at room temperature, a solution of 124.bmg of M-chlorosuccinimide is added dropwise in 5 ml of ice-cold -1 acetic acid. Then stir for 3.5 hours at room temperature. After that, the glacial acetic acid is removed, the residue is treated with water and, with the help of a 2M sodium hydroxide solution, the pH value is set to 10. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried over 50% magnesium sulfate, and the solvent is removed. The residue is purified by preparative chromatography, fractions containing the product are combined, acetonitrile is removed, alkalized and extracted three times with ethyl acetate. -. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated. The residue is treated with water, acidified with 1095 hydrochloric acid and freeze-dried.

81 mg of the target product is obtained as a solid. 99 ISM5, KI (A): 2.15 min.; MS (EB", MAN"): 300.11.

GF! Example 47 (2-Bromo-4-methylthiophen-3-yl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine 60 R l in, t

At room temperature, in a reaction vessel, to a solution of 15 mg of the salt of trifluoroacetic acid (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)aminoamine (example 45) in 0.bml of ice of acetic acid 65 is added dropwise to a solution of mg of M-bromosuccinimide in 0.5 ml of glacial acetic acid and stirred for 0.5 hours at room temperature. Then the acetic acid is removed and the residue is mixed with a saturated solution of potassium carbonate and ethyl acetate. After separation of the organic phase, it is extracted twice with ethyl acetate.

The combined organic phases are dried over magnesium sulfate and then the desiccant is filtered off. The residue remaining after removal of the solvent is purified by preparative chromatography. Fractions containing the product are combined, acetonitrile is removed, mixed with a saturated solution of sodium bicarbonate and extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered.

After removal of ethyl acetate, the residue is treated with toluene and then dried under high vacuum. 8.1 mg of the target compound are obtained.

IISM5, K(0): 1.4 Bkhv.; MS (EB", MAN"): 343.96. 70 Example 48

K2-Chloro-4-methylthiophen-3-yl)-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl))amine hydrochloride a) 1,4-Dioxaspiro|(4, 5|dec-b -ilamine 7

The required amine precursor is obtained according to (UK patent 1131191). At the same time, 2-chlorocyclohexanone is introduced into the interaction with phthalimide, obtaining 2-(2-oxocyclohexyl)isoindole-1,3-dione, which is catalyzed with the help of ethylene glycol in the presence of p-toluenesulfonic acid to obtain 2-(1,4-dioxaspiro(4, 5|dec-6b-yl)isoindole-1,3-dione After treatment with hydrazine hydrate to cleave off the phthalimide residue, the title 1,4-dioxaspiro|4,5|dec-6b-yl amine is obtained.

B). 1-(1,4-Dioxaspiro|4,5|dec-b-yl)-3-(4-methylthiophen-3-yl)thiourea vv g id a o

A solution of 296.2 mg of 3-isothiocyanato-4-methylthiophene (see Example La) in 10 ml of absolute tetrahydrofuran is added dropwise to a solution of 30 mg of 1,4-dioxaspiro(4,5|dec-b6-ylamine in 10 ml of absolute tetrahydrofuran - tetrahydrofuran, stir for 2 hours at room temperature and then remove the solvent.

The residue is purified by preparative chromatography, the fractions containing the product are combined, removed with acetonitrile, alkalized and extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered. 428 mg of target product is obtained.

YSM5, KI (A): 3.57 min.; MS (EB", MAN): 313.19. hec) 1-(1,4-Dioxaspiro|4,5|dec-6b-yl)-2-methyl-3-(4-methylthiophen-3-yl) isothiourea y- «: shen - c 393 mg of 1-(1,4-dioxaspiro|4,5|dec-6b-yl)-3-(4-methylthiophen-3-yl)isothiourea is dissolved in 8.5 ml "» of absolute tetrahydrofuran and mixed with a solution of 179 mg of methyl iodide in 0.5 ml of absolute tetrahydrofuran. Then it was stirred for 2 days in a sand bath at a temperature of 70 2C. After that, the reaction mixture was mixed with ethyl acetate and washed 2 times with water. The organic phase was dried over magnesium sulfate and after filtering the solvent is removed. The residue is purified by preparative chromatography,

The fractions containing the product are combined, acetonitrile is removed, alkalized and extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered. They receive 59 mg of the target product, which is used in the next stage. and ISM5, VI(S): 1.05 min.; MS (E5", MAN): 327 4. c 50 a) M-(1,4-Dioxaspiro(4,51dec-6b-yl)-M'-(4-methylthiophen-3-yl)guanidine - C and

Ge) In a reaction vessel, 58.8 mg of 1-(1,4-dioxaspiro|4,5|dec-6-yl)-2-methyl-3-(4-methylthiophen-3-yl)isothiourea is mixed with 2 ml of a 7M solution of ammonia in methanol and heated for 16 hours at a temperature of approximately 1009C in a sand bath. After removing the solvent, 51 mg of an oily product are obtained, which are directly introduced into the interaction further. 60 ISM8, VI (C): 1.00 min.; MS (EB", MAN): 296.4. e). M-(2-Chloro-4-methylthiophen-3-yl)-M'-(1,4-dioxaspiro|4,5|dec-6b-yl) )guanidine bo Ge «ve V r

49 mg of M-(1,4-dioxastro|4,5|dec-b-yl)-M''(4-methylthiophen-3-yl)uguanidine is dissolved in 3 ml of glacial acetic acid and slowly mixed with a solution of 20.3 mg of M -chlorosuccinimide in ml of glacial acetic acid. After stirring for several hours and standing for the end of a week at room temperature, the glacial acetic acid is removed, the residue is treated with water and with the help of a 2N sodium hydroxide solution, the pH value is set at the level of 10. The alkaline phase is extracted three times with ethyl acetate, the combined organic phases are dried over sulfate magnesium, filter and concentrate. The residue is purified by preparative chromatography, fractions containing the product are combined, acetonitrile is removed, alkalized and extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered. After removing the 7/0 solvent, 24 mg of the target product are obtained, which are directly used in the next step.

