RU2575477C2 - Compounds for treating clostridium difficile associated diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a bibenzoimidazol derivative of general formula

wherein R¹ is pyridyl; R² represents an aromatic 9-merous bicyclic ring system, wherein one or two carbon atoms can be substituted by N, O, or S; or to its pharmaceutically acceptable salt, hydrate or solvate. The invention also refers to a combination based on the compound of formula (I) and an additional specified agent, a pharmaceutical composition based on the compound of formula (I), a method of treating Clostridium difficile infection and a method of eliminating Clostridium difficile bacterium.

EFFECT: produced are new bibenzoimidazol derivatives possessing effective biological properties.

14 cl, 2 tbl, 2 ex

Description

FIELD OF THE INVENTION

The present invention relates to compounds that can be used to treat Clostridium difficile infections and diseases caused by Clostridium difficile, to compositions containing such compounds, and to methods of treating diseases associated with Clostridium difficile (CDAD) using such compounds.

State of the art

Antibacterials and Clostridium difficile

The creation of drugs with antibacterial effect is one of the most important achievements in 20th century medicine. It was possible to fight previously incurable diseases, and it seemed that with the help of new incredible medicines many diseases would be completely defeated. However, despite such significant advances in their treatment, infectious diseases are the third leading cause of death in the United States (Clin. Infect. Dis., 2004, 38, 1279-1286) and remain one of the most significant public health problems worldwide. The drug resistance rates of all major pathogenic bacteria are growing rapidly, and the increase in the number of nosocomial (nosocomial) infections, as well as the severity (Infectious Disease Society of America, 2004, Bad Bugs, No Drugs) is of particular concern. The advent of multi-drug resistant pathogens has made many modern first-line drugs completely ineffective against many diseases.

Of particular concern is a variety of bacterial pathogens classified as spore-forming bacteria. Bacterial spores (endospores) are latent non-reproductive structures formed by bacteria in response to stress due to adverse environmental conditions. Once environmental conditions become favorable, spores germinate and bacteria multiply. In the case of pathogenic bacteria, germination in the human host can result in disease.

Bacterial spores are extremely resistant to many factors and environmental conditions, including radiation, dehydration, temperature, food shortages, and chemical agents. Such natural resistance to the action of chemical agents allows spores to persist for many months in such important places as hospitals and other medical centers, as well as in food production facilities where standard cleaning and detergents, germicidal agents and sterilization methods do not lead to destruction of bacteria. In the case of food production, the presence of spores can have serious consequences, from simple food spoilage to the spread of foodborne pathogens and food poisoning. Recently, attention has been drawn to the risks associated with the disputes of Bacillus anthracis, the causative agent of anthrax. Such spores can be easily obtained in the form of a dry powder, which can be distributed in a variety of ways and used as a bioterrorist agent. Anthrax causes the greatest concern of all bioterrorist drugs (CDC Emerg. Infect. Dis., 2004, 5 (4), 552-555). This statement can be illustrated by “postal” attacks of anthrax in the United States in 2001. Then, 22 cases of infection were confirmed, resulting in 5 deaths, and the cost of cleaning and disinfection after these attacks was estimated at about $ 1 billion .

Among spore-forming bacteria, gram-positive endospore-forming bacteria of the genus Bacillus and Clostridium occupy an important place. Examples of bacteria of the Bacillus genus that are associated with human health problems include, but are not limited to, B. anthracis and B. cereus. Bacillus anthracis is especially important as the causative agent of anthrax. Anthrax infection can occur by ingestion, inhalation, or skin contact with Bacillus anthracis spores, resulting in three different clinical forms of the disease. Skin infection accounts for about 95% of all infections and is usually well controlled with appropriate antibiotics. If untreated, about 20% of cases of cutaneous anthrax lead to death. Intestinal infection is characterized by acute intestinal inflammation, which leads to nausea, loss of appetite, vomiting, fever, abdominal pain, vomiting with blood, and severe diarrhea. The intestinal form of anthrax leads to death in 25-60% of cases. The most severe form of the disease is a pulmonary anthrax, which often leads to death even with timely and intensive antibiotic therapy. The ability of anthrax causative agent spores to easily spread through the air over a wide area and induce a pulmonary disease makes anthrax the main bioterrorist drug.

Representatives of the genus Clostridium are gram-positive, spore-forming obligate anaerobes. Examples of species of clostridia that cause human disease include, but are not limited to C. perfringens, C. tetani, C. botulinium, C.sordellii, and C. difficile. Clostridia species are associated with a variety of human diseases, including tetanus, gas gangrene, botulism, and pseudomembranous colitis and can cause food poisoning.

Of particular importance is the disease caused by Clostridium difficile. Clostridium difficile causes diseases associated with Clostridium difficile (CDAD), and over the past 10 years there has been a ten-fold increase in the number of cases of CDAD, with hypervirulent and drug resistant strains currently becoming endemic. Recent NRA data show that in 2006, there were 55,681 cases of C. difficile infection in patients 65 years of age and older (8% more than in 2005) in England. Perhaps the most worrisome are cases of CDAD that are not related to the use of antibiotics.

Clostridium difficile is a commensal intestinal bacterium whose population is controlled by normal intestinal flora. However, the bacterium is a causative agent of diseases associated with C. difficile (CDAD) and has been identified as the main cause of the most serious manifestation of CDAD-pseudomembranous colitis. CDADs are associated with a wide range of symptoms, from mild diarrhea to pseudomembranous colitis, toxic megacolon, and death. The main risk factor for the development of CDAD is the use of antibiotics that destroy the normal intestinal bacterial flora, which causes excessive growth of Clostridium difficile. Although clindamycin is the main antibiotic associated with CDAD, this disease is now associated with almost all antibiotics, including antibiotics belonging to the classes of fluoroquinolones, cephalosporins, macrolides, p-lactams and many others.

The greatest concern is CDAD in a hospital setting, and CDAD is of particular concern among older patients for whom mortality rates are particularly high. The incidence of CDAD has risen sharply in recent years. More than 55,000 cases were reported in the UK in 2006 (Report of the Infection Control Division of the Health Protection Agency in 2007).

The mortality rate in the USA increased from 5.7 cases per million people in 1999 to 23.7 cases per million people in 2004. C. difficile colonization rates in the population reach 3%, although hospitalization leads to a sharp increase in colonization levels reaching 25% Of particular concern is the emergence of new endemic strains. A particularly relevant example is the hypervirulent BI / NAP1 strain (also known as ribotype 027), which exhibits increased production of toxins A and B, as well as the production of additional new binary toxins.

The decisive factor associated with the species of clostridia is the high level of bacterial spores present in hospital settings. Recently, it has been shown that many of the standard cleaning agents used in hospitals are not effective at eliminating clostridial spores in the environment, resulting in ineffective disease control (Infect Cont. Hosp. Epidemiol., 2007, 28, 920-5). Excessive sporulation characteristic of strains such as BI / NAP1 contributes significantly to the problem under consideration.

Although the main risk factors associated with CDAD are due to antibiotic use and age (CMAJ, 2008, 179 (8), 767-772; J. Antimicrob. Chem., 2003, 51, 1339-1350), there are many other related CDAD factors, including, for example, the use of proton pump inhibitors, the use of H2 receptor antagonists, the use of diuretics, prolonged hospital stay, the use of tube feeding, mechanical ventilation and predisposing concomitant diseases.

The acidity of the gastric juice is part of the natural defense mechanism against the ingested (by mouth) pathogens, and any decrease in acidity in the stomach can result in the colonization of the usually sterile upper gastrointestinal tract, which can lead to disruption of the normal intestinal microflora. In this regard, the use of gastric acid suppressants, such as proton pump inhibitors (PPI), histamine H2 receptor antagonists (H2Ra), is associated with an increased risk of C. difficile colony formation and subsequent development of CDAD. The use of PPI and H2Ras has previously been associated with other intestinal infections, such as travelers' diarrhea, salmonellosis, and cholera. Dial et al. Confirmed that the risk of CDAD is increased when using drugs that suppress the acidity of gastric juice, both outside the hospital (JAMA, 2005, 294 (23), 2989-2995) and in hospital settings (CMAJ, 2004, 171 (1 ). 33-38).

Proton pump inhibitors (PPIs) include (but are not limited to) omeprazole (moose, prilosek, zegeride), lansoprazole (prevacid, zotone, inhibitol), esomeprazole (nexium), pantoprazole (protonix, somak, pantolok, pantozol, zurka ) and rabeprazole (rabecid, asifex, soars, rabelok).

H2Ra antagonists include cimetidine (tagamet), ranitidine (zinetak, zantak), famotidine, (pepsidin, pepsid), roxatidine (roxit) and nizatidine (tazak, axide), but not

limited only to them.

Triple therapy using PPI or H2Ra together with a combination of two antibiotics is a common treatment method designed to kill Helicobacter pylori infections (Aliment. Pharmacol. Ther., 2001,15 (5), 613-624;

Helicobacter., 2005, 10 (3 '), 157-171). However, there are several reports that the indicated triple therapy can lead to CDAD as a side effect (Am. J. Gastroenterol., 1998, 93 (7), 1175-1176; J. Int. Med., 1998, 243 (3), 251-253; Aliment. Pharm. Ther., 2001, 15 (9), 1445-1452; Med. Sci. Monit, 2001, 1 (4), 751-754). Conventional antibacterial agents used to treat Helicobacter pylori infections are a combination of agents selected from (but not limited to metronidazole, amoxicillin, levofloxacin and clarithromycin, many of which are directly associated with the development of CDAD.

The currently used treatments are extremely limited; especially in light of the fact that almost all classes of antibiotics can act as the cause of the development of the disease. The only FDA approved drug for treating CDAD is vancomycin, although metronidazole is also widely used. The widespread use of vancomycin for the treatment of CDAD is of concern because of its bacteriostatic effect against clostridia, the relatively high cost and possible selection of both resistant C. difficile strains and other bacteria (especially Enterococcus spp.). A key problem for both metronidazole and vancomycin is the high relapse rate, with at least 20% of patients experiencing at least one relapse episode. It is believed that relapse occurs due to the inability to destroy spores of clostridia during treatment, which as a result leads to their subsequent germination and pathogenic state. This inability to control the formation of spores creates an opportunity for prolonged infection of the hospital environment. For this reason, agents capable of destroying vegetative cells and controlling endospores would have a significant advantage.

The key to choosing therapy for treating CDAD is to discontinue any antimicrobial treatment, followed by the proper use of either vancomycin or metronidazole. Both drugs are usually administered orally, although metronidazole can also be administered intravenously, and in severe cases, vancomycin can be administered in other ways, including through the colon, nasal gastric tube, or as a vancomycin-holding enema. Additional antibiotics reported to be used in the treatment of CDAD include fusidic acid, rifamycin and its analogs, teicoplanin and bacitracin, although none of them have efficacy superior to that of vancomycin or metronidazole. In addition to stopping the antibacterial treatment that caused the disease, the use of antiperistaltic drugs, opiates or loperamide should be avoided, since they can slow down the removal of toxins produced by C. difficile and aggravate the damage to the colon caused by toxins. These agents can also cause bowel obstruction and cause toxic dilatation of the colon. (J. Med. Microbiol, 2005, 54, 101-111; JAMA, 1993, 269, 71-5; Postgrad. Med. J, 1990, 66 (777), 582).

Alternative therapies, used as standard single drugs or in combination with antibacterial agents, either aim to restore the natural population of microorganisms in the intestines and reduce the levels of toxins produced by C. difficile, or boost the immune system (for reviews see Antibiotic Treatment for Clostridium difficile-Associated Diarrhea in Adults, Cochrane Database of Systematic Reviews 2007, Issue 3, Art. No .: CD 004610; Clin. Inf. Dis, 2008, 46 (S1), S32-S42; Clin. Inf. Dis „2007 45 (S2), S122-S128; J. Med. Microbiol., 2005, 54, 101-111 and references cited therein). Thus, alternative treatments for CDAD include the administration of Saccharomyces boulardii or Lactobacillus acidophilus in combination with antibiotics, fecal transplantation and, in severe cases where all other therapies fail, surgery. Although the incidence of colectomy is low (up to 3% of cases), it is associated with a high mortality rate (up to 60%).

In this regard, there is an urgent need for new and effective agents for the treatment of diseases associated with spore-forming bacteria, especially those caused by representatives of the genus Clostridium and Bacillus, and, in particular, diseases associated with infection with the bacterium Clostridium difficile. This need is especially acute in light of the refractory nature of the bacterium Clostridium difficile, which is resistant to many broad-spectrum antibiotics (including p-lactam and quinolone antibiotics) and the frequency with which resistance occurs (Antimicrob. Agents Chemother., 1985, 28 (6) : 842-844).

State of the art

In the publications of international applications WO 2007056330, WO 2003105846 and WO 2002060879 various 2-aminobenzimidazoles are described which act as antibacterial agents.

WO2007148093 discloses various 2-aminobenzothiazoles as antibacterial agents.

