Nicotine receptor agonists and methods of using thereof for treating inflammatory diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

 

Cross-reference to related applications

Partial continuation of application No. 10/890987 filed July 15, 2004, which is a partial continuation of application No. 10/469999, filed February 24, 2004, which is a national application of PCT/CA02/00412, received 25 March 2002; these applications are fully incorporated in the present description by reference.

The level of technology

a) the technical Field to which the invention relates

The present invention relates to the treatment of inflammatory diseases, including various lung diseases, by introducing agonists nicotine receptors or their analogs and derivatives.

b) Description of the prior art

Due to the fact that a healthy man or woman each hour inhales more than one cubic meter of air, the defense mechanisms of the lungs usually deal with large numbers of particles, antigens, infectious agents, toxic gases and fumes present in the air we breathe. As a result of interaction of these particles with the immune system and other defense mechanisms of the lungs occurs-controlled inflammatory reaction, which is usually protective and beneficial for the body. Typically, this process is self-regulating, maintaining the integrity of the surface of the respiratory epithelium is Uta and alveoli, where gas exchange occurs. However, in some cases, there is no mechanism for such regulation of the inflammatory response, and therefore increases the likelihood of tissue damage. Depending on the type of environmental exposure, genetic predisposition and the presence of a number of pathogenic factors on different parts of the respiratory sent too many cells of the inflammatory infiltrate, causing discomfort or illness.

Inflammatory response to inhaled or internal stimuli is characterized by a nonspecific increase in vascular permeability, release of mediators of inflammation and chemotaxis, including histamine, eicosanoids, prostaglandins, cytokines and chemokines. These mediators modulate the expression of molecules that cause adhesion of leukocytes with endothelial cells, involving cells of the inflammatory infiltrate present in the blood.

More specific inflammatory response involves recognition of inhaled antigens and the induction of acute and specific immune response against these antigens. This reaction causes asthma, allergic pneumonitis (HP) and possibly sarcoidosis. Impaired repair mechanisms following the defeat of the lung may contribute to Vozniknovenie the Yu fibrosis and loss of function in the case of asthma, fibrosis of the lung, chronic obstructive pulmonary disease (CPD) and chronic allergic pneumonitis (HP).

In scientific literature it was noted earlier that allergic pneumonitis much less likely to occur in smokers than non-smokers (1-4). Sarcoidosis also less common in smokers than non-smokers (5, 6). The mechanisms that determine the favorable effects of cigarette smoke on the development of allergic pneumonitis and other inflammatory diseases is still not known but may be related to the immunomodulatory effects of nicotine. There are clinical data on asthma de novo or worsening after Smoking cessation. It is difficult to prove the validity of this phenomenon, while the protective effect of nicotine in the prevention or treatment of asthma, apparently, are outweighed by the negative effects of tobacco smoke, containing thousands of components.

Protective effect of Smoking was also demonstrated in the case of other diseases, among which the most studied is ulcerative colitis, inflammatory bowel disease (7, 8). Nicotine has been used successfully in the treatment of this disease (9, 10). Other studies were aimed at identifying the possible therapeutic value of nicotine in the treatment of Alzheimer's disease and P is arkinson (11, 12).

The nicotine receptors are pentamerone composed of five polypeptide subunits, which act as licenzawiki ion channels. When the binding of the ligand to the receptor is the conformational change of the specified polypeptide, resulting opens the Central channel that allows sodium ion to move from the extracellular fluid into the cytoplasm. Identified four types of subunits: α, β, γ and δ. The receptor may consist of any combination of the above four types of subunits (13). The results of recently completed studies have shown that alveolar macrophages (AM) can Express the α subunit-7 (14), while the epithelial cells of the bronchi Express subunit α 3, α 5 and α-7 (15) and lymphocytes Express subunit α-2, α-5, α-7, β-2 and β-4 (14). Fibroblasts (16) and smooth muscle cells of the respiratory tract (17) also Express these receptors. Thus, the resident cells of the lung (S, dendritic cells, epithelial cells, fibroblasts, etc.) and cells involved in the case of inflammatory diseases (lymphocytes, polymorphonuclear cells), Express receptors for nicotine.

Activation of nicotine receptors in lymphocytes affects the transmission of signals within the cell, causing incomplete cell activation. Treatment with nicotine actually stand which increases the activity of protein kinases, which in turn increases the activity of phospholipase A2 (PLA2). PLA2 is responsible for splitting postinst-2-phosphate (PIP2) to produce Inositol-3-phosphate (IP3) and diacylglycerol (DAG) (18, 19). The constant presence of IP3 in the cage, apparently, leads to desensitization of the reserves of calcium and causes depletion (19). This observation helps to explain the fact that lymphocytes exposed to nicotine, does not release sufficient amounts of calcium in the cytoplasm, is required for the activation of transcription factors, such as NFk-B (20).

Nicotine, the major pharmacological component of cigarette smoke is one of the most well-known agonists of receptors nicotine (21). This natural substance has been well studied anti-inflammatory and immunosuppressive properties (22) and may have antifibrosis properties (23). The smoke of cigarettes with high nicotine content has more pronounced immunosuppressive effect on animals than smoke cigarettes with low nicotine content (24). In addition, the effect of nicotine on rats inhibits a specific reaction of the antibodies to the antigens and induces tolerance of T cells (25). Despite the increase in the number of alveolar macrophages (AM) in smokers, they have a lower capacity to secrete inflammatory cytokines under the influence of entoto is of Sina ((20, 25, 26)), and nicotine, apparently, is a necessary component of this inhibition (26). In one study it was shown that peripheral blood lymphocytes of smokers are characterized by high expression of FAS ligand (FASL) and that nicotine increases the expression of FASL in lymphocytes of non-smokers, suggesting that nicotine may affect apoptosis (27). In addition, it is known that nicotine exerts an inhibitory effect on the proliferation and production of extracellular matrix in gingival fibroblasts human in vitro (23). It is interesting to note that the effects of nicotine, probably increases the expression of nicotine receptors (28). Nicotine by itself is a safe substance, not causing any lasting side effects (48-49). A cause of lung diseases, heart and arteries, caused by smoke, is not the nicotine, and thousands of other chemicals present in the inhaled smoke. The main problem is that nicotine crosses the blood-brain barrier, causing addictive. The harmful effects of cigarette smoke is evident. Although nicotine is not related to the toxic effects of cigarette smoke, it is still associated with such exposures.

Agonists nicotine can reduce the activation of T cells; indeed it is established that nicotine affects Express the T-cell co-stimulating molecules CD28 and CTLA4 (29).

The path of costimulatory B7/CD28/CTLA4 plays a major regulatory role in the activation of T cells and homeostasis (30, 31). This mechanism includes two transmission signals. A positive signal causes the binding of B7 molecules (CD80/CD86) with receptors CD28 T cells, resulting in potentiation of responses T-cell proliferation, activation, and expression of cytokines and survival) (32). The negative signal causes the interaction of B7 with CTLA4 on activated T-cells, resulting in the weakening of the reactions of T cells (33, 34). The balance between the signals produced by CD28 and CTLA4, can alter the activation of T cells.

In the scientific literature have previously described that in humans (35) and mice (36), with an active form of allergic pneumonitis (HP), there is an increase in the expression of B7 molecules in alveolar macrophages (AM). In addition, it was found that blockade of the path of costimulatory B7-CD28 in mice inhibited lung inflammation (36). The results showed that the expression of B7 molecules in alveolar macrophages lower in smokers than non-smokers, and that infection with influenza virus in vitro can increase the expression of B7 in the alveolar macrophages of healthy humans in the absence of such effect in the alveolar macrophages of smokers, although it is not known whether this is a consequence of the effects of nicotine or other substances present in cigarette smoke (35). The increase of B7 molecules was also found in the case of asthma (37, 38) and sarcoidosis (39).

Epibatidine is the most potent agonist nicotine, currently known (40). The specified agent has anti-inflammatory and analgesic properties. Its analgesic effect in two hundred times higher than that of morphine (40). It is also known that this molecule inhibits the proliferation of lymphocytes in vitro (41). Linking epibatidine with is a nonspecific receptor (42). Unfortunately, epibatidine toxic side effects mainly on the cardiovascular system and the Central nervous system that does not allow him to use as anti-inflammatory agents for the treatment of lung diseases (40).

Dimethylphenylpiperazinium (DMPP) is a non-specific synthetic agonist nicotine (13). This substance has almost the same effect on the receptor that nicotine, depending on the type of cells involved in the stimulation (43). The advantage of this substance in comparison with nicotine and other agonists nicotine is that its chemical configuration prevents the penetration through the blood-brain barrier, does not thereby causing addiction or other effects on the Central nervous system (13). Anti-inflammatory properties DMPP not enough good about isany in the scientific literature. However, it is established that the continuous application of an in vivo can reduce the number of leukocytes, to reduce cytokine production by splenocytes and reduce the activity of natural killer cells (44). In addition, it was investigated the effect of DMPP on smooth muscle cells of the respiratory tract. DMPP causes an initial transient contraction followed relaxing effect when the contacting of the cells with the indicated agonist over a longer period of time (45). Bronchodilatory effect does DMPP particularly suitable for the treatment of asthma, as currently on the market there are other potent bronchodilators (B2 agonists). However, the properties of the above receptor agonist nicotine are important because this drug can be administered safely subjects with asthma and COPD, due to its anti-inflammatory properties. In addition, there is no obvious evidence that DMPP has any toxic effects on major organs such as heart, brain, liver or lungs.

Corticosteroids are potent anti-inflammatory drugs. Their systematic use causes severe side effects that make it impossible for their continued use. Inhalation bad absorber is that steroids are suitable for the treatment of airway inflammation. When used in low doses, these drugs have little side effects or no side effects. However, higher doses increase the likelihood of candidiasis of the mouth, paralysis of the vocal cords, cataracts, and osteoporosis. Inhalation steroids do not affect the interstitial tissue of the lungs and do not cause antifibrotic action (57).

The recently established drugs, such as anti-leukotrienes, suitable for the treatment of asthma in some cases (58), but have no effect in the treatment of COPD and other lung diseases. These drugs have anti-inflammatory properties only in relation to inflammation caused by leukotrienes (59). In the treatment of diseases of the interstitial tissue of the lungs, such as IPF, sarcoidosis, HP and POOR mainly use systemic corticosteroids. This treatment is effective in the case of some inflammatory diseases, but, unfortunately, causes serious side effects and does not eliminate fibrotic changes. Immunosuppressive agents such as cyclophosphamide and azathioprine, sometimes used in the treatment of severe forms of IPF, but their therapeutic value has not been confirmed, and in most cases is very limited (60). Pulmonary fibrosis is essentially the C is a progressive disease, not curable, the majority of subjects suffering from IPF die from this disease (61).

Despite advances in the treatment of inflammatory diseases, including inflammatory diseases of the lungs, the application of existing drugs or agents often cause unwanted side effects. For example, inflammation due to COPD, apparently, is resistant to corticosteroids, there is therefore a need to develop new anti-inflammatory drugs for the treatment of this disease (46).

Similarly, despite the use of corticosteroids and other immunosuppressive remedies for the treatment of pulmonary fibrosis, have only a minimal effectiveness (47).

Thus, there is a need for a new and reliable methods of treatment of inflammatory diseases, including inflammatory diseases of the lungs, which would alleviate the symptoms of these diseases without causing any side effects.

The invention

The present invention relates to a new method of treatment of inflammatory diseases. In particular, the object of the invention is a new method of treatment of inflammatory lung diseases by introducing an agent that binds to a receptor nicotine or modulates the function of the receptor nicotine is, such as receptor agonists nicotine, their analogs or derivatives.

One object of the present invention is a method of treatment or prevention of inflammatory diseases of the lung, which includes the introduction of an effective amount of a compound that modulates the function of receptors nicotine.

Another object of the present invention are compounds of the formula:

where R1and R2independently denote a lower alkyl with 1-10 carbon atoms;

Ha denotes CH or N;

Ya means one or more substituents selected from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylthio with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, alkanol with 1-6 carbon atoms, aralkyl, aryl with 6-10 carbon atoms and 3 to 10-membered heterocycle;

n means an integer from 0 to 2;

J means the counterion.

