DRUG FORMULATION FOR TREATING OR PREVENTING ALLERGIC REACTIONS RELATED TO IgE INCREASE IN MAMMALS

The present invention relates to low molecular weight inhibitors of the reaction of IDE (immunoglobulin E) to allergens useful in the treatment of allergy and / or asthma or any diseases for which IDE is pathogenic.

It is estimated that asthma affects 10 million people in the United States, or approximately 5% of the population. Estimated costs of asthma in the United States exceed $ 6 billion. Approximately 25% of patients with asthma who seek an ambulance need hospitalization, and most of the general direct medical expenses go to inpatient hospital treatment (ambulance) for more than 1.6 billion dollars. Expenses on medicines, which increased between 1985 and 1990 by 54%, came close to 1.1 billion dollars (KeiIu, Rpagtasoepigar 12: 133-213 (1997)).

According to the National Outpatient Outpatient Survey, asthma accounts for 1% of all outpatient visits, and this disease continues to be an important cause of school abduction. Despite improving understanding of the disease process and the best medicine, the incidence of asthma and the severity of asthma in the United States and throughout the world continues to grow (Ministry of Health and Humanitarian Services of the United States, 1991, publication No. 91-3042). Thus, asthma represents a serious threat to the health of society.

The pathophysiological processes that cause the appearance of an asthmatic episode can be divided into two phases; both distinguish between bronchoconstriction, which causes difficulty breathing, compression of the chest and shortness of breath. The asthmatic reaction of the first, early phase, is called allergens, stimuli or physical load. Allergens cross-link molecules of immunoglobulin E (IDE), bound to the receptors of the functional cells, forcing them to release a certain number of previously formed mediators of inflammation, includingincluding histamine. Additional initiators include osmotic changes in the tissues of the respiratory tract afterphysical loading or inhalation of cold dry air. The reaction of the second, late phase, is characterized by infiltration of activated eosinophils and other inflammatory cells in the respiratory tract tissue, epithelial excision and the presence of a very viscous mucus in the respiratory tract. Violation, caused by an inflammatory reaction, leaves the respiratory tract under primary influence or sensitized, so that for the induction of further symptoms of asthma requires less initialisation.

Several drugs are available for palliative asthma treatment; however, their effectiveness varies greatly. The short-acting L2-adrenergic agonists, terbutaline and albuterol, which have long been the basis of asthma treatment, are primarily effective during the early phase as bronchodilators. Newer long-acting L2-agonists, salmetherol andformoterol, can reduce the bronchoconstriction component of the late reaction. However, since L2-agonistine has a significant anti-inflammatory activity, they do not affect bronchial hyperresponsiveness.

Numerous other drugs are targeted at specific aspects of early or late asthmatic reactions. For example, antihistamines such as loratadine inhibit early histamine-mediated inflammatory reactions. Some of the more advanced antihistamines, such as azelastin and ketotifen, may have anti-inflammatory, and weak bronchodilator effect, but they currently have no established efficacy in the treatment of asthma. Such phosphodiesterase inhibitors, such as theophylline / xanthine, may weaken late inflammatory responses, but there is clear evidence that these compounds reduce bronchial hyperreactivity. Such anticholinergics, as the bicarbonate, used in cases of acute asthma to inhibit the severe contraction of the bronchi, do not affect the inflammation of the early and late phases, do not affect the bronchial hyperreactivity,

Corticosteroid drugs, such as budesonide, are the most potent anti-inflammatory agents. Inhibitors exempting inflammatory mediators, such as cromolin and nedocromil, act by stabilizing mast cells and thereby inhibiting the inflammatory response to the allergen in the late stage. Thus, cromolin and nedocromil, as well as other corticosteroids, reduce bronchial hyperreactivity by minimizing the sensitizing effect of inflammatory respiratory failure. Unfortunately, these anti-inflammatory agents do not have the effect of bronchodilation.

Several new agents are being developed that inhibition of specific aspects of asthmatic inflammation. For example, leukotriene receptor antagonists (ICI-204, 219, assoyiae) specifically inhibit

mediated by leukotrienes of the effect. Leukotrienes are involved in the onset of inflammation of the respiratory ways, and in bronchoconstriction.

Thus, despite the fact that a large number of medicines for asthma are currently available, these compounds are primarily palliative and / or have significant side effects. Consequently, the newest therapeutic approaches aimed at the underlying cause, rather than the cascade of symptoms, would be highly desirable. Asthma and allergy have a general dependence on mediated events. Of course, it is known that overproduction of IDEE is the main cause of allergies in general and allergic asthma in particular (Oiriappep ABB SPEDD, AP RER MesiSp. 29: 73-81 (1994)). Thus, compounds that lower the IdE levels can be effective in treating the causes behind asthma and allergy.

None of the modern therapies eliminates excess circulating EID. The hypothesis that the reduction of IDEplasm may reduce the allergic reaction was confirmed by recent clinical outcomes with the anti-idiomic anti-IDE antibody SSR-51901 and the recombinant humanized monoclonal antibody gPiMAV-E25. Indeed, three companies, Tapohovovovetv Ips., SepipeisP Ips. and Mowagii AU work together to develop a human Anti-Ida antibody (ViOmoGIS ToSau, EheSchug 26, 1997, p.2) that will treat allergies and asthma by neutralizing excess IDEs. Company Tapoh has already successfully tested anti-ide antibody SRSR-51901, which reduced the weight and duration of nasal symptoms of allergic rhinitis in the phase II test on 155 patients (Zsgir №2080, KIoU, 24, 1995, p. 26). The SepepisP company recently revealed positive results of Phases II / III in 536 patients with recombinant humanized monoclonal antibody rPiMAV-E25 (ViOmogISToSau, Vol. 10, 1998, pIi). This injected hPiMAV-E25 antibody (higher dose of 300 mg every 2-4 weeks as needed) provided 50% -not a decrease in the number of days when the patient needed additional emergency medications (antihistamines and anti-inflammatory drugs) compared to placebo . Additional data on this product is expected in 2000. Positive test results of Anti-Eid antibodies show that therapeutic strategies aimed at lowering IED regulation can (a higher dose of 300 mg every 2-4 weeks as needed) provided 50% -not a decrease in the number of days when the patient needed additional emergency medications (antihistamines and antifungals) compared to placebo. Additional data on this product was expected in 2000 . Positive test results of Anti-Eid antibodies show that therapeutic strategies aimed at lowering IED regulation can (a higher dose of 300 mg every 2-4 weeks as needed) provided 50% -not a decrease in the number of days when the patient needed additional emergency medications (antihistamines and antifungals) compared to placebo. Additional data on this product was expected in 2000 . Positive test results of Anti-Eid antibodies show that therapeutic strategies aimed at lowering IED regulation can

be effective.

Disclosure of the invention

The present invention contemplates a family of family members for use in the treatment of a condition associated with a surplus level of IDE. The benzimidazole inhibitors of the IED according to the present invention are presented

in which X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, SE, OSez, OOnN₂, POLO and NNOSO · -. P is selected from the group consisting of H, H2, C2H5, C3H7, C4H9, CH₂Rii and CH₂SbN4-E (p-), R1 and P2 are independently selected from the group consisting of H, aryl, substituted aryl, cycloalyl, substituted cycloalyl, multi-ring cycloalyl, benzyl, substituted benzyl, and the like. The bonds are alkyl, aryl, CE, СНз, ОСнз, ОН, С ^ СООР, СООН, etc.

In accordance with another aspect of the invention there is disclosed a compound for use in the treatment of an allergic state comprising a diacil benzimidazole inhibitor IdE disclosed above and at least one additional active ingredient combined in a pharmaceutically acceptable diluent. Additional active ingredients may be selected from the group consisting of short-acting ²2-adrenergic agonists such as egturbutaline and albuterol, long-acting b2-adrenergic agonists such as salmetherol and formoterol, antihistamines such as loratadine, azelastin and ketotifen, phosphodiesterase inhibitors, anticholinergic agents, corticosteroids, inhibitors of release of an inflammatory mediator or leukotriene receptor antagonist.

In accordance with another aspect of the invention, a family of symmetric and asymmetric diacyl and monoacyl benzimidazole compounds is disclosed for use in the treatment of an allergic condition comprising the following species:

<tr><td><p>Structure</p></td><td><p>VIAA</p></td></tr><tr><td><p></p></td><td><p>h</p></td><td><p></p></td><td><p>^WITH27^N20 ^ 4 ° 2</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p>СІ.ССР</p><p>5.47</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIIA</p></td></tr><tr><td><p>^WITH27^N19th^SEVEN4 ° 2</p></td></tr><tr><td><p>ίίοορ</p><p>624</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIAO</p></td></tr><tr><td><p>° 26^η19th^ν5 ° 2</p></td></tr><tr><td><p></p></td><td><p>O.SHZR</p><p>4.26</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>B1AE</p></td></tr><tr><td><p>° 30^η26^ν4 ° 5</p></td></tr><tr><td><p>/</p></td><td><p>ССООР</p><p>4.62</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIAAR</p></td></tr><tr><td><p>^ 27^N18^SI2^M4 ° 2</p></td></tr><tr><td><p>SCHOS</p><p>6.97</p></td></tr>

<tr><td><p>Sirukitra</p></td><td><p>VIAS »</p></td></tr><tr><td><p></p></td></tr><tr><td><p></p></td><td><p>^WITH27^N18^SI2^M4 ° 2</p></td></tr><tr><td><p>SSSR</p></td></tr><tr><td><p></p></td><td><p>5.31</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>VIAN</p></td></tr><tr><td><p>^with27^N18^C12^and4 ° 2</p></td></tr><tr><td><p>SIXCP</p><p>6.14</p></td></tr>