ISM5, CS): 1.09 min; MS(E5", MAN): 330.4.

U (2-Chloro-4-methylthiophen-3-yl)-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)amine hydrochloride and 24 mg of M-(2-chloro-4-methylthiophen-3- yl)-M'-(1,4-dioxaspiro(4,5|dec-b-yl)guanidine is dissolved in 1 ml of 2N hydrochloric acid and stirred for 30 minutes at room temperature. Then 1 ml of concentrated hydrochloric acid is added and stirred for the next two hours . This is then diluted with a small amount of water and freeze-dried. The residue is mixed with toluene, which is distilled off in vacuo. After this process is repeated twice, 22 mg of the target product remains as a solid.

ISM5, VI (B): 0.95 min.; MS (EB", MAN"): 268.07.

Example 49 ch 2-Chloro-3M-(2-benzimidazolylamino)-4-methylthiophenebenzenesulfonate same as BU o i pro no i che Ж -- same 250 mg of 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene are dissolved in bml of tetrahydrofuran and mixed with a solution of 150 mg of benzenesulfonic acid in bml of tetrahydrofuran. After vacuum filtration of the sediment and drying at a temperature of 75 °C in a high vacuum, the target product is obtained. Colorless crystals; t.pl.: 235960.

Example 50 2-Chloro-3M-(2-benzimidazolylamino)-4-methylthiophene methanesulfonate

Obtained similarly to the method described in example 49 from 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene with -I one equivalent of methanesulfonic acid. Colorless crystals; m.p.: 22796. -1 Example 51 2-Chloro-3M-(2-benzimidazolylamino)-4-methylthioPhenbenzoate i sl 20 I no

и ее и и 59 Obtained similarly to the method described in example 49 from 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene with

HF) with one equivalent of benzoic acid. For isolation, the reaction mixture is concentrated to half and then 7 is mixed with 30 ml of diethyl ether. Colorless crystals; t.pl.: 19890,

Example 52 2,A4-Dichloro-3M-(2-benzimidazolylamino)thiophene hydrochloride 60 to 65 weight a) Methyl ester of 33-acetylaminothiophene-2-carboxylic acid

To a mixture of 942 g of methyl ester of 3-aminothiophene-2-carboxylic acid and 1000 ml of toluene, add 567 ml of acetic anhydride dropwise while simultaneously heating in an oil bath, then boil under reflux for 1.5 hours and then cool in a bath of with ice to a temperature of about 0 260.

The crystals are filtered, washed 2 times with a small amount of cold isopropanol and 2 times with isopropyl ether. From the filtrate, by further concentration and crystallization, methyl ester of 3-acetylaminothiophene-2-carboxylic acid can be obtained. T.pl.: 93-95960.

B) Methyl ester of 3-acetylamino-4,5-dichlorothiophene-2-carboxylic acid

17.9 g of sulfuryl chloride is added dropwise to a solution of 19.9 g of methyl ester of 3-acetylaminothiophene-2-carboxylic acid in 100 ml of chloroform with 70 stirring with a magnetic stirrer and a reaction temperature of 20-30

AXIS". Then the next 2 people are stirred at a temperature of 402C and refluxed for another 15 minutes. After distillation of the solvent under reduced pressure, the residue is mixed with ethyl acetate, and after standing, the crystals are filtered off. T.pl.: 136-13820. c) Methyl ether of 3-acetylamino-4-chlorothiophene-2-carboxylic acid

A mixture of 25 g of 3-acetylamino-4,5-dichlorothiophene-2-carboxylic acid methyl ether, approximately 10 g of triethylamine, 00 ml of methanol, and 1 g of palladium-on-carbon is hydrogenated at room temperature and normal pressure until the absorption of hydrogen stops. After filtering off the catalyst, the filtrate is concentrated by distillation under reduced pressure until crystallization begins, then it is mixed with water and the solid substance is filtered off. Colorless crystals from isopropanol. T.pl.: 142-14796. a) Methyl ether of 3-amino-4-chlorothiophene-2-carboxylic acid 7 g of methyl ester of 3-acetylamino-4-chlorothiophene-2-carboxylic acid in a mixture with 5 ml of methanol and 5 ml of concentrated hydrochloric acid are stirred for 4 hours at a temperature of 60 C, for 5 hours at reflux and for the next 3 days at room temperature. The sediment that may form is filtered off, and approximately 1/3 of the solvent volume is removed by distillation under reduced pressure. After adding approximately 100 ml of water, the mixture is stirred for a further 15 minutes at room temperature, the colorless crystals are filtered off and dried in a stream of air. T.pl.: 62-6496. f) 3-Amino-4-chlorothiophene 18.02 g of methyl ester of 3-amino-4-chlorothiophene-2-carboxylic acid is added to a solution of 11.1 g of KOH and 1 bO0 ml of water, then refluxed for 3 hours and after cooling is added dropwise to a solution of 1.5 ml of concentrated hydrochloric acid in 30 ml of water heated to a temperature of 602C. At the same time, they come to a pronounced release of CO 5. After further stirring at a temperature of 60 °C for about 40 minutes, they are left to cool, then 50-100 ml of methyl tert-butyl ether are poured in and alkalized with the help of a concentrated solution of sodium hydroxide, and the aqueous phase is separated into dividing line. The aqueous phase is extracted a further 2 times with methyl-tert-butyl ether and the combined organic phases after extraction in a separatory funnel are washed once with water. The organic phase is dried, the solvent is distilled off and the oily amorphous residue is chromatographed on a silica gel column using a mixture of 1 part ethyl acetate and 1 part toluene. 7) 4-Chloro-3-thienyl isothiopianate « du To a solution of 1.1 g of 3-amino-4-chlorothiophene in 20 Oml of anhydrous tetrahydrofuran, add 1.46 g of thiocarbonyldiimidazole and stir for one hour at room temperature. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, the organic phase is treated twice with water in a separatory funnel, dried and the solvent is again distilled off under vacuum. 4-chloro-3-thienyl isothiocyanate is obtained in the form of a dark oil, which is then introduced into the interaction further without further purification operations. a) M-(2-Aminophenyl)-M'-(4-chloro-3-thienyl)thiourea - 15 0.86g of 1,2- of diaminobenzene (o-phenylenediamine), stirred for about 20 hours at room temperature and the solvent is distilled off under reduced pressure. The residue is treated with water, extracted with ethyl acetate, the solvent is again distilled off and the residue is purified using medium pressure column chromatography on silica gel using a mixture of ethyl acetate and toluene in a ratio of 1:11. Brownish-yellow solid substance with 70 color. also P) 4-Chloro-3M-(2-benzimidazolylamino)thiophene