Another object of the present invention is a pharmaceutical composition for the treatment of inflammatory diseases of the lungs, which contains the receptor agonist nicotine and pharmaceutically acceptable filler.

Another object of the present invention are the two which is a method of inducing relaxation of smooth muscles of the respiratory tract, which includes the introduction of an effective amount of a compound of the formula:

where R1, R2, Xa, Ya and J have the values indicated above.

Another object of the present invention is a method of inducing agonistic reactions nicotine receptor cells of the lung, which includes the introduction of an effective amount of an agonist of the receptor of nicotine.

Brief description of drawings

The accompanying drawings illustrate the present invention but do not limit its scope.

Figure 1 shows the total and differential number of cells in bronchoalveolar washing fluid (BAL).

Figure 2 shows the expression of mRNA of IFN-γ in the selected mononuclear cells in the lung.

Figure 3 shows the expression of mRNA of TNF-α induced by LPS stimulation for 24 hours.

Figure 4 shows the expression of mRNA of TNF-α induced by stimulation of the SR within 24 hours.

Figure 5 shows the expression of mRNA of IL-10 induced by LPS stimulation for 24 hours.

Figure 6 shows the expression of mRNA of IL-10 induced by stimulation of the SR within 24 hours. The effect of nicotine was carried out in a number of 160 μm (60% reduction of expression) and 80 μm (90% reduction in expression) together with the effect of DMPP.

7 shows the expression of mRNA of IFN-γ induced in cells RAW 264.7 LPS stimulation for 24 the aces.

On Fig(a) and (b) shows the expression of D80 induced by LPS (38%) or antigen SR (35%).

Figure 9 shows the expression of mRNA of IFN-γ in T-lymphocytes isolated from BAL of subjects suffering from allergic pneumonitis (HP).

Figure 10 shows the expression of CD86 in the total number of cells isolated from BAL of healthy subject.

Figure 11 shows the BAL cells obtained from mice that were subjected to DMPP, nicotine and epibatidine.

On Fig shown significant inhibitory effect of DMPP on pneumonia detected by the increase in the number of animals.

On Fig shows the levels of TNF in the BAL of mice that were subjected to the effects of DMPP.

On Fig shows the effect of intraperitoneal administration of increasing doses of DMPP to the accumulation of the total number of cells in BAL of mice with asthma.

On Fig shows the differential number of cells depending on the dose.

On Fig shows the effect of intraperitoneal administration of the second dose of DMPP to the accumulation of the total number of cells in BAL of mice with asthma.

On Fig shows the differential number of cells depending on the second dose.

On Fig shows the levels of IL-5 in BAL control mice, mice with asthma, and mice exposed to test compounds.

On Fig shows the resistance of the lungs after stimulation methacholine in healthy mice, mice suffering from asthma is, and mice with asthma, which was inserted in the nose of 0.5 mg/kg DMPP.

On Fig shows the calculation provoking shock dose to increase the resistance of the lungs to 200% (RS 200).

On Fig shows the expression of mRNA of IL-4 induced by LPS stimulation for 24 hours.

On Fig shows the effect of DMPP on the transfer of eosinophilic leukocytes in the blood.

On Fig shows the impact of mecamylamine, which is an antagonist of nicotine on the inhibitory effect of DMPP on the transfer of eosinophilic leukocytes in the blood.

On Fig shows the impact of additional agonist nicotine (nicotine, epibatidine and tsitizin) on the transfer of eosinophilic leukocytes in the blood.

On Fig shows the effect of DMPP on the expression of mRNA of collagen 1A fibroblasts lungs of a healthy person.

On Fig shows the effect of nicotine on the expression of mRNA of collagen 1A fibroblasts of the human lung.

On Fig shows the impact of epibatidine, which is another agonist nicotine on the expression of mRNA of collagen 1A fibroblasts of the human lung.

On Fig shows the effect of DMPP, ASM-002, ASM-003, ASM-004 and ASM-005 on the release of tumor necrosis factor (TNF).

On Fig shows the effect of DMPP, ASM-002, ASM-003, ASM-004 and ASM-005 on the reactivity of smooth muscles of the Airways of the trachea in mice.

On Fig shows the effects of ASM-002 on pneumonia.

Figure 3 shows the impact of ASM-002 on the resistance of the lung in a model of asthma in mice.

On Fig shows the comparative effects of ASM-002 and prednisone on inflammation of the lungs.

On Fig shows the effects of ASM-002 in a model of allergic reactions of the lung in dogs.

On Fig shown relaxing effect ASM-002 on the muscles of the trachea in mice.

On Fig shown relaxing effect ASM-002 on the muscles of the bronchial rings in dogs.

On Fig shown relaxing effect ASM-002 on the muscles of the bronchial rings in humans.

On Fig shows the inhibitory activity of ASM-002 on the strong release of inflammatory mediators by human blood cells isolated from subjects with asthma.

On Fig shows the comparative effects of ASM-002, DMPP and dexamethasone on the production of TNF LPS-stimulated blood monocytes.

On Fig shows the inhibition of LTC4 production under the influence of ASM-002.

On Fig shows the effects of nicotine, ASM-N1, ASM-N2, ASM-N3, ASM-N4 and ASM-002 on the production of TNF.

Description of the preferred embodiments of the invention

Other objectives, advantages and features of the present invention will be better understood when reading the following description of preferred embodiments of the invention, without limiting its scope, which is given only as an example with reference to the accompanying drawings.

The idea of using nicotine or other AGON the ists receptors nicotine, their analogs or derivatives for the treatment of inflammatory lung diseases is new. Despite a pronounced anti-inflammatory and immunosuppressive action of nicotine and other agonists of receptors nicotine, their analogues or derivatives, in the scientific literature has not been previously described suitability of these agents for treatment of allergic and other inflammatory lung diseases. The disadvantages of cigarettes, are the main reasons for the lack of interest in the application of agonists nicotine, their analogs or derivatives for the treatment of lung diseases.

Thus, the present invention relates to the use of agonists of receptors nicotine, such as DMPP, their analogues and derivatives, for the treatment of inflammatory lung diseases such as asthma, COPD, interstitial fibrosis of the lung tissue (IPF), sarcoidosis, allergic pneumonitis (HP) and obliterative bronchiolitis with organizing pneumonitis (VOOR). This drug can be administered orally or, depending on specific diseases or conditions, by means of delivery in the easy method of aerosolization using a different and preferred carriers to minimize systemic effects.

Anti-inflammatory, immunosuppressive and/or bronchodilator properties and minimal side effe what you agonists of receptors nicotine, derivatives and analogs do these medicines are ideal for medical applications in the treatment of a number of lung diseases that are characterized by inflammation of the bronchi or interstitial tissue. These diseases are diseases such as asthma, COPD, IPF, sarcoidosis, HP and POOR.

One way of implementing the present invention relates to a method of treatment or prevention of inflammatory diseases of the lung, which includes the introduction of an effective amount of a compound that modulates the function of receptors nicotine.

In one embodiment, the present invention this method is intended for the treatment of inflammatory lung diseases.

In one embodiment of the invention, the compound suitable for use in the method according to the present invention, is a receptor agonist nicotine.

In one embodiment of the invention, the agonist nicotine receptors are selected from the group including dimethylphenylpiperazinium (DMPP), nicotine, epibatidine, tsitizin, acetylcholine and its analogues.

In another embodiment, the invention compounds suitable for use in the method according to the present invention, are:

i) a compound of the formula:

where R1and R2n is dependent mean lower alkyl with 1-10 carbon atoms;

Ha denotes CH or N;

Ya means one or more substituents selected from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylthio with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, alkanol with 1-6 carbon atoms, aralkyl, aryl with 6-10 carbon atoms and 3 to 10-membered heterocycle;

n means an integer from 0 to 2;

J means counterion; or

ii) a compound of the formula:

where R3selected from groups of the formula

and

Xb denotes N or N+-R10;

R4means one or more substituents selected from the group including hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, alkylamino with 1-10 carbon atoms, alkanol with 1-10 carbon atoms, aralkyl, aryl with 6-10 carbon atoms;

each of R10, R11and R12independently mean alkyl with 1-10 carbon atoms;

when is slowiy the presence of the counterion, when Xb means N+-R10; or

iii) a compound of the formula:

where XC denotes NR13or N+-R13R14where R13and R14independently denote alkyl with 1-10 carbon atoms;

R5means 3-10-membered heterocycle;

subject to the availability of the counterion, when XC means N+-R13R14; or

iv) a compound of the formula:

where W denotes O or S;

each of Yc and Yd are independently selected from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, alkylamino with 1-10 carbon atoms, alkanol with 1-10 carbon atoms, aralkyl, aryl with 6-10 carbon atoms;

where Xd denotes NR15or N+-R15R16where R15and R16independently denote alkyl with 1-10 carbon atoms;

subject to the availability of the counterion, when Xd means N+-R15R16.

In another embodiment, an invention compound, suitable for use in the method according to the present invention, has the formula:

where R1and R2independently mean is alkyl with 1-10 carbon atoms;

Ha denotes CH or N,

Ya means one or more substituents selected from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, alkylamino with 1-10 carbon atoms, alkanol with 1-10 carbon atoms, aralkyl, aryl with 6-10 carbon atoms and 3 to 10-membered heterocycle;

n means an integer from 0 to 2.

J means the counterion.

In another embodiment of the invention R1and R2independently denote optionally substituted lower alkyl with 1-10 carbon atoms;

Ha means SN;

Ya means one or more substituents selected from the group comprising hydrogen, halogen, amino, amido, hydroxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms and alkanol with 1-6 carbon atoms;

n is 1 or 2;

J denotes halogen.

In another embodiment, the invention compounds suitable for use in the method according to the present invention have the formula:

where R1and R2independently denote optionally substituted lower alkyl with 1-6 carbon atoms;

Ha means SN;

Ya means one or not is how many deputies, selected from the group comprising hydrogen, halogen, amino, amido, hydroxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, lower alkanol with 1-6 carbon atoms;

n is 1 or 2;

J denotes halogen.

In an additional embodiment of the invention R1and R2independently selected from the group comprising methyl, ethyl, n-propyl or isopropyl;

Ha means SN;

Ya mean hydrogen;

n is 1 or 2;

J denotes halogen.

In an additional embodiment of the invention the compound has the formula:

where R1and R2independently selected from the group comprising methyl, ethyl, n-propyl or isopropyl;

Ya mean hydrogen;

J denotes halogen.

In another embodiment, an invention compound, suitable for use in the method according to the present invention, has the formula:

In another embodiment, an invention compound, suitable for use in the method according to the present invention has a formula selected from the following formulas:

and

In another embodiment, an invention compound, suitable for use in the method according to the present invention has a formula selected from the following fo the mule:

or

One way of carrying out the invention relates to a method of the present invention, which used a compound of the formula:

where R3selected from groups of the formula

or

Xb denotes N or N+-R10;

R4means one or more substituents selected from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, alkylamino with 1-10 carbon atoms, alkanol with 1-10 carbon atoms, aralkyl, aryl with 6-10 carbon atoms;

each of R11and R12independently mean alkyl with 1-10 carbon atoms;

subject to the availability of the counterion, when Xb means N+-R10.

In one embodiment of the invention R4means one or more substituents selected from the group comprising hydrogen, halogen, amino, amido, hydroxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms and alkanol with 1-6 carbon atoms; R11and R12independently mean all with 1-6 atoms of plastics technology : turning & is Yes.

In another embodiment of the invention R4means one or more substituents selected from hydrogen and halogen; R11and R12independently denote alkyl with 1-6 carbon atoms.

In another embodiment, an invention compound, suitable for use in the method according to the present invention has a formula selected from the following formulas:

and

One way of carrying out the invention relates to a method of the present invention, which used a compound of the formula:

where XC denotes NR13or N+-R13R14where R13and R14independently denote alkyl with 1-10 carbon atoms;

R5means 3-10-membered heterocycle;

subject to the availability of the counterion, when XC means N+-R13R14.