In WO 2006076009, WO 2004041209 and article Bowser et al. (Bioorg. Med. Chem. Lett., 2007, 17, 5652-5655) describes various derivatives of substituted benzimidazole that can be used as antibacterial agents that can reduce the resistance, virulence or reproduction rate of microbes. It is reported that the compounds do not exhibit their own antimicrobial activity in vitro.

US Pat. No. 5,824,698 describes various dibenzimidazoles as broad-spectrum antibiotics that are active against both gram-negative and gram-positive bacteria, including Staphylococcus spp. And Enterococcus spp. However, this patent does not report anaerobic activity spore-forming bacteria and, in particular, there is no data on activity against any bacteria of Clostridium spp. (including C. difficile).

U.S. Patent Application US 2007/0112048 Al describes various bi- and triarylimidazolidines and bi- and triarylamidines as broad-spectrum antibiotics that are active against both gram-negative and gram-positive bacteria, including Staphylococcus spp., Enterococcus spp. and Clostridium spp. However, the compounds of general formula (I) described in this application are not disclosed in this document.

In an article by Chaudhuri et al. (J. Org. Chem., 2007, 72, 1912-1923) describes various bis-2- (pyridyl) -1H-benzimidazoles (including compounds of formula I as described herein) as agents that bind to DNA There is no evidence of potential antibacterial activity in this document.

Disclosure of invention

Thus, a first aspect of the present invention is a compound of general formula (I)

where R ¹ selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, and this optional substitution is carried out by one or more substituents selected from halogen, CN, NO ₂ , R ³ , OR ³ , N (R ³ ) ₂ , COR ³ , CO ₃ R ³ , C (= O) SR ³ , SR ³ , S (= O) R ³ , SO ₂ R ³ , NR ⁴ C (= O) R ³ , NR ⁴ CO ₂ R ³ , OS (= O) NR ³ R ⁴ , NR ⁴ SO ₂ R ³ , C (= NR ⁴ ) NR ³ R ⁴ , C (= S) NR ³ R ⁴ , NR ⁴ C (= NR ⁴ ) NR ³ R ⁴ , NR ⁴ C (= S) NR ³ R ⁴ , NR ⁴ C (= O) NR ³ R ⁴ , CONR ³ R ⁴ and SO ₂ NR ³ R ⁴ ;

R ² represents an optionally substituted aromatic 8-14 membered fused bicyclic or tricyclic ring system in which one or more carbon atoms can be substituted with N, O, S, SO or SO ₂ , and this optional substitution is carried out by one or more substituents, selected from halogen, CN, NO ₂ , R ³ , OR ³ , N (R ³ ) ₂ , COR ³ , CO ₂ R ³ , C (= O) SR ³ , SR, S (= O) R ³ , SO ₂ R ³ , NR ⁴ C (= O) R ³ , NR ⁴ CO ₂ R ³ , OC (= O) NR ³ R ⁴ , NR ⁴ SO ₂ R ³ , C (= NR ⁴ ) NR ³ R ⁴ , C ( = S) NR ³ R ⁴ , NR ⁴ C (= NR ⁴ ) NR ³ R ⁴ , NR ⁴ C (= S) NR ³ R ⁴ , NR ⁴ C (= O) NR ³ R ⁴ , CONR ³ R ⁴ and SO ₂ NR ³ R ⁴ ;

R ^{3 is} selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclyl, C ₄ -C ₇ heterocyclyl, and 5- or 6-membered aryl or heteroaryl any of which may be optionally substituted with one or more substituents selected from halogen, CN, NO ₂ , R ⁴ , OR ⁴ , N (R ⁴ ) ₂ , COR ⁴ , CO ₂ R ⁴ , C (= O) SR ⁴ , SR ⁴ , S (= O) R ⁴ , SO ₂ R ⁴ , NR ⁴ C (= O) R ⁴ , NR ⁴ CO ₂ R ⁴ , OC (= O) NR ⁴ ) ₂ , NR ⁴ SO ₂ R ⁴ , C (= NR ⁴ ) N (R ⁴ ) ₂ , C (= S) N (R ⁴ ) ₂ , NR ⁴ C (= NR ⁴ ) N (R ⁴ ) ₂ , NR ⁴ C (= S) N ( R ⁴ ) ₂ , NR ⁴ C (= O) N (R ⁴ ) ₂ , CON ( ^R 4) ₂ and SO ₂ N (R ⁴ ) ₂ ;

R ^{4 is} selected from hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₇ carbocyclyl, optionally substituted with one or more halogen atoms;

or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof for use in a method for treating diseases associated with Clostridium difficile (CDAD).

Some of the compounds of general formula (I) are new. Thus, according to the invention, the authors also invented those compounds of general formula (I) that are new, together with methods for their preparation, compositions containing them, and their use as pharmaceuticals.

Therefore, another object of the invention is a compound of General formula (I)

R ^{1 is} selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, such optional substitution being carried out by one or more substituents selected from halogen, CN, NO ₂ , R ³ , OR ³ , N (R ³ ) ₂ , COR ³ , CO ₂ R ³ , C (= O) SR ³ , SR ³ , S (= O) R ³ , SO ₂ R ³ , NR ⁴ C (= O) R ³ , NR ⁴ CO ₂ R ³ , OC (= O ) NR ³ R ⁴ , NR ⁴ SO ₂ R ³ , C (= NR ⁴ ) NR ³ R ⁴ , C (= S) NR ³ R ⁴ , NR ⁴ C (= NR ⁴ ) NR ³ R ⁴ , NR ⁴ C (= S) NR ³ R ⁴ , NR ⁴ C (= O) NR ³ R ⁴ , CONR ³ R ⁴ and SO ₂ NR ³ R ⁴ ;

R ² is an optionally substituted aromatic 8-14 membered fused bicyclic or tricyclic ring system in which one or more carbon atoms can be substituted with N, O, S, SO, or SO _2, such optional substitution being carried out by one or more substituents selected from halogen, CN, NO ₂ , R ³ , OR ³ , N (R ³ ) ₂ , COR ³ , CO ₂ R ³ , C (= O) SR ³ , SR ³ , S (= O) R ³ , SO ₂ R ³ , NR ⁴ C (= O) R ³ , NR ⁴ CO ₂ R ³ , OS (= O) NR ³ R ⁴ , NR ⁴ SO ₂ R ³ , C (= NR ⁴ ) NR ³ R ⁴ , C ( = S) NR ³ R ⁴ , NR ⁴ C (= NR ⁴ ) NR ³ R ⁴ , NR ⁴ C (= S) NR ³ R ⁴ , NR ⁴ C (= O) NR ³ R ⁴ , CONR ³ R ⁴ and SO ₂ NR ³ R ⁴ ;

R ^{3 is} selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclyl, C ₄ -C ₇ heterocyclyl, and 5- or 6-membered aryl or heteroaryl any of which may be optionally substituted with one or more substituents selected from halogen, CN, NO ₂ , R ⁴ , OR ⁴ , N (R ⁴ ) ₂ , COR ⁴ , CO ₂ R ⁴ , C (= O) SR ⁴ , SR ⁴ , S (= O) R ⁴ , SO ₂ R ⁴ , NR ⁴ C (= O) R ⁴ , NR ⁴ CO ₂ R ⁴ , OC (= O) NR ⁴ ) ₂ , NR ⁴ SO ₂ R ⁴ , C (= NR ⁴ ) N (R ⁴ ) ₂ , C (= S) N (R ⁴ ) ₂ , NR ⁴ C (= NR ⁴ ) N (R ⁴ ) ₂ , NR ⁴ C (= S) N ( R ⁴ ) ₂ , NR ⁴ C (= O) N (R ⁴ ) ₂ , CON (R ⁴ ) ₂ and SO ₂ N (R ⁴ ) ₂ ;

R ^{4 is} selected from hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₇ carbocyclyl, optionally substituted with one or more halogen atoms;

or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof.

The compound according to the above definition can be used in therapy or for prophylaxis, for example, for the treatment of a bacterial infection or disease (for example, for the treatment of CDAD).

Another object of the invention is a method of treating a bacterial infection or bacterial disease (eg, CDAD) in a subject, comprising administering to said subject an effective amount of a compound according to the above definition.

Another object of the invention is a method of killing a bacterium or inhibiting, reducing or preventing its growth, comprising contacting said bacterium with a compound according to the above definition. In such embodiments, the bacterium is preferably Clostridium difficile.

Also described are combinations comprising a compound of the invention according to the above definition and various additional agents as described below.

In the claims set forth below, other objects of the present invention are presented.

DETAILED DESCRIPTION OF THE INVENTION

All publications, patents, patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety and for all purposes, as if each individual publication, patent, or patent application were specifically and individually included in the description. by reference, and their contents have been given here in full.

Definitions and General Parameters

It is intended that the following terms used in this application, unless specifically indicated otherwise, have the meanings set forth below in addition to any broader (or narrower) meanings used in the art.

Unless otherwise indicated by context, it should be understood that the use of the singular in this document includes the plural and vice versa. Moreover, when using the singular, as well as the expression "one or more" and the expression "at least" it is implied that all these options are equivalent to each other.

As used herein, the term “comprise,” or variations thereof, such as “comprises” or “comprising,” is to be understood as indicating the inclusion of any specified entity (eg, attribute, element, characteristic, property, method / method step or limitation) or groups of entities (for example, signs, elements, characteristics, properties, stages of a method / method or restrictions), but not the absence of other entities or a group of entities. Therefore, the term “comprising” as used herein is inclusive or non-limiting and does not exclude the presence of additional non-listed entities or stages of a method / method.

The phrase "consisting essentially of" is used herein to indicate the need for specific entity (s) or steps, in addition to those that in practice do not affect the nature or functioning of the claimed invention.

As used herein, the term "consisting" is used only to indicate the presence of a specified entity (for example, a feature, element, characteristic, property, stage of a method / method or restriction) or a group of entities (for example, feature elements, characteristics, properties, stages of a method / method or restrictions).

As used herein, the term “disease” is used to mean any abnormal condition that adversely affects physiological function and is associated with specific symptoms. The term is widely used to refer to any diseases, diseases, abnormalities, pathologies, disorders, conditions or syndromes in which the physiological function is impaired, regardless of the nature of the etiology (or even regardless of whether the etiological basis of the disease is established at all). Thus, the term encompasses conditions arising from trauma, injury, surgery, radiological ablation, poisoning, or malnutrition.

As used herein, the term “bacterial disease” refers to any disease that involves bacteria (for example, that is caused, exacerbated by bacteria, associated with bacteria, or characterized by the presence of bacteria) that lives and / or multiplies in the body and / or cells of the subject. Thus, the term includes diseases that are caused or exacerbated by bacterial toxins (which can also be called “bacterial intoxication” here). The more specific term “Clostridium difficile disease” is interpreted accordingly.

As used herein, the term “Clostridium difficile-associated disease” (CDAD) is used to mean any disease in which the Clostridium difficile bacterium is involved (for example, caused, exacerbated by this bacterium, associated with or characterized by the presence of the bacterium) that lives or (multiplying) in the body of the subject. Thus, this term covers all diseases, disorders, pathologies, symptoms, clinical conditions or syndromes in which a bacterium of the species Clostridium difficile acts as an etiological agent, or in which an infection is suspected, detected, or occurs in one or more strains of Clostridium difficile such an infection. Thus, the term includes various forms of colitis, pseudomembranous colitis, diarrhea, and antibiotic-associated disease.

As used herein, the term “Clostridium difficile selective agent” is used to indicate a compound that exhibits bacteriostatic and / or bactericidal activity against one or more strains of C. difficile bacteria, but which does not exhibit bacteriostatic and / or bactericidal activity in the relationship of one or more representatives of the natural flora of the digestive system, selected from: (a) Escherichia spp. (eg Escherichia coli); (b) Bacteroides spp. (e.g. B. fragilis); (c) Fusobacterium spp .; (d) Eubacterium spp. (e) Ruminococcus spp .; (f) Peptococcus spp .; (g) Peptostreptococcus spp .; (h) Bifidobacterium spp .; (i) Lactobacillus spp .; (j) Enterococcus spp. (e.g. E. faecium); (k) species of clostridia other than C. difficile (e.g. C. perfringens); (1) Enterobacter spp .; (m) Serratia spp .; (n) Klebsiella spp .; (o) Proteus spp .; (p) Pseudomonas spp. and (q) Veillonella spp.

Preferred Clostridium difficile selective agents exhibit bacteriostatic and / or bactericidal activity against one or more strains of C. difficile bacteria, but do not exhibit bacteriostatic and / or bactericidal activity against (a) Escherichia coli; or (b) B. fragilis.

Thus, some preferred Clostridium difficile selective agents of the invention exhibit bacteriostatic and / or bactericidal activity against one or more strains of C. difficile bacteria, but do not have bacteriostatic and / or bactericidal activity against B. fragilis.

As used herein, the term “bacterial infection” is used to define a condition in which a subject is infected with a bacterium. The infection may be symptomatic or asymptomatic. In the latter case, the subject can be identified as infected on the basis of various tests, including, for example, biochemical tests, serological tests, tests for microbiological cultures and / or microscopy.