^with27^N18^c12^and4 ° 2

SIXCP

6.14

<tr><td><p>Sirukiura</p></td><td><p>B1A.I</p></td></tr><tr><td><p>^WITH26^N24^M4 ° 2</p></td></tr><tr><td><p>CBSS</p><p>5.45</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>VIAI</p></td></tr><tr><td><p>^with25^N18^m4 ° 2⁵</p><p>USSR</p></td></tr>

5.20

<tr><td><p>Structure</p></td><td><p>ΒΙΑΜ</p></td></tr><tr><td><p>^sgLy&gt; &lt;_&gt; / °</p></td><td><p>^with30^N24^M4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5 74</p></td></tr>

<tr><td><p>Structure</p></td><td><p>ΒΙΑΝ</p></td></tr><tr><td><p>Ou ΥΛτν ° °</p></td><td><p>^ε22^Η18^Ν4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>3.9V</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIAO</p></td></tr><tr><td><p>IN</p><p>SG ·</p></td><td><p>^with28^N26^m4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.76</p></td></tr>

<tr><td><p>Structure</p></td><td><p>ΒΙΑΕ</p></td></tr><tr><td><p>'AND</p><p>at⁴·</p></td><td><p>^with28^N24^m4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.2V</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIVA</p></td><td><p></p></td><td><p>Structure</p></td><td><p>EHV</p></td></tr><tr><td><p></p></td><td><p>^ 27^N19th^with,^ 4®2</p></td><td><p></p></td><td><p></p></td><td><p>θ27^Η18^0I2^Ν4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>6.26</p></td><td><p></p></td><td><p>С1.ОСР</p><p>7.04</p></td></tr>

<tr><td><p>From the structure</p></td><td><p>VIVS</p></td></tr><tr><td><p></p></td><td><p>^ε28^Η21º^{, Ν}4θ3</p></td></tr><tr><td><p>The USSR</p><p>6.38</p></td></tr>

<tr><td><p>Structure</p></td><td><p>ΒΙΒΟ</p></td></tr><tr><td><p>^with26^N18^{s, m}5 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.08</p></td></tr>

<tr><td><p>From the structure</p><p>'' AuwA</p><p>/</p></td><td><p>ΒΙΒΕ</p></td><td><p></p></td><td><p>Structure</p></td><td><p>WIPO</p></td></tr><tr><td><p>^with30^N25^{s, m}4 ° 5</p></td><td><p></p></td><td><p></p></td><td><p>^WITH27^N17^WITH,3^N4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.62</p></td><td><p></p></td><td><p>4 ·</p></td><td><p>The USSR</p><p>7.77</p></td></tr>

<tr><td><p>Structure</p><p>_l ° \</p></td><td><p>VIVS</p></td></tr><tr><td><p></p></td><td><p>^WITH27^N17^WITH,3^M4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>6.11</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Siruk yu Ra</p></td><td><p>Evil</p></td></tr><tr><td><p></p></td><td><p>^ 27 ^ 25 ^^ 4θ2</p></td></tr><tr><td><p>CIOSR</p><p>6.61</p></td></tr>

<tr><td><p>From the structure</p><p>-Oto ^ рЪ-</p></td><td><p>VIVN</p></td></tr><tr><td><p>^WITH27^N17^WITH,3^M4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>6.04</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Strikuur</p></td><td><p>ΒΙΒδ</p></td></tr><tr><td><p>C26^N23C^{| 4th}4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>6 25</p></td></tr>

<tr><td><p>There is a structure</p></td><td><p>VIVK</p></td></tr><tr><td><p></p></td><td><p>θ25 ^ 17θ ^ 4®2 ^</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>6.00</p></td></tr>

<tr><td><p>Structure</p></td><td><p>Evil</p></td></tr><tr><td><p>WITH₂₅N₁₇CLOSE₄AT₂5</p></td></tr><tr><td><p>The USSR</p><p>6.00</p></td></tr>

CIOSR

6.00

<tr><td><p>(structure</p></td><td><p>Eighth</p></td></tr><tr><td><p></p></td><td><p>^WITH30^N23^{C, M}4®2</p></td></tr><tr><td><p>CIOSR</p><p>6.54</p></td></tr>

<tr><td><p>The hands of the tour</p></td><td><p>WIPO</p></td></tr><tr><td><p>WITH₂DN₂7 CIMDO₂</p></td></tr><tr><td><p>sysrr</p><p>7.37</p></td></tr>

WITH₂д ^ 27 СІДо2

The USSR

7.37

<tr><td><p>Structure</p></td><td><p>VIVO</p></td></tr><tr><td><p></p></td><td><p>^with28^N25^{s, m}4®2</p></td></tr><tr><td><p>The USSR</p><p>6.56</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIVN</p></td></tr><tr><td><p></p></td></tr><tr><td><p>-X</p><p>Hg-</p></td><td><p>^WITH2B^N23^SEVEN4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>6.08</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WSI</p></td></tr><tr><td><p></p></td><td><p>^WITH28^N22^M4 ° 3</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p><p>5.58</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>WISS</p></td></tr><tr><td><p></p></td><td><p>° 29^Η24^Ν4 ° 4</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p><p>5.70</p></td></tr>

<tr><td><p>Structure</p></td><td><p>Wisconsin</p></td></tr><tr><td><p>^WITH28^N21^CLOSE40s</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p><p>6.35</p></td></tr>

<tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>WSI</p></td></tr><tr><td><p>^with27^N21^m5 ° 3</p></td></tr><tr><td><p>CIOSR</p><p>4.39</p></td></tr>

<tr><td><p>Structure</p><p>/</p></td><td><p>WSI</p></td></tr><tr><td><p>^WITH31^N28^M4 ° 6</p></td></tr><tr><td><p>CIOSR</p><p>4.83</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WAX</p></td></tr><tr><td><p>θ28^Η20^α2^Ν4 ° 3</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p><p>.7.09</p></td></tr>

<tr><td><p>With Iriura</p></td><td><p>WISS</p></td></tr><tr><td><p></p></td><td><p>^ 28 ^ 20 ^ 2 ^ 4 ^ 3</p></td></tr><tr><td><p>CIOSR</p><p>5.43</p></td></tr>

<tr><td><p>Structure</p><p>at</p></td><td><p>BUSIN</p></td></tr><tr><td><p></p></td><td><p>^WITH28^N2O^C12^M4 ° 3</p></td></tr><tr><td><p>CIOSR</p><p>6.26</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WSI</p></td><td><p></p></td><td><p>Structure</p></td><td><p>WSI</p></td></tr><tr><td><p></p></td><td><p>^with28^N28^m4 ° 3</p></td><td><p></p></td><td><p></p></td><td><p>^ 27 ^ 26^Ν4θ3</p></td></tr><tr><td><p>USSR</p><p>6.12</p></td><td><p></p></td><td><p>puss</p><p>5.56</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>WAX</p></td></tr><tr><td><p></p></td><td><p>^with26^N20^m4 ° 3⁸</p></td></tr><tr><td><p>CSR</p><p>5.32</p></td></tr>

Structure

WSI

^with26^N20^m4 ° 3⁵

CIOSR

5.32

<tr><td><p>From the structure</p></td><td><p>WISM</p></td></tr><tr><td><p></p></td><td><p>θ31^Η26^Ν4 ° 3</p></td></tr><tr><td><p>CIOSR</p><p>5.85</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WISM</p></td></tr><tr><td><p></p></td><td><p>° 23^Η20^Ν4θ3</p></td></tr><tr><td><p>(Hosr</p><p>4.09</p></td></tr>

<tr><td><p>Structure</p></td><td><p>whiskey</p></td></tr><tr><td><p>° 29^η30^ν4 ° 3</p></td></tr><tr><td><p>CIOSR</p><p>6.68</p></td></tr>

CIOSR

6.68

<tr><td><p>Structure</p><p>$</p></td><td><p>wax</p></td></tr><tr><td><p></p></td><td><p>^WITH20^N28^M4 ° 3</p></td></tr><tr><td><p>CIOSR</p><p>5.88</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WAX</p></td></tr><tr><td><p></p></td><td><p>^WITH29^N26^M4 ° 3</p></td></tr><tr><td><p>. &lt;/</p></td><td><p>CIOSR</p></td></tr><tr><td><p>5.39</p></td></tr>

<tr><td><p>Structure</p></td><td><p></p></td><td><p>WOW</p></td></tr><tr><td><p>^with26^N19th^m5 ° 2</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>CIOSR</p><p>4.60</p></td></tr>

<tr><td><p>.Structure</p></td><td><p>whine</p></td></tr><tr><td><p></p></td><td><p>^with26^N18^{s, m}5 ° 2</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p><p>5.37</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIOEE</p></td></tr><tr><td><p>° 29^Η25^Ν5 ° 5</p></td></tr><tr><td><p>/</p></td><td><p>rub</p><p>3.95</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VYRE</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>^with26^N17^with,2 ^ 5 ° 2</p></td></tr><tr><td><p></p></td><td><p>Oh oh</p></td><td><p>CIOSR</p><p>6.You</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIA</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>^WITH26^N17^SI2^M5 ° 2</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>4.44</p></td></tr>

<tr><td><p>Sirukuria</p></td><td><p>the run</p></td></tr><tr><td><p>^WITH26^N17^C12^M5 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.27</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Sirukuria</p></td><td><p>VILLA</p></td></tr><tr><td><p>^with25^N23^N5 ° 2</p></td></tr><tr><td><p>CZSR</p><p>4.58</p></td></tr>