In one embodiment of the invention R13and R14independently denote alkyl with 1-6 carbon atoms.

In another embodiment of the invention R13and R14independently denote alkyl with 1-6 carbon atoms; and R5means 3-6-membered heterocycle.

In another embodiment of the invention R13and R14independently denote alkyl with 1-6 carbon atoms; and R5means optional replacement of the military pyridyl.

In another embodiment, an invention compound, suitable for use in the method according to the present invention has a formula selected from the following formulas:

and

One way of carrying out the invention relates to a method of the present invention, which used a compound of the formula:

where W denotes O or S;

each of Yc and Yd independently means a Deputy chosen from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, alkylamino with 1-10 carbon atoms, alkanol with 1-10 carbon atoms, aralkyl, aryl with 6-10 carbon atoms;

where Xd denotes NR15or N+-R15R16where R15and R16independently denote alkyl with 1-10 carbon atoms;

subject to the availability of the counterion, when Xd means N+-R15R16.

In one embodiment of the invention Yc and Yd independently denote one or more substituents selected from the group comprising hydrogen, halogen, amino, amido, hydroxyl, alkyl with 1-6 carbon atoms, ALK is XI with 1-6 carbon atoms and alkanol with 1-6 carbon atoms.

In one embodiment of the invention W means About; Yc and Yd independently denote one or more substituents selected from the group comprising hydrogen, halogen, amino, amido, hydroxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms and alkanol with 1-6 carbon atoms; and means Xd NR15or N+-R15R16where R15and R16independently denote alkyl with 1-6 carbon atoms.

In another embodiment of the invention W means About; Yc and Yd independently denote one or more substituents selected from hydrogen and halogen; and means Xd NR15or N+-R15R16where R15and R16independently denote alkyl with 1-6 carbon atoms.

In another embodiment, an invention compound, suitable for use in the method according to the present invention has a formula selected from the following formulas:

and

In one embodiment of the invention, the inflammatory lung disease is chosen from the group comprising asthma, chronic obstructive pulmonary disease (COPD), interstitial fibrosis of the lung tissue (IPF), sarcoidosis, allergic pneumonitis (HP), chronic allergic pneumonitis and obliterative bronchiolitis with organizing pneumonia is ω (VOOR).

In one embodiment of the invention, the inflammatory lung disease is chosen from the group comprising asthma, chronic obstructive pulmonary disease (COPD), interstitial fibrosis of the lung tissue (IPF), sarcoidosis, allergic pneumonitis (HP) and chronic allergic pneumonitis.

In other embodiments the invention, the inflammatory lung disease is chronic obstructive pulmonary disease (COPD);

sarcoidosis;

allergic pneumonitis (HP).

In another embodiment of the invention, the inflammatory lung disease is asthma.

In one embodiment of the invention, the compound suitable for use in the method according to the present invention, be administered orally, parenterally, topically or by inhalation.

Alternative the specified connection be administered orally, topically or by inhalation.

In one embodiment of the invention, the compound suitable for use in the method according to the present invention, administered orally.

One way of carrying out the invention relates to compounds of the present invention suitable for preparation of medicines for the treatment of inflammatory lung diseases.

One way of carrying out the invention relates to new compounds of the formula:

where R1and R2independently denote a lower alkyl with 1-10 carbon atoms;

Ha denotes CH or N;

Ya means one or more substituents selected from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylthio with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, alkanol with 1-6 carbon atoms, aralkyl, aryl with 6-10 carbon atoms and 3 to 10-membered heterocycle.

n means an integer from 0 to 2;

J means the counterion.

In another embodiment of the invention R1and R2independently denote optionally substituted alkyl with 1-6 carbon atoms;

Ha means SN;

Ya means one or more substituents selected from the group comprising hydrogen, halogen, amino, amido, hydroxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms and alkanol with 1-6 carbon atoms;

n is 1 or 2;

J denotes halogen.

In one embodiment of the invention the compound has the formula:

where R1and R2independently denote optionally substituted alkyl with 1-6 carbon atoms;

X is CH;

Y represents one or several who are deputies, selected from the group comprising hydrogen, halogen, amino, amido, hydroxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkanol with 1-6 carbon atoms;

n is 1 or 2;

J denotes halogen.

In another embodiment of the invention R1and R2independently selected from the group comprising methyl, ethyl, n-propyl or isopropyl;

X is CH;

Y represents hydrogen;

n is 1 or 2;

J denotes halogen.

In an alternative embodiment of the invention the compound has the formula:

where R1and R2independently selected from the group comprising methyl, ethyl, n-propyl or isopropyl;

Y represents hydrogen;

J denotes halogen.

In another embodiment of the invention the compound has the formula:

The first receptor agonists nicotine include dimethylphenylpiperazinium (DMPP), nicotine, epibatidine, tsitizin, acetylcholine and its analogues.

Alternative receptor agonists nicotine, which can be used for the treatment and applications of the present invention, include the following receptor agonists nicotine and its analogs.

1. DMPP and its analogs

Connection R1R2XYN
DMPPCH3CH3SN-1
CH3CH2CH2CH3SN-1 or 2
CH2CH3CH2CH3SN-1 or 2
CH2CH3CH3SN-1 or 2
CH3CH3SN-2
CH3-N -1
N-Nhalogen1

2. Nicotine and its analogs

ConnectionXR1R1R2
NicotineN3N
N3N
N3N
N4N
N 3halogen
N3N
N3N

3. Analogues simple piridinovogo ether

ConnectionXR1R1R2n
AboutN-1
Aboutaryl, alkyl, substituted phenyl51
Abouthalogen6 1
AboutN-
R1and R2=alkyl, n=1 or 2
1,2 or 3
NCN-
R1and R2=alkyl, n=1 or 2
1,2 or 3

4. Epibatidine and its analogs

ConnectionR1R2
Epibatidine
X=halogen
N

X=halogen
N
N
N

X=halogen
N or CH3(alkyl)

R1and R2=alkyl,
n=1 or 2
N or CH3(alkyl)


X=N+(CH3)3
N or CH3(alkyl)

5. Trimetaphan and its analogs

ConnectionRX
Trimetaphan-
halogen
N+(CH3)3-
N+(CH2CH3)3-

6. Tsitizin and its analogs

ConnectionRWXYZ
TsitizinNONNN
nBuONNN
HOhalogenNhalogen
HSNNN
(CH3)2O or ShalogenNhalogen
(CH2CH3)CH3O or SN NN
(CH2CH3)2O or SNNN

7. Acetylcholine and its analogues

ConnectionR
AcetylcholineN+(CH3)3
N+(CH2CH3)2CH3
N+(CH2CH3)3

8. N-Methylcarbamyl and its analogs

ConnectionR
N-methylcarbamylN+(CH3)3
*N+(CH2CH3)2CH3
*N+(CH2CH3)3

9. AVT-418 and its analogs

ConnectionR
AVT-418CH3
(CH3)2
(CH2CH3)CH3
(CH2CH3)2

10. GTS-21 and its counterparts

ConnectionR1R2
GTS-21OCH3OCH3
N+(CH3)3OCH3
OCH3N+(CH3)3

11. Arcolin and its analogs

ConnectionR
ArcolinCH3
(CH3)2
(CH2CH3)CH3
(CH2CH3)2

12. Lobelin and its analogs

ConnectionR
LobelinN
(CH3)2
(CH2CH3)CH3
(CH2CH3)2

13. Analogues of frontotomia-433

ConnectionRnm
NH243
N+(CH3)31,2,3 or 41,2 or 3
is the N+(CH2CH3)2CH31,2,3 or 41,2 or 3
N+(CH2CH3)31,2,3 or 41,2 or 3

14. Azabicycles counterparts

ConnectionRRnm
-22
-22
-22
-22
CH31 or 21 or 2
CH31 or 21 or 2

15. Analogues SIB-1553

ConnectionRn
CH31 (Treo)
CH30 (Erythro)
CH30 (Treo)
(CH3)20 or 1
(CH2CH3)CH30 or 1
(CH2CH3)20 or 1

16. Analogues of Imidacloprid

ConnectionRXYZ
NO2ClHNH
HClN3S
NO2ClN3S
N+(CH3)3ClHNH
NO2N+(CH3)3HNH
NO2ClN+(CH3)3NH

Of particular interest for the treatment of inflammatory lung diseases are the following analogues of DMPP formula:

p> where R1means methyl or ethyl, R2means methyl, ethyl or propyl, X is CH, Y represents hydrogen, n is 1 or 2.

The term “lower alkyl” means a linear, branched or cyclic hydrocarbon portion containing 1-10 carbon atoms, preferably 1-6 carbon atoms, which may have one or more nancysinatra in the chain and may be optionally substituted. Examples of such groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl, allyl, vinyl, acetylenyl, Etiler, propenyl, Isopropenyl, butenyl, Isobutanol, hexanol, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexatriene, heptenyl, heptadienyl, heptatriene, octenyl, octadienal, octatriene, octatetraene, PROPYNYL, butynyl, pentenyl, hexenyl, cyclopropyl, cyclobutyl, cyclohexenyl, cyclohexadienyl and cyclohexyl. The term “lower alkyl” also means alkali, in which one or more hydrogen atoms substituted by a halogen atom, i.e. alkylhalogenide. Examples of such groups include, but are not limited to, trifluoromethyl, deformity, vermeil, trichloromethyl, dichloromethyl, chloromethyl, triptorelin, defloratin, foradil, trichlorethyl, dichlorethyl, chloroethyl, CHLOROFORMATES, chloriform the Tyl, dichloromethyl.

The term “lower alkoxy” means alkyl, covalently associated with the adjacent atom through an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, tert-pentyloxy, hexyloxy, etexilate, neosaxitoxin.

The term “lower alkylthio” means alkyl, covalently associated with the adjacent atom by an atom of sulfur. Examples of such groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio and tert-butylthio.

The term “lower alkylamino” means alkyl, covalently associated with the adjacent atom by a nitrogen atom, and represents monoalkylamines or dialkylamino, in which the alkyl groups may be the same or different. Examples of such groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamine, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine, isopentylamine, neopentylene, tert-pentylamine, hexylamine, isohexane, neohexane.

The term “lower alkanol” means “alkyl” portion, in which one of the hydrogen atoms replaced by a hydroxyl group. Those who min “alkanol” also means alkanol, in which one or more carbon atoms substituted with halogen. Examples of such groups include, but are not limited to, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, propylene glycol, cyclopropanol, triptorelin or formeterol.

The term “aralkyl” means an aryl group attached to the adjacent atom through With1-6the alkyl. Examples of such groups include, but are not limited to, benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl and naphthylmethyl.

The term “aryl” means a carbocyclic part containing at least one ring bentinho type (i.e. can be monocyclic or polycyclic) with 6-10 carbon atoms, which may be optionally substituted by one or more substituents. Alternatively, the specified ring may contain 6 carbon atoms. Examples of such groups include, but are not limited to, phenyl, tolyl, dimetilfenil, AMINOPHENYL, aniline, naphthyl, antril, phenanthrol or biphenyl.

The term “acyl” means a radical selected from carboxylic acid, obtained by substitution of the group-HE. Like kindred acid acyl radical may be straight chain, branched chain or a cyclic aliphatic or aromatic radical. Examples of such groups include, but are not limited to the mi, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl, isocaproic, acryloyl, propiolic, methacryloyl, crotonoyl, isotretinoin, benzoyl, Naftoli, toluoyl, cynnamoyl, furoyl, glycerol, salicyloyl.

The term “acyloxy” means acyl, covalently associated with the adjacent atom through an oxygen atom. Examples of such groups include, but are not limited to, formyloxy, atomic charges, propionyloxy, butyryloxy, isobutyryloxy, valeriote, isovalerianic, pivaloyloxy, caprolace, isocaproate, acryloyloxy, propionoxy, methacryloyloxy, crotonville, isocrotonic, benzoyloxy, naphthyloxy, toluole, hydrotroilite, tropolone, cinnamoyloxy, pyrolox, glycerols, tropolone, benzyloxy, salicyluric, antilogic, venerologic, veratrole, piperonylic, protocatechuic, gallopoulos, while the preferred groups are formyloxy, atomic charges, propionyloxy, butyryloxy, isobutyryloxy, valeriote, isovalerianic, pivaloyloxy, benzoyloxy, naphthyloxy.