The terms "bacteriostatic" and "bactericidal" are the terms used in the prior art to determine the ability to prevent the growth of bacteria (or reduce its speed) and to mediate (directly or indirectly) the cellular destruction of bacterial cells, respectively. These terms are not mutually exclusive, and many drugs have both bacteriostatic and bactericidal effects (in some cases, in a dose-specific or target-specific manner). Generally, bactericidal therapy leads to better results, and bactericidal agents are preferred.

As used herein, the term “broad-spectrum antibiotic” refers to an agent that is bactericidal and / or bacteriostatic for a variety of bacteria, including both gram-positive and gram-negative bacteria.

The term "multi-resistant" (MDR) as used herein for a bacterium refers to a bacterium that is resistant to two or more classes of antibiotics, including antibiotics selected from, but not limited to, penicillin, methicillin, quinolone, macrolide and / or vancomycin.

As used herein, the terms “treating” or “treating” refer to an intervention (eg, administering an agent to a subject) that cures, improves or alleviates the symptoms of a disease or eliminates (or alleviates) the cause (s) (eg, pathogenic bacterium). In this case, this term is used as a synonym for the term "therapy". Thus, the treatment of an infection in accordance with the invention can be characterized by the direct or indirect bacteriostatic and / or bactericidal action of the compound of the invention.

In addition, the terms “treating” or “treating” as used herein refer to an intervention (for example, administering an agent to a subject) that prevents the onset or slows the progression of the disease or reduces (or eliminates) the incidence in the group of patients treated. In this case, the term is used as a synonym for the term “prophylaxis”.

The term "subject" (which should be understood to include the concepts of "individual", "animal", "patient" or "mammal" in cases where the context permits) defines any subject, especially a mammalian subject for whom treatment is indicated. Mammalian subjects include humans, primates, domestic animals, farm animals, domestic animals, and rodents such as mice, rats, hamsters, and guinea pigs. In preferred embodiments, the subject is a human.

The term "gram-positive bacterium" is a special term that designates in the prior art a specific class of bacteria that group together based on some characteristics of staining of cell walls.

The term "gram-positive bacterium with a low content of G + C" is a special term for a specific subclass of evolutionarily related gram-positive bacteria based on a set of bases in DNA. This subclass includes Streptococcus spp., Staphylococcus spp., Listeria spp., Bacillus spp., Clostridium spp., Enter ococcus spp. And Lactobacillus spp.

The term "minimum inhibitory concentration" or "MIC" refers to the lowest concentration of test compound that is necessary in order to inhibit a bacterial isolate in vitro. A common method for determining the antibiotic MIC is to prepare several tubes containing serial dilutions of the test compound, which are then inoculated with the test bacterial isolate. After incubation at the appropriate atmosphere and temperature, the antibiotic MIC can be determined from the tube with the lowest concentration in which no turbidity is observed.

The term “combination”, as used herein with reference to two or more compounds and / or agents (also referred to herein as components), means a substance in which two or more compounds / agents are linked. The terms "combined" and "combination" in this context are interpreted accordingly.

The combination of two or more compounds / agents in combination may occur physically and nonphysically. Examples of physically combined combinations of compounds / agents include:

- compositions (for example, unitary preparations) containing two or more compounds / agents in a mixture (for example, in the same unit dose);

- compositions containing a substance in which two or more compounds / agents are chemically / physically chemically bonded (for example, by crosslinking, agglomeration of molecules, or by binding to the remainder of a common carrier);

- compositions containing a substance in which two or more compounds / agents are chemically / physico-chemically “packed” together (for example, placed on or in liposomes, particles (eg, micro- or nanoparticles) or in drops of an emulsion);

- pharmaceutical kits, pharmaceutical packaging, patient packaging in which two or more compounds / agents are packaged or are together (for example, as part of a unit dose package).

Examples of compounds / agents combined in combination by a non-physical route include:

- a substance (eg, a non-unitary preparation) containing at least one of two or more compounds / agents, together with instructions for extemporal association of at least one compound / agent to form a physical association of two or more compounds / agents;

- a substance (for example, a non-unitary preparation) containing at least one of two or more compounds / agents, together with instructions for combination therapy with two or more compounds / agents;

- a substance containing at least one of two or more compounds / agents, together with instructions for administration to a group of patients to whom the other (s) of two or more compounds / agents have already been (or are) administered;

- a substance containing at least one of two or more compounds / agents in an amount or in a form that are specially adapted for use in combination with the other (s) of two or more compounds / agents.

As used herein, the term “combination therapy” is intended to mean therapies that include the use of a combination of two or more compounds / agents (as defined above). Thus, references to “combination therapy”, “combinations” and the use of compounds / agents “in combination” in the present invention may refer to compounds / agents that are administered as part of one general treatment regimen. Essentially, the nosology of each of two or more compounds / agents can be different: they can all be administered at the same time or at different times. Therefore, it is understood that the combination compounds / agents can be administered sequentially (for example, before or after) or simultaneously, in the same pharmaceutical preparation (i.e. together), or in different pharmaceutical preparations (i.e. individually). At the same time in one pharmaceutical preparation means a unitary preparation, while simultaneously in various pharmaceutical preparations means a non-unitary preparation. The posologies of each of two or more compounds / agents in combination therapy may also differ with respect to the route of administration.

As used herein, the term “pharmaceutical kit” means a set of one or more unit doses of a pharmaceutical composition together with dispensing devices (eg, a measuring device) and / or delivery devices (eg, an inhaler or syringe), all of which are not necessarily contained in one common package . In pharmaceutical kits containing a combination of two or more compounds / agents, the individual compounds / agents may be unitary or non-unitary preparations. Unit doses may be in blister packs. The pharmaceutical kit may also optionally contain instructions for use.

As used herein, the term “pharmaceutical package” means a set of one or more unit doses of a pharmaceutical composition, optionally contained within a general external package. In pharmaceutical packages containing two or more compounds / agents, the individual compounds / agents may be unitary or non-unitary preparations. Unit doses may be contained in blister packs. The pharmaceutical packaging may optionally further contain instructions for use.

As used herein, the term "patient packaging" means a package of drugs prescribed to a patient that contains pharmaceutical compositions for the entire course of treatment. Patient packs usually contain one or more blister packs. Packages for the patient have advantages over traditional prescription drugs, where the pharmacist allocates a stock of medicines for the patient from a large batch, since the patient always has access to the instructions for use that are usually not in the prescription. It has been demonstrated that the inclusion in the patient package of the package leaflet for use improves patient compliance with the instructions of the attending physician.

The combinations according to the invention can have a more effective therapeutic effect, compared with the therapeutic effect of the individual compounds / agents when administered separately.

As used herein, the term “effective amount” or “therapeutically effective amount” of a compound refers to an amount that can be administered to a subject without undue toxicity, irritation, allergic reaction or other problems or complications, and corresponding to a reasonable ratio of beneficial effect and risk, but sufficient when this to ensure the desired effect, for example, treatment or prevention, manifested in a permanent or temporary improvement in the condition of the subject. This amount varies from subject to subject, depending on the age and general condition of the individual, the form of administration and other factors. Thus, although it is not possible to indicate in advance the exact effective amount, specialists in this field can determine the corresponding "effective" amount in each individual case using routine research and their knowledge. A therapeutic outcome in this context includes the elimination or alleviation of symptoms, reduction of pain or discomfort, prolonged survival, improved mobility, and other markers of clinical improvement. The therapeutic result does not have to be a complete cure.

As used herein, the term “prophylactically effective amount” refers to an amount effective at a dosage and for periods of time necessary to achieve the desired prophylactic result. Typically, since a prophylactic dose is administered to subjects before the disease or at an early stage of the disease, the prophylactically effective amount is less than the therapeutically effective amount.

The term "effective" includes such advantages and effects as additivity, synergism, reduced side effects, reduced toxicity or improved rates or activity. Preferably, an effective action reduces the doses of each or any of the components administered to the patient, and thereby reduce toxicity while obtaining and / or maintaining the same therapeutic effect. A synergistic effect in the present context refers to a therapeutic effect obtained by a combination of components that is greater than the sum of the therapeutic effects of the components of the combination used individually. An additive effect in the present context refers to a therapeutic effect obtained by a combination that is greater than the therapeutic effect of any of the combination components used individually.

The term “adjuvant compound” (or “adjuvant”) as used herein is intended to mean any compound that provides an effective combination (as defined herein) in combination with a compound of the invention. Thus, the auxiliary compound may act as a complement to the compound of the invention, or may otherwise contribute to the effectiveness of the combination (for example, by giving a synergistic or additive effect or enhancing the activity of the compound of the invention).

The term “complementary” used when using the compounds and combinations of the invention in therapy or prophylaxis refers to uses where the substances are administered together with one or more other drugs, interventions, treatment regimens, or therapies (such as surgery and / or radiation). Thus, additional therapies may include simultaneous, separate or sequential administration / application of the substances of the invention and other treatments. Thus, in some embodiments, the additional use of the compounds of the invention is reflected in the pharmaceutical compositions of the invention. For example, additional use may be reflected in a particular dosage form or in preparations in which the compound of the invention is mixed with other drug (s) with which it is used additionally (or physically associated with other drugs in a single dose) . In other embodiments, the additional use of the compounds or compositions of the invention may be reflected in compositions included in the pharmaceutical kits of the invention in which the compound of the invention is packaged with the other drug (s) (for example, as part of a unit dose unit) with which it is additionally used. In other embodiments, additional use of a compound of the invention may be reflected in information and / or instructions packaged with the compound and / or posology.

The term “pharmaceutically acceptable derivative” as applied to a compound of the invention means compounds that are prepared (or can be prepared) by chemical derivatization of the starting compounds of the invention. Pharmaceutically acceptable derivatives are thus suitable for administration to mammalian tissue or for use in contact with mammalian tissue without undue toxicity, irritation or an allergic reaction (i.e., according to a reasonable combination of benefit and risk). Preferred derivatives are derivatives obtained (or those that can be obtained) by alkylation, esterification or acylation of the starting compounds of the invention. Derivatives can be active in pure form or can be inactive until they are subjected to in vivo processing. In the latter case, the derivatives of the invention act as prodrugs. Particularly preferred prodrugs are ester derivatives that are esterified to one or more hydroxyl groups and which are activated by in vivo hydrolysis. Other preferred prodrugs are covalently bound compounds that release the active parent drug of general formula (I) after cleavage of the covalent bond or bonds in vivo.

The pharmaceutically acceptable derivatives of the invention retain some or all of the activity of the parent compound. In some cases, with derivatization, activity increases. Derivative preparation can also complement the activity of a compound with other types of biological activity, for example, bioavailability.

The term "pharmaceutically acceptable salt", as applied to the compounds of the invention, refers to any non-toxic additive salt of an organic or inorganic acid and a free base of a compound that is suitable for use in contact with mammalian tissues, does not cause excessive toxicity, irritation, allergic reaction, and which corresponds to a reasonable balance of benefits and risks. Suitable pharmaceutically acceptable salts are well known in the art. Examples are salts of inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric and phosphoric acids), organic carboxylic acids (e.g., acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxy dihydroximaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, o-aminobenzoic, cinnamon, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acids) and organic sul background acids (e.g. methanesulfonic acid and n-toluenesulfonic acid). The compounds of the invention can also be converted into salts by reaction with an alkali metal halide, for example sodium chloride, sodium iodide or lithium iodide. Preferably, the compounds of the invention are converted into salts by reaction with a stoichiometric amount of sodium chloride in the presence of a solvent such as acetone.

Said salts and free bases of the compounds may exist in either hydrated or substantially anhydrous form. Crystalline forms of the compounds of the invention are also provided, and, as a rule, the addition salts of acids and compounds of the invention are crystalline substances that are soluble in water and various hydrophilic organic solvents, have higher melting points and increased solubility compared to the same compounds in free base form.

The term “pharmaceutically acceptable solvate” as applied to the compounds of the invention refers to any pharmaceutically acceptable solvate form of the compound that preserves the biological effectiveness of such a compound. Examples of solvates include the compounds of the invention in combination with water (hydrates), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or acetone. Also included are miscible solvate mixture compositions, such as a compound of the invention in combination with a mixture of acetone and methanol. In a preferred embodiment, the solvate comprises a compound of the invention in combination with a mixture containing about 20% ethanol and about 80% acetone. Thus, structural formulas include both hydrated and non-hydrated forms of a compound having the indicated structure.

The term "pharmaceutically acceptable prodrug", as applied to the compounds of the invention, refers to any pharmaceutically acceptable compound which, under physiological conditions or as a result of solvolysis, can be converted into the compound, into a pharmaceutically acceptable salt of such a compound, or into a compound that has at least part of the antibacterial activity of the specified compound (for example, is active against Clostridium difficile).

The term "pharmaceutically acceptable metabolite", as applied to the compounds of the invention, refers to a pharmaceutically active product resulting from the metabolism of a particular compound or its salt in the body.

Prodrugs and active metabolites of a compound of the invention can be identified using conventional techniques known in the art (see, for example, Bertolini et al., J. Med. Chem., 1997, 40, 2011-2016).