To a solution of 0.5 g of M-(2-aminophenyl)-M'-(4-chloro-3-thienyl)thiourea in 25 ml of anhydrous tetrahydrofuran, add a solution of 0.169 g of sodium hydroxide in 5 ml of water and then a solution of 0.363 g of p-toluenesulfonic acid chloride in 1 ml tetrahydrofuran. It is stirred for 3 hours at room temperature, then the solvent 59 is distilled off under reduced pressure, the residue is treated with water and extracted with ethyl acetate. After distilling off the solvent

HF) the product is purified by medium pressure chromatography on silica gel using a mixture of 20 parts of ethyl acetate, 7 to 10 parts of n-heptane and 3 parts of glacial acetic acid as an eluent.

A small part of 4-chloro-3M-(2-benzimidazolylamino)thiophene in ethyl acetate with the help of a solution of hydrogen chloride in diethyl ether is converted into 60 4-chloro-3M-(2-benzimidazolylamino)thiophene hydrochloride and characterized. Colorless crystals; t.pl.: 256-26026. i) 2,4-Dichloro-3M-(2-benzimidazolylamino)thiophene hydrochloride

A solution of 0.3 g of 4-chloro-3M-(2-benzimidazolylamino)thiophene in 1 ml of glacial acetic acid is mixed with a solution of 0.16 g of M-chlorosuccinimide in 5 ml of glacial acetic acid. The reaction mixture is stirred for 15 minutes at a temperature of 4092 and for about 4 hours at room temperature, then the glacial acetic acid is distilled off under reduced pressure and the residue is treated with water. After alkalizing with a solution of sodium hydroxide, it is extracted with ethyl acetate, washed with water, the organic phase is dried and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography under medium pressure using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid as eluent and then precipitated from ethyl acetate by adding a solution of hydrogen chloride in diethyl ether. Colorless crystalline product; t.pl.: 264-26820.

Example 53 2-Bromo-4-chloro-3M-(2-beneimidazolylamino)thiophene hydrochloride

To a solution of 0.5 g of 4-chloro-3M-(2-benzimidazolylamino)thiophene in 15 ml of glacial acetic acid 19 is added dropwise a solution of 0.356 g of M-bromosuccinimide in bml of glacial acetic acid and stirred for the next 15 minutes at room temperature. The solvent is distilled off, the residue is treated with water and alkalized with sodium hydroxide solution. After extraction with ethyl acetate, the organic phase is washed with water, dried and evaporated under reduced pressure. The residue is chromatographed under conditions of medium pressure on silica gel using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid as an eluent. After distillation of the solvent, the residue is treated with ethyl acetate (2-bromo-4-chloro-3M-(2-benzimidazolylamino)thiophene hydrochloride is precipitated by adding a solution of gaseous hydrogen chloride in diethyl ether. Colorless crystalline product; mp: 2664-2662.

Example 54 (2,4-Dichlorothiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)amine hydrochloride ch 29 a). 1-(-2-Amino-4-fluorophenyl)-3-(4-chlorothiophen-3Z-yl)thiourea He) i, zo i - 8 9b0Omg of 4-fluoro-1,2-phenylenediamine is dissolved in 25 ml of tetrahydrofuran and with stirring a solution of 4-chloro-3-thienyl isothiocyanate (example 52c) in 15 ml of tetrahydrofuran is added dropwise. The solution is stirred for about three hours at room temperature and left to stand overnight. The reaction mixture is then concentrated and the residue is purified by preparative HPLC. Fractions containing the product are combined, acetonitrile in.

C5 REMOVE, basify and extract three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered. After removing the solvent, 625 mg of the target product is obtained.

YSM5, KE (R): 1.28 min.; MS (EVB", MAN): 302.0. c) (4-Chlorothiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)amine . and. Dissolve 625 mg of 1-(2-amino-4-fluorophenyl)-3-(4-chlorothiophen-3-yl)thiourea in tetrahydrofuran and mix with a solution of 0.207 g of NaOH in 10 mL of water. A solution of 0.395 g of hydrogen chloride - 15 p-toluic acid in 1 Oml of tetrahydrofuran is added dropwise for 5 minutes. After completion, the supplements are stirred for an hour at room temperature. For processing, the reaction mixture is mixed with water and ethyl acetate and the phases are separated in a separatory funnel. The aqueous phase is extracted three times with ethyl acetate, the combined ethyl acetate phases are dried over sl magnesium sulfate, clarified with charcoal, filtered and concentrated. Get 1Z35mg of the target product.