The term “halogen atom” means a fluorine atom, chlorine atom, bromine atom and iodine atom.

The term “counterion” refers ion, which is present in ionic form connections to preserve electroneutrality. Examples of the counterion used here in the meaning of the Institute include, not limited to, fluoride, chloride, bromide, iodide, sulfate, sulfonate.

The term “independently” means that the Deputy may have the same or different values for each element.

The term “heterocycle” means a 3-10-membered optionally substituted saturated, unsaturated or aromatic cyclic part of which is interrupted by at least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N). Alternatively, the heterocycles can be a 3-6-membered ring, or a 5-6-membered ring. The heterocycles may be monocyclic or polycyclic rings. Examples of such groups include, but are not limited to, azepine, aziridine, azmil, azetidine, diazepines, datadesigner, dioxazines, DIOXOLANYL, dithiazole, furanyl, isooxazolyl, isothiazolin, imidazolyl, morpholinyl, morpholino, oxetanyl, oxadiazolyl, oxiranyl, oxazinyl, oxazolyl, piperazinil, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl, pyrazolyl, pyrrolyl, pyrrolidinyl, tetrazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazines, thiadiazines, triazinyl, triazinyl and tiopronin, forosocial, imidazothiazoles, teenistujail, theNational, imidazopyridines, cyclopentadienyl, pyrrolopyrazole, theNational, thiadiazolidine, thiazolo azinil, triazolopyrimidines, triazolopyridines, oxazolopyridine, oxazolopyridine, benzoxazolyl, benzisothiazole, benzothiazolyl, imidazopyridines, purinol, pyrazolopyrimidines, imidazopyridines, benzimidazolyl, indazoles, benzoxadiazole, benzodioxolyl, benzodithiol, indolizinyl, indolinyl, isoindolyl, properidine, properity, benzofuranyl, isobenzofuranyl, thienopyrimidines, cyanopyridyl, benzothiazyl, cyclopentadienyl, cyclopentadienyl, benzoxazines, benzothiazines, hintline, naphthyridine, chinoline, ethenolysis, benzopyranyl, pyridopyrimidines and pyridopyrimidines.

In accordance with the purposes of this application the term “animal” means human primates, domestic animals (such as horses, cows, pigs, goats, sheep, cats, dogs, Guinea pigs, mice, etc) and other mammals. This term is usually used to refer to living organisms with highly developed cardiovascular system.

In accordance with the purposes of the present invention agonists, agents or ligands are molecules or compounds that bind to the nicotine receptor and modulate its function. Preferred agents are specific to the receptor and does not penetrate the blood-brain barrier, such as DMPP. Acceptable agents can be found in many chemical is lasso, although typically they are organic compounds and preferably low molecular weight organic compounds. Low molecular weight organic compounds have a molecular weight of more than 150 and less than about 4500, preferably less than about 1500, more preferably less than 500. Typical classes of such compounds include peptides, saccharides, steroids, heterocyclic compounds, polycyclic compounds, substituted aromatic compounds, and the like.

Agonists nicotine does not necessarily have to replace all medicines currently used for the treatment of inflammatory diseases of the lungs and airway obstruction, often associated with these diseases. Bronchodilators are still an effective means for the immediate withdrawal of bronchospasm. However, bronchodilators do not resolve the cause of the inflammation.

Agonists nicotine can be used as drugs, when you can replace steroids or reduce their dose. Due to the directed delivery to the lung phagocytes these drugs can reduce inflammation of the Airways and interstitial tissue. One important advantage of agonists nicotine compared with corticosteroids is that, panimoliitto fewer side effects, these agonists can have a direct effect on fibroblasts and, thus, prevent or eliminate fibrosis of the Airways and lungs that are not able to do corticosteroids. Fibrosis of the interstitial tissue is the hallmark of IPF, the main consequence of HP and sarcoidosis, and fibrosis of the Airways is a hallmark of chronic asthma (57).

Other substances also pass a comprehensive examination as a possible new drugs for the treatment of inflammatory lung diseases. Special attention is paid to many cytokines (such as IL-5, IL-13, IL-16, and the like) (62). It is believed that due to the complicated structure of the respiratory tract, smitten of inflammation, any one specific cytokine or mediator of inflammation may not have a significant impact on the treatment of the aforementioned diseases of the lungs. Agonists of receptors nicotine, their analogues and derivatives like corticosteroids directionally affect a wide range of inflammatory reactions. It is their potential suitability for the treatment of inflammatory lung diseases.

Selected agents can be modified to enhance the effectiveness, efficiency, sustainability, pharmaceutical compatibility and similar properties. Structure determination agent can be used to identify, with the building or additional screening agents. For example, the identified peptide agents can be modified by varying the above-described method, for example, to strengthen their proteolytic stability. Other methods of stabilization may include encapsulation, for example, liposomes, etc. Binding agents receive any methods known to experts in this field.

Agents that affect the function of the receptor nicotine and are intended for therapeutic use, you can enter any known means. Low molecular weight organic compounds are preferably administered orally; other compositions and agents are preferably administered parenterally, usually in a pharmaceutically or physiologically acceptable carrier, for example, in physiological solution with phosphate buffer or the like media. These compositions are typically added to maintain physiological fluids, such as blood or synovial fluid.

Another object of the present invention is a pharmaceutical composition for the treatment of inflammatory diseases of the lung containing the agonist nicotine receptors and a pharmaceutically acceptable filler.

The carrier or excipient must be “acceptable” from the viewpoint of compatibility with other ingredients of the drug and the absence of harmful effects on the recipient.

And alternativnyj variant embodiment of the invention relates to pharmaceutical compositions for the treatment of inflammatory lung diseases, which contains:

i) a compound of the formula:

where R1and R2independently denote a lower alkyl with 1-10 carbon atoms;

Ha denotes CH or N;

Ya means one or more substituents selected from the group including halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylthio with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, alkanol with 1-6 carbon atoms, aralkyl, aryl with 6-10 carbon atoms and 3 to 10-membered heterocycle;

n means an integer from 0 to 2;

J means counterion; or

ii) a compound of the formula:

where R3selected from groups of the formula

or

Xb denotes N or N+-R10;

R4means one or more substituents selected from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, alkylamino with 1-10 carbon atoms, alkanol from 1-10 and what Ohm carbon, aralkyl, aryl with 6-10 carbon atoms;

each of R10, R11and R12independently mean alkyl with 1-10 carbon atoms;

subject to the availability of the counterion, when Xb means N+-R10; or

iii) a compound of the formula:

where XC denotes NR13or N+-R13R14where R13and R14independently denote alkyl with 1-10 carbon atoms;

R5means 3-10-membered heterocycle;

subject to the availability of the counterion, when XC means N+-R13R14; or

iv) a compound of the formula:

where W denotes O or S;

each of Yc and Yd independently means a Deputy chosen from the group comprising hydrogen, halogen, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, urea, sulfate, sulfite, sulfonate, sulfonamide, phosphate, phosphonate, acyl, acyloxy, alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, alkylamino with 1-10 carbon atoms, alkanol with 1-10 carbon atoms, aralkyl, aryl with 6-10 carbon atoms;

where Xd denotes NR15or N+-R15R16where R15and R16independently denote alkyl with 1-10 carbon atoms;

subject to the availability of the counterion, when Xd means N+-R15R16;

and pharmaceutically priemel the range of the filler.

In one embodiment of the invention the pharmaceutical composition of the present invention may further contain one or more drugs selected from the group comprising a bronchodilatory, anti-inflammatory agent, an antagonist of leukotriene receptor or an inhibitor of phosphodiesterase (PDE), such as PDE IV.

In another embodiment of the invention bronchodilators means are β2 agonists or anticholinergics.

In another embodiment of the invention anti-inflammatory agent is a corticosteroid.

In another embodiment of the invention the inhibitor DE is DE IV.

Another variant of implementation of the present invention relates to a combination comprising a therapeutically effective amount of the compounds suitable for use in the method according to the present invention, and a therapeutically effective amount of at least one or more medicines.

The specialist in this area should be clear that when the need or desire to use additional medication can be easily adjusted ratio of means used. It should be noted that the scope of combinations of the present invention is not restricted to those mentioned above drug what Redstone and may include any drugs, used for the prevention and treatment of inflammatory lung diseases.

The content of peptide agents will typically range from about 50 to 500 μg/ml of Alternative input dose of these agents may be acceptable in the range from about 1 mg to 10 g or more per kg of body weight. The composition may contain other additives, such as stabilizers, bactericides, etc. These additives may be present in conventional amounts.

It should be noted that it is necessary for the treatment of a number of compounds of the present invention can vary not only depending on the particular compound, but also on the method of administration, the nature of the subject to treatment of the disease, the age and condition of the subject, and ultimately determined by the treating physician or veterinarian. Enter the amount can be determined empirically, for example, in the range from about 10 μg to 1000 mg/kg, from 10 μg to 100 mg/kg or 10 μg to 1 mg/kg of body weight of the recipient.

The desired dose may be a single dose or divided dose, administered at intervals of time, such as two, three, four or more doses per day.

In those cases, when the connection or combination of the present invention, intended for therapeutic purposes, can be administered to the subject in view of the crude chemical product, the active ingredient is preferably included in the pharmaceutical compositions.

Many of these drugs are intended for administration along with therapeutic peptides by injection, topical application, intratracheal/nasal administration, for example, in the form of an aerosol, intraocular injection or using implants (such as collagen, osmotic pumps, implants containing appropriately transformed cells, etc).

The pharmaceutical compositions also include compositions designed for oral, nasal, local (including transbukkalno and sublingual administration), percutaneous or parenteral (including intramuscular, subcutaneous and intravenous) or by inhalation. Drugs can be a separate dosage form and may be obtained by any means known in the field of pharmacy. All known methods include the stage of combining the active compound with liquid carriers or finely ground solid carriers or by both jointly and, if necessary, the stage of the molding product to obtain the desired product.

Pharmaceutical compositions intended for oral administration, can be a separate dosage form such as capsule, cachet or tablet and, containing a predetermined amount of the active ingredient; a powder or granules; solution, suspension or emulsion. The active ingredient may also be part of the bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrators or wetting agents. The tablets may be coated by methods well known in the field. Liquid preparations for oral administration can consist, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be obtained in the form of a dry product intended for restoration of water or other appropriate media immediately before use. Such liquid preparations may contain conventional additives such as suspendresume agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.

The compounds and combinations according to the present invention can be also intended for parenteral administration (for example, in the form of injections, in particular, injection loading dose or continuous infusion) and may be obtained in the form of a uniform dosage form in ampoules filled syringes, containers for infusion of small what about the volume or packings for repeated administration in combination with an added preservative. These compositions can be represented as suspensions, solutions or emulsions in oily or aqueous carriers can contain substances that produce compositions, such as suspendida, stabilizing and/or dispersing agents. Alternative active ingredient may be a powder obtained by aseptic selection of sterile solid or by lyophilization from solution, which is designed to restore an appropriate carrier, for example, sterile pyrogen-free water, immediately before use.

Compositions intended for the local introduction of the oral cavity include pellet, containing the active ingredient in a flavored basis such as sucrose, Arabic gum or tragant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum; and liquid mouth rinse containing the active ingredient in an acceptable liquid carrier.

The compounds and combinations according to the present invention is intended for administration by inhalation, usually imposed by insufflator, spray, cylinder under pressure, or other aerosol device. The cylinders under pressure, can contain acceptable propellant, this is AK DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other acceptable gas. In the case of a pressurized aerosol, the dosage can be made by valve, measuring the required amount of the drug.

Alternatively, the compounds and combinations according to the present invention is intended for administration by inhalation, can be a dry powder, for example, a powder mix of the compound and acceptable powder base, such as lactose or starch. The powdered composition may be obtained in the form of a standardized dosage forms, for example, capsules or cartridges, gelatin or blister packs from which the powder can be entered using the inhaler or insufflator.