The term “pharmaceutically acceptable complex” as applied to compounds of the invention refers to compounds or compositions in which the compound of the invention forms part of a component. Thus, the complexes of the invention include derivatives in which the compound of the invention is physically bonded (e.g., by covalent or non-covalent binding) to another residue or residues. Thus, the term includes multidimensional compounds of the invention. Such multimers can be generated by linking or placing several copies (duplicates) of the compound of the invention in close proximity to each other (for example, via a bridge or the remainder of the medium).

The term "bioisostere" (or simply isostere) is a special term used in the prior art to refer to analogues of a drug in which one or more atoms (or groups of atoms) are replaced by atoms (or groups of atoms) having steric and / or electronic characteristics, similar to the characteristics of the atoms that they replace. Substitution of a hydrogen atom or a hydroxyl group with a fluorine atom is a frequently used bioisosteric substitution. Force substitution (C / Si exchange) is a relatively recent method for producing isosteres. Such an approach involves replacing one or more specific carbon atoms in a compound with silicon (for a review, see Tacke and Zilch (1986) Endeavor, New Series 10: 191-197). Force-substituted isosteres (silicon isosteres) can exhibit improved pharmacological properties, for example, they can be better tolerated by the patient, have a longer half-life, or exhibit increased activity (see, for example, Englebienne (2005) Med. Chem., 1 (3 ): 215-226). Similarly, replacing an atom with one of its isotopes, for example, replacing hydrogen with deuterium, can also lead to improved pharmacological properties, for example, to a longer half-life (see, for example, Kushner et al. (1999) Can J Physiol Pharmacol. 77 (2) : 79-88). In its broadest aspect, the present invention includes all bioisosteres (and, more specifically, all silicon bioisosteres) of the compounds of the invention.

In its broadest aspect, the present invention includes all optical isomers, racemic forms and diastereoisomers of the compounds described herein. Those skilled in the art are well aware that due to the presence of asymmetric carbon atoms in the compounds of the invention, these compounds can be prepared in optically active and racemic forms. If a compound of the present invention has a chiral center or other form of an isomeric center, it is understood that all forms of such an isomer or such isomers, including enantiomers and diastereoisomers, are encompassed by the present invention. Compounds of the invention containing a chiral center (or several chiral centers) can be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture can be separated using well-known methods, and individual isomers can be used individually. Thus, references to the compounds of the present invention include products as a mixture of diastereoisomers, individual diastereoisomers, a mixture of enantiomers, as well as individual enantiomers.

Thus, the present invention includes all optical isomers and their racemic forms of the compounds of the invention, and unless otherwise indicated (for example, by using structural formulas with the notation “dotted wedge”), it is intended that the compounds provided herein cover all possible optical isomers of compounds that fall under such an image. In cases where the stereochemical form of the compound is important for pharmaceutical use, the invention contemplates the use of an isolated eutomer.

As used herein, the term “alkyl” means a linear or branched saturated hydrocarbon chain. The term “C ₁ -C ₆ alkyl” refers to a linear or branched saturated hydrocarbon chain containing from one to six carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-hexyl. The term "C ₁ -C ₉ alkyl" refers to a linear or branched saturated hydrocarbon chain containing from one to nine carbon atoms. The term “C ₁ -C ₁₅ alkyl” refers to a linear or branched saturated hydrocarbon chain containing from one to fifteen carbon atoms. Alkyl groups of the invention may optionally be substituted with one or more halogen atoms.

The term “C ₁ -C ₄ alkyl” has the same meaning, except that it contains from one to four carbon atoms.

The term “C ₂ -C ₆ alkenyl” refers to a linear or branched hydrocarbon chain containing from two to six carbon atoms and at least one carbon-carbon double bond. Examples include ethenyl, 2-propenyl and 3-hexenyl.

The term “C ₁ -C ₆ haloalkyl” refers to a C ₁ -C ₆ alkyl group as defined above substituted with one or more halogen atoms.

As used herein, the term “alkenyl” means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. The term “C ₁ -C ₆ alkenyl” refers to a linear or branched unsaturated hydrocarbon chain containing from one to six carbon atoms. The term “C ₁ -C ₉ alkenyl” refers to a linear or branched unsaturated hydrocarbon chain containing from one to nine carbon atoms. The term “C ₁ -C ₁₅ alkenyl” refers to a linear or branched unsaturated hydrocarbon chain containing from one to fifteen carbon atoms. C ₁ -C ₆ alkenyl is preferred. Examples include ethenyl, 2-propenyl and 3-hexenyl. Alkenyl groups of the invention may optionally be substituted with one or more halogen atoms.

As used herein, the term “alkynyl” means a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. The term “C ₁ -C ₆ alkynyl” refers to a linear or branched unsaturated hydrocarbon chain containing from one to six carbon atoms. The term “C ₁ -C ₉ alkynyl” refers to a linear or branched unsaturated hydrocarbon chain containing from one to nine carbon atoms. The term “C ₁ -C ₁₅ alkynyl” refers to a linear or branched unsaturated hydrocarbon chain containing from one to fifteen carbon atoms. C ₁ -C ₆ alkynyl is preferred. Examples include ethynyl, 2-propynyl and 3-hexynyl. The alkynyl groups of the invention may optionally be substituted with one or more halogen atoms.

The term “heterocyclyl” means a saturated or partially saturated 3-14 membered ring system (except where other quantities of ring atoms are indicated) similar to cycloalkyl, but in which at least one of the carbon atoms is substituted with N, O, S, SO or SO ₂ . Examples include piperidine, piperazine, morpholine, tetrahydrofuran and pyrrolidine.

As used herein, the term “carbocyclyl” means a mono- or polycyclic residue containing 3 or more (eg 3-14, 3-10 or 3-8) carbon atoms. The carbocyclyl residues of the invention may optionally be substituted with one or more halogen atoms. Mono and bicyclic carbocyclyl residues are preferred. Carbocyclyl residues may be saturated or partially unsaturated and include, inter alia, fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and bridging systems such as norbornyl and adamantyl.

Saturated carbocyclyl radicals, which are referred to herein as “cycloalkyls”, are preferred, and the term “cycloalkyl” is used to mean a saturated 3-14 membered carbocyclic ring, including fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bridging systems such as norbornyl and adamantyl. The cycloalkyl radicals of the invention may optionally be substituted with one or more halogen atoms.

As used herein, the term “aryl” means a 5-14- (eg 5-10) membered aromatic mono-, bi- or tricyclic group, at least one ring of which is aromatic. So, bicyclic aryl groups can contain only one aromatic ring. Examples of aromatic moieties are benzene, naphthalene, imidazole and pyridine. The term also includes bicyclic or tricyclic systems in which one or more rings is aromatic. Indan is an example of this type of system.

As used herein, the term “heteroaryl” refers to aryl moieties (as defined above) that contain heteroatoms (eg, nitrogen, sulfur, and / or oxygen). The term also includes systems in which an aromatic ring is fused to a saturated or partially saturated ring. Examples include the ring systems of pyridine, pyrimidine, furan, thiophene, indole, isoindole, indoline, benzofuran, benzimidazole, benzimidazoline, quinoline, isoquinoline, tetrahydroisoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole indide. Unless otherwise indicated, it should be understood that the term “aryl” includes heteroaryl groups as defined above.

The aryl and heteroaryl groups of the invention may optionally be substituted with one or more halogen atoms.

As used herein, the term “halogen” refers to fluoro, chloro, bromo or iodo. In the general formulas of the compounds of the present invention (and, in particular, in the general formula (I), as described below), the order of bonds of these rings may vary when different possible heteroatoms imply specific requirements for the order of bonds in order to meet the aromaticity condition and prevent antiaromaticity and stabilize tautomeric forms due to localization. In such cases, an appropriate bond order in the ring structures in the structural formulas of the present invention is contemplated.

The term "symmetric" as applied to compounds of formula (I) may mean compounds in which the substituents R ¹ and R ^{2 are the} same.

The term "asymmetric" as applied to compounds of formula (I) may mean compounds in which the substituents R ¹ and R ^{2 are} different.

(2) Compounds of the invention

(2) Structures

Particularly preferred compounds of the general formula (I) are listed in Table 1 (below):

Table 1

Connection Name

Table 1 Connection number Connection Name one 2- (2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazol-2-yl) thieno [2,3-b] pyridine 2 2- (benzo [and] thiophen-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole 3 2- (benzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole four 6- (2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazol-2-yl) benzo [d] imidazole 5 2- (benzo [b] thiophen-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole 6 2- (1H-indol-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole 7 2- (2,3-dihydrobenzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole 8 2- (imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole 9 2- (benzo [d] [1,3] dioxol-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole

10 2- (benzofuran-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole eleven 2- (2 '- (pyridin-4-yl) -1H, 1'H- [5,5'-bibenzo [d] imidazole] -2-yl) thieno [2,3-c] pyridine 12 2- (imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-3-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole 13 2- (2 '- (pyridin-3-yl) -1H, 1'H- [5,5'-bibenzo [d] imidazole] -2-yl) thieno [2,3-b] pyridine

In each case, the invention includes pharmaceutically acceptable salts, hydrates, solvates, complexes, bioisosteres, metabolites or prodrugs of each of these compounds.

References to specific compound numbers refer to the numbers in table 1. Some of the compounds of general formula (I) are new. Thus, according to the invention, the invention includes those compounds of general formula (I) that are new, as compounds as such, together with methods for their preparation, compositions containing them, and their use as pharmaceuticals.

Thus, the invention includes a compound selected from:

2- (2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazol-2-yl) thieno [2,3-b] pyridine,

2- (benzo [b] thiophen-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (benzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

6- (2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [(1] imidazol-2-yl) benzo [(1] imidazole,

2- (benzo [b] thiophen-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [(1] imidazole,

2- (1H-indol-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [(1] imidazole,

2- (2,3-dihydrobenzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole,

2- (imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (benzo [d] [1,3] dioxol-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (benzofuran-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (2 '- (pyridin-4-yl) -1H, 1'H- [5,5'-bibenzo [d] imidazole] -2-yl) thieno [2,3-c] pyridine,

2- (imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-3-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (2 '- (pyridin-3-yl) -1H, 1'H- [5,5'-bibenzo [a] imidazole] -2-yl) thieno [2,3-b] pyridine, or its pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug, as well as compositions (eg, pharmaceutical compositions) containing these compounds.

(b) Function

(i) Effect on Clostridium difficile strains and selectivity for Clostridium difficile strains

Preferred compounds of the invention may be Clostridium difficile selective agents as defined hereinabove.

Particularly preferred Clostridium difficile selective agents exhibit bacteriostatic and / or bactericidal activity against one or more strains of C. difficile, but do not exhibit bacteriostatic and / or bactericidal activity (MIC> 64 μg / ml) against B.fragilis ATCC25285,

Even more preferred Clostridium difficile selective agents exhibit bacteriostatic and / or bactericidal activity against one or more strains of C. difficile, but do not exhibit bacteriostatic and / or bactericidal activity (MIC> 64 μg / ml) against both Bacteroides fragilis ATCC25285, and Escherichia coli ATCC25922.

Preferred compounds of the invention that are Clostridium difficile selective agents can thus be used to treat CDAD. At the same time, the existing intestinal flora is not disturbed to any significant degree from a clinical point of view. Thus, such compounds can be used as antimicrobial agents that do not cause antibiotic-associated diseases (as described herein) and / or the spread of antibiotic-resistant strains of intestinal pathogens.

Compounds of the invention that act as Clostridium difficile selective agents can be identified by determining the relative antibacterial activity of the compound against Clostridium difficile and one or more indicator organisms representative of the normal intestinal flora. Suitable indicator organisms for this purpose include: (a) Escherichia spp. (E.g. Escherichia coli); (b) Bacteroides spp. (e.g. B. fragilis); (c) Fusobacterium spp .; (d) Eubacterium spp. (e) Ruminococcus spp .; (f) Peptococcus spp .; (g) Peptostreptococcus spp .; (h) Bifidobacterium spp .; (i) Lactobacillus spp .; (j) Enterococcus spp. (e.g. E. faecium); (k) species of clostridia other than C. difficile (e.g. C. perfringens); (I) Enterobacter spp .; (m) Serratia spp .; (n) Klebsiella spp .; (o) Proteus spp .; (p) Pseudomonas spp. and (q) Veillonella spp.

Alternatively or additionally, the compounds of the invention acting as selective for Clostridium difficile agents can be identified by quantifying stool cultures for a series of stool samples obtained from subjects who have been given doses of the test compound. An in vitro variant of this approach is based on determining whether a test compound leads to significant changes in intestinal flora when incubated with diluted and filtered fecal samples in vitro. In this case, changes in the flora can be detected by determining the effect of the test compound on the relative number of bacteria - representatives of two or more of the following species: (a) Escherichia spp. (For example Escherichia colt); (b) Bacteroides spp. (e.g. B. fragilis); (c) Fusobacterium spp .; (d) Eubacterium spp. (e) Ruminococcus spp .; (f) Peptococcus spp .; (g) Peptostreptococcus spp .; (h) Bifidobacterium spp .; (i) Lactobacillus spp .; (j) Enterococcus spp. (e.g. E. faecium); (k) species of clostridia other than C. difficile (e.g. C. perfringens); (1) Enterobacter spp .; (m) Serratia spp .; (n) Klebsiella spp .; (o) Proteus spp .; (p) Pseudomonas spp. and (q) Veillonella spp.