<tr><td><p>Structure</p></td><td><p>whiskey</p></td></tr><tr><td><p></p></td><td><p>^with24^N17^m5 ° 2²</p></td></tr><tr><td><p>The USSR</p><p>433</p></td></tr>

<tr><td><p>Sgroupeurp</p></td><td><p>intestine</p></td></tr><tr><td><p>^with29^N23^N5 ° 2</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>4.87</p></td></tr>

<tr><td><p>Structure</p></td><td><p>ΒΙΟΝ</p></td></tr><tr><td><p>° 21^η17^ν5 ° 2</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>3.11</p></td></tr>

<tr><td><p>Sirukuria</p></td><td><p>vua</p></td></tr><tr><td><p></p></td><td><p>^with27^N25^N5 ° 2</p></td></tr><tr><td><p>The USSR</p><p>4.89</p></td></tr>

<tr><td><p>Sirukuria</p></td><td><p>UP</p></td></tr><tr><td><p>^with27^N27^m5 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.70</p></td></tr><tr><td><p></p></td></tr>

<tr><td><p>Structure</p></td><td><p>VUC</p></td></tr><tr><td><p>iU</p></td><td><p>° 27^Η23^Ν5 ° 2</p></td></tr><tr><td><p>sysrr</p><p>4.41</p></td></tr>

<tr><td><p>Structure</p><p>** · «</p></td><td><p>ΒΙΕΑ</p></td></tr><tr><td><p></p></td><td><p>^with30^N26^N4 ° 5</p><p>sysrr</p><p>4.B2</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Strukhura</p><p>'■ ■ ■ o</p></td><td><p>VIEP</p></td></tr><tr><td><p></p></td><td><p>θ31^Η28^Ν4 ° 6</p><p>CIOSR</p><p>4.93</p></td></tr>

<tr><td><p>Strikuur</p><p>Α'θ-φγ ·</p></td><td><p>WIRE</p></td></tr><tr><td><p>^WITHZO^N25^SEVEN4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>569</p></td></tr><tr><td><p></p></td></tr><tr><td><p>.Structure</p></td><td><p>VIEO</p></td></tr><tr><td><p>^with29^N25^m5 ° 5</p></td></tr><tr><td><p>CIOSR</p><p>3.63</p></td></tr>

<tr><td><p>.Structure</p><p>* · Β</p><p>7</p></td><td><p>81Eye</p></td></tr><tr><td><p>^WITH33^N32^M4 ° 8</p></td></tr><tr><td><p>The USSR</p><p>4.17</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>VIEP</p></td></tr><tr><td><p>^WITHZO^N24^SI2^M4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>4.66</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIEI</p></td></tr><tr><td><p>^with30^N32^m4 ° 5</p></td></tr><tr><td><p>CIOSR</p><p>5.36</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>WEIGHT</p></td></tr><tr><td><p>^with28^N24^m4 ° 5⁵</p></td></tr><tr><td><p>The USSR</p><p>4.55</p></td></tr>

<tr><td><p>Structure</p><p>''•AT</p></td><td><p>VIER</p></td></tr><tr><td><p>^with30^N24^with,2^m4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>6.32</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>WIN</p></td></tr><tr><td><p>^WITH30^N24^WITH,2^M4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>5.49</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>VIEZ</p></td></tr><tr><td><p>° 29^η30^ν4 ° 5</p></td></tr><tr><td><p>CIOSR</p><p>460</p></td></tr><tr><td><p></p></td></tr>

<tr><td><p>Structure</p><p>""•at</p></td><td><p>VIEI</p></td></tr><tr><td><p></p></td><td><p>θ28^Η24^Ν4 ° 5^δ</p></td></tr><tr><td><p>SCHOS</p><p>4.55</p></td></tr>

<tr><td><p>Structure</p></td><td><p>OWN</p></td></tr><tr><td><p></p></td><td><p>° 33^η30^ν4 ° 5</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>5.09</p></td></tr>

<tr><td><p>Structure</p><p>""at</p><p>and</p></td><td><p>ΒΙΕΝ</p></td></tr><tr><td><p>^{/ 0} in</p></td><td><p>^with25^N24^m4 ° 5</p></td></tr><tr><td><p></p></td><td><p>SEASR</p></td></tr><tr><td><p></p></td><td><p>3.33</p></td></tr>

<tr><td><p>Structure</p><p>• L</p></td><td><p>VIEO</p></td></tr><tr><td><p>^WITH34^N36^M4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>5.99</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIER</p></td></tr><tr><td><p>^WITH31^N34^m4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>5.92</p></td></tr>

<tr><td><p>Structure</p><p>£</p></td><td><p>WEIGHT</p></td></tr><tr><td><p>V^and·</p></td><td><p>° 31^η30^ν4 ° 5</p></td></tr><tr><td><p>The USSR</p></td></tr><tr><td><p></p></td><td><p>463</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIRV</p></td></tr><tr><td><p>^WITH27^N17^SI3 ^ 4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>7.78</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIRS</p><p>^with28^N20^Si2^M4 ° 3</p><p>I.O.E.R.</p><p>7.12</p></td></tr>

<tr><td><p>Structure</p><p>and</p><p>.- ^^^^^^</p></td><td><p>WIRA</p></td></tr><tr><td><p>^WITH26^N17^C12^M5 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.82</p></td></tr>

<tr><td><p>With the troika</p><p>at</p><p>'° XG&gt; -u &lt;£</p><p>/</p></td><td><p>VIRE</p></td></tr><tr><td><p>° 30^Η24^ea2^Ν4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>6.35</p></td></tr>

<tr><td><p>Structure</p><p>with"</p></td><td><p>VIRP</p></td></tr><tr><td><p></p></td><td><p>WITH₂7^N16^SI4^M4 ° 2</p><p>The USSR</p><p>8.51</p></td></tr>

Structure

VIRN

^ 27 ^ 16 ^^^ 4¾

CSR

7.68

<tr><td><p>Structure</p></td><td><p>VIRM</p></td><td><p></p></td><td><p>Structure</p><p>and</p></td><td><p>ΒΙΡΝ</p></td></tr><tr><td><p>^WITHZO^N22^WITH,2^M4 ° 2</p></td><td><p></p></td><td><p>ΛνΥΎ, Η&gt; °</p></td><td><p>θ22 ^ 16 ^ 2 ^ 4¾</p></td></tr><tr><td><p></p></td><td><p>ziozir</p><p>7.28</p></td><td><p></p></td><td><p>CIOSR</p><p>5.51</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WIRA</p></td><td><p></p></td><td><p>Structure</p><p>$</p></td><td><p>VIRN</p></td></tr><tr><td><p></p></td><td><p>θ28 ^ 24 ^ 2 ^ 4θ2</p></td><td><p></p></td><td><p></p></td><td><p>^WITH28^N22^SI2^M4 ° 2</p></td></tr><tr><td><p>.</p><p>in·</p></td><td><p>CIOSR</p></td><td><p></p></td><td><p>in</p></td><td><p>CSR</p></td></tr><tr><td><p>7.30</p></td><td><p></p></td><td><p></p></td><td><p>6.82</p></td></tr>

<tr><td><p>Sirukiura</p><p>and</p></td><td><p>ΒΙΟΑ</p></td></tr><tr><td><p>^ x</p></td><td><p></p></td><td><p>^WITH27^N18^C12^M4 ° 2</p></td></tr><tr><td><p></p></td><td><p>С1ССР</p><p>5.34</p></td></tr>

C irruk iurya

at

Wisconsin

^WITH27^N17^WITH,3^M4 ° 2

puss

6.12

<tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>visa</p></td></tr><tr><td><p>^with28^N20^c12^m4 ° 3</p></td></tr><tr><td><p>C10SR</p><p>5.46</p></td></tr>

<tr><td><p>Structure</p><p>and</p></td><td><p></p></td><td><p></p></td><td><p>B1E0</p></td></tr><tr><td><p>^ X</p></td><td><p></p></td><td><p>yi ~ '</p><p>= 7</p></td><td><p>^WITH26^N17^{C |}2^M5 ° 2</p></td></tr><tr><td><p></p></td><td><p>\with</p></td><td><p></p></td><td><p>SCHOS</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p>4.16</p></td></tr>

<tr><td><p>Syrukgur</p></td><td><p>WSI</p></td></tr><tr><td><p>^WITHZO^N24^WITH,2^M4 ° 5</p></td></tr><tr><td><p>/</p></td><td><p>С1.00Р</p><p>4.69</p></td></tr>

<tr><td><p>Structure</p><p>€ »</p></td><td><p>WSIS</p></td></tr><tr><td><p>0 Ã</p></td><td><p>^WITH27^N16^WITH,4^M4 ° 2</p></td></tr><tr><td><p>SLORO</p><p>6.85</p></td></tr>

<tr><td><p>Structure</p></td><td><p>B1C0</p></td></tr><tr><td><p>AT</p></td><td><p>and</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>^WITH27^N16^C14^M4 ° 2</p></td></tr><tr><td><p>V ®</p></td><td><p>ŻζΥ G.</p></td><td><p>C10SR</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>5.19</p></td></tr>

<tr><td><p>Structure</p></td><td><p>BUSIN</p></td></tr><tr><td><p>° 27^Η16^α4^Ν4θ2</p></td></tr><tr><td><p>The USSR</p><p>6.02</p></td></tr>