To study the effects of agonists nicotine in the treatment of inflammatory lung diseases were used two animal models: model of allergic pneumonitis and model of asthma. In both models investigated the effects of receptor agonists nicotine (selective and non-selective) on the physiology and pneumonia. In vitro studies were performed using cells of the inflammatory infiltrate, obtained in experimental animals or humans, as well as commercially available cell line, with the aim of the study would be what about the identification of mechanisms, allowing agonists nicotine to reduce inflammation.

Experiments were initially performed using nonspecific agonists, i.e. agonists, communicating with all subunits of the receptors nicotine (nicotine, dimethylphenylpiperazinium (DMPP) and epibatidine) (13, 42). In addition, the test was performed agonist specific to the β4 subunit, in particular, tsitizina (42), in order to identify anti-inflammatory action in the case of specific stimulation.

Example 1

In vivo allergic pneumonitis.

1. Inflammation, like allergic reactions

Determined the effects of agonists nicotine on chronic allergic pneumonitis (HP) in mice.

It is established that stimulation of nicotine receptors by nicotine weakens the immune response to antigens of HP due to the suppression of inflammatory cytokines and inhibition of specific antigen-mediated cellular activity.

As mentioned above, this model was chosen because of allergic pneumonitis is much less common in smokers than non-smokers (50), and also because the model is well described in the scientific literature. Allergic pneumonitis induced by injection of antigen Saccharopolyspora rectivirgula (SR), the etiological factor of lung disease among farmers (51), calling the th occurrence of one of the forms of allergic pneumonitis. Mice simultaneously intraperitoneally (IP) was administered nicotine in doses from 0.5 to 2.0 mg/kg twice a day. Introduction nicotine significantly reduced the total number of cells detected in bronchoalveolar washing fluid (BAL) of these mice. As shown in figure 1, the greatest exposure to nicotine has had on the population of lymphocytes. It is established that a significant inhibition of the total number of cells in mice exposed to nicotine, mainly due to the decrease of lymphocyte population. Macrophages and lymphocytes were isolated from the lungs and stimulated with antibody against CD3 and recombinant IL-2. Then measured the production of these cells mRNA IFN-γ, a cytokine that is known, mediates the development of HP and other inflammatory lung diseases (52). In the cells of animals exposed to nicotine were observed significantly lower expression of mRNA of IFN-γ than cells from control animals. Figure 2 shows a significant inhibition of mRNA IFN-γ.

Example II

An in vitro study of the effects of agonists nicotine on the expression of cytokines

To further clarify the mechanisms underlying suppressor action of nicotine in the model, in vivo, was using the cell line of alveolar macrophages.

The effects of nicotine or DMPP on the expression of mRNA of TNF-α and IL-10 in cells AMJ2-C11 determined what Ecodom RT-PCR. These cytokines mediate the development of inflammatory lung diseases, such as HP, asthma and sarcoidosis (52-55). Under the influence of nicotine and DMPP was a significant decrease in the mRNA expression of TNF (decrease in the expression of up to 98% in LPS-stimulated cells exposed to 40 μm nicotine), regardless of dose. Figure 3 shows the test results as % expression, with 100% expression occurred only in the group stimulated LS. The intensity of the bands was determined by dividing the intensity of the bands of TNF-α on the same β-actin. Treatment of stimulated cells with different doses of 40-160 μm nicotine and DMPP) induced a decrease in the mRNA expression of TNF-α. The greatest effect was achieved by treatment with nicotine at a concentration equal to 40 microns (98% reduction of expression), all doses of DMPP caused 60-50% reduction in expression. Similar results were obtained for the SR-stimulated cells. Figure 4 shows the results corresponding to the data shown in figure 5. Treatment of stimulated cells with different doses (80 and 160 μm nicotine and 40-160 μm DMPP) caused a decrease in the mRNA expression of TNF-α. Nicotine has an effect on the expression of mRNA only at a dose equal to 160 μm, while DMPP, input 40 and 80 μm doses, reduced the mRNA expression of TNF-α up to 60%. This is not dose-dependent response can be made the thread desensitization of nicotine receptors due to the presence of a large number of agonist in the environment. The expression of mRNA of IL-10 was also reduced as a result of processing by nicotine and DMPP. The maximum decrease of expression was under the influence of nicotine in a dose equal to 40 microns (LPS stimulation; 88% reduction in the mRNA expression; the results are shown in figure 5). Treatment of stimulated cells with different doses of 40-160 μm nicotine and DMPP) reduced the expression of mRNA of IL-10. The greatest decrease in expression (87% reduction) occurred under the influence of nicotine at a dose of 40 μm. DMPP caused 55-40% reduction in expression for all three doses. At the dose of DMPP equal to 80 μm, was observed in 87% reduction in the mRNA expression of IL-10 in SR-stimulated cells; the results are shown in Fig.6. Processing SR-stimulated cells with different doses (80 and 160 μm nicotine and 40-80 μm DMPP) caused a decrease in the mRNA expression of IL-10. The greatest decrease in the mRNA expression when handling nicotine occurred at the dose of 160 μm (60% reduction of expression) and at the dose of 80 μm (90% reduction in expression) in the case of treatment of DMPP.

Another cell line macrophages (RAW 264.7, ATSS) were used for studying the effects of DMPP on the expression of IFN-γ by the method of RT-PCR, as the cells AMJ2-C11, apparently, does not Express mRNA of IFN-γ (data not shown). Cells were stimulated with 50 μg/ml of antigen SR and incubated with DMPP in doses of 40 to 160 μm. The DMPP treatment reduced the expression of INF-γ in these cells by 75% at a dose equal the th 40 microns. 7 shows the results corresponding to the data shown in figure 5. Treatment of stimulated cells with different doses of DMPP caused a decrease in the expression of mRNA of IFN-γ. The greatest decrease in expression (80% reduction) occurred in the processing of DMPP in a dose equal to 40 microns.

Example III

In vitro effect of agonist nicotine on the expression of co-stimulating molecules

The effects of nicotine and DMPP on the expression of B7 molecules (CD80) was investigated in vitro. Cells AMJ2-C11 (alveolar macrophages mouse received from ATS) were incubated with 40 μm nicotine or DMPP and stimulated by antigen LPS (0.1 ág/ml) or SR (50 μg/ml) for 48 hours. The percentage of expression of CD80 in the treated cells was equal to roughly half of the expression found in raw cells stimulated by LPS and SR. On Fig(a) shows that treatment with nicotine (40 μm for 48 hours) reduced expression in LPS-stimulated cells by 20%. On Fig(b) also shows that the processing of DMPP (40 μm for 48 hours) reduced expression in LPS-stimulated cells by 17% and SR-stimulated cells by 20%.

Example IV

The study of cells in bronchoalveolar washing fluid (BAL) of the person (alveolar macrophages and lymphocytes)

Since one purpose of the present invention is the treatment of subjects with DMPP or similar drugs is a war funds the effect of this drug was tested on lymphocytes obtained from subjects suffering from allergic pneumonitis (HP). In subjects suffering from HP, performed bronchoalveolar lavage. Lymphocytes were separated from other cells in BAL, stimulated RNA and incubated with DMPP. The effect of doses of DMPP was determined by the production of cytokine mRNA (by RT-PCR for IFN-γ. Figure 9 shows that the effect of DMPP reduces the expression of IFN-γ in these cells.

Alveolar macrophages were isolated as a result of performing bronchoalveolar lavage in healthy subjects. In SR-stimulated cells treated with nicotine or DMPP also saw a nearly twofold decrease in CD86 expression compared to untreated cells. Figure 10 shows that cells treated with DMPP, expressed on 50% less CD96 than untreated cells.

Example V

Study on the effects of other agonists nicotine on acute inflammation induced by stimulation SR

Instillation into the nose mice antigens Saccharopolyspora rectivirgul (SR), which are the causative factor of lung disease among farmers, causes an immediate inflammatory response in the lung. Neutrophils are the first inflammatory cells infiltration, directed to the site of inflammation. Administration to mice of DMPP (0.5 mg/kg), nicotine (0.5 mg/kg) and epibatidine is a (2 µg/kg) had a significant inhibitory effect on SR-induced inflammation. Figure 11 shows that the introduction of nicotine and epibatidine had a significant inhibitory effect on SR-induced inflammation within 24 hours. Agonists nicotine was injected into the nose in a volume of 50 μl, every 6 hours, mice were killed 24 hours after instillation of the SR.

A significant inhibitory effect occurred with the introduction of nicotine and epibatidine and was absent when the introduction of DMPP. However, after increasing the number of mice that were injected or not injected DMPP, up to 15 animals were found significant inhibition compared to the group that did not enter DMPP (Fig).

The levels of TNF (proinflammatory cytokine) are lower in bronchoalveolar washing fluid of mice that were injected DMPP (Fig shown that DMPP significantly reduces the levels of TNF in bronchoalveolar wash liquid), which implies that at lower concentrations of TNF can decrease inflammation.

Example VI

Model of asthma in vivo

Similar experiments were performed using mice sensitized with ovalbumin. DMPP was reduced as the inflammatory reaction and an allergic reaction to Invalidovna allergens and metafolin.

Groups of mice Balb/c were senzibilizirani by intraperitoneal injection of 20 μg OVA protein (egg albumin; Sigma-Aldrich), emulsified in 2 the g of aluminum hydroxide in PBS. After 4 weeks in the nose were administered a loading dose, equal to 1.5%/50 μl of OVA. The stimulation produced daily for 3 consecutive days and within 24 hours after the last injection of aerosol in mice was determined by allergic inflammation in the lungs. Groups of mice were subjected to DMPP in different concentrations throughout the period of stimulation. The wash liquid obtained as a result of performing bronchoalveolar lavage (BAL), centrifuged with an acceleration of 400 g to separate the cells from the liquid. On Fig shows that the number of cells was significantly higher in VA-stimulated mice, which did not enter DMPP. The introduction of DMPP in doses of 0.5 and 2.0 mg/kg significantly reduced the number of cells. On Fig shown that OVA-stimulated mice (OVA OVA) was discovered more eosinophilic leukocytes and lymphocytes in AL compared with the control group (sal sal). Introduction DMPP significantly reduced the number of eosinophilic leukocytes and lymphocytes in BAL in all groups (n=8; p<0,05). On Fig shown that the content of eosinophilic leukocytes and lymphocytes in AL OVA-stimulated mice (OVA OVA) was significantly higher compared with the control group (sal sal). Introduction DMPP significantly reduced the number of eosinophilic leukocytes and lymphocytes in AL in all groups (n=8; p<0,05). On Fig shown that the introduction of DMPP in doses of 0.1 and 0.5 mg/kg significantly reduced the number e is sinophilic of leukocytes and lymphocytes, the most effective dose DMPP, providing anti-inflammatory action, was equal to 0.5 mg/kg

To determine the levels of IL-5 in lung used supernatant. Measured total and differential number of cells in BAL. On Fig shown that stimulation VA increased levels of IL-5 in BAL, while the introduction of DMPP had a substantial inhibitory effect on the levels of IL-5 in the group of mice that were administered 0.5 mg/kg DMPP.

This experiment was repeated with the introduction of optimal doses of DMPP to determine the reactivity of the respiratory tract.

Measurement of increased reactivity of the Airways

Increased airway reactivity (AHR) under the influence of methacholine measured the shot of mice with a tracheotomy and ventilation fan, controlled by computer (FlexiVENT™).

Mice were administered increasing doses of methacholine (0 mg/kg of 32.5 mg/kg) via the jugular vein. On Fig shown that DMPP reduced resistance of the lungs as a percentage compared to mice suffering from asthma, which was not subjected to treatment. On Fig shown that DMPP significantly reduced RS in the treated mice compared to mice suffering from asthma, which was not subjected to treatment (p=0.04; n=6).