Thus, the subject invention includes a selective against Clostridium difficile agent selected from:

2- (2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazol-2-yl) thieno [2,3-b] pyridine,

2- (benzo [b] thiophen-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (benzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

6- (2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazol-2-yl) benzo [d] imidazole,

2- (benzo [b] thiophen-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole,

2- (1H-indol-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole,

2- (2,3-dihydrobenzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole,

2- (imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (benzo [d] [1,3] dioxol-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (benzofuran-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (2 '- (pyridin-4-yl) -1H, 1'H- [5,5'-bibenzo [d] imidazole] -2-yl) thieno [2,3-c] pyridine,

2- (imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-3-yl) -1H, 1'H-5,5'-bibenzo [d] imidazole,

2- (24pyridin-3-yl) -1H, 1'H- [5,5'-bibenzo [d] imidazole] -2-yl) thieno [2,3-b] pyridine,

or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof.

(ii) Effect on spore germination

The compounds of the invention can inhibit or prevent spore germination.

Compounds that inhibit spore germination can be identified in vitro by detecting changes in refractive power, heat resistance, and staining of endospores: germinating endospores become a dark phase that is sensitive to heat and stained with some dyes.

(iii) Effect on spore overgrowth

The compounds of the invention can inhibit or prevent the growth of spores.

Spore overgrowth inhibiting compounds can be identified by in vitro microscopy of spore exposed to germination agents.

(iv) Bactericidal and / or bacteriostatic effect

The compounds of the invention may be bactericidal and / or bacteriostatic agents.

Bactericidal compounds are preferred as defined hereinabove. Such bactericidal compounds may also be bacteriostatic (for example, depending on the target bacteria and concentration).

III. Medical use

(a) Treatment of C. difficile infection

The compounds of the invention find use in the treatment of Clostridium difficile infection or diseases associated with Clostridium difficile.

Especially preferred is the treatment of diseases associated with Clostridium difficile (CDAD). This term refers to a set of symptoms and diseases associated with C. difficile infection or intoxication. CDAD includes diarrhea, bloating, flu-like symptoms, fever, loss of appetite, abdominal pain, nausea, dehydration, and inflammation of the intestines (colitis). The most serious manifestation of CDAD is pseudomembranous colitis (PMC), which is detected histologically by colitis with mucous plaques and clinically by severe diarrhea, abdominal colic and general toxicity.

The compounds of the invention find use in the treatment of all forms of CDAD, including diarrhea, bloating, flu-like symptoms, fever, loss of appetite, abdominal pain, nausea, dehydration, colitis and pseudomembranous colitis.

The invention also finds use in the treatment of intoxication with clostridial exotoxins, including the toxin A (TcdA), toxin B (TcdB) and / or the binary CDT toxin produced by the bacterium Clostridium difficile. Thus, the compounds of the invention find use in the treatment of diseases caused (or aggravated) by the presence of Clostridium difficile-produced toxin A (TcdA), toxin B (TcdB) and / or binary CDT toxin.

(b) Treatment of antibiotic-associated diseases

The term “antibiotic-associated disease” refers to conditions arising from changes in the relative amounts of microorganisms that make up the normal intestinal flora, caused by (partial) destruction of the flora as a result of antibiotic administration. Such diseases occur when the administration of antibiotics (in particular broad-spectrum antibiotics) makes possible the growth of pathogenic organisms (due to excessive growth from endogenous populations, usually restrained by normal intestinal flora, or due to the formation of colonies of opportunistic microorganisms in places devoid of normal intestinal flora by the action of antibiotics).

Antibiotic-associated diseases usually manifest as diarrhea (and its associated dehydration), abdominal cramps, tenesmus, and fever. They can also lead to various forms of colitis, including pseudomembranous colitis (PMC). Thus, antibiotic-associated disease includes antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAS).

Antibiotic-associated disease is often caused by toxin-producing strains of Clostridium difficile, Staphylococcus aureus (including the methicillin-resistant strain of S. aureus) and Clostridium perfringens. The bacterium Clostridium difficile is the most common cause of nosocomial AAD and causes most cases of AAS. The bacteria multiplies in the colon of patients who have received broad-spectrum antibiotics or anti-cancer chemotherapy.

Thus, the compounds of the invention find use in the treatment of antibiotic-associated diseases, including AAD and AAS. Particularly preferred for such use are the selective compounds of the invention (as described above), since such compounds do not substantially harm the normal intestinal flora.

The compounds of the invention find use in the prevention of an antibiotic-associated disease, including AAD and AAS. With this use, the compounds of the invention can be administered in conjunction with other antibiotics or treatments that can cause changes in the relative amounts of microorganisms that make up the normal intestinal flora.

Thus, the compounds of the invention can be used to treat subjects who have been treated (or treated) with broad-spectrum antibiotics.

(c) Treatment of colitis, pseudomembranous colitis and diarrhea

As indicated above, colitis, pseudomembranous colitis (PMC) and diarrhea imply the presence of bacteria selected from Clostridium difficile, Staphylococcus aureus and Clostridium perfringens.

Accordingly, the compounds of the invention find use in the treatment of colitis, pseudomembranous colitis (PMC) or diarrhea.

Especially preferred is the treatment of pseudomembranous colitis.

IV. Additional substances for use in the combinations according to the invention

(a) General information

In addition to the compounds of the invention, the invention also provides for the use of one or more of the following additional substances as additional components of the invention.

Thus, the invention relates to compositions comprising compounds of the invention in combination with one or more substances selected from the substances described below.

(b) Antiviral supplements

The combinations preferably further comprise one or more auxiliary antiviral agents. Such antiviral adjuvants may be selected from one or more of: (a) viral enzyme inhibitors (for example, selected from (i) protease inhibitors, (ii) helicase inhibitors and (iii) polymerase inhibitors); (b) nucleoside / nucleotide reverse transcriptase inhibitors; (c) non-nucleoside reverse transcriptase inhibitors; (d) integrase inhibitors; (e) maturation inhibitors; (f) cytokines or cytokine stimulating factors; (g) inhibitors of the entry of the virus into the cell, for example selected from: (i) an addition inhibitor; (ii) a coreceptor binding inhibitor;

and (iii) a membrane fusion inhibitor.

(c) Antibacterial supplements

The compounds of the invention can be used in combination with distinguished antibacterial agents, including (but not limited to only one) one or more antibiotics selected from the following:

- Aminoglycosides (e.g. amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin and paromomycin).

- Ansamycins (e.g. geldanamycin and herbimycin).

- Carbacephemes (e.g. loracarbef).

- Carbapenems (e.g. ertapenem, doripenem, imipenem / cilastatin and meropenem).

- Cephalosporins (first generation), including, for example, cefadroxil, cefazolin, cefazolin, cephalotin / cephalosin and cephalexin.

- Cephalosporins (second generation), including, for example, cefaclor, cefamandol, cefoxitin, cefprosil and cefuroxime.

- Cephalosporins (third generation), including, for example, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftisoxime, ceftriaxone and cefdinir.

- Cephalosporins (fourth generation), including, for example, cefepime.

- Glycopeptides (e.g. vancomycin and teicoplanin).

- Macrolides (e.g. azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin and spectinomycin).

- Monobactams (e.g. aztreonam).

- Penicillins (e.g. amoxicillin, ampicillin, azlocillin, carbencillin, cloxacillin, dicloxacillin, flucloxacillin, meslocillin, nafcillin, penicillin, piperacillin and ticarcillin).

- Polypeptides (e.g. bacitracin, polymyxin B and colistin).

- Quinolones (e.g. ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin and trovafloxacin).

- Sulfonamides (e.g. mafenide, pronosyl, sulfacetamide, sulfamethisol, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (co-trimoxazole, TMP-SMX)).

- Tetracyclines (e.g. demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline).

- Aminocoumarins (e.g. novobiocin, albamycin, cumericin and chlorobiocin).

- Oxazolidinones (e.g. linezolid and AZD2563).

- Lipopeptides (e.g. daptomycin).

- Streptogramins (e.g. quinupristine / dalphopristine).

- Glycyl cyclins (e.g. tigecycline).

- Lantibiotics (for example, type A lantibiotics (such as nisin, subtilin, epidermine, mutacin II, mutations I & III) and type B lantibiotics (such as mersacidin, actagardine and cinnamycin).

Other suitable antibiotics useful as additional agents include one or more antibiotics selected from the following: arsphenamine, chloramphenicol, clindamycin, linkoamycin, ethambutol, fosfomycin, fusidovoy acid, furazolidone, isoniazid, linezolid, metronidazole, mupiridinicin, pyramidinocin quinupristine / dalphopristine, rifampin / rifampicin and tinisadol.

Thus, the compounds of the invention can be used in combination with one or more antibiotics selected from: penicillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, capreomycin, cycloserine, azlocillin, carbenicillin, carbenicillin ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, ethambutol, ethionamide, minocycline, oxytetracycline, tetracycline, quinolone, c inoxacin, nalidixic acid, fluoroquinolones (e.g. levofloxacin, moxafloxacin and gatifloxacin, ciproloxacin, enoxacin, grefafloxacin), kanamycin, levofloxacin, lomefloxacinacin, amoxloxacinacin, aminoxylacinacin, -sulfamethoxazole, co-amoxiclav, cephalotin, cefuroxime, ceftriaxone, vancomycin, gentamicin, amikacin, metronidazole, chloramphenicol, streptomycin, nitrofurantoin, co-trimoxazole , rifamycin and their derivatives (e.g. rifampicin, rifabutin and rifapentin), isoniazid, pyrazinamide, kirromycin, thiostrepton, micrococin, fusidic acid, thiolactomycin and fosmidomycin.

Other suitable antibacterial supplements may be selected from the agents listed in the table below:

Compound Class DU-6859 Fluoroquinolone Erythromycin stinoprat Macrolide Oritavancin Glycopeptide Telavancin Glycopeptide Dalbavancin Glycopeptide Ceftobiprol Medocaril Cephalosporin Tebipenem pivoxil Carbapenem Iclaprim DHFR ORT-80 Diphimycin Ceftaroline fosamil Cephalosporin RX-3341 Fluoroquinolone Cetromycin Ketolide TD-1792 Dimer glycopeptide-β-lactam

EDP-420 Macrolide Rx-1741 Oxazolidinone MK-2764 Glycycline Nemonoxacin Fluoroquinolone Flopristine + Linopristine Streptogramin Topopenem Carbapenem Ramoplanin Glycolipodepsypeptide Linezolid Oxazolidinone Cefditoren pivoxil Cephalosporin Ertapenem Carbapenem Hemifloxacin Fluoroquinolone Daptomycin Lipopetid Telithromycin Lipopetid Tigecilin Glycycline

(d) Antifungal supplements

The compounds of the invention can be used in combination with various antifungal agents (antimycotics).

(e) Antiprotozoal supplements

The compounds of the invention can be used in combination with various antiprotozoal agents, including chloroquine, doxycycline, mefloquine, metronidazole, eplornithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofantrin, primaquine, pyriminidicinamicinoxidine, pyriminidicinamicinoxidine, pyriminidicinamicinoxidine, pyriminidicinamicinoxidine, pyriminidinamine sulfadicinamicinoxidine, sulfimenicidinamine sulfadicinamicinoxidine, pyriminidicinamicinoxidine, pyriminidicinamicinoxidine, gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibog luconate, pentamidine isethionate, trimethoprim-sulfamethoxazole, pyrimethamine and sulfadiazine, but not limited to.

(f) Other additional funds

The compounds of the invention can be administered together with a variety of other combination therapy agents that treat or prevent side effects resulting from the treatment of infections and / or representing the consequences (complications) of an infection. Additional agents of this type may or may not have anti-infective activity and include, for example, PPI and H2RA (as described above).

Thus, the compounds of the invention can be additionally used together with PPI, including omeprazole (elk, clot, zegeride), lansoprazole (prevacide, zotone, inhibitol), esomeprazole (nexium), pantoprazole (protonix, somak, pantolok, pantozol, zurkal, pan) and rabeprazole (rabecid, asifex, soars, rabelok), but not limited to them.

The compounds of the invention may also be additionally used with, but not limited to, but not limited to, H2RA antagonists including cimetidine (tagamet), ranitidine (zinetak, zantak), famotidine (peptidin, peptcid), roxatidine (roxit), and nizatidine (tazac, axide).

The compounds of the invention can also be additionally used in triple therapy with proton pump inhibitors (PPIs) or H2RA antagonists together with a combination of two antibiotics (including but not limited to antibiotics selected from metronidazole, amoxicillin, levofloxacin and clarithromycin).