<tr><td><p>From the structure</p></td><td><p>WIL</p></td></tr><tr><td><p>^ 26 ^ 22 ^ 2 ^ 4¾</p></td></tr><tr><td><p>The USSR</p><p>5.33</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>WISM</p></td></tr><tr><td><p>^WITHZO^N22^WITH,2^M4 ° 2</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>5.62</p></td></tr>

<tr><td><p>.Structure</p><p>at</p></td><td><p>ΒΙΟΝ</p></td></tr><tr><td><p>СХ / tА. in"</p></td><td><p>^ 22 ^ 16®2 ^ 4θ2</p></td></tr><tr><td><p>CIOSR</p><p>3.6 $</p></td></tr>

<tr><td><p>Structure</p><p>V?</p><p>Bb</p></td><td><p>inouo</p></td></tr><tr><td><p>^WITH31^N28^WITH,2^M4 ° 2</p></td></tr><tr><td><p></p></td><td><p>The USSR</p></td></tr><tr><td><p></p></td><td><p>6.5</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WSIS</p></td></tr><tr><td><p>^WITH28^N26^SI2^M4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>6.44</p></td></tr>

6.44

<tr><td><p>Structure</p></td><td><p>inouo</p></td></tr><tr><td><p>" -0 ^ her ·</p></td><td><p>^WITH28^N24^C12 ^ 4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.64</p></td></tr>

<tr><td><p>Structure</p><p>$</p></td><td><p>WAX</p></td></tr><tr><td><p>her ·</p></td><td><p>028 ^ 22 ^ 2 ^ 4 ^ 2</p></td></tr><tr><td><p>CIOSR</p><p>5.16</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>Wina</p></td></tr><tr><td><p>^WITH27^N18^SI2^M4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>6.17</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VINV</p></td></tr><tr><td><p>I27^Η17 · 3^Ν4^O2</p></td></tr><tr><td><p>The USSR</p><p>6.95</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WINS</p></td></tr><tr><td><p>^WITH28^N20^SI2^m4 ° 3</p></td></tr><tr><td><p>The USSR</p><p>6.29</p></td></tr>

The USSR

6.29

<tr><td><p>The structure</p></td><td><p>ΒΙΗβ</p></td></tr><tr><td><p></p></td><td><p>026^N17^withІ2^m5 ° 2</p></td></tr><tr><td><p></p></td><td><p>USSR</p><p>4.99</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>HE IS</p></td></tr><tr><td><p>^with30^N24^with,2 ^ ° 5</p></td></tr><tr><td><p>/</p></td><td><p>sysrr</p><p>5.52</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WINR</p></td></tr><tr><td><p></p></td><td><p>^WITH27^N16^WITH,4^M4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>7.6 «</p></td></tr>

<tr><td><p>Structure</p><p>in</p></td><td><p>wars</p></td></tr><tr><td><p></p></td><td><p>^WITH27^N16^SI4 ^ 4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>6.85</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIINI</p></td></tr><tr><td><p></p></td><td><p>^with27^N24^with,2 ^ 4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>6.71</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VINZ</p></td></tr><tr><td><p>^ 26 ^ 22 ^ * 2 ^ 4 ^ 2</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>6.16</p></td></tr>

<tr><td><p>S'yurukiur</p></td><td><p>WINC</p></td></tr><tr><td><p></p></td><td><p>^ 25^N16^WITH,2^M4 ° 2</p><p>5</p></td></tr><tr><td><p>sysrr</p><p>5.91</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIINI</p></td></tr><tr><td><p>^WITH25^N16^WITH,2^M4 ° 2</p><p>5</p></td></tr><tr><td><p>sysrr</p><p>5.91</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WINM</p></td></tr><tr><td><p></p></td><td><p>^with30^N22^with,2^M4 ° 2</p></td></tr><tr><td><p>SCHOS</p></td></tr><tr><td><p></p></td><td><p>6.45</p></td></tr>

<tr><td><p>Structure</p></td><td><p>ΒΙΗΝ</p></td></tr><tr><td><p></p></td><td><p>□ 2 2 N1 Β ^ * 2 * ^ 4θ2</p></td></tr><tr><td><p>The USSR</p><p>4.68</p></td></tr>

<tr><td><p>Structure</p><p>&lt;hu</p></td><td><p>DOWRY</p></td></tr><tr><td><p>^WITH31^N28^SI2^M4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>7.34</p></td></tr>

7.34

<tr><td><p>Structure</p></td><td><p>WINR</p></td></tr><tr><td><p>^WITH28^N26^WITH,2^M4 ° 2</p></td></tr><tr><td><p>sysrr</p><p>7.27</p></td></tr><tr><td><p></p></td></tr>

<tr><td><p>Structure</p><p>· &lt;</p></td><td><p>DOWRY</p></td></tr><tr><td><p>.in··</p></td><td><p>^WITH28^N24^WITH,2 ^ 4 ° 2</p></td></tr><tr><td><p>SCHOS</p></td></tr><tr><td><p></p></td><td><p>6.47</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WINC</p></td></tr><tr><td><p>.-IN-</p></td><td><p>^WITH28^N22^SI2^M4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>5.99</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VICS</p></td></tr><tr><td><p></p></td><td><p>^with26^N20^m4 ° 3⁵</p></td></tr><tr><td><p></p></td><td><p>CSR</p></td></tr><tr><td><p></p></td><td><p>5.32</p></td></tr>

<tr><td><p>Sirukiura</p></td><td><p>WIC</p></td></tr><tr><td><p>^WITH25^N17^SEVEN4 ° 2⁵</p></td></tr><tr><td><p>puss</p><p>5.9V</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>VICO</p></td></tr><tr><td><p>^with24^N17^m5 ° 2⁵</p></td></tr><tr><td><p>CIOSR</p><p>4.02</p></td></tr>

<tr><td><p>Structures</p></td><td><p>WEIGHT</p></td></tr><tr><td><p></p></td><td><p>^WITH2e^N24^M4 ° 5⁵</p></td></tr><tr><td><p>1</p></td><td><p>CIOSR</p><p>4.55</p></td></tr>

<tr><td><p>Structure</p></td><td><p>WIC</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>^ε25^Η16^ει2^Ν4 ° 2</p><p>8</p></td></tr><tr><td><p></p></td><td><p>About ¢ 1</p></td><td><p>CSR</p><p>6.71</p></td></tr>

<tr><td><p>Structure</p></td><td><p>° h</p></td><td><p>ΒΙΚΟ</p></td></tr><tr><td><p>AT</p></td><td><p></p></td><td><p>^WITH25^N16^SI2^M4 ° 2</p><p>3</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p><p>5.05</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VICC</p></td></tr><tr><td><p></p></td><td><p>^with23^N16^m4 ° 2³2</p></td></tr><tr><td><p>CIOSR</p><p>4 04</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIEW</p></td></tr><tr><td><p></p></td><td><p>θ24 ^ 22 ^ 4θ2 ^</p></td></tr><tr><td><p>sysrr</p><p>5.19</p></td></tr>

From the structure

ΒΙΚΜ

SA

LNA

^δ28^Η22^Ν4 ° 2^δ

SiSR

5.48

<tr><td><p>Structure</p></td><td><p>Vika</p></td><td><p></p></td><td><p>Structure</p></td><td><p>Vika</p></td></tr><tr><td><p>coll¹·</p></td><td><p>^ 26 ^ 24 ^ 4θ2^δ</p></td><td><p></p></td><td><p>SL</p></td><td><p>^δ26 ^ 22 ^ 4θ2^δ</p></td></tr><tr><td><p>USSR</p><p>5.50</p></td><td><p></p></td><td><p>USSR</p><p>5.02</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIA</p></td></tr><tr><td><p>'ф-'Сь ^ -ИЗ</p></td><td><p>^δ25^Η1β^Ν4 ° 2^δ</p></td></tr><tr><td><p>USSR</p></td></tr><tr><td><p></p></td><td><p>5.20</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIV</p></td></tr><tr><td><p>^δ25 ^ 17® ^ 4θ2^δ</p></td></tr><tr><td><p>USSR</p><p>5.98</p></td></tr>

<tr><td><p>Structure</p></td><td><p>vis</p></td></tr><tr><td><p>^with26^N20^m4 ° 3³</p></td></tr><tr><td><p>USSR</p><p>5.32</p></td></tr>

USSR

5.32

<tr><td><p>From the structure</p></td><td><p>NOT IN</p></td></tr><tr><td><p>° 28^Η24^Ν4 ° 5^δ</p></td></tr><tr><td><p>/</p></td><td><p>USSR</p><p>4.55</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIEW</p></td></tr><tr><td><p></p></td><td><p>^δ24^Η17^Νδ ° 2^δ</p><p>USSR</p><p>4.02</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>WHIRLPOOL</p></td></tr><tr><td><p></p></td><td><p>^WITH25^N16^SI2^M4 ^ 2</p><p>5</p></td></tr><tr><td><p>oh a</p></td><td><p>USSR</p><p>6.71</p></td></tr>

<tr><td><p>Structure</p></td><td><p>wines</p></td></tr><tr><td><p>сч-'а ^ ЯЭ '·</p></td><td><p>^à25 ^ .16^ε* 2^Ν4 ° 2</p><p>5</p></td></tr><tr><td><p>The USSR</p><p>5.88</p></td></tr>

<tr><td><p>Structure</p></td><td><p>us</p></td></tr><tr><td><p></p></td><td><p>^with25^N24^m4 ° 2⁵</p></td></tr><tr><td><p></p></td><td><p>The USSR</p></td></tr><tr><td><p></p></td><td><p>5.74</p></td></tr>