Example VII

The effect of the agonist on the expression of mRNA of IL-4

In addition, research is Wali effect of the agonist on the expression of mRNA of IL-4, which is a cytokine, which, as is well known, mediates the development of asthma (53). Nicotine reduced the mRNA expression of IL-4 to 92% at a dose equal to 40 microns (Fig.9). DMPP completely blocked the expression of mRNA of IL-4. On Fig the results corresponding to figure 5. Cells were treated with different doses of 40-160 μm nicotine and DMPP). The effects of nicotine reduced the mRNA expression of IL-4 (decrease in the expression of up to 90% in the group which was administered to 40 μm nicotine). As was shown above, the expression of mRNA of IL-4 was absent during stimulation of cells by antigen SR.

Example VIII

The effects of various agonists on the transfer of eosinophilic leukocytes

For further investigation of the debilitating effects of agonists nicotine on inflammation in asthma, the authors of the present invention tested the effect of different agonists on the transfer of eosinophilic leukocytes.

Infiltration of eosinophilic leukocytes and other inflammatory cells infiltration in the lung tissue is an important feature of asthma and cause inflammation and increased airway responsiveness. The transfer cells of the inflammatory infiltrate from the bloodstream into the lungs includes the penetration of the vascular endothelium, basal membrane and components of the extracellular matrix. Cells of the inflammatory infiltrate penetrate through the basal membrane, thus producing about Ainazi. In preliminary in vitro experiments investigated the effects of various agonists nicotine penetration of treated eosinophilic leukocytes of blood through an artificial basement membrane (chemotactic camera with a coating of Martigel®). DMPP inhibited migration of eosinophilic leukocytes, depending on the dose (Fig shown that DMPP inhibits the transfer of eosinophilic leukocytes through the artificial basement membrane depending on dose), although the action is reversible with the introduction of such an antagonist as mecamylamine (MONTHS) (Fig shown that mecamylamine inverts the effect of DMPP, from which it follows that for the inhibitory effect of DMPP required activation of nicotine receptors). The above inhibitory effect was further confirmed by other agonists nicotine, including nicotine, epibatidine and tsitizin (Fig), which reduce the transfer of eosinophilic leukocytes from the blood. The results are expressed as percentage of inhibition (cells treated with agonists) compared to control cells not treated with the indicated agonists.

The results show that agonists nicotine reduce the synthesis or activation of proteases that destroy the components of the basal membrane, inhibiting in this way the migration of eosinophilic leukocytes in the mucosa is bolocco lungs.

Example IX

The effects of agonists nicotine on the production of collagen

Asthma is characterized by structural changes of the Airways, including subepithelial deposition of collagen, which can be a cause of chronic disease. This process can be caused by an imbalance between collagen synthesis and its destruction by fibroelastoma (56). In preliminary experiments, the authors present invention studied the effects of agonists nicotine on the synthesis of collagen A1 produced primary normal fibroblasts. Gene expression of collagen A1 was determined by the method of RT-PCR.

The results are expressed as percentage values of gene expression in cells treated with agonists, compared with untreated cells.

DMPP inhibits gene expression of collagen A1 depending on the dose (Fig). Nicotine has a weak inhibitory effect in a dose of 1 and 10 μm and higher concentrations have no effect (Fig), probably due to desensitization of the receptors. For inhibition may be required a lower dosage, which will be tested in the future. The inhibitory effect was also observed when using epibatidine (Fig).

Similar tests were performed using the following analogues of DMPP, with whom Holocene equivalent results.

Example X

Impact analogues DMPP

On the basis of the results obtained for the DMPP were created four (4) analog DMPP that experienced in relation to the anti-inflammatory action, less pronounced increased reactivity and relaxing effect on smooth muscle. Like DMPP, ASM-002, ASM-003, ASM-004 and ASM-005 are synthetic agonists acetylcholine receptors in nicotine. These compounds are high hydrophilic due to the structure of Quaternary salt and therefore not penetrate the blood-brain barrier. Therefore, it is unlikely that these compounds are able to cause addiction.

Example XI

Anti-inflammatory effect

The effects of analogues of DMPP on vysvobojdenie of tumor necrosis factor (TNF)

The monocytes were isolated from the blood of subjects with asthma, using gradient density ficoll pack, left to clutch with tablets for tissue culture and stimulated with LPS (100 ng/ml) for 18 hours at 37°C with the addition of nicotine in increasing concentrations or without the addition of nicotine. The release of TNF, a strong Pro-inflammatory mediator, was measured in the supernatant of cell cultures using ELISA method. The results are expressed as percentage values of the release from LPS-stimulated raw cells (Fig). For IP the connection ASM-005, all tested analogs had inhibitory effect on the release of TNF (n=8-10; p from 0.01 to 0.007).

Example XII

The effects of analogues of DMPP on the production of leukotriene C4 (LC4)

Eosinophilic blood leukocytes, are cells of the inflammatory infiltrate characterized by the greatest increase in the case of asthma, were isolated by the method of negative selection using conjugated with beads of monoclonal antibodies against CD16 and method of sorting cells with magnetic activation. The cells were pre-incubated for 18 hours with different analogues of DMPP and then stimulated with 1 μm of platelet activating factor (PAF) for the production of LTC4, the concentration of which was measured using enzyme immunoassay.

The results show that 3 out of 4 tested analogues can reduce the release of LTC4 (table 1).

Table 1
The effect of DMPP and its analogues on the release of LTC4
LTC4 (PG/ml)
-1725,80
DMPP545,00
ASM-002246,40
SM-003 613,90
ASM-004601,60

Example XIII

Relaxing effect on smooth muscle

The effects of analogues of DMPP on the reactivity of smooth muscles of the respiratory tract trachea

To demonstrate the relaxing effects of analogues of DMPP on smooth muscle cells of the respiratory tract were performed isometric studies using remote trachea of mice. Tracheal rings, pre-reduced using methacholine in a submaximal concentration (10-5), mounted isometrically with pressure sensors in baths for bodies containing bicarbonate Krebs solution at 37°C, was barbotirovany 95% O2-5% CO2and added to baths analogues in total doses. Recorded voltage changes. The results are expressed as percentage of maximum contraction (Fig).

Like DMPP its analogues caused a relaxation of smooth muscles of the trachea, pre-reduced using methacholine, depending on the dose.

The results show that ASM-002, ASM-003, ASM-004 and ASM-005, which are new synthetic analogues, would have the same anti-inflammatory and relaxing effect on smooth muscles that DMPP.

Example XIV

Mod is any disease in mice

The impact of ASM-002 on pneumonia

Mice sensitized with ovalbumin, (n=8) induced by allergen and simultaneously introduced into the nose ASM-002 in increasing concentrations (0.5-4 mg/kg/day) for 3 days. The number of cells selected by bronchoalveolar lavage were used as measures of inflammation of the lungs.

As shown in Fig, ASM-002 significantly inhibited depending on the dose of inflammation cells in the lungs of mice with asthma (ED50=0,71 mg/kg, n=8).

Example XV

The infection model in mice

The impact of ASM-002 on the resistance of the lung in a model of asthma in mice

The reaction of light on bronchosoothe agent, metafolin, measured in the apparatus Flexi-vent®. Animals sensitized with ovalbumin, within 3 days was administered in the nose ASM-002 (4 mg/kg) 10 minutes before stimulation methacholine, after which the condition of these animals was compared with state VA-sensitized animals were not subjected to the effects of ASM-002. When performing this experiment also investigated the negative control group desensibilization animals and the positive control group, which was introduced salbutamol (ventolin) for 10 minutes prior to stimulation methacholine.

The obtained results show (Fig) about the increasing resistance of the lungs due to methacholine, OV-sensitized mice compared with negative control group. In mice which were injected ASM-002, there was a significant decrease (return to initial level) resistance of the lungs compared with control mice (n=8, p<0,02). This energy was similar to the effect of salbutamol (ventolin™), the most famous bronchodilator, currently used in asthma to relieve symptoms narrowing of the bronchi (n=4, p<0,02).

Example XVI

Model of asthma in dogs

12 dogs of this model, sensitized in vivo by Ascaris Ascaris suum, used to perform cross-examination. Were randomly generated four groups of 3 dogs in each, which are stimulated by the allergen, with each animal alternative was introduced ASM-002 (4 mg/kg 2 times per day in the diet) or prednisone (1 mg/kg 1 time per day in the diet), the most well-known corticosteroid used to treat inflammation in asthma, or were not subjected to any impact.

Comparative effects of ASM-002 and prednisone TM on pneumonia

Inflammation of the cells was determined in bronchoalveolar lavage.

As shown in Fig, ASM-002 (8 mg/kg) significantly inhibited the inflammation of the cells in the lungs of dogs suffering from asthma, with the same efficiency as the prednisone™, the most commonly used anti-inflammatory drug (n=12,p< 0,05).

Example XVII

The impact of ASM-002 in the model increased reactivity of the lung in dogs

Increased reactivity is defined as the ability of the lung to respond (to increase the resistance of the lung) on non-specific external stimuli, such as metafolin, or allergens. Sensitized allergen dog with high reactivity (suffering from asthma) responds to metacholine in lower concentrations compared to a dog that does not have allergies. In a similar way to reducing the high reactivity of the lung indicates increasing concentrations of methacholine required to induce the same level of resistance of the lungs.

Dogs entered metafolin in increasing concentrations with simultaneous treatment of ASM-002 or prendisone™ and record the resistance of the lungs.

As shown in Fig, ASM-002 reduced resistance to lung in 7 out of 12 dogs with increased reactivity. None of the 12 dogs were observed reduction increased reactivity with the introduction of prednisone (p=0.005).

Example XVIII

Miorelaksiruyuschee properties of ASM-002

To further demonstrate relaxing actions ASM-002 on the smooth muscle cells of the respiratory tract was performed isometric studies using remote trachea of mice, bronchial rings from the lungs of dogs and bronchus is the material of the rings from resected human lung. As described above, tracheal or bronchial rings, pre-reduced using methacholine in a submaximal concentration, mounted isometrically with pressure sensors in baths for bodies containing bicarbonate Krebs solution at 37°C, was barbotirovany 95% O2-5% CO2and added to baths ASM-002 total doses. Recorded voltage changes. The results are expressed as percentage values of the maximum reduction for the mouse (Fig, p=0.002), dogs (Fig, p=0.004), and human (FIH).

The results obtained in examples XIV-XVIII, show that ASM-002 has a relaxing effect on pre-constricted trachea of mice, bronchi of dogs and humans.

Example XX

In vitro studies

As was shown in the previous examples, the anti-inflammatory activity of ASM-002 was observed in vivo in mice and dogs. For further studies indicated effects were tested the ability of drugs to inhibit the release of 2 strong inflammatory mediators by human blood cells isolated from subjects with asthma.

The tumor necrosis factor (TNF) is a mediator released during inflammation. Monocytes human blood stimulated in vitro with lipopolysaccharide (LPS) to produce large amounts of TNF, it is time to relax is whether ASM-002 in increasing doses and measured the levels of TNF (Fig, EU50=3 μm, n=6, p=0,0045 at 5 μm, 0,0014 at 10 μm and 0,0003 at 50 μm). With the introduction of ASM-002 was observed inhibition of release of TNF depending on the dose.

Example XXI

Comparative effects of ASM-002, DMPP and dexamethasone on the production of TNF LPS-stimulated monocytes blood

As shown in Fig, the results obtained are expressed as percentage of the untreated control cells by adding all medicines in a concentration of 40 μm and represent the average of 5 different experiments (5 subjects). ASM-002 inhibits the release of TNF from monocytes of the blood of man is similar to dexamethasone and DMPP (p=0.02-0,001).

Leukotrien4(LTC4) is a lipid mediator of inflammation produced in the case of asthma, which release large quantities of eosinophilic leukocytes in the blood.

Eosinophilic leukocytes human blood was isolated from the blood of subjects with asthma, stimulated in vitro by platelet activating factor (PAF) for producing large amounts of LTC4 and was treated with 80 μm ASM-002 or not subjected to any impact.

There was significant inhibition of the production of LTC4 ASM-treated eosinophilic leukocytes (Fig, p=0,0007). The results represent the average of 6 different experiments (6 subjects).