Various probiotics may be used as additional agents, including, for example, Saccharomyces boulardii or Lactobacillus acidophilus cells. Probiotics are monocultures or mixed cultures of living microorganisms that contribute to the restoration of the patient’s natural intestinal microflora impaired by the antimicrobial agent that induces CDAD, or even the agent used to treat CDAD. In addition, such microorganisms can stimulate the patient's immune system and cause the production of enzymes that destroy the toxins associated with C. difficile. Specific microorganisms of interest are Saccharomyces spp. ("For example, Saccharomyces boulardii and Saccharomyces cerevisiae) and Lactobacillus spp. For example Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillum, not limited to, but not limited to Lactobacobus bulgarus bulgarumus. any other traditional probiotic composition or microorganism that is a normal element of the human gastrointestinal tract.

Also, prebiotics can be used as additional substances - drugs aimed at stimulating the growth of the intestinal flora. For example, it has been shown that the use of oligofructose increases the content of Bifidobacterium spp. and reduces the frequency of subsequent relapses in patients. For this reason, the introduction of any antibacterial agent with a narrow spectrum of activity against Clostridium species in combination with therapy aimed at restoring a normal population of intestinal microorganisms can provide significant advantages.

Other approaches aimed at restoring normal intestinal flora include fecal biotherapy and fecal enemas prepared from the stool of healthy individuals that contain normal intestinal microorganisms. Thus, fecal bacteriotherapy can also be additionally used with the compounds of the invention.

In order to block the effect of toxins produced by C. difficile, absorbents that bind and isolate various types of bacteriotoxins can be used as additional agents. Ion exchange resins, such as bile acid sequestrants, cholestyramine or colestipol, bind to C. difficile cytotoxins and thus lead to a decrease in the degree of intestinal infection with toxins. However, ion-exchange resins are also known to bind to drugs, such as vancomycin, and, therefore, can lead to insufficient levels of the antibacterial agent at the site of infection. Other absorbents that can be further used with the compounds of the invention include polymers such as Synsorb 90 and Tolevamer.

Although it is believed that probiotic therapy improves the immune system response in patients with CDAD, for the treatment of such patients, especially in cases of relapse, when any further antimicrobial treatment will further increase intestinal flora disturbances, for example, intravenous administration of immunoglobulin (J. Antimicrob Chem., 2004, 53, 882-884). Thus, the compounds of the invention can be further used in conjunction with various immunoglobulins.

Although CDAD patients generally avoid the use of diarrhea-reducing medications, in some cases it can be suggested that the use of such agents in combination with antibacterial agents may be useful, for example, when trying to increase antimicrobial levels at the site of infection and / or increase the duration of contact of the antibacterial agent with the intestinal pathogen. Such agents may include loperamide (lopex, imodium, dimor, pepto), diphenoxylate (lomotil, co-phenotrop), diphenoxin (motofen), and racecadotril, but are not limited to them. Thus, the compounds of the invention can be additionally used together with various antidiarrheal agents, including any of the preparations listed above.

Combination therapy agents that treat or prevent any of the following side effects can be used as part of the same course of treatment as the compounds of the invention: (a) lipodystrophy and wasting disease; (b) lipoatrophy of the face;

(c) hyperlipidemia; (d) fatigue; (e) anemia; (f) peripheral neuropathy; (g) nausea; (h) diarrhea; (i) hepatotoxicity; (j) osteopenia; (k) dehydration; and (1) osteoporosis.

Said treatment or prophylaxis may include administering a compound as defined above as an additional agent to one or more of the following treatments or interventions:

(a) cancer therapy;

(b) AIDS therapy;

(c) an immune suppressing intervention;

(d) patient management after graft / implant transplantation;

(e) surgery for fungal infection of the nail or wound cleansing;

(f) topical antifungal therapy (e.g., an antimycotic selected from azoles, allylamines (e.g., terbinafine) or morpholine (e.g., amorolfine);

(g) systemic antifungal therapy;

(h) antibiotic therapy;

(i) antiviral therapy;

(j) anti-inflammatory therapy (e.g., steroids);

(k) administration of analgesics;

(l) administration of antipruritic drugs;

(m) administration of probiotics;

(n) fecal bacteriotherapy; or

(o) skin transplantation.

Thus, the invention may include the treatment or prophylaxis of a group of patients with whom one or more types of treatment or intervention are listed (a) to (o).

(g) Additional treatments

Treatment or prophylaxis may include administering such a compound as defined above as an adjunct to one or more of the following treatments or interventions:

1. Therapy of cancer;

2. Types of intervention, suppressing the immune system;

3. Types of intervention that stimulate the immune system;

4. Patient management after graft / implant transplantation;

5. Surgery of fungal infection of the nail or wound cleansing;

6. Anti-inflammatory therapy (eg, steroids);

7. Introduction of analgesics;

8. The introduction of antipruritic drugs;

9. Surgery;

10. Ablation of cells or tissues;

11. Radiotherapy;

12. Cryotherapy;

13. Therapy with fecal transplantation (fecal bacteriotherapy);

14. Therapy with probiotics; or

15. Skin transplantation.

Thus, the invention may include the treatment or prophylaxis of a group of patients with whom one or more types of treatment or intervention are performed (or have been) from (1) to (15).

(V) Posology

The compounds of the present invention can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, aerosol (via the airways), rectal, vaginal and topical (including buccal and sublingual) administration.

The amount of compound administered can vary widely in accordance with the particular dosage unit used, the duration of treatment, the age and sex of the patient in need of treatment, the nature and stage of the disease, and the particular compound selected.

Typically, an effective amount of a compound administered is in the range of about 0.01 mg / kg to 10,000 mg / kg per day. A unit dosage unit may contain from 0.05 to 500 mg of the compound, and can be taken once or several times a day. The compound can be administered with a pharmaceutical carrier using the usual standard dosage forms orally, parenterally or topically, as described below.

The preferred route of administration is oral. Usually a suitable dosage is from 0.01 to 500 mg per kilogram of body weight of the recipient per day, preferably from 0.1 to 1000 mg per kilogram of body weight per day, and most preferably from 1 to 5 mg per kilogram of body weight per day.

The desired dose is preferably in the form of a single dose for daily administration. However, you can also use two, three, four, five or six, or more parts of the dose, administered at appropriate time intervals during the day. The indicated parts of the dose can be administered in unit dosage forms containing 0.001-100 mg, preferably 0.01-10 mg, and most preferably 0.5-1.0 mg of the active ingredient per unit dosage.

In determining the effective amount or dose, the attending physician considers a number of factors, including (but not limited to only this) the activity and duration of action of the compounds used, the nature and severity of the disease to be treated, as well as gender, age, body weight, general health and individual response the reaction of the patient in need of treatment, and other relevant circumstances. Those skilled in the art will recognize that dosages can also be determined using Goodman & Goldman, The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.

The amount of compound that can be combined with carrier materials to form a monolithic dosage form varies depending on the subject in need of treatment and the particular route of administration. For example, a preparation intended for oral administration to humans may contain from about 0.5 mg to about 7 g of active substance, optionally with an appropriate suitable amount of carrier substance, which may vary from about 5 to about 95 percent of the total composition. Unit dosage units of a compound of the invention typically contain from about 1 mg to about 500 mg of the active ingredient, for example 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The effectiveness of a particular dosage of a compound of the invention can be determined by monitoring the effect of a given dosage on disease progression or prophylaxis.

(VI) Drugs

The compound of the invention may take any form. It can be synthetic, purified or isolated from natural sources using methods described in the art.

Typical pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, dairy, apple, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, asparaginic, glutamic, benzoic, aminobenzoic, methylbenzoic, i-hydroxybenzoic, phenylacetic, almond, embonic (pamoy), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexyl minosulfonic, alginic, (3-hydroxybutyric, galactaric and galacturonic acids.

Suitable pharmaceutically acceptable addition salts include metal ion salts and organic ion salts. Metal ion salts include, but are not limited to, the corresponding alkali metal salts (group Ia), alkaline earth metal salts (group IIa), and other physiologically acceptable metal ions. Such salts can be obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc ions. Organic salts can be obtained from tertiary amines and quaternary ammonium salts, including in particular trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts may be prepared by those skilled in the art by conventional methods from the corresponding compounds.

Pharmaceutical compositions may include stabilizers, antioxidants, colorants and diluents. Pharmaceutically acceptable carriers and additives are selected so as to minimize the side effects of the pharmaceutical compound and not to alter the characteristics of the compound to such an extent that the treatment becomes ineffective.

Pharmaceutical compositions may be administered enterally and / or parenterally. The oral (intragastric) route is a typical route of administration. Pharmaceutically acceptable carriers can be in solid dosage forms, including tablets, capsules, pills and granules, which can be obtained with coated coatings and membranes, such as intersolubility coatings and others known in the art. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.

Parenteral administration includes subcutaneous, intramuscular, intradermal, intravenous and other routes of administration known in the art. Forms for enteral administration include solutions, tablets, sustained release capsules, enteric coated capsules, and syrups.

When administered, the pharmaceutical composition may have a body temperature or close to it.

Compositions intended for oral use may be prepared by any of the methods known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more substances selected from the group consisting of sweeteners, flavoring and aromatic substances, dyes and preservatives, in order to obtain pleasant-looking and taste pharmaceutical preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. Said excipients can, for example, be inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example corn starch or alginic acid, binding agents, for example starch, gelatin or gum, and glidants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods, for example, in order to slow down their destruction of the gastrointestinal tract and thereby provide a prolonged action over a long period of time. For example, delayed action substances such as glyceryl monostearate or glyceryl distearate can be used.

Oral formulations may be hard gelatin capsules in which the active ingredients are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin; or soft gelatin capsules in which the active ingredients are pure or mixed with water or an oil medium, for example with peanut butter, liquid paraffin or olive oil.

Aqueous suspensions may be prepared which contain the active substances in admixture with excipients suitable for preparing aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabian gum; dispersing agents or wetting enhancing agents may be natural phosphatides, for example lecithin, or condensation products of alkylene oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylenoxycetanol condensation products or non-ethylene oxide condensation products derivatives of fatty acids and hexitol, such as, for example, polyoxyethylene sorbitan monooleate, or ethylene oxide condensation products with partial esters - derivatives of hexitol anhydrides and fatty acids, for example polyoxyethylene sorbitan monooleate.

Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl-n-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin .

Oily suspensions may be prepared by suspending the active ingredient in omega-3 fatty acid, vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as paraffin oil. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

Sweeteners, such as those presented above, and flavoring agents may be added to provide a palatable oral preparation. Such compositions can be stored by adding an antioxidant, such as ascorbic acid.

In dispersible powders and granules suitable for the manufacture of an aqueous suspension by adding water, the active ingredient is mixed with a dispersing agent or a wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Additional excipients, for example, sweeteners, flavoring and coloring agents, may also be used.

Syrups and elixirs containing the compound of the invention can be made using sweeteners, for example glycerol, sorbitol or sucrose. Such preparations may also contain irritating agents, preservatives, taste and aroma enhancers, and coloring agents.

The compound of the invention can be administered parenterally, for example subcutaneously, intravenously or intramuscularly, or by infusion methods in the form of sterile injectable aqueous or oily suspensions. Such suspensions may be prepared by methods known to those skilled in the art using suitable dispersing or wetting agents and suspending agents as mentioned above, as well as other suitable agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. For this purpose, you can use any light non-volatile oil, including synthetic mono - or diglycerides. In addition, omega-3 polyunsaturated fatty acids are used to make injection preparations.

The administration of drugs can also be carried out by inhalation, using preparations in the form of aerosols or solutions for nebulizers, or rectally, using preparations in the form of suppositories, obtained by mixing the drug with a suitable non-irritating excipient, which is a solid at ordinary temperature, but becomes liquid at rectal temperature and therefore melts in the rectum, releasing the medicine. Such substances are cocoa butter and polyethylene glycols.

The present invention also encompasses buccal and sublingual administration, which include administration of lozenges, lozenges or chewing gum preparations containing the compounds of the invention described herein. The compounds can be applied to a taste base, usually sucrose and acacia gum or tragacanth.

Other methods of administering the compounds of the invention include the use of skin patches that release drugs directly onto the skin and / or through the skin of a subject.

Topical systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, lotions, solutions or suspensions.

The compositions of the present invention can be supplemented with auxiliary substances, such as thickeners, preservatives, surfactants and substances that promote absorption. Thickeners include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other substances known to those skilled in the art. Such substances are usually used in amounts ranging from about 0.01% to about 2% (mass) of the weight of the pharmaceutical composition.

Preservatives are optionally used to prevent microbial growth before or during application of the compositions. Suitable preservatives include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, EDTA disodium salt, sorbic acid and other substances known to those skilled in the art. Typically, such preservatives are used in amounts ranging from about 0.001% to about 1.0% (mass) of the weight of the pharmaceutical composition.

The solubility of the components of the compositions of the present invention can be increased using surface-active substances (surfactants) or a suitable co-solvent in the composition. Such cosolvents include polysorbates 20, 60, and 80, polyoxyethylene / polyoxypropylene based surfactants (e.g., Pluromc F-68, F-84, and P-103), cyclodextrin, or other materials known to those skilled in the art. Typically, such cosolvents are used in an amount of from about 0.01% to about 2% (mass) of the pharmaceutical composition.