YSM5, KE (R): 0.90 min.; MS (EV", MAN): 268.0. 1 s) (2,4-Dichlorothiophen-3-yl)-(5-Fluoro-1H-benzimidazol-2-yl)amine hydrochloride

GF) 85 mg of (4-chlorothiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)amine is dissolved in 4 ml of glacial acetic acid and at room temperature and intensive stirring is slowly mixed with a solution of 42 mg of M-chlorosuccinimide in 4 ml of glacial acetic acid. After the additions are finished, the mixture is stirred for 45 minutes at room temperature, then for 5 hours at a temperature of 5023. After the addition of the next 4 mg of M-chlorosuccinimide, it is stirred for another hour at a temperature of 502. Then the reaction mixture is mixed with 20 ml of toluene and the glacial acetic acid is driven off. The residue is dissolved in ethyl acetate and eluted with a saturated solution of potassium carbonate. The ethyl acetate phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC, fractions containing the product are combined, acetonitrile is removed, alkalized and extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered.

After removing the solvent, the residue is mixed with water and 2N hydrochloric acid and freeze-dried. 17mg of target product is obtained.

IISM5, KE): 2.65 min.; MS (EB", MAN): 301.93.

Example 55 (2-Bromo-4-chlorothiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)amine hydrochloride e iv Ks M to B5Omg (4-Chlorothiophen-3-yl)-(5-fluoro -1H-benzimidazol-2-yl)yaamine (example 545) is dissolved in 4 ml of glacial acetic acid and slowly mixed with a solution of ЗЗмг at room temperature and intensive stirring

of M-bromosuccinimide in 4 ml of glacial acetic acid. At the end of the addition, stir for 45 minutes at room temperature, and then the reaction mixture is mixed with 20 ml of toluene and the glacial acetic acid is distilled off. 75 The residue is dissolved in ethyl acetate and washed with a saturated solution of potassium carbonate. The ethyl acetate phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative chromatography, fractions containing the product are combined, acetonitrile is removed, alkalized and extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered. After removing the solvent, the residue is mixed with water and 2N hydrochloric acid and freeze-dried. 27 mg of target product is obtained.

IISM5, KE): 2.29 min.; MS (EB", MAN"): 347.87.

Example 56 (2,4-Dichlorothiophen-3-yl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine hydrochloride a). 1-(2-Amino-4,5-difluorophenyl)-3-(4-chlorothiophen-z-yl)thiourea

AND

For example, 1.02 g of 1,2-diamino-4,5-difluorobenzene is added to 15 ml of absolute tetrahydrofuran and a solution of 1.25 g of 4-chloro-3-thienyl isothiocyanate (example 52c) in 15 ml of absolute tetrahydrofuran is added dropwise. Further implementation of the method similar to example 54a) leads to obtaining 77 mg of the target compound.

ISM5, VI (R): 1.32 min.; MS (E5B", MAN): 320.0 im c) (4-Chlorothiophen-3-yl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine

What is it about?

20 77 mg of 1-(2-amino-4,5-difluorophenyl)-3-(4-chlorothiophen-3-yl)thiourea is added to 20 ml of tetrahydrofuran and mixed with a solution of 240 mg of MasOn in 1 ml of water and after that add a solution of 528 mg of tosyl chloride in 1 Oml of tetrahydrofuran. Further implementation of the method similar to example 545) leads to obtaining 275 mg of the target compound.

ISM5, VI (R): 0.95 min.; MS (EB", MAN"): 286. p). (2,4-Dichlorothiophen-3-yl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine hydrochloride - I vat ch y book 1 20 125mg (4-chlorothiophen-3-yl)-(5 ,6-difluoro-1H-benzimidazol-2-yl)yamine is introduced into ml of acetic acid and a solution of 59 mg of chlorosuccinimide in 2 ml of acetic acid is added drop by drop. Further implementation of the method similar to example 54c) leads to obtaining 58 mg of the target product.

IISM5, KE): 2.97 min.; MS (EB", MAN"): 319.88.

Example 57 (2-Bromo-4-chlorothiophen-3-yl)-(5,6-difluoro-1H-benzimidazol-2-yl). amine hydrochloride and 125 mg of (4-chlorothiophen-3-yl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine (example 555) are dissolved in 1 ml of glacial acetic acid and slowly mixed with the solution at room temperature and intensive stirring 78 mg

of M-bromosuccinimide in 2 ml of glacial acetic acid. Further implementation of the method similar to example 55) leads to obtaining 77 mg of the target product. for ISM8, VI (E): 2.39 min.; MS (E8", Maine"): 365.86.

Example 58 4-Chloro-3M-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride

AND

I I in a) M-(2-Amino-3-methylphenyl)-M'-(4-chloro-3-thienyl)thiourea 70 Obtained similarly to the method specified in example 529) from 4-chloro-3-thienyl isothiocyanate and 1 ,2-diamino-3-methylbenzene and using medium pressure column chromatography on silica gel using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 1 part of ethyl acetate. Brownish-yellow solid substance; t.pl.: 193-19626. c) 4-Chloro-3M-(4-methyl-2-benzimidazolylamino)thiophene

Obtained similarly to the method specified in example 52P) with

M-(2-amino-3-methylphenylphenyl)-M'-(4-chloro-3-thienylthiourea) and when using medium pressure column chromatography on silica gel using a mixture of 10 parts of dichloromethane and 1 part of methanol in the form of an amorphous foamy product. 4-chloro-3M-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride is carried out in ethyl acetate with the help of diethyl ether saturated with gaseous hydrogen chloride. Crystalline product; mp: 325-32796,

Example 59 2,4-Dichloro-3M-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride

Obtained similarly to the method specified in example 521) from 4-chloro-3M-(4-methyl-2-benzimidazolylamino)thiophene and M-chlorosuccinimide in glacial acetic acid with similar treatment. Crystalline product; t.pl.: 296-29826. --