<tr><td><p>Structure</p></td><td><p>eyelashes</p></td></tr><tr><td><p>θ24^Η22^Ν4 ° 2^δ</p></td></tr><tr><td><p></p></td><td><p>The USSR</p><p>5.19</p></td></tr>

<tr><td><p>Structure</p></td><td><p>MIC</p></td></tr><tr><td><p></p></td><td><p>° 23^Η16^Ν4 ° 2^δ2</p></td></tr><tr><td><p>The USSR</p><p>4.84</p></td></tr>

<tr><td><p>Structure</p><p>■ 5</p></td><td><p>I see you</p></td></tr><tr><td><p>-O ^</p><p>0^and-</p></td><td><p>^WITH26^N24^M4 ° 2⁵</p></td></tr><tr><td><p>USSR</p><p>5.50</p></td></tr>

<tr><td><p>Structure</p><p>■ 5</p></td><td><p>MIC</p></td></tr><tr><td><p></p></td><td><p>^ε26^Η22^Ν4 ° 2^δ</p></td></tr><tr><td><p>The USSR</p><p>5.02</p></td></tr>

<tr><td><p>With irukuira</p></td><td><p>vis</p></td><td><p></p></td><td><p>Sirukiura</p></td><td><p>wines</p></td></tr><tr><td><p>ΟρκΗ ^ ΟΙ ^ Ν ^ Ο?</p></td></tr><tr><td><p>^ 26 ^ 22θ * 2 ^ 4θ2</p></td></tr><tr><td><p>СХООР</p><p>6.12</p></td></tr><tr><td><p>SYUR</p><p>5.29</p></td></tr>

<tr><td><p>Structure</p></td><td><p>ΒΙΙΑ</p></td></tr><tr><td><p>■ -is</p></td><td><p>^WITH27^N26^m4 ° 2</p></td></tr><tr><td><p></p></td><td><p>СС06Р</p></td></tr><tr><td><p></p></td><td><p>6.01</p></td></tr>

<tr><td><p>Structure</p></td><td><p>I'm scared</p></td></tr><tr><td><p>θ27 ^ 25θ ^ 4θ2</p></td></tr><tr><td><p>USSR</p><p>6.78</p></td></tr>

<tr><td><p>Structure</p></td><td><p>NOT IN</p></td></tr><tr><td><p>^WITH30^N32^you4 ° 5</p></td></tr><tr><td><p>/</p></td><td><p>СС06Р</p><p>5.36</p></td></tr>

<tr><td><p>Structure</p><p>θΊ'Ό-Αθνο</p></td><td><p>VIEW</p></td></tr><tr><td><p>° 26^Η25^Ν5 ° 2</p></td></tr><tr><td><p>SIXCP</p><p>4.82</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>'1</p><p>WNR</p></td></tr><tr><td><p>^WITH27^N24^C12^M4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>7.51</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Sirukiura</p></td><td><p>WINE</p></td></tr><tr><td><p>^WITH27^N24^WITH,2^M4 ° 2</p></td></tr><tr><td><p>ССООР</p><p>6.68</p></td></tr>

<tr><td><p>Structure</p></td><td><p>I'm scared</p></td></tr><tr><td><p>^ 26^N23^C1M4 ° 2</p></td></tr><tr><td><p>SCHOS</p><p>6.22</p></td></tr>

<tr><td><p>Strikuur</p></td><td><p>vis</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p>^with27^N26^m4 ° 3</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p>CSR</p><p>5.56</p></td></tr>

<tr><td><p>Structure</p></td><td><p></p></td><td><p></p></td><td><p>Vio</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p>^with25^N23^m5 ° 2</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p>CIOSR</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p>4.26</p></td></tr>

<tr><td><p>Structure</p></td><td><p>you are</p></td></tr><tr><td><p>^with29^N30^m4 ° 5</p></td></tr><tr><td><p>/</p></td><td><p>CSR</p><p>4.80</p></td></tr>

<tr><td><p>Structure</p></td><td><p>whirlpool</p></td></tr><tr><td><p>^with26^N22^and2^M4 ° 2</p></td></tr><tr><td><p>oh a</p></td><td><p>SCHOS</p><p>6.95</p></td></tr>

<tr><td><p>Structure</p></td><td><p>whiskey</p></td></tr><tr><td><p>θ29^Η28^Ν4 ° 2^δ</p></td></tr><tr><td><p>CIOSR</p><p>6.37</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>WOW</p></td></tr><tr><td><p>^with31^N30^m4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>6.64</p></td></tr>

<tr><td><p>Structure</p></td><td><p>ΒΙΟΙ</p></td></tr><tr><td><p>^ 29 ^ 28 ^ 4θ2^δ</p></td></tr><tr><td><p>CIOSR</p><p>6.37</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p><p>'OTh,</p></td><td><p>WOW</p></td></tr><tr><td><p>^WITH31^N29^SEVEN4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>7.41</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIA</p></td></tr><tr><td><p>^ε32^Η32^Ν4 ° 3</p></td></tr><tr><td><p>The USSR</p><p>6.75</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>ΒΙΟΕ</p></td></tr><tr><td><p>° 34^Η36^Ν4 ° 5</p></td></tr><tr><td><p>The USSR</p><p>5.B9</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VISUAL</p></td></tr><tr><td><p>^with30^N29^m5 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>5.45</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>VYRE</p></td></tr><tr><td><p>^WITH31^N28^SI2^M4 ° 2</p></td></tr><tr><td><p>The USSR</p><p>8.14</p></td></tr>

<tr><td><p>Structure</p><p>&lt;\ 'OT._L.</p></td><td><p>VIA</p></td></tr><tr><td><p>^WITH31^N28^SI2^M4 ° 2</p></td></tr><tr><td><p>SCHOS</p><p>6.48</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VION</p></td></tr><tr><td><p>^WITH31^N28^WITH,2^M4 ° 2</p></td></tr><tr><td><p>SCHOS</p><p>7.31</p></td></tr>

<tr><td><p>Structure</p></td><td><p>VIR6</p></td><td><p></p></td><td><p>Structure</p></td><td><p>VIRN</p></td></tr><tr><td><p>^WITH28^N26^C12^M4 ° 2</p></td><td><p>^WITH28^N26^C12^M4 ° 2</p></td></tr><tr><td><p>SSSR</p><p>6.41</p></td><td><p>CIOSR</p><p>7.24</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>VIRK</p></td><td><p></p></td><td><p>Structure</p></td><td><p>VIRI</p></td></tr><tr><td><p></p></td><td><p>WITH₂6^N26^N4 ° 2⁵</p></td><td><p></p></td><td><p></p></td><td><p>^ 26 ^ 26 ^ 4θ2®</p></td></tr><tr><td><p></p></td><td><p>SSSR</p><p>6.30</p></td><td><p></p></td><td><p></p></td><td><p>CIOSR</p><p>6.30</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>FAITH</p></td><td><p></p></td><td><p>Structure</p></td><td><p>VIRV</p></td></tr><tr><td><p>OGODOGO</p></td><td><p>^WITH28^N28^M4 ° 2</p></td><td><p></p></td><td><p></p></td><td><p>¢ 28 ^ 27 ^^ 4 ^ 2</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p></td><td><p></p></td><td><p></p></td><td><p>SSSR</p></td></tr><tr><td><p></p></td><td><p>6.57</p></td><td><p></p></td><td><p></p></td><td><p>7.34</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Siriukurl</p></td><td><p>B1RS</p></td><td><p></p></td><td><p>Structure</p><p>x- \</p></td><td><p>WIRA</p></td></tr><tr><td><p></p></td><td><p>^with29^N30^m4 ° 3</p></td><td><p></p></td><td><p>OusuL-O</p></td><td><p>^ε27^Η27^Ν5 ° 2</p></td></tr><tr><td><p></p></td><td><p>SSSR</p></td><td><p></p></td><td><p></p></td><td><p>SSSR</p></td></tr><tr><td><p></p></td><td><p>6.68</p></td><td><p></p></td><td><p></p></td><td><p>5.38</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Structure</p></td><td><p>VIRE</p></td><td><p></p></td><td><p>S'yurukiur</p></td><td><p>VIRP</p></td></tr><tr><td><p></p></td><td><p>^WITH31^N34^M4 ° 5</p></td><td><p></p></td><td><p>^WITH28^N26^WITH,2^M4 ° 2</p></td></tr><tr><td><p>/</p></td><td><p>SSSR</p><p>5.92</p></td><td><p></p></td><td><p>CIOSR</p><p>8.07</p></td></tr>

<tr><td><p>S'irukiur ha</p><p>b</p></td><td><p>VIAA</p></td></tr><tr><td><p>^with28^N26^m4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>5.76</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure _</p><p>• d</p><p>$</p></td><td><p>VIA</p></td></tr><tr><td><p>^with29^N28^m4 ° 3</p></td></tr><tr><td><p>O.O.S.R.</p><p>5.88</p></td></tr>

<tr><td><p>Structure _ύ</p><p>• g</p><p>/</p><p>b</p></td><td><p>whine</p></td></tr><tr><td><p>28^Η25 o'clock^{| N |}4 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>6.54</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure _</p></td><td><p>viola</p></td></tr><tr><td><p>^O27^Η25^Ν5 ° 2</p></td></tr><tr><td><p>CIOSR</p><p>4.57</p></td></tr>