Pharmaceutically acceptable excipients and carriers include all of the above and the like. The above considerations regarding effective formulations and methods of administration are well known in the art and are described in general manuals. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott, Williams and Wilkins), 2000; Lieberman et al., Ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980) and Kihbe et al., Ed .. Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).

Thus, in those embodiments where a pharmaceutically acceptable excipient is formulated from a compound of the invention, any suitable excipient may be used, including, for example, inert diluents, disintegrants, binders, glidants, sweeteners, substances giving flavor and aroma, coloring matter and preservatives. Suitable inert diluents include sodium and calcium carbonates, sodium and calcium phosphates and lactose, and corn starch and alginic acid are suitable disintegrants. Binding agents may include starch and gelatin, while glidants, if present, are usually magnesium stearate, stearic acid or talc. The pharmaceutical compositions may take any suitable form, including, for example, tablets, elixirs, capsules, solutions, suspensions, powders, granules, nail polishes, varnishes and veneers, skin patches and sprays.

The pharmaceutical composition may be in the form of a kit of several components, the kit may contain the composition of the invention together with instructions for use and / or several different components in a standard unit dose.

For oral administration, the compound of the invention can be formulated in solid or liquid preparations, such as capsules, pills, tablets, lozenges, lozenges, melts, powders, granules, solutions, suspensions, dispersions and emulsions (these solutions, suspensions, dispersions and emulsions can be either aqueous or non-aqueous). Solid unit dosage forms may be in the form of a capsule, which is usually a gelatin-type hard or soft shell capsule containing, for example, surfactants, glidants, and inert fillers such as lactose, sucrose, calcium phosphate and corn starch. Oral tablets may include a compound of the invention, in pure form or with pharmaceutically acceptable excipients, such as inert diluents, disintegrants, binders, glidants, sweeteners, flavor and aroma agents, and preservatives. Suitable inert diluents include sodium and calcium carbonates, sodium and calcium phosphates and lactose, while corn starch and alginic acid are suitable disintegrants. Binders may include starch and gelatin, while glidants, if present, are usually magnesium stearate, stearic acid or talc. If desired, tablets may be coated with a substance, such as, for example, glyceryl monostearate or glyceryl distearate, which slows down absorption in the gastrointestinal tract. Capsules for oral administration include hard gelatin capsules in which the compound of the invention is mixed with a solid diluent, and soft gelatin capsules in which the active ingredient is mixed with water or oil such as peanut oil, paraffin oil or olive oil.

Formulations for rectal administration may be suppositories with a suitable base, for example coconut oil or salicylate. Preparations suitable for vaginal administration can be made in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, also suitable carriers known in the art.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention are generally provided in sterile aqueous solutions or suspensions buffered to the appropriate pH and isotonicity.

Suitable aqueous vehicles include Ringer's solution, isotonic sodium chloride solution. Aqueous suspensions of the invention may include suspending agents, such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and tragacanth gum and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl-n-hydroxybenzoate.

The compounds of the invention may also be presented as liposome compositions.

In yet another embodiment, the compounds of the invention are formed into tablets using conventional tablet bases such as lactose, sucrose and corn starch, in combination with binders such as acacia gum, corn starch or gelatin; disintegrants which are intended to facilitate disintegration and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch and guar gum; glidants to improve the flowability of the granulate during tabletting and to prevent the tabletting material from sticking to the surfaces of the molds and punch, such as, for example, talc, stearic acid or magnesium, calcium or zinc stearates; dyes, colorants and substances that add taste and aroma, to improve the aesthetic qualities of tablets and in order to make tablets more pleasant for the patient.

Suitable excipients for use in liquid oral dosage forms include diluents such as water and alcohols, for example ethanol, benzyl alcohol and polyethylene alcohols, with or without a pharmaceutically acceptable surfactant, suspending or emulsifying agent.

The compounds of the invention may also be administered parenterally, i.e., subcutaneously, intravenously, intramuscularly or intraperitoneally. In such embodiments, the compound is used in the form of doses for injection in a physiologically acceptable diluent with a pharmaceutically acceptable carrier (which may be a sterile liquid or mixture of liquids). Suitable liquids include water, saline, aqueous glucose and related compounds solutions, alcohol (such as ethanol, isopropanol or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketals (such as 2,2-dimethyl-1, 3-dioxolane-4-methanol), ethers (such as poly (ethylene glycol) 400), oil, fatty acid, ester or fatty acid glyceride or acetylated fatty acid glyceride with the addition of a pharmaceutically acceptable surfactant (such ak soap or a detergent), suspending agent (such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose), or emulsifying agent and other pharmaceutically acceptable adjuvants or without it.

Suitable oils that can be used in the parenteral compositions of the present invention are oils of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil and mineral oil.

Suitable fatty acids include oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal salts of ammonium and triethanolamine and fatty acids, and suitable detergents include cationic detergents, for example dimethyldialkylammonium halides, alkyl pyridinium halides and alkylamines acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates; alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides and polyoxyethylene polypropylene copolymers; and amphoteric detergents, for example, alkyl-β-aminopropionates and quaternary ammonium salts of 2-alkylimidazoline, as well as mixtures thereof.

Compositions of the present invention for parenteral administration usually contain from about 0.5 to about 25% (mass) of the compounds of the invention in solution. Preservatives and buffers may also be used. In order to minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) from about 12 to about 17. The amount of surfactant in such compositions varies from about 5 to about 15% ( masses). The surfactant may be a single component having the above HLB, or may be a mixture of two or more components having the desired HLB. Typical surfactants used in preparations for parenteral administration are representatives of the class of esters of fatty acids and polyethylene sorbitol, for example sorbitol monolaurate, and high molecular weight ethylene oxide adducts with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The compounds of the invention may also be administered topically, and upon such administration, the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may contain one or more of the following substances: petrolatum lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Preparations for topical administration may contain a compound of the invention in a concentration of from about 0.1 to about 10% w / v, (weight per unit volume).

When used as an additional component, the compounds of the invention can be prepared for use with one or more other drugs. In particular, the compounds of the invention can be used in combination with analgesics, anti-inflammatory drugs (e.g., steroids), immunomodulators and antispasmodics.

Thus, the additional use can be reflected in a specific dosage form, developed for compatibility (or to obtain a synergistic effect) with other drug (s) (s), or in preparations in which the compound is mixed with one or more anti-inflammatory agents, cytokines or immunosuppressants (or in which it is physically associated with other (s) drug (s) in the unit dose). Additional uses may also be reflected in the pharmaceutical kits of the invention in which the compound of the invention is packaged together (for example, as part of a unit dose kit) with antimicrobial and / or anti-inflammatory agents. Additional use may also be described in information and / or instructions relating to the co-administration of a compound with antimicrobial and / or anti-inflammatory agents.

(Vii) Examples

Below the invention will be described with reference to specific examples. They play an illustrative role only: it is understood that the examples in no way limit the scope of the requested exclusive rights or the scope of the described invention. The mentioned examples represent the best currently known embodiment of the invention in practice.

HPLC-UV-MS was performed on a Gilson 321 instrument with detection using a Gilson 170 DAD detector and on a Finnigan AQA mass spectrometer with electrospray ionization. An HPLC column using a Phenomenex Gemini C18 (150 × 4.6 mm) or a Phenomenex Gemini C18 50 x 4.6 mm 3µ column was used. Preparative HPLC was performed on a Gilson 321 instrument with detection of Gilson 170 DAD. Fractions are isolated using a fraction collector "Gilson 215". A Phenomenex Gemini C18 Preparative HPLC column (150 × 10 mm) and a mobile acetonitrile / water phase were used.

¹ H NMR spectra were recorded on a Bruker instrument with an operating frequency of 300 MHz. NMR spectra were obtained for solutions in CDCl ₃ , CD ₃ OD or DMSO-d ₆ (indicated in ppm) using chloroform (7.26 ppm), methanol (3.35 ppm) or DMSO-d ₆ (2.50 ppm). When describing the multiplicity of peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), ush. (expanded), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), obsc. (“Blurry”), arr. (apparent). The interaction constants are given in hertz (Hz).

Column chromatography is carried out either by flash chromatography (silica gel, 40-65 μm) or by using an automated purification system (Biotage® SP1 ™ purification system or ISCO CombiFlash Companion system). Reactions using microwave radiation are carried out in the Initiator 8 ™ reactor (Biotage) or in the Explorer 48 system (CEM).

The following abbreviations are used: DMSO (dimethyl sulfoxide), DMF (dimethylformamide), IMS (industrial denatured alcohols), IPA (isopropyl alcohol), TLC (thin layer chromatography), Boc (trit-butyloxycarbonyl), RT (retention time), DCM (dichloromethane) , TFA (trifluoroacetic acid), LC-MS (liquid chromatography-mass spectrometry), NMR (nuclear magnetic resonance), DME (1,2-dimethoxyethane).

MICs are determined by micro-dilution in liquid culture media in accordance with the CLSI protocols described in Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Seventh Edition [Ml 1-A7, Vol.27, No2, Jan 2007] and Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Seventh Edition [M7-A7, Vol. 26, No. 2, Jan 2006].

Example 1. Obtaining compounds of General formula (I) Method 1

4- (2- (Pyridin-4-yl) -1H-benzo [(1] imidazol-5-yl) benzene-1,2-diamine (Intermediate A)

Sodium metabisulfite is added to a stirred solution of 3,3'-diaminobenzidine (3.857 g, 18 mmol) and 4-pyridinecarboxaldehyde (1.41 ml, 15 mmol) in IPA (22.5 ml) and H ₂ O (7.5 ml) (2.852 g, 15 mmol). The suspension is heated and boiled for 16 hours. The resulting yellow suspension was poured into water (200 ml) and the precipitate was filtered off. The yellow solid was triturated in hot methanol and filtered to give intermediate A as an insoluble precipitate (1.672 g, 5.5 mmol, 37%).

LC-MS: RT = 1.05 min, MH ⁺ 302.1; ¹ H NMR (d ₆ -DMSO): 13.17 (1H, br s), 8.76 (2H, d, J-6.0), 8.09 (2H, d, J = 6.0) 7.64 (2H, br s), 7.42 (1H, d, J = 8.4), 6.91 (1H, d, J = 1.9), 6.77 (1H, dd, 7 = 8.0 and 1.9), 6.60 (1H, d, J = 8.0) and 4.58 (4H, br.s).

4- (2- (pyridin-3-yl) -1H-benzo [(1] imidazol-5-yl) benzene-1,2-diamine (Intermediate B)

To a stirred solution of 3,3'-diaminobenzidine (5.00 g, 23.36 mmol) and 3-pyridinecarboxaldehyde (1.98 ml, 21.02 mmol) in IPA (16 ml) and H ₂ O (16 ml) sodium metabisulfite (4.44 g, 23.36 mmol). The suspension is heated to 160 ° C in a microwave system (CEM), then cooled to room temperature. The resulting yellow suspension was poured into water (150 ml), the precipitate was filtered off and dried. The solid was purified by silica gel column chromatography eluting with pure EtOAc to 9: 1 (EtOAc-MeOH) to give intermediate B as a yellow solid (3.92 g, 13.03 mmol, 62%).

LC-MS: RT = 1.44 min, MH ⁺ 302.3; ¹ H NMR (d ₆ -DMSO): 13.05 (1H, br.s), 9.37 (1H, d, J = 2.0), 8.69 (1H, dd, J = 4.7 and 1.5), 8.51 (1H, dt, J = 8.1 and 1.9), 7.70-7.58 (3H, m), 7.41 (1H, dd, J = 8.5 and 1.5), 6.93 (1H, d, Y-2.0), 6.79 (1H, dd, J = 8.0 and 2.0), 6.62 (1H, d, J = 8.0) and 4.58 (4H, br s).

2- (2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [(1] imidazol-2-yl) thieno [2,3-b] pyridine (Compound 1)

A mixture of 4- (2- (pyridin-4-yl) -1H-benzo [d] imidazol-5-yl) benzene-1,2-diamine (intermediate A) (50 mg, 0.17 mmol), thieno [ 2,3-b] pyridin-2-carbaldehyde (33 mg, 0.20 mmol) and Na ₂ S ₂ O ₅ (38 mg, 0.20 mmol) in IPA-H ₂ O (3: 1, 8 ml) heated under microwave at 170 ° C for 10 minutes The mixture was absorbed on silica gel, purified by column chromatography, eluted (from 95: 5 EtOAc-MeOH to 85:15 EtOAc-MeOH) to give the title compound as a yellow solid (30 mg, 0.07 mmol, 40%) .

LC-MS: RT = 1.38 min, MH ⁺ 445.1; ¹ H NMR (MeOD): 8.74 (2H, dd, J = 4.7 and 1.6), 8.58 (1H, dd, J = 4.7 and 1.6), 8.31 (1H dd, J = 8.1 and 1.6), 8.10 (2H, dd, J = 4.7 and 1.6), 7.78 (1H, s), 7.90-7.62 ( 6H, m) and 7.48 (1H, dd, J = 8.1 and 4.7).