Example 60 y

Trans-(Za5,7ab5)-4-Chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride is a)trans-5, 5-3M-(2-Aminocyclohexyl)-M 7-(4-chloro-3-thienyl)thiourea

It is obtained similarly to the reaction indicated in example 15) from 4-chloro-3-thienyl isothiocyanate («| and « trans-5,5-1,2-diaminocyclohexane by separation by column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of dichloromethane, 5 parts of n-heptane, 5 parts of methanol and 1 part - with 35-3790th aqueous solution of ammonia in the form of an amorphous product of a dark color, which is used further without further purification. "» B). trans-(Za5,7a5)- 4-Chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine

Obtained similarly to the method specified in example 52P) from trans-5,5-3M-(2-aminocyclohexyl)-M'-(4-chloro-3-thienyl)thiourea, p-toluenesulfonic acid chloride.// and -i by further application medium pressure column chromatography on silica gel using a mixture of -1 with 10 parts of dichloromethane and 1 part of methanol in the form of an amorphous foamy product. Preparation of trans-5,5-4-chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride is carried out in 1 ethyl acetate and a small amount of ethanol with the help of saturated gaseous with hydrogen chloride of diethyl sl 50 ether. Crystalline product; t.pl.: 196-200.

Example 61 -. and trans-(Zak,7ak)-4-Chloro-3M-(Zak,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride svy z - sha (F; also "7 co a)trans-(1k,2kK)-3M-(2-Aminocyclohexyl)-IM'-(4-chloro-3-thienyl)uthiourea

It is obtained analogously to the reaction indicated in example 15) from 4-chloro-3-thienyl isothiocyanate (in trans-(1k,2k)-(-)-1,2-diaminocyclohexane by further separation by column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part of 35-3795th aqueous solution of ammonia in the form of an amorphous product of a dark color, which is used further without further purification.

B). trans-(Zac,7ac)-4-Chloro-3M-(Zac,4,5,6,7,7a-hexahydro-1H-2-beneimidazolyl)-3-thienylamine 65 Obtained similarly to the method specified in example 52P) from trans -K,K-3M-(2-aminocyclohexyl)-M'-(4-chloro-3-thienyl)thiourea, p-toluenesulfonic acid chloride.// and by subsequent application of medium pressure column chromatography on silica gel using a mixture of 10 parts ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part of a 35-3790 aqueous solution of ammonia in the form of an amorphous oily product. Preparation of transo-K,kK-4-chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride is carried out in ethyl acetate and a small amount of ethanol with the help of saturated gaseous hydrogen chloride diethyl ether. Crystalline product; t.pl.: 240-24496,

Example 62 cis-4-Chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride

a) cis-3M-(2-Aminocyclohexyl)-M'-(4-chloro-3-thienyl)thiourea

It is obtained analogously to the reaction indicated in example 15) from 4-chloro-3-thienyl isothiocyanate («| and cis-1,2-diaminocyclohexane by further separation by column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part of a 35-3790th aqueous solution of ammonia in the form of an amorphous product of a dark color, which is used further without further purification.

B) cis-4-Chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine

Obtained similarly to the method indicated in example 52P) from cis-ZM-(2-aminocyclohexyl)-IM'-(4-chloro-3-thienyl)thiourea, p-toluenesulfonic acid chloride and by further application of medium pressure column chromatography on silica gel using a mixture from 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part of a 35-3790 aqueous solution of ammonia in the form of a brown oily product. Preparation of 4-chloro-ZM-(cis-Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride is carried out in ethyl acetate and a small amount of ethanol with the help of diethyl ether saturated with gaseous hydrogen chloride. Crystalline product; t.pl.: 228-23126. "--

Example 63 transo-K,K-2,4-Dichloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride o

Chi Shi. uh-

Obtained similarly to the method specified in example 52i) by introducing into the interaction transo-K,kK-4-chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine Kk ! M-chlorosuccinimide and similar processing. Crystalline product. Foaming with sublimation, starting at a temperature of 16596.

Example 64 - c cis-2,4-Dichloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride a g Ya a

NE she -I se Be

Obtained similarly to the method indicated in example 52i) by introducing into the interaction - cis-4-chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine with M-chlorosuccinimide and by similar treatment. Crystalline product; t.pl.: 270-27496,

Example 65 i-th 4-Chloro-3M-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride ah in kn o a). 1-M-(2-Amino-3-chlorophenyl)-3-M-(4-chloro-3-thienyl)thiourea is obtained from 3-chloro-1,2-diaminobenzene and 4-chloro-3-thienyl isothiocyanate similarly method described in example 15) and by crystallization from diisopropyl ether in the form of a solid substance with two melting temperatures of 60: m.p. 1: 152-1559C upon recrystallization; t.pl. 2: »310960, c). 4-Chloro-3M-(4-chloro-2-benzimidazolylamino)thiophene

It is obtained similarly to the method described in example 52P) by the interaction of 1-4-(2-amino-3-chlorophenyl)-3-M-(4-chloro-3-thienyl)thiourea with hydrogen chloride/p-toluenesulfonic acid and column chromatography on silica gel according to using a mixture of 3 parts toluene and 1 part ethyl acetate as 65 eluent and subsequent distillation of the solvent under reduced pressure in the form of a foamy amorphous product, which is then converted into hydrochloride.

with). 4-Chloro-3M-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride

It is obtained by treating a solution of 4-chloro-3M-(4-chloro-2-benzimidazolylamino)thiophene in ethyl acetate with a saturated solution of gaseous hydrogen chloride in diethyl ether in the form of a crystalline precipitate. 800 Tlo 276-28096.

Example 66 2,4-Dichloro-3M-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride!

Obtained similarly to the method specified in example 52I) from 4-chloro-3M-(4-methyl-2-benzimidazolylamino)thiophene and M-chlorosuccinimide in glacial acetic acid with similar treatment. Crystalline product; t.pl.: 294-29726.