Received re ulitity show what ASM-002 provides comprehensive anti-inflammatory and bronchodilatory effect and reduces the increased reactivity, and this action can be very effective to alleviate the symptoms and treatment of asthma and other obstructive respiratory diseases.

Example XXII

Other analogues of acetylcholine receptors in nicotine

Other analogs, such as nicotine, tsitizin and epibatidine described in the present description of the invention, can also be used as inhibitors of the nicotine receptors in the treatment of inflammation of the lungs.

Anti-inflammatory effect

Monocytes human blood were isolated by density gradient ficoll pack, left to clutch with tablets for tissue culture and stimulated with LPS (100 ng/ml) for 18 hours at 37°C with the addition of nicotine analogs in ascending concentrations or without the addition of such analogs. The results presented in Fig, the significance levels shown in table 2.

Table 2
The significance levels of the effects of analogues of nicotine on LPS stimulation
Concentration (M)Nicotine p=ASM-N1
p=
ASM-N2
p=
ASM-N3
p=
ASM-N4
p=
10-40,0340,0110,0060,0370,035
10-5to 0.0320,0150,0010,0080,039

When increasing concentrations of the four analogues of nicotine was observed a significant decrease in the release of TNF.

Example XXIII

1-Phenylpiperazine (1 EQ.), Iodate (1 EQ.) and sodium carbonate (2 equiv.) was mixed with tert-butanol. The mixture was heated under reflux for 20 hours. Then the mixture was dissolved in chloroform and was extracted three times with water. The organic layer is washed three times 1 N. aqueous solution of HCl. The aqueous layer was podslushivaet pellets of NaOH to achieve a basic pH. Basically the aqueous layer then was extracted three times with chloroform, the combined organic extracts were dried over Na2SO4and was evaporated to dryness. The crude product was purified flash chromatography on silica gel using a gradient of 0-5% Meon in chloroform. The desired product was obtained as a yellow oil (yield 52%).

N-Ethylvinylbenzene (1 EQ., 0.6 mmol) and itmean (excess >10 EQ., 1 ml) was stirred in a simple ether at room temperature for 4 days. The resulting white precipitate ASM-003 were isolated by filtration under vacuum (yield 75%).

Example XXIV

1-Phenylpiperazine (1 EQ.), iodopropane (1 EQ.) and sodium carbonate (2 equiv.) mixed in tert-butanol. The mixture was heated under reflux for 20 hours. Then the mixture was dissolved in chloroform and was extracted three times with water. The organic layer is washed three times 1 N. aqueous solution of HCl. The aqueous layer was podslushivaet pellets of NaOH to achieve a basic pH. Basically the aqueous layer was extracted three times with chloroform, the combined organic extracts were dried and evaporated to dryness. The crude product was purified flash chromatography on silica gel using a gradient of 0-5% Meon in chloroform. The desired product was obtained as a yellow oil (yield 83%).

N-Propylpiperonyl (1 EQ., 0.6 mmol) and itmean (excess >10 EQ., 1 ml) were mixed and stirred in a simple ether at room temperature for 2 days. Then the mixture was heated under reflux for 48 hours with an additional number of iodomethane (>10 EQ.) and a mixture of THF and simple ether (1:1). The mixture was evaporated and diluted in a simple broadcast the formation of a white precipitate ASM-004, which were isolated by filtration under vacuum (yield 86%).

Example XXV

N-Ethylvinylbenzene obtained in example XXIII, (1 equiv, 0.5 mmol) and Iodate (excess >10 EQ., 1 ml) was stirred in a simple ether at room temperature for 2 days. Then the mixture was heated under reflux for 48 hours with an additional number of iodata (>10 EQ) and the mixture of THF and simple ether (1:1). The mixture was evaporated and diluted in a simple ether with the formation of a white precipitate ASM-005, which was isolated by filtration under vacuum (yield 62%).

or

N-Ethylvinylbenzene (1 EQ., of 3.94 mmol) and Iodate (excess >10 EQ., 3 ml) was stirred in acetonitrile at room temperature. The mixture was evaporated and diluted in a simple ether with the formation of a white precipitate ASM-005, which was isolated by filtration under vacuum (yield 27%).

Example XXVI

N-Propylpiperonyl (1 EQ., 0.51 mmol) and Iodate (excess >10 EQ., 1 ml) was stirred in a simple ether at room temperature for 2 days. Then the mixture was heated under reflux for 48 hours with an additional number of iodata (>10 EQ.) and a mixture of THF and simple ether (1:1). The mixture was evaporated and diluted in a simple ether with the formation of a white precipitate, which was isolated by filtration under vacuum (yield 11%).

or

N-Propylphenyl erasin (1 EQ., 0.1 mmol) and Iodate (excess >10 EQ., 1 ml) was stirred in acetone, heated under reflux for 24 hours. The mixture was evaporated and diluted in a simple ether with the formation of a white precipitate, which was isolated by filtration under vacuum (yield 75%).

Example XXVII

N-Propylpiperonyl (1 EQ., of 0.53 mmol) and iodopropane (excess >10 EQ., 1 ml) was stirred in a simple ether at room temperature for 2 days. Then the mixture was heated under reflux for 48 hours with an additional number of iodopropane (>10 EQ., 1 ml) and a mixture of THF and simple ether (1:1). The mixture was evaporated and diluted in a simple ether with the formation of a white precipitate, which was isolated by filtration under vacuum (yield 10%).

Example XXVIII

Iadanza (1 EQ., of 1.47 mmol), N-methylhomopiperazine (1.2 EQ., of 1.76 mmol), ethylene glycol (2 EQ., to 2.94 mmol), CuI (5 mol.%) and K3RHO4(2 EV., to 2.94 mmol) suspended in isopropanol (3 ml) in a flame dried round bottom flask under nitrogen atmosphere. The mixture was heated under reflux with stirring for 17 hours. The resulting mixture was cooled to room temperature and added water (5 ml). The mixture was extracted with simple ether (4×10 ml), the combined organic extracts were washed with saturated salt solution, dried over Na2/sub> SO4and was evaporated to dryness in vacuum. The crude product was purified flash chromatography on silica gel using a gradient from 0% to 7.5% 2 M solution of NH3MeOH in chloroform. The desired product was obtained as a yellow oil (yield 64%).

N-Methylphenylhydrazine (1 EQ., 0.36 mmol) and itmean (excess >10 EQ., 1 ml) was stirred in a simple ether at room temperature for 25 hours. The mixture was evaporated in vacuo, diluted in a simple ether and the resulting white solid was filtered under vacuum. Was obtained iodide 1,1-dimethyl-4-pergamonbrassey (yield: 66%). Melting point: 158-160°C.

1H NMR DMSO-d6 (h/m): (q, 2H) 7.18 in (q, 2H) 6,74, (t, 1H) 6,64, (Sirs, 2H, 3,74), (m, 2H) 3.52, the (m, 2H) 3,44, (t, 2H) 3,40, (s, 6H) 3,17, (Sirs, 2H) 2,21.

13C NMR DMSO-d6: 149, 129, 117, 112, 66, 65, 53, 47, 43, 22.

Example XXIX

Nicotine (160 mg, 0,987 mmol) was dissolved in diethyl ether (5 ml), was added an excess of iodomethane (33 EQ., 2 ml) and stirred in the dark at night at room temperature for 15 hours.

The mixture was filtered under vacuum and the solid is washed with diethyl ether. There was obtained a white precipitate ASM-N1 (yield 91%).

1H NMR (acetone-d6 (h/m): (m, 1H) 1,75, (m, 1H) 1,85, (m, 1H) 2,0 (s, 3H) and 2.26 (m, 2H) 2,42, (m, 1H) 3,25 (t, 1H) 3,59, (s, 3H) 4,67 (t, 1H) 8,21, (d, 1H) 8,66, (d, 1H) 9,13, (s, 1H) which 9.22.

Example XXX

To the previously obtained compound salt of nicotine (ASM-1) (100 mg, 0.32 mmol) in anhydrous dichloromethane (15 ml) was added excess iodomethane (33 EQ., of 0.64 ml) and stirred in the dark at night at room temperature for 18 hours.

The mixture was filtered under vacuum and the solid is washed with diethyl ether. There was obtained a white precipitate (yield 26%).

1H NMR (acetone-d6 (h/m): (m, 3H) and 2.26 (m, 1H) 2,71, (s, 3H) 2,82, (s, 3H) 3,14 (m, 1H) 3,76, (m, 1H) 3,86, (s, 3H) and 4.40 (t, 1H) 5,04, (t, 1H) 8,31, (d, 1H), cent to 8.85 (d, 1H), 9,17, (s, 1H) 9,31.

Example XXXI

Nicotine (390 mg, 2.4 mmol) was dissolved in diethyl ether (10 ml), was added an excess of iodata (33 EQ., 6.3 ml) and stirred in the dark at room temperature for 7 days.

The solvent is evaporated and added dichloromethane (100 ml) to precipitate a yellowish-white substance ASM-N4.

The organic layer was evaporated and the resulting oil was washed with diethyl ether education ASM-N3.

1H NMR (acetone-d6 (h/mn) of the AFM N3: (t, 3H) 1,70, (m, 1H) 1,82, (m, 1H) 1,95, (s, 3H), and 2.26 (m, 3H) 2,43, (m, 1H) 3,30 (m, 1H) 3,70 (q, 2H) put down $ 4.95 (m, 1H) to 8.20 (d, 1H) 8,69, (d, 1H) 9,29, (s, 1H) 9,39.

1H NMR (acetone-d6 (h/mn) of the AFM N4: (2T, 3H) 1.2 and 1.5 (t, 3H) 1,75, (m, 1H) 1,85, (m, 2H) 2,05 (s, 3H) 2,41, (m, 1H) 2,71, (m, 2H) 3,45, (2Q, 2H) 3,78, and 3.95 (m, 1H) 4,12 (q, 2H) 4,98, (m, 1H) 8,27, (d, 1H) 8,86(d , 1H) 9,40 (s, 1H) 9,56.

Example XXXII

ASM-C1 was obtained using iodomethane (10 EQ.) the dichloromethane for 1 hour in the dark in accordance with the description, shown in example XXIX. The results of the study were consistent with the structure of the compound.

Example XXXIII

ASM-C2 was obtained using formaldehyde and formic acid by the method described in the publication J. Med. Chem. (2001), 44, 3946-3955. The results of the study were consistent with the structure of the compound.

Example XXXIV

ASM-C3 were obtained using iodomethane (40 EQ.) in dichloromethane for 20 hours in the dark in accordance with the description given in example XXIX. The results of the study were consistent with the structure of the compound.

Example XXXV

ASM-C4 was obtained with the use of ethylene oxide by the method described in publication II Farmaco 54 (1999) 438-451. The results of the study were consistent with the structure of the compound.

Example XXXVI

ASM-C5 were obtained using iodomethane (40 EQ.) in dichloromethane for 18 hours in the dark in accordance with the description given in example XXIX. The results of the study were consistent with the structure of the compound.

Example XXXVII

The dihydrochloride (+)-epibatidine was treated with triethylamine (10 EQ.) in dichloromethane for 1 hour at room temperature, then epibatidine was isolated by the standard method of separation of the Oia.

ASM-E1 was obtained using epibatidine, formaldehyde and formic acid by the method described in the publication J. Med. Chem. 2001, 44, 3946-3955. The results of the study were consistent with the structure of the compound.

Example XXXVIII

ASM-E1 was obtained using iodomethane (40 EQ.) in dichloromethane for 17 hours at room temperature in accordance with the description given in example XXIX. The results of the study were consistent with the structure of the compound.

Although the present invention is described with reference to preferred embodiments of the invention, it can be modified within the scope of the invention, and the invention corresponds to the attached claims.