The following compounds are prepared analogously using the corresponding intermediates and are purified by crystallization or column chromatography, when necessary:

2- (Benzo [b] thiophen-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [a] imidazole (Compound 2)

LC-MS: RT = 1.51 min, MH ⁺ 444.2; ¹ H NMR (MeOD): 8.64 (2H, m), 8.01 (2H, m), 7.93 (1H, m), 7.79-7.89 (3H, m), 7.51 -7.78 (5H, m), 7.34 (2H, m).

2- (Benzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [(1] imidazole (Compound 3)

LC-MS: RT = 1.23 min, MH ⁺ 428.1; ¹ H NMR (MeOD): 8.76 (2H, dd, J = 4.7 and 1.6), 8.40 (1H, d, J = 1.6), 8.15-8.08 (3H , m), 8.00-7.60 (8H, m) and 7.02 (1H, dd, J = 2.2 and 0.9).

6- (2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [(1] imidazol-2-yl) benzo [(1] imidazole

(Compound 4)

LC-MS: RT = 1.09 min, MH ⁺ 428.5; ¹ H NMR (MeOD): 8.75 (2H, dd, J = 4.6 and 1.7), 8.42 (1H, br.s), 8.32 (1H, s), 8.12 ( 2H, dd, 7 = 4.6 and 1.7), 8.07-7.71 (7H, m) and 7.62 (1H, dd, J = 8.4 and 1.7).

2- (benzo [b] thiophen-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [(1] imidazole

(Compound 5)

LC-MS: RT = 1.26 min, MH ⁺ 444.2; ¹ H NMR (MeOD): 8.65 (2H, dd, J = 4.6 and 1.7), 8.49 (1H, t, J = 1.1), 8.01-7.99 (4H , m), 7.78-7.51 (7H, m) and 7.43 (1H, d, J = 5.5).

2- (1H-indol-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [(1] imidazole (Compound 6)

LC-MS: RT = 1.16 min, MH ⁺ 427.3; ¹ H NMR (MeOD): 8.64 (2H, dd, J = 4.6 and 1.7), 8.25 (1H, d, J = 1.1), 8.01 (2H, dd, J = 4.6 and 1.7), 7.83-7.43 (6H, m), 7.50-7.43 (2 N, m) 7.25 (1H, d, J = 3.2) and 6.51 (1H, dd, J = 3.2 and 0.8).

2- (2,3-Dihydrobenzofuran-5-yl) -2 '- (pyridin-4-yl) -1H, 3'H-5,5'-bibenzo [d] imidazole (Compound 7)

LC-MS: RT = 1.21 min, MH ⁺ 430.1; ¹ H NMR (d ₆ -DMSO): 8.76 (2H, dd, J = 4.6 and 1.6), 8.09 (2H, dd, J = 4.6 and 1.6), 8, 03 (1H, s), 7.92 (2H, dd, J = 8.2 and 1.8), 7.84-7.52 (5H, m), 6.93 (1H, d, J = 8 3), 4.62 (2H, t, J = 8.7) and 3.28 (2H, m, J = 8.8).

2- (Imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5.5'-bibenzo [(1] imidazole (Compound 8)

LC-MS: RT = 1.11 min, MH ⁺ 428.1; ¹ H NMR (MeOD): 9.18 (1H, s), 8.76 (2H, dd, 7 = 4.6 and 1.6), 8.12 (2H, dd, J = 4.6 and 1 6), 8.04 (1H, s), 8.00 (1H, dd, J = 9.4 and 1.7) and 7.95-7.64 (8H, m).

2- (Benzo [(1] [1,3] wild: sol-5-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [(1] imidazole (Compound 9)

LC-MS: RT = 1.23 min, MH ⁺ 431.8; ¹ H NMR (MeOD): 8.76 (2H, dd, J = 4.7 and 1.6), 8.13 (2H, dd, J = 4.6 and 1.6), 7.93-7 61 (8H, m), 7.02 (1H, d, J = 8.1) and 6.09 (2H, s).

2- (Benzofuran-2-yl) -2 '- (pyridin-4-yl) -1H, 1'H-5,5'-bibenzo [(1] imidazole (Compound 10)

LC-MS: RT = 1.48 min, MH ⁺ 428.5; ¹ H NMR (MeOD): 8.64 (2H, dd, J = 4.6 and 1.7), 8.00 (2H, dd, 7 = 4.6 and 1.7) and 7.79 (2H , m), 7.65-7.52 (6H, m), 7.49 (1H, d, J = 0.9) 7.33 (1H, dt, J = 7.3 and 1.3), 7.23 (1H, doublet of doublets, J = 7.5 and 1.0).

2- (2 '- (Pyridin-4-yl) -1H, 1'H- [5,5'-bibenzo [(1] imidazole] -2-yl) thieno [2,3-s] pyridine

(Compound 11)

LC-MS: RT = 1.36 min, MH ⁺ 445.2; ¹ H NMR (MeOD): 9.14 (1H, s), 8.70 (2H, d, J = 5.4), 8.41 (1H, d, J = 5.5), 8.05 ( 2H, d, J = 5.5), 7.98 (1H, s) and 7.91-7.55 (7 N, m) 2- (Imidazo [1,2-a] pyridin-6-yl) -2 '- (pyridin-3-yl) -1H, 1'H-5,5'-bibenzo [(1] imidazole

(Compound 12)

LC-MS: RT = 1.80 min, MH ⁺ 428.7; ¹ H NMR (d ₆ -DMSO): 13.26 (2H, br s), 9.52 (1H, s), 9.45 (1H, d, J = 2.0), 8.76 (1H dd, J = 4.8 and 1.5), 8.60 (1 N, dt, J = 8.0 and 1.8), 8.20 (1H, s), 8.07 (1 N, dd, J = 9.4 and 1.7), 7.95 (2H, d, J = 7.0), 7.85-7.73 (4H, m) and 7.70-7.63 (3H , m). 2- (2 '- (Pyridin-3-yl) -1H, 1'H- [5,5'-bibenzo [(1] imidazole] -2-yl) thieno [2,3-b] pyridine

(Compound 13)

LC-MS: RT = 2.33 min, MH ⁺ 446.1; ¹ H NMR (d ₆ -DMSO); 13.33 (2H, br.s), 9.39 (1H, d, J = 2.2), 8.70 (1H, dd, J = 4.8 and 1.6), 8.63 (1H dd, J = 4.6 and 3.0), 8.54 (1H, dt, J = 8.0 and 2.0), 8.41 (1H, dd, J = 8.0 and 1.6 ), 8.17 (1H, s), 8.07-7.69 (4H, m), 7.69-7.58 (3H, m) and 7.52 (1H, dd, J = 8.0 and 4.6).

Example 2. The activity of the compounds according to the invention

A list of preferred compounds of general formula (I) together with their minimum inhibitory concentration (MIC) for Clostridium difficile ATCC700057 and a panel of indicator bacteria of the intestinal flora are summarized in table 2 (below).

In the table above, the following notation is used to indicate MIC values:

MIC≤1 μg / ml = ++++

MIC ≤4 μg / ml = +++

MIC≤32 μg / ml = ++

MIC≥64 μg / ml = +

The following bacterial strains were used:

Bacteroides fragilis ATCC 25285

Escherichia coli ATCC25922

Lactobacillus paracasei Zl 83

Bifidobacterium dentium NCTC 11816

B. adolescentis MWR144

Staphylococcus aureus ATCC29213

Enterococcus faecalis ATCC29212.

Indicator strains are representatives of the normal intestinal flora, and, therefore, they are a model of the microbial flora of the intestine. Thus, the data obtained show that the compounds of the invention are selective agents for Clostridium difficile (as defined above), i.e. exhibit bacteriostatic and / or bactericidal activity against C. difficile, but do not harm the normal intestinal flora. Therefore, the compounds of the invention are useful in the treatment of CDAD without causing a pathological disorder of the normal intestinal flora.

(Viii) Equivalents

The foregoing description sets forth in detail the currently preferred embodiments of the present invention. When considering this description, specialists in this field can imagine a lot of all kinds of options and changes that are possible in its implementation. It is implied that such changes and variations are covered by the attached claims.

Claims (14)

1. The compound of formula (I)

in which R ¹ is pyridyl;
R ² represents an aromatic 9-membered bicyclic ring system in which one or two carbon atoms may be substituted with N, O, or S;
or a pharmaceutically acceptable salt, hydrate or solvate thereof. 2. The compound according to claim 1, in which R ² represents an aromatic condensed 5- and 6-membered bicyclic ring system. 3. The compound according to claim 2, in which R ² represents (a) a thienopyridinyl group or (b) a benzothiophenyl group, or (c) a benzofuranyl group, or (d) a pyridylimidazolyl group, or (e) a benzodioxolyl group, or (f ) indolyl group. 4. The compound according to claim 1, which is selected from the following compounds:
2- (2 ′ - (pyridin-4-yl) -1H, 1′H-5,5′-bibenzo [d] imidazol-2-yl) thieno [2,3-b] pyridine,
2- (benzo [b] thiophen-2-yl) -2 ′ - (pyridin-4-yl) -1H, 1′H-5,5′-bibenzo [d] imidazole,
2- (benzofuran-5-yl) -2 ′ - (pyridin-4-yl) -1H, 1′H-5,5′-bibenzo [d] imidazole,
6- (2 ′ - (pyridin-4-yl) -1H, 3′H-5,5′-bibenzo [d] imidazol-2-yl) benzo [d] imidazole,
2- (benzo [b] thiophen-5-yl) -2 ′ - (pyridin-4-yl) -1H, 3′H-5,5′-bibenzo [d] imidazole,
2- (1H-indol-5-yl) -2 ′ - (pyridin-4-yl) -1H, 3′H-5,5-bibenzo [d] imidazole,
2- (2,3-dihydrobenzofuran-5-yl) -2 ′ - (pyridin-4-yl) -1H, 3′H-5,5′-bibenzo [d] imidazole,
2- (imidazo [1,2-a] pyridin-6-yl) -2 ′ - (pyridin-4-yl) -1H, 1′H-5,5′-bibenzo [d] imidazole,
2- (benzo [d] [1,3] dioxol-5-yl) -2 ′ - (pyridin-4-yl) -1H, 1′H-5,5′-bibenzo [d] imidazole,
2- (benzofuran-2-yl) -2 ′ - (pyridin-4-yl) -1H, 1′H-5,5′-bibenzo [d] imidazole,
2- (2 ′ - (pyridin-4-yl) -1H, 1′H- [5,5′-bibenzo [d] imidazole] -2-yl) thieno [2,3-c] pyridine,
2- (imidazo [1,2-a] pyridin-6-yl) -2 ′ - (pyridin-3-yl) -1H, 1′H-5,5′-bibenzo [d] imidazole, and
2- (2 ′ - (pyridin-3-yl) -1H, 1′H- [5,5′-bibenzo [d] imidazole] -2-yl) thieno [2,3-b] pyridine
or their pharmaceutically acceptable salts, hydrates or solvates. 5. A combination intended for the treatment of diseases associated with Clostridium difficile (CDAD), comprising an effective amount of a compound according to any one of the preceding paragraphs and an additional agent selected from (a) vancomycin, (b) metronidazole, (c) probiotic, (d) a prebiotic, (e) a bacteriotoxin sequestrant (e.g., ion exchange resin), (f) an intravenous immunoglobulin, and (g) an antidiarrheal agent. 6. The combination according to claim 5, containing a compound according to any one of paragraphs. 1-4 and a probiotic selected from Saccharomyces spp. and / or Lactobacillus spp. 7. The combination according to any one of claims 5 to 6, in which the compound and additional agent are physically or nonphysically associated with each other. 8. A pharmaceutical composition for the treatment of diseases associated with Clostridium difficile (CDAD), containing an effective amount of a compound according to any one of claims 1 to 4 or a combination according to any one of claims 5 to 7. 9. The compound according to any one of claims 1 to 4 for use in a method for the treatment of diseases associated with Clostridium difficile (CDAD). 10. A method of treating a Clostridium difficile infection or a disease associated with Clostridium difficile in a subject, comprising administering to said subject an effective amount of a compound according to any one of claims 1-4, a combination according to any one of claims 5-7 or a pharmaceutical composition according to claim 8 . 11. The compound of claim 9 or the method of claim 10 for use in a method of treating CDAD while maintaining normal intestinal flora. 12. The compound or method according to claims 9-11, wherein the CDAD is selected from (a) colitis, (b) pseudomembranous colitis, (c) diarrhea, and (d) antibiotic-associated disease. 13. The compound of claim 12, wherein the antibiotic-associated disease is selected from (a) antibiotic-associated diarrhea and (b) antibiotic-associated colitis for use in the treatment of a subgroup of patients selected from (a) subjects who have been treated or treated with proton pump inhibitors, (b) subjects treated or treated with H2 receptor antagonists, (c) subjects treated or treated with diuretics, (d) hospitalized subjects, (e) subjects with constant tube feeding, (f) subjects undergoing mechanical ventilation, (g ) subjects who have been treated or treated with probiotics; and (g) subjects who have been treated or treated with vancomycin and / or metronidazole. 14. A method of destroying a Clostridium difficile bacterium or inhibiting, reducing or preventing its growth, comprising contacting said bacterium with a compound according to any one of claims 1 to 4.