Analogously to the compounds specified in the implementation examples, the following thiophene derivatives can be obtained: 2-bromo-4-chloro-3M-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride; t.pl.: 284-2862S; 2-bromo-4-chloro-3M-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride; t.pl.: 304-30620; trans-K,K-2-bromo-4-chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride; decomposition temperature: 21590; trans-(Za5,7a5)-2-bromo-4-chloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride; t.pl.: 243-25490; 2,4-dibromo-3M-(2-benzimidazolyl)-3-thienylamine hydrochloride; 2,4-dimethyl-3M-(2-benzimidazolyl)-3-thienylamine hydrochloride; 2,4-dimethyl-3M-(4-methyl-2-benzimidazolyl)-3-thienylamine hydrochloride; ch 29 2,4-dimethyl-ZM-(5-fluoro-2-benzimidazolyl)-3-thienylamine hydrochloride; Ge) 2-chloro-3M-(4-butoxy-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride; 2-chloro-3M-(4-trifluoromethyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride; 2-chloro-3M-(4-methylsulfonyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride.

Pharmacological data --

Yuyu test description

This test determined the recovery of the intracellular pH value (pH ;) after acidification, which is used in the case of a normally functioning MNE also in the absence of bicarbonates. For this o pH value o; was determined using the pH-sensitive fluorescent dye VCESE |- (2,7-bis(2-carboxyethyl)-5,6-carboxyfluorescein; Sariospet; used as a precursor

From VSESE-AM). Cells were first loaded with ALL. Fluorescence was ALL determined in "Caiiio -

RIsogezsepse Zresigoteiyeg" (spectrometer for determining the measure of fluorescence) |Rpoyup Tesppoiodu Ipiegpaiopai|,

Zotzshii Vhypemzhisk, Moscow State University, USA) at excitation wavelengths of 5О5 nm and 440 Ohm and emission wavelength of 5О35 nm and converted to pH| using calibration curves. Cells already under load with "

Everything was incubated in MN.CI-buffer (pH 7.4) (MN.CI-buffer: 115mM Masi, 20mM MN,CI, 5mM KSI, 1mM Sasi", mM 7 70 Ma5o,, 20mM Nerez, 5mM glucose, mg/ ml of bovine serum albumin; with the help of a 1M MAOH solution, the pH value is set at the level of 7.4). Intracellular acidification was induced by adding 975 μl of buffer containing no MH.CI (see below) to 25 μl aliquots of cells incubated in MH.Cl buffer. The subsequent rate of pH recovery was recorded in the case of MNE within two minutes, in the case of MNE2 within 5 minutes and in the case of MNEZ within three minutes. In order to calculate the inhibitory capacity of the substances being tested, cells were first examined in buffers in which complete or no eating occurred. no pH recovery. To completely restore the pH value (10095), the cells were incubated in a buffer containing Ma" (133.8 mM Ma, 4.7 mM KSI, 1.25 mM Sas, 1.25 mM Mosi, 0.97 mM Ma»HPO, 0.23mM ManRo, 5mMm sl Nerez, 5mM glucose; with the help of a 1M solution of MaNH, the pH value is set at the level of 7.0.) To determine

Value 095 cells were incubated in a buffer containing no Ma" (133.8 mM choline chloride, 4.7 mM KSI, 1.25 mM Sas, 125 mM Moas, 0.97 mM CoHPO, 023 mM KNoPO), 5 mM Nerev5z, 5 mM glucose; with the help of a 1M solution of KOH - M, the pH value is set at the level of 7.0). The tested substances were introduced into the buffer containing Ma "7.

Recovery of the intracellular pH value in the case of each concentration of the tested substance was expressed as a percentage of the maximum recovery. From the values of pH recovery expressed as a percentage, the IC5o value of the corresponding substance for individual subtypes was calculated using the Zidt-Rioi program

ME

F) yu in the tent 2 chlorine ZM Zal BT Tateksvpdro with benamidayula methyl zlenyaemnidroklria

Zhlovzk (zvenamdayul i metitatentemn years 11111111 vv Zvromakhluorya Mobenzmidyazhultyamno) tofentdrayuorid 11111111 53 OMA(AMNES)

bldictorzkotenamidajlilemino) tofetidvokyunya 11111111 zadictriniaametittenadayutiemno fenov 11111111 11 olvimneyuu transu glya dichlor ZM BT Tatekovtdro in zoekamidiaul ztentyamndraluri

Adichlor-ZM-y-chloro-obenzimidazolylamino iofendhydrochloride 111 o Zh Zk ropes without desopiteminodmethyltofendvoklivia 1111

Zvrom Zk benamidayul i metitatentamn roy 11111111 vant, l g brom ZK Za 557 Tateksepdvo 1 2 benzmyanogi "methyl zemlyam drevnya i chor furenyamdyazolt i methita tenet 11111111 (INobenzimidazol.oil) (opori methyltophen-zylmethylamine 11111111

Claims (17)