<tr><td><p>Structure of the student</p><p>4</p></td><td><p>YOU</p></td></tr><tr><td><p>^with31^N32^m4 ° 5</p></td></tr><tr><td><p>USSR</p><p>5.11</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure ~</p><p>/</p><p>• 0</p></td><td><p>whine</p></td></tr><tr><td><p>028 ^ 012 ^ 02</p></td></tr><tr><td><p>CIOSR</p><p>5.61</p></td></tr>

<tr><td><p>Structure _l</p><p>/</p><p>l</p></td><td><p>wagg</p></td></tr><tr><td><p>Ο2 &amp; Η24ΟΙ2Ν4Ο2</p></td></tr><tr><td><p>ziozir</p><p>7.27</p></td></tr><tr><td><p></p></td></tr><tr><td><p>Structure at</p><p>· &lt;</p><p>55th</p></td><td><p>Jun</p></td></tr><tr><td><p>Oga ^ o ^^ Og</p></td></tr><tr><td><p>shhosrr</p><p>6.44</p></td></tr>

<tr><td><p>With trokiura uh</p></td><td><p>whiskey</p></td><td><p></p></td><td><p>Structure h</p></td><td><p>wow</p></td></tr><tr><td><p></p></td><td><p>026 ^ 24 ^ 402 ^</p></td><td><p></p></td><td><p></p></td><td><p>026^Η24N4 ° 25</p></td></tr><tr><td><p>AND</p></td><td><p>Si. SRF</p><p>5.50</p></td><td><p></p></td><td><p>£</p></td><td><p>CIOSR</p><p>eating</p></td></tr>

<tr><td><p>Structure</p><p>in</p><p>t</p></td><td><p>VICC</p></td></tr><tr><td><p>^with26^N22^m4 ° 2⁵</p></td></tr><tr><td><p>SIOOR</p><p>5.02</p></td></tr>

<tr><td><p>Structure -</p><p>.r</p></td><td><p>WEIGHT</p></td></tr><tr><td><p>^WITH31^N30^M4 ° 5</p></td></tr><tr><td><p></p></td><td><p>CIOSR</p></td></tr><tr><td><p></p></td><td><p>4.63</p></td></tr>

In accordance with yet another aspect of the present invention, there is disclosed a method of preparing a medicament for treating a condition associated with an excess of EID. This compound has the formula:

wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, SE, O, O, N, N, N, N, N, N, E,. E is selected from the group consisting of H, CH2, C2H3, C3H7, C4H9, C3HR7, and CH2SbN4-E (p--). Ei and E2 are selected independently from the group consisting of H, aryl, substituted aryl, cycloaryl, substituted cyclo-aryl, multi-ring cyclo-aryl, benzyl, substituted benzyl, and the like. The carriers are alkyl, aryl, CE, CH, OH, N, C, -COOO, COOH, and the like.

In accordance with yet another aspect of the present invention, there is disclosed a method for treating a mammal having a condition associated with an excess of EID. The method comprises administering to a mammal an amount of a compound sufficient for

wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino groups, alkylamino groups, nitro groups, cyano groups, CEs, OSEs, SOCH2, SOCHNRs and I \ INSOEi. R is selected from the group consisting of H, H2, C2H5, C3H7, C4H9, C6R1 and CH2SbN4-E (p--). R1 ​​and P2 are selected independently from the group consisting of H, aryl, substituted aryl, cycloalyl, substituted tsykpoarylu, multiple-tsykloarylu, benzyl, substituted benzyl, alkyl, tsykpoalkilu substituted tsykpoalkilu, multiple-tsykpoalkilu, aliphatic compounds coupled with rings cyclopropyl, substituted cyclopropyl, tsykpobutylu substituted tsykpobutylu, cyclopentyl, zamischenohotsyklopentylu, tsykpoheksylu substituted tsykpoheksylu, tsykpoheptylu, Zama cycloheptyl, bicycloheptyl, bicyclooctyl, bicyclononyl, substituted bicycloalkyl, adamantyl substituted adamantyl and the like, in which at least one of the radicals R1 and P2 is an aromatic group. The substituents are alkyl, aryl, SE, CH, OH, n, OH, COOP, COOH, and others like that.

In an embodiment of the method disclosed above, at least one additional active ingredient may be taken in combination with the administration of the compound. The additional active ingredient may be combined with said compound in a pharmaceutically acceptable diluent and administered simultaneously to a mammal. An additional active ingredient may be a short-acting b2-adrenergic agonist selected from the group consisting of terbutaline andalburetrole. In one embodiment, the additional active ingredient may be a long-acting b2-adrenergic agonist selected from the group consisting of salmetherol and formoterol or antihistamine selected from the group consisting of loratadine, azelastin and ketotriphen. In yet another embodiment, an additional active mammal may be an inhibitor of phosphodiesterase, an anticholinergic agent, a corticosteroid,

The compound is usually taken at a dosage of from about 0.01 mg to about 100 mg per kilogram body weight per day divided doses of the compound for at least two consecutive days with regular periodic intervals.

Other variants within the scope of the present invention may be more fully understood from the following detailed description.

Detailed description of the best performance

The present invention is directed to low molecular weight IEDE inhibitors (synthesis and / or release) useful in the treatment of allergy and / or asthma, or any diseases in which IDE is pathogenic. The specific compounds discussed herein have been identified for their ability to suppress the levels of the IEDs both in the tests of the νίνο and in the tests. The development and optimization of the regimens of clinical treatment can be traced by specialists according to the descriptive tests below νίνο and πίνο.

Test Ex νίνο

This test begins with the initiation of the antigen and the νίνο and measures the secondary reaction of the antibody and antibody. The basic protocol has been documented and optimized for a range of parameters, including: the dose of antigen for initiation, the time interval after initiation, the number of cultivated cells and the concentration of antigen to detect the secondary reaction of Eid (and other immunoglobulins) and i niacin, a fetal tick syndrome (FBS) provides the optimal response of the Ida epidemiology, the importance of C1E4 + -initiated T-cells of the ip-specific B-kpitin, as well as the specificity of the EbISA test for IDE (MagnesiumApAcAc, SeIiIiTiTiPiOd 5: 471-4 89 (1991), incorporated herein by reference).

The actual protocol used for this project was adapted for analysis with greater productivity. BABB / sBuI mice were immunized intraperitoneally with 10 μg of DNA-CBN absorbed by 4 mg of bellies and were killed in 15 days. The spleens were withdrawn and homogenized in a tissue defibrillator, washed twice and contained in 1EMEM, supplemented with 10% FBS, 100 don / ml penicillin, 10μg / ml streptomycin and 0.0005% 2-mercaptoethanol. The cultures of the spleen cells (2-cells of cells / ml, 0.2 ml / cell in four copies, 96-cell plates) were established in the presence or absence of NN-KBN (10 ng / ml). Test compounds (2 μg / ml and 50 ng / ml) were added to a spleen cell culture containing the antigen and incubated at 7 ° C for 8 days in an atmosphere of 10% CO2.

The superficial layer of culture was harvested after 8 days, and the immunoglobulins were measured by modifying a specific isotype selective test of EBIS described in Magnesia and apS KαίZ (see above). The test was modified to facilitate high performance. EBISA plates were prepared by coating the NR-KBN overnight. After blocking with a bovine serum albumin (ABS), the aliquot of the surface layer of each culture was diluted (1: 4 in phosphate buffered saline solution (ABS) with ABS, sodium azide and Tumep 20), added to the plates of the EbISA and incubated overnight in the empty box at 4 ° C. Eid levels were calculated after successive incubations with biotinilated intramuscular Goat Goat (L-SAME), AR-streptavidin and substrate.

The same method was used to measure the antigen-specific IDSI, except that the surface shariculture was diluted 200-fold, and L-SAME was replaced with a biotinylated antimusted IDC goat (L-

SAMSI). IdS2a was measured in plates of EBIS coated with NN-KBN, followed by dilution of a 1: 20 surface culture layer and incubation with biotinylated antimyacha IDS2a goat (L-SAMSA2a). The quantity of each isotype was determined by comparison with the standard curve. The level of certainty of the total antibodyapproximately was 200-400 pg / ml, and there was cross-reactivity, in volume less than 0,001%, with any othermizotype Id in EBISL for IDE.

Test Ip νίνο

The compounds whose activity was detected in the νίνο test (above) were additionally tested for activity when inhibiting the reactions of IdE and νίνο. Mice that received irradiation of a low dose prior to immunization with a carrier, showed an increased reaction of IDE to sensitization by antigen in 7 days. The acceptance of test compoundsaccumulated immediately before and after sensitization antigen, measured the ability of these modules to suppress the reaction of IDEA. The levels of IdE, IDCI and IdS2a in serum were compared.

Female females of VLBV / sVI mice were irradiated with a dose of 250 rads 7 hours after the start of the daylight cycle. Two hours later, the mice were immunized intraperitoneally with 2 μg of KI_N in 4 mg of bellies. After 6 days, injections of drugs began for two to seven days, once or twice a day. Usually intraperitoneal injections and oral oral administration were made as suspensions (150 μp / injection) in saline solution with 10% ethanol and 0.25% methylcellulose. Each group consisted of 5-6 mice. On the second day of drug administration, 2 μg of DNA-CBN was injected intraperitoneally in 4 mg of colostrum, immediately after morning drug injection. Mishamulyatsya blood 7-21 days after the introduction of NN-KBN.