The formula of the invention 1. Compounds of formula (1): с Я Удер- ВМИНЕ that ры ЖЕ ЭИй (о) ОО Я some and - where и- КИ and К2, independently of each other, mean Н, РЕ, СИ, Вг, И, СМ . or 4 carbon atoms; n means zero or 1; X means an oxygen atom, MH, M-CH»3 or B(O)K; "Kk means zero, 1 or 2; d means zero, 1, 2, Z, 4, 5 or 6; no) c 27 means a hydrogen or Spot atom; Из» t means zero, 1, 2, Z or 4; KZ means a hydrogen atom, methyl, E, SI, Bg, I, CM, 5(0)K-CH3, -MO" or -0O-CH"U; Kk means zero, 1 or 2; K4 means a hydrogen atom, cycloalkyl with 3, 4, 5 or b carbon atoms, alkenyl with 2, 3 or 4 carbon atoms, and alkenylalkyl with 3 or 4 carbon atoms, ethynyl or alkylalkynyl with 3 or 4 carbon atoms or -C,No IN; - And r means zero, 1, 2, C or 4; U means a hydrogen atom or trifluoromethyl; and K5 and Kb mean a hydrogen atom or together mean a bond; cl 20 K7 and kK8, independently of each other, mean (C5-C5)-alkyl-, (Co-Cv)-alkenyl, (Co-Cv5)-alkynyl, (C5-Cv)-cycloalkyl or (C./- C)-cycloalkenyl; and or K7 and K8 together mean an alkylene chain consisting of 3-8 carbon atoms, and its hydrogen atoms may be unsubstituted, partially or completely substituted by fluorine atoms; 29 or GF) K?7 and K8 together mean the remainder of 60 zho OB zani, and K5 and KbE together form a connection; 65 КИ10 and К11, independently of each other, mean an atom of hydrogen, fluorine, chlorine, bromine, methyl, CM, OH, -O-CH»U, MO», Mne or -SEz; KU and K12 mean a hydrogen atom or E; or one of the substituents KO and K12 means a hydrogen atom, and the other means P, SI, Vg, I, CM, MO", СООН, СО-МК1ЗК14, 5ОО-МК1З3К14, alkenyl with 2, C or 4 carbon atoms, alkenylalkyl with C or 4 carbon atoms, ethynyl, alkylalkynyl with 3 or 4 carbon atoms or -(X)5-CaHza-2; КИЗ and К14, the same or different, mean a hydrogen atom or an alkyl with 1, 2, 3 or 4 carbon atoms; or КИЗ and К14, together with the nitrogen atom to which they are connected, form a saturated 5-, 6- or 7-lene cycle; 70 n means zero or 1; X means an oxygen atom, MH, M-CH»3 or B(O)K; Kk means zero, 1 or 2; d means zero, 1, 2, Z, 4, 5 or 6; and 27 means a hydrogen or Spot atom; t means zero, 1, 2, C or 4; and their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts. 2. Compounds according to claim 1, in which КИ and К2, independently of each other, mean Н, Е, СИ, Вг, СН3, СЕз, ЗОСНаз or 50О2МН», and at most one of the substituents КИ and К2 means a hydrogen atom; KZ means a hydrogen atom, E or SI; KA means a hydrogen atom, an alkyl with 1, 2, 3 or 4 carbon atoms or cyclopropyl; K5 and Kb mean a hydrogen atom or together mean a bond; K?7 and K8 together mean an alkylene chain consisting of 3, 4, 5, 6, 7 or 8 carbon atoms; сч or К?7 and К8 together mean the remainder i) ее - то - Я ю ве ю and К5 and КбЕ together form a connection; ych- KO and K11, independently of each other, mean a hydrogen atom, OH, a fluorine or chlorine atom; KU Its K12 mean a hydrogen atom; у- or one of the substituents КО and К12 means a hydrogen atom, and the other means Е, СИ, В, СМ, СООН, СО-МК13К14, 502-МК1З3К14 or -(X)y-СаНод-2; " KIZ and K14, the same or different, mean a hydrogen atom or methyl; n means zero or 1; - c X means an oxygen atom, MH, M-CH»z or 5(O)k; h Kk means zero, 1 or 2; -» d means zero, 1, 2, Z or 4; 7 means a hydrogen atom or CE"; and their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts. -and 3. Compounds according to claim 1 and/or 2, in which - КИ and КГ, independently of each other, mean РЕ, СИ, Вг, СН" or СЕ"; KZ means a hydrogen atom; o KA means a hydrogen atom, methyl or ethyl; c 20 K5 and Kb mean a hydrogen atom or together mean a bond; K?7 and K8 together mean an alkylene chain consisting of 3, 4, 5, 6, 7 or 8 carbon atoms; -z or K?7 and K8 together mean the remainder of ШЕ 60, and К5 and КбЭ together form a connection; KO and K11, independently of each other, mean a hydrogen atom, OH or a fluorine atom; KU and K12 mean a hydrogen atom; or in one of the substituents KO and K12 means a hydrogen atom, and the other means BE, SI, Vg or "(X)a-СаНод-4; n means zero or 1; X means an oxygen atom, MH, M-CH»3 or B(O)K; Kk means zero, 1 or 2; 4 means zero or 1; 7 means a hydrogen atom or CE"; and their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts. 4. Compounds of formula (I) according to one or more of claims 1, 2 and 3, selected from the group including transo-K,K-2-chloro-3M-(Za,4,5,6,7,7a- hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine; trans-K,K-2-bromo-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine; 70 2-chloro-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine; 2-bromo-3M-(2-benzimidazolyl)-4-methyl-3-thienylamine; 2-chloro-3M-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine; 2-chloro-3M-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine; 2-chloro-3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene; 2-bromo-3M-(4-chloro-2-benzimidazolylamino)-4-methylthiophene; 2-bromo-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene; 2-chloro-3M-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene; 2-chloro-3M-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene; (1H-benzimidazol-2-yl)-(2-chloro-4-methylthiophen-3-yl)methylamine; (2-bromo-4-methylthiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)amine; 2-chloro-3M-(2-benzimidazolylamino)-4-methylthiophene; 2,4-dichloro-3M-(2-benzimidazolylamino)thiophene; 2-bromo-4-chloro-3M-(2-benzimidazolylamino)thiophene; 2,4-dichloro-3M-(4-methyl-2-benzimidazolylamino)thiophene; sc transo-K,K-2,4-dichloro-3M-(Za,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine and 2,4-dichloro-3M-( 4-chloro-2-benzimidazolylamino)thiophene; i) as well as their pharmaceutically acceptable salts. 