Antigen-specific antibodies IdE, IdSi and IdS2a were measured using EBISA. Periorbital specimens were centrifuged at 14000 rpm for 10 minutes; the elements that had risen to the surface were diluted five times in saline and centrifuged again. The antibody concentrations of each specimen were determined using EBISA four dilutions (in triplicate) and compared with the standard curve: anti-IDP (1: 100 to 1: 800), anti-IDP IdS2a (1: 100 to 1: 800), and anti -DNS Idris (1: 1600to 1: 12800).

Diazyl benzimidazole inhibitors go

Several species, described by the generic formula, were synthesized, and their effectiveness was evaluated in the lowering of the IED in the νίνο and in the νίνο tests.

wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CE₃, OSE₃, NO2, SOHNP, and NOSPO1. K is selected from the group consisting of H, CH2, C2H5, C3H7, C4H9, CH2R1 and CH2S6N4-RF-). B · and K2 are selected independently from the group consisting of H, aryl, substituted aryl, cycloaryl, substituted cycoporyl , multiple-tsykpoarylu, benzyl, substituted benzyl, alkyl, cycloalkyl, substituted cycloalkyl, multiple-cycloalkyl, aliphatic compounds coupled with rings, tsykpopropilu substituted cyclopropyl, tsykpobutylu substituted tsykpobutylu, cyclopentyl, zamischenohotsykpopentylu, cyclohexyl, substituted cyclohexyl, tsykpoheptylu, Deputy schenoho tsykpoheptylu, bitsykpoheptylu, bitsyklooktylu, bitsykpononilu substituted bitsykloalkilu, adamantyl, substituted adamantylui the like, wherein at least one of the radicals and 1¾-ι is aromatic group. The substituents are alkyl, aryl, SEZ, CH, OSN, OH, CM, SOOK, COOH, and the like.

Synthesis of combinator library

The diacyl benzimidazole compounds of the present invention have been prepared by such reactions with synthesis in which the desired acid chlorides are selected from the groups R1 and R2 listed in the Table.

6

Synthesis of compound 3: 4-nitro-1,2-phenylenediamine (10 g, 65.3 mmol) and 4-aminobenzoic acid (8.95 g, 65.3 mmol) was placed in a round-bottomed flask and phosphorus oxychloride (95 mL) was slowly added. The reaction mixture was allowed to stir under counterflow conditions. After 18 hours, the reactions allowed to cool, and then slowly poured into a water-ice mixture in the Erlenmaier flask under vigorous mixing. A greenish-yellow precipitate fell out, which was then filtered and washed off by a large amount of water. The residue was then dried to give 16.9 g of a crude product. Mass spectral analysis (positive ion) showed the presence of compound 3.

Synthesis of Compound 4: Benzimidazole 3 (800 mg, 3.14 mmol) was dissolved in dry pyridine (5 ml) in a scintillation vessel, and the necessary acid chlorides (1.1 eq) were slowly added. Reactions were carried out in an oven at 60 ° C. By

For 16 hours, the reaction was cooled to room temperature, and distilled water was added. A precipitate was filtered off, washed with water and dried up in the air. Water sharecreasted with ESAs Ac (6x50ml), dried over anhydrous No. 2504, and the solvent was removed in vacuo to give a colored solid. By positive-ion mass spectroscopy it was found that the required monoacylate product is present in the initial sediment, as well as in the organic layer. Therefore, the solid residues obtained were combined and used as such for the recovery step.

Recovery of Compound 4: Raw monoacylation of nitrobenzimidazole 4 (1.22 g, 3.40 mmol) was dissolved in MeOH (20 mL), and a minimum amount of TNE was added for complete dissolution. A catalytic amount of 10% Pb in C was added, and the solution degassed and remained stirred under pressure of 3.4 atm in the atmosphere of No. 4 for an hour. After completion of the reaction, after observation by thin-layer chromatography, the reaction mixture was filtered through selitol and the solvent was removed under reduced pressure to give 979 mg of a blue-colored residue.

General organic analyzes

HPI-C mass spectrographic data were obtained with the help of Sizol zeti-rgER NRII-C with UV detector Siisol 170 IZiobe Agga and mass spectrographic detector PE 5sieh ARI 100І_С. The Shaiges 600E detector from the UHFs 490E was also used to record the HPI_S data. The compounds were eluted with a gradient of CH2CI2 (from 0.0035% TEA) and H2O (from 0.01% TEA). Both HPI-C tools used Columns Abualidi C18 60A 5μ50mm x 4.6 mm of the company TIozol Ilzigiteli Sutrat. Mass spectra were obtained by direct injection and electro-aerosol ionization on a mass spectrograph detector PE 5sieh ARI 100І_С. Thin-layer chromatography was made using aluminum coated plates Megsk 60E-254. Flash chromatography was performed on silica gel Megsk 60 (230-400 mesh), purchased from the company EM 5SePiIiTiS.

Synthesis of symmetric diamides

The symmetrical diacyl benzimidazole compounds of the present invention were generally prepared from 2- (4-aminophenyl) -5-aminobenzimidazole, which was formed by the restoration of 2- (4-nitrophenyl) -5-nitrobenzimidazole.

N

2- (4-pyrimidone Naph) -bipyridine-2-nitrobenzene

2- (4-nitrophenyl) -6-nitrobenzimidazole

Dinitrobenzimidazole was prepared as follows: a mixture of 4-nitrophenylenediamine (6.4g, 41.83mmol) and 4-nitrobenzoic acid (7.86g, 47mmol) was dissolved in ROSI3 (250ml) and heated to an outflow for 2 hours. The reaction mixture was cooled, poured onto ice and stirred for 30 minutes. The solid substance formed, filtered and washed with methanol and sodium bicarbonate to removeacid, which did not react, and left to dry overnight, giving the expected product in the form of browncrystalline solid (5.8g). The product was determined using an aerosol mass spectrometry (melting point&gt; 300 ° C).

2- (4-aminophenyl) -5-aminobenzimidazole was prepared by suspending the aforementioned solid (75g) in TNE (75ml) to which Pb-C (10% Pb by weight) was added. The flask was purged with hydrogen and stirred overnight under a glass hood with hydrogen. Thin layer chromatography and mass spectrometry showed that the starting material was still in place, so the reaction was left to continue during the weekend. Thin layer chromatography showed completion of the reaction, the reaction was filtered through selitate and washed with methanol. The solvent was removed under reduced pressure, with the formation of a dark brown solid (0.37 g), which was used without further purification.

Alternatively, 2- (4-aminophenyl) -5-aminobenzimidazole was prepared by this reduction: 2- (4-nitrophenyl) -6-nitrobenzimidazole (8.9 g, 31 mmol) was suspended in concentrated NCl (100 mL), to which was added tin chloride (42.3 g, 180 mmol). The reaction mixture was heated to an outflow for 5 hours. The mixture was cooled to room temperature and the hydrochloric acid salt of the expected product was precipitated with the addition of ethanol. The resulting solid was filtered, re-dissolved in water, and the solution was digested by the addition of concentrated ammonium hydroxide. The resulting precipitate was filtered and dried overnight under vacuum to give the expected product as a gray solid (6,023g, 26.9mmol, 87%). The product was determined by electro-aerosol mass-spectrography and HPI-C (temperature melting 222-227 ° C).

2- (4-aminophenyl) -5-methoxy benzimidazole was synthesized from 2- (4-nitrophenyl) -5-methoxy benzimidazole prepared as follows: 1,2-diamino-4-methoxybenzene (1.26 g, 10 , 0 mmol) was mixed with 4-nitrobenzoic acid (1.67 g, 9.8 mmol) and dissolved in ROSI3 (10 mL), and heated to an outflow for 2.5 hours. The reaction mixture cooled down and carefully poured over the ice. The resulting solids were filtered off, washed nsNOEe and used without further purification.

2- (4-aminophenyl) -5-methoxy benzimidazole was prepared by dissolving 1 g of the aforementioned nitrobenzimidazole in 30% of 25? 9H2O (20 ml) with stirring at room temperature for 21 h. The reaction mixture was diluted with water and extracted with ESA. The combined organic extracts were dried on sodium sulfate and concentrated in vacuo. The product was determined using mass spectroscopy.

2- (4-aminophenyl) -5,6-dichloro benzimidazole was synthesized from 2- (4-nitrophenyl) -5-dichloro benzimidazole to be prepared as follows: 1,2 diamino-4,5-dichlorobenzene (1,68 g , 10.0 mmol) was mixed with 4-nitrobenzene to a solution (1.58 g, 9.3 mmoles), dissolved in ROSI3 (10 ml), and heated to an outflow for 2.5 hours. The reaction mixture cooled down and carefully poured over the ice. The resulting solidsfiltered, washed away with NNOS₃ and used without further purification.

2- (4-aminophenyl) -5,6-dichloro benzimidazole was prepared by dissolving 1 g of the aforementioned nitrobenzimidazole in 30% of 25? 9H2O (20 ml) with stirring at room temperature for 21 h. The reaction mixture was diluted with water and extracted with ESA. The combined organic extracts were dried on sodium sulfate and concentrated in vacuo. The product was determined using mass spectroscopy.

2- (4-aminophenyl) -7-methyl benzimidazole was synthesized from 2- (4-nitrophenyl) -7-methyl benzimidazole to prepare it by mixing 1,2-diamino-3-methylbenzene (1.24 g, 10.0 mmol ) from 4-

nitrobenzoic acid (1.69 g, 9.8 mmol), dissolution in ROSI3 (10 mL), and heating for efflux for 2.5 hours. The reaction mixture cooled down and carefully poured over the ice. The resulting solid was filtered, washed with NNOSA and was used without further purification.

2- (4-aminophenyl) -7-methyl benzimidazole was synthesized by dissolving 1 g of the aforementioned nitrobenzimidazole in 30% of 25? 9H2O (20 ml) with stirring at room temperature for 4.5 hours. The reaction mixture was diluted with water and extracted with ESA. The combined organic extracts were dried on sodium sulfate and concentrated in vacuo. The product was determined using mass spectroscopy.

2- (4-aminophenyl) -6-methyl benzimidazole was synthesized from 2- (4-nitrophenyl) -6-methyl benzimidazole to be prepared by mixing 1,2-diamino-4-methylbenzene (1.24 g, 9.8 mmol ) from 4-

nitrobenzoic acid (1.6 g, 9.9 mmol) and dissolution in ROSI3 (10 mL) and heating for efflux for 2.5 hours. The reaction mixture cooled down and carefully poured over the ice. The resulting solidsfiltered, washed No. HCO3 and used without further purification.

2- (4-aminophenyl) -6-methyl benzimidazole was synthesized by dissolving 1 g of the aforementioned nitrobenzimidazole in 30% of N28-9H2O (20 ml) with stirring at room temperature for 4.5 hours. The reaction mixture was diluted with water and extracted with ESA. The combined organic extracts were dried on sodium sulfate and concentrated in vacuo. The product was determined using mass spectroscopy.

2- (4-aminophenyl) -5,6-dimethyl benzimidazole was synthesized from 2- (4-nitrophenyl) -5,6-dimethylbenzimidazole, which was prepared by mixing 1,2-diamino-4,5-dimethylbenzene (1 , 38g, 10.1mmol) with 4-nitrobenzoic acid (1.69g, 9.9mmol) and dissolving in ROSIZ (10ml) and heating for evaporation for 2.5 hours. The reaction mixture cooled down and carefully poured over the ice. The resulting solidsubstance was filtered, washed with NNOSAs and used without further purification.

2- (4-aminophenyl) -5,6-dimethyl benzimidazole was synthesized by dissolving 1 g of the aforementioned nitrobenzimidazole (31.1) in 30% of 28? 9H2O (20 ml) with stirring at room temperature for 4.5 hours. The reaction mixture was diluted with water and extracted with ESA. The combined organic extracts were dried on sodium sulfate and concentrated in vacuo. The product was determined using mass spectroscopy.

2- (4-atipore-1 -5, b-diphenyl) piperidine

2- (4-aminophenyl) -5,6-dimethyl benzimidazole

The next preparation of symmetric diamides was carried out in one of the following ways:

Method A: 2- (4-aminophenyl) -6-aminobenzimidazole (1 mmol) was suspended in THP (5 ml), to which IIEA (2.5 mmol) was added, and the mixture was cooled to -78 ° C. To the above-mentioned cooled mixture was added silychloride (2.5 mmol), and the mixture was allowed to warm up to room temperature overnight. To the reaction was added water (2 ml) and extracted with the help of ELAs. The combined organic extracts were washed with combined HNO3 (water) and concentrated under reduced pressure. The resulting residue was purified on silica gel (hexanes / ESAs or MENON / CH2Cl2) or by reverse-phase HPI-C (OH3θN / H2θ).

Method B: 2- (4-aminophenyl) -6-aminobenzimidazole (1 mmol) and 0MAR (cat.) Were dissolved in pyridine (5 mL). To the above solution, acid chloride (2.5 mmol) was added and the reaction was stirred overnight at 60 ° C. The reaction was cooled to room temperature, and water was added to precipitate the product. The solids collected were collected by filtration, washing the solid with hexanes and water, and NθΗΟθ3 (water). The resulting residue was purified on silica gel (hexanes / EuAc or MENON / CH2Cl2) or using a reverse-phase HPI-C (CH2CH2O).

Method B: 2- (4-aminophenyl) -6-aminobenzimidazole (1 mmol) was suspended in THP (10 mL) to which K2CO3 (2.5 mmol) in water (0.5 mL) was added and the mixture cooled to -78 ° C. To the above-mentioned cooled mixture, acid chloride (2.5 mmol) was added, and the mixture was left to warm to room temperature at night. Water was added to the reaction (10 ml) and extracted with ESA. Combined organic extracts were rinsed together with NaHCO3 (water) and concentrated under reduced pressure. The resulting residual was purified on silica gel (hexanes / ESAs or MESON / CH2CI2) or by means of a reverse-phase HPI-C (SOSO).

Method G: Carboxylic acid (2.2mmol), E1EC (2.2mmol) and OMAR (Cat.) Dissolved in hotpyridine. To the aforementioned solution was added 2- (4-aminophenyl) -6-aminobenzimidazole (1 mmol), and the mixture warmed overnight to 60 ° C. The cooled reaction mixture was split between water and ESA. The organic layer was washed with NaHCO3, dried over Na 2 O 4, and concentrated in vacuo. The resulting residual was purified on silica gel (hexanes / ESAs or MESON / CH2CI2) or by means of a reverse-phase HPI-C (SOSO).

Types of diacilic benzimidazoles

They were synthesized and tested for their ability to suppress the IEDs of such species, covered by the uncovered generic formula. These types are listed above in the "Disclosure" section.

The activity of lowering regulation is

All revealed species have been protesting for their ability to suppress the IED as in the test νίνο, and also in the νίνο test. All of them were active in both tests. The activity (IC50) of the species in the test ex νίνο were in the range from about 100 pM to 1 nM. In the ip νίνο test, the dose of IC50 was in the range of about 100 μg / kg bodyweight per day to about 10 mg / kg body weight per day. Diazyl benzimidazole compounds as a whole were more potent than monoacyl compounds.

Inhibition of the reaction of IDE

The inhibitory activity of small molecules according to the present invention has been protested in the experiments described above and in vivo tests. All of the above compounds were active in suppressing the reaction of IDE. In the test, νίνο I-XI generations gave 50% inhibition at concentrations of 1 pM to 10 μM. In the ηηνίνο test, the compounds were effective at concentrations ranging from less than about 0.01 mg / kg / day to about 25 mg / kg / day when taking divided doses (for example, from two to four times a day) for at least two or seven consecutive days. Thus, Thus, low molecular weight inhibitors of the present invention are considered to be useful in reducing the antigen-induced increase in the concentration of IED and, therefore, in the treatment of EID-dependent processes, such an allergy in general and allergic asthma in particular.

Treatment regimens

The number of compounds of the inhibitor Eid, which may be effective in treating an allergy or condition, will depend on the nature of the violation and can be determined by standard clinical techniques. The exact dose that it is worth to use in this situation will also depend on the choice of the compound and the severity of the condition, and should be selected in accordance with the viewpoint of the practitioner and the condition of each patient. Corresponding doses can be determined and corrected by a practicing physician based on dose-response relationships between patient levels, as well as standard lung and hemodynamic changes indices. In addition, the experts understand that variations in the dose can be determined without excessive experiments by passing the protocol (protocols) discussed here for the purpose of screening and screening (see, for example, Nazadada et al., J. Massi, Spit 40: 395-407 (1997) and Oiyituugi her ai., Yipi. Yeah IttipspagtasisI. 15: 573-579 (1993); using similar experiments νίνο and ίηνίνο tests to determine the dose dependence - a reaction to suppress Eid derivatives of naphthalene; Included are links using the link).

At first, the acceptable dosage of the compounds generally ranges from about 0.001 mg to about 300 mg per kilogram of body weight per day divided doses, more preferably between about 0.01 mg and 100 mg per kilogram of body weight per day divided doses. The compounds are preferably administered systemically in the form of pharmaceutical formulations suitable for such routes as oral, aerosol, intravenous, subcutaneous, or any other route that may be effective in providing a systemic dosage of the active compound. The pharmaceutical formulations are well known in the art. Treatment regimen preferably contains a periodic treatment. Moreover, long-term therapy may be prescribed, if it turns out that allergic reactions are triggered by the long-term exposure of the allergen (allergens). Reception once a day or two times a day was effective in suppressing the reaction of IDE to the emergence of one antigen in animals, if this method was continuous for two or seven consecutive days. Thus, in a better embodiment, the compound is taken for at least the following two days with regular periodic intervals. However, the treatment regimen, including the frequency of dose administration and the duration of treatment, may be determined by a practitioner and modified as necessary to ensure optimal lowering of the IED, depending on the nature of the allergen, the dose, frequency and duration of exposure to the allergen, and from the standard clinical indices. in a better embodiment, the compound is taken for at least the next two days with regular periodic intervals. However, the treatment regimen, including the frequency of dose administration and the duration of treatment, may be determined by a practitioner and modified as necessary to ensure optimal lowering of the IED, depending on the nature of the allergen, the dose, frequency and duration of exposure to the allergen, and from the standard clinical indices. in a better embodiment, the compound is taken for at least the next two days with regular periodic intervals. However, the treatment regimen, including the frequency of dose administration and the duration of treatment, may be determined by a practitioner and modified as necessary to ensure optimal lowering of the IED, depending on the nature of the allergen, the dose, frequency and duration of exposure to the allergen, and from the standard clinical indices.

In one embodiment of the present invention, a depressing Eid compound may be taken in combination with one or more other disclosed low molecular weight inhibitors to perform an optimal lowering of the patient's EidE response. Additionally, it is anticipated that one or more compounds under the actual inventions may be taken in combination with other, already known or expanded later therapies for treatment as a cause underlying allergies or asthma and their acute symptoms. Such combination therapies as contemplated in the scope of the present invention include the mixing of one or more low molecular weight inhibitors with one or more additional ingredients, the effectiveness of which is known to reduce at least one of the symptoms of a disease state.