5. Compounds of formula (I) and/or their pharmaceutically acceptable salts according to one or more of claims 1-4, suitable as a medicinal product. "- zo 6. Use of the compound of formula (I) and/or its pharmaceutically acceptable salts according to one or more of claims 1-4 for obtaining a medicinal product for the treatment or prevention of respiratory impulse disorders, especially sleep-related breathing disorders, such as suspended breathing, or snore; for the treatment or prevention of acute and chronic kidney diseases, especially acute renal failure or chronic renal failure, or intestinal function disorders; for the treatment or prevention of high blood pressure, especially essential hypertension, diseases of the central nervous system, especially diseases resulting from increased excitability of the central nervous system, such as epilepsy or convulsions provoked by the central nervous system, and diseases central nervous system, especially states of fear, depression and psychosis; for the treatment or prevention of acute and chronic injuries, diseases and mediated subsequent diseases of organs or tissues caused by the phenomena of ischemia or reperfusion, arrhythmias, atherosclerosis, hypercholesterolemia, diseases, the primary or secondary cause of which is the proliferation of cancer cells, hypertrophy or hyperplasia of the prostate, fibrotic diseases of internal organs, heart failure or congestive heart failure, thrombosis, gall bladder dysfunction, etc.? damage by ectoparasites, diseases due to endothelial dysfunction, Charcot syndrome, protozoan diseases, especially malaria; for the treatment of states of shock, diabetes and diabetic late damage, acute or chronic inflammatory diseases; as well as to obtain a medicinal product for conservation and storage - and transplants for surgical procedures, to obtain a medicinal product for use in surgical operations and organ transplantation; to obtain a medicinal product to prevent tissue changes caused by aging, to preserve health and increase life expectancy, to reduce cytotoxic effects, or for use as diagnostic tools. 7. Application according to point b of the compound of formula (I) and/or its pharmaceutically acceptable salts to obtain a medicinal product for the treatment or prevention of respiratory impulse disorders, especially sleep-related breathing disorders, such as suspended breathing. 8. Application according to item b of the compound of formula (I) and/or its pharmaceutically acceptable salts to obtain a medicinal product for the treatment or prevention of snoring. 9. Application according to point b of the compound of formula (I) and/or its pharmaceutically acceptable salts for obtaining a medicinal product for the treatment or prevention of acute and chronic kidney diseases, especially acute F) renal failure or chronic renal failure. ka 10. Use according to point b of the compound of formula (I) and/or its pharmaceutically acceptable salts to obtain a medicinal product for the treatment or prevention of bowel function disorders. in 11. Use of the compound of formula (I) and/or its pharmaceutically acceptable salts according to one or more of claims 1-4 in combination with other drugs or biologically active substances to obtain a drug for the treatment or prevention of respiratory impulse disorders, especially sleep-related disorders breathing, such as suspended breathing, or snoring; for the treatment or prevention of acute and chronic kidney diseases, especially acute renal failure or chronic renal failure, 65 or disorders of bowel function; for the treatment or prevention of high blood pressure, especially essential hypertension, diseases of the central nervous system, especially diseases resulting from hyperexcitability of the central nervous system, such as epilepsy or convulsions provoked by the central nervous system, and diseases of the central nervous system, especially states of fear, depression and psychosis; for the treatment or prevention of acute and chronic injuries, diseases and mediated subsequent diseases of organs or tissues caused by the phenomena of ischemia or reperfusion, arrhythmias, atherosclerosis, hypercholesterolemia, diseases whose primary or secondary cause is the proliferation of cancer cells, hypertrophy or hyperplasia of the prostate, fibrous internal diseases organs, heart failure or congestive heart failure, thrombosis, gallbladder function disorders, ectoparasite damage, diseases due to endothelial dysfunction, Charcot syndrome, protozoan diseases, especially malaria; for the treatment of states of shock, diabetes and diabetic late damage, acute or chronic inflammatory diseases; or to obtain a medicinal product for conservation and storage of transplants for surgical procedures, to obtain a medicinal product for use in surgical operations and organ transplantation; to obtain a medicinal product to prevent tissue changes caused by aging, to preserve health and increase life expectancy, and to reduce cytotoxic effects. 12. Application according to claim 11 of the compound of formula (I) and/or its pharmaceutically acceptable salts in combination with other drugs or biologically active substances to obtain a drug for the treatment or prevention of respiratory impulse disorders, especially sleep-related breathing disorders, such as respiratory arrest in dream. 13. Use according to claim 11 of the compound of formula (I) and/or its pharmaceutically acceptable salts in combination with other drugs or biologically active substances to obtain a drug for the treatment or prevention of snoring. 14. Use according to claim 11 of the compound of formula (I) and/or its pharmaceutically acceptable salts in combination with other drugs or biologically active substances to obtain a drug for the treatment or prevention of acute and chronic kidney diseases, especially acute renal failure or chronic kidney disease kidney failure. 15. Use according to claim 11 of the compound of formula (I) and/or its pharmaceutically acceptable salts in combination with i) other medicinal products or biologically active substances to obtain a medicinal product for the treatment or prevention of intestinal dysfunction. 16. Medicinal product intended for humans, animals or for plant protection, containing an effective amount of the compound of formula (1) or its pharmaceutically acceptable salt according to one or more of claims 1-4 together with pharmaceutically acceptable carriers and impurities. at 17. Medicinal product according to claim 16, which is characterized by the fact that it contains an effective amount of the compound of formula (I) and/or its pharmaceutically acceptable salt according to one or more of claims 1-4 together with pharmaceutically acceptable carriers and impurities in combination with other pharmacological biologically active substances or medicinal products. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 12, 15.12.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. " - . and? -i -i 1 1 - ime) 60 b5