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Contents for capsules:

ASM-002 10 mg

Prednisolone 0.5 mg

Lactose 44,5 mg

Microcrystalline cellulose 35 mg

Magnesium stearate 10 mg

Mix the components of the capsule and granularit. If necessary, fill with granular gelatin capsule

Table a
Lower the following table illustrates the activity indicators included in the formula of the invention compounds according to examples: for anti-inflammatory action of TNP-IC 50; for muscle relaxant actions IC50Iso
EntryCompoundIC50TNF (µm)S Iso (µm)
ASM-0022.38127.05
ASM-0083.37f59.92
ASM-0092.0370.87
ASM-0100.8378.92
ASM-0160,47 BS**85.94

ASM-017BS27.71
ASM-0180.79 BS40.59
ASM-02133.0437.02
ASM-02232.3873.12
ASM-02455.6868.84
ASM-025At 37.6455.98

ASM-03323556
ASM-034At 56.5488.06
ASM-037NI‡59.89
ASM-048At 70.91ND
ASM-049 176.589.59
ASM-05513.5120

ASM-057494353.79
ASM-05855432.72
ASM-064tox371.2
ASM-06722.7138.03
ASM-06859.216.77
ASM-07021.06110.93
ASM-071 2.7486.42

ASM-0723.7153.62
ISO : isometry which is a mesure of myorelaxation;
BS means Bell Shape curve (IC50 is not calculated);
NI: No Inhibition at the concentration tested and
Tox: No conclusion were drawn on the IC50''s because the tested concentration was detrimental to the cultured cells.

1. Method for the treatment or prevention of inflammatory lung diseases selected from the group comprising asthma, chronic obstructive pulmonary disease (COPD), interstitial fibrosis of the lung tissue (IPF), sarcoidosis, allergic pneumonitis (HP), chronic allergic pneumonitis and obliterative bronchiolitis with organizing pneumonitis (WOOR), which includes the introduction of an effective amount of
i) compounds of the formula:

where R1and R2independently denote alkyl with 1-10 carbon atoms;
Ha denotes CH or N;
Ya means one or more substituents selected from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms, possibly substituted by one or more halogen atoms, and alkoxy with 1-10 carbon atoms;
n means an integer of 0 or 2;
J means the counterion, predstavlyalsya ion compounds to preserve electroneutrality, for example, a halogen, sulfate, sulfonate; or
ii) compounds of the formula:

where R3selected from
or
b means N or N+-R10;
R4means one or more substituents selected from hydrogen, halogen;
each of R10, R11and R12independently mean alkyl with 1-10 carbon atoms;
subject to the availability of the counterion, when b means N+-R10; and provided that the compound (ii) is not nicotine.

2. The method according to claim 1, wherein the compound has the formula:

where R1and R2independently denote alkyl with 1-10 carbon atoms;
Ha denotes CH or N;
Ya means one or more substituents selected from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-6 carbon atoms, substituted by one or more halogen atoms, and alkoxy with 1-6 carbon atoms;
n means an integer of 0 or 2;
J means the counterion, which represents an ion compounds to preserve electroneutrality, for example, halogen, sulfate, sulfonate.

3. The method according to claim 2, in which R1and R2independently selected from methyl, ethyl, n-propyl or isopropyl;
Ha means SN;
Ya mean hydrogen;
n = 2;
J denotes halogen.

4. The method according to claim 1, in which the decree is Noah compound has the formula:

where R1and R2independently selected from methyl, ethyl, n-propyl or isopropyl;
Ya mean hydrogen;
J denotes halogen.

5. The method according to claim 1, in which the indicated compound has the formula:
or

6. The method according to claim 1, wherein the compound has the formula;

where R3selected from
or
b means N or N+-R10;
R4means one or more substituents selected from hydrogen and halogen;
each of R11and R12independently mean alkyl with 1-10 carbon atoms;
subject to the availability of the counterion, when b means N+-R10,
provided that the compound (ii) is not nicotine.

7. The method according to claim 6, in which the compound is selected from compounds of the formula:
and

8. The method according to claim 1, in which the specified inflammatory lung disease is asthma.

9. The method according to claim 1, in which the specified connection is administered by direct injection or infusion, vnutritrahealno, nose, eyes, transdermally, orally, parenterally, topically or by inhalation.

10. The method according to claim 9, in which the specified connection is out administered orally, topically, or by inhalation.

11. The compound of the formula:

where R1and R2independently denote alkyl with 1-10 carbon atoms;
Ha denotes CH or N;
Ya means one or more substituents selected from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms, possibly substituted by one or more halogen atoms, alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms;
n means an integer of 0 or 2;
J means the counterion, which represents an ion compounds to preserve electroneutrality, for example, halogen, sulfate, sulfonate.

12. Connection by claim 11, in which R1and R2 are independently selected from methyl, ethyl, n-propyl or isopropyl;
X is CH;
Y represents hydrogen;
n = 2;
J denotes halogen.

13. Connection claim 11 having the formula:

where R1and R2independently selected from methyl, ethyl, n-propyl or isopropyl;
Y represents hydrogen;
J denotes halogen.

14. Connection claim 11 having the formula:
or

15. Pharmaceutical composition having activity against TNP (tumor necrosis Factor, which is the mediator released during inflammation and muscle relaxant effect, containing an effective quantity is STV
i) compounds of the formula:

where R1and R2independently denote alkyl with 1-10 carbon atoms;
Ha denotes CH or N;
Ya means one or more substituents selected from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms, possibly substituted by one or more halogen atoms, alkoxy with 1-10 carbon atoms;
n means 0 or 2;
J means the counterion, which represents an ion compounds to preserve electroneutrality, for example, halogen, sulfate, sulfonate;
and pharmaceutically acceptable filler.

16. The way to reduce the release of TNF and inducing relaxation of smooth muscles of the Airways and reduce the increased reactivity of the Airways in patients with asthma or chronic obstructive pulmonary disease (COPD), which includes the introduction of an effective amount of the compounds of formula:

where R1and R2independently denote alkyl with 1-10 carbon atoms;
Ha denotes CH or N;
Ya means one or more substituents selected from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms, possibly substituted by one or more halogen atoms, alkoxy with 1-10 carbon atoms;
n means an integer of 0 or 2;
J means the counterion, the stand is engaged in an ion compounds to preserve electroneutrality, for example, a halogen, sulfate, sulfonate.

17. The connection 11 of the formula (I):

where R1and R2independently denote alkyl with 1-10 carbon atoms;
Ha denotes CH or N;
Ya means one atom of hydrogen or halogen;
n means 2;
J means the counterion, which represents an ion compounds to preserve electroneutrality, for example, halogen, sulfate, sulfonate.

18. The connection 11 of the formula (I):

where R1and R2independently selected from methyl, ethyl, n-propyl or isopropyl;
Ha denotes CH or N;
Ya mean hydrogen or halogen;
n means 2;
J means the counterion, which represents an ion compounds to preserve electroneutrality, for example, halogen, sulfate, sulfonate.

19. The compound according to any one of p and 18, where Ha represents CH.

20. The compound according to any one of p and 18, where J represents fluoride, chloride, bromide, iodide, sulfate or sulfonate.

21. The connection 11 of the formula:

where J represents a sulfonate.

22. The method according to claim 1 or 16, where the compound is a compound of the formula:

where R1and R2independently selected from methyl, ethyl, n-propyl or isopropyl;
Ha denotes CH or N;
Ya mean hydrogen or halogen;
will oznachaet 2;
J means the counterion, which represents an ion compounds to preserve electroneutrality, for example, halogen, sulfate, sulfonate.

23. The method according to item 22, where Ha represents CH.

24. The method according to item 22 or 23, where Ha represents fluoride, chloride, bromide, iodide, sulfate or sulfonate.

25. The method according to any one of claims 1 and 16, where the compound is a compound of the formula

where J represents a sulfonate.

26. The method of treatment or prevention according to claim 1, comprising introducing one or more drugs selected from bronchodilators, anti-inflammatories, antagonist of leukotriene receptors and phosphodiesterase inhibitors.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein R means dihydrosubstituted C2-C6alkyl group, and Cy represents spiro[4.5]dec-6-yl, spiro[2.5]oct-4-yl, spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl or 1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl-group. Said compounds act as nociceptive receptor antagonists, and are applied e.g. as agents improving acceptability of narcotic analgesics, relieving narcotic analgesic dependence or narcomania; as an analgesic intensifier; antiobesity agents or appetite suppressants; agents for treating decreasing cognition and senile dementia /amnesia; agents for treating developing cognition disorder; therapeutic agents in schizophrenia; agents for treating neurodegenerative diseases; antidepressants or therapeutic agents in affective disorder; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents in polyuria; and therapeutic agents in hypotension and similar.

EFFECT: preparation of the compounds acting as nociceptive receptor antagonists.

11 cl, 5 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: described is an improved method for synthesis of 3(5)-pyridyl-substituted 5(3)-amino-1,2,4-triazoles of general formula (I)

, where R denotes 2-pyridyl, 3-pyridyl or 4-pyridyl, involving reaction of pyridine carboxylic acid of general formula (II)

, where R assumes said values, with an aminoguanidine hydrocarbonate in the presence of hydrochloric acid in molar ratio acid (II): aminoguanidine hydrocarbonate: hydrochloric acid = 1.0:1.0:1.3-1.5, while boiling the reaction mixture with gradual distillation of water at atmospheric pressure until temperature of the reaction mixture equals 165-180°C and then holding the reaction mixture at this temperature for 3-5 hours and then adding an alkali solution in water, boiling alkaline solution and extraction of the end product by filtering after neutralisation of the reaction mixture and cooling.

EFFECT: method enables to obtain said compounds from cheaper material, increases output of end products and shortens duration of the synthesis process.

1 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula 1a, where X denotes a halogen or C1-C4halogenalkyl; Z denotes N or CR9; each R5 independently denotes halogen or C1-C4halogenalkyl; R9 denotes H, halogen or C1-C4halogenalkyl; R10 denotes H or C1-C4alkyl; and n is an integer from 0 to 3, involving bringing 2-pyrazoline of formula 2a, where X, Z, R5, R9, R10 and n assume values given above, into contact with bromine in a medium of a suitable inert organic solvent at temperature 80-180°C.

EFFECT: obtaining pyrazoles of formula 1a with high output and purity.

7 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of (R)-2-arylpropionamide of the formula (I): , wherein Ar means aryl of the formula (IIIb): F-Arb wherein Arb means phenyl mono- or poly-substituted with the following groups: chlorine, fluorine atom; F means hydrogen atom, linear or branched (C1-C5)-alkyl residue, benzoyl, 2,6-dichlorophenylamino-, 2,6-dichloro-3-methylphenylamino-group; R means hydrogen atom, (C1-C4)-alkyl; X means linear or branched (C1-C6)-alkylene optionally substituted with the group -CO2R4 wherein R4 means hydrogen atom or linear or branched (C1-C6)-alkyl group, phenyl or phenylmethylene group; R1, R2 and R3 mean independently linear or branched (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C3-C6)-alkenyl, aryl, aryl-(C1-C3)-alkyl, or R1 and R2 in common with nitrogen atom (N) to which they are attached form nitrogen-containing 6-membered heterocyclic ring of the formula (II) , and R3 has values indicated above independently wherein in the formula (II) Y means a simple bond, methylene group, oxygen atom, nitrogen atom or sulfur atom; p means a whole number 2; Z- means a pharmaceutically acceptable counterion of quaternary ammonium salts. Also, invention relates to using compound of the formula (I) in treatment of psoriasis, pemphigus and pemphigoid, rheumatic arthritis, intestine chronic inflammatory pathology including ulcerous colitis, acute respiratory distress-syndrome, idiopathic fibrosis, mucoviscidosis, pulmonary chronic obstructive disease and glomerulonephritis, and also for prophylaxis and treatment of injure caused by ischemia and reprefusion. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to chemotaxis of polymorphonuclear leukocytes and monocytes induced by complement C5a fractions and comprising compound of the formula (I) in mixture with a suitable carrier. Also, invention relates to a method for synthesis of compounds of (R)-2-arylpropionamide of the formula (I) that involves interaction of amides of the formula (IV) given in the invention description with compounds of the formula R3Zwherein Z means a leaving group, such as chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate. Invention provides synthesis of (R)-2-arylpropionic acid omega-aminoalkylamide quaternary ammonium salts used for inhibition of chemotaxis activation induced by the C5a complement component.

EFFECT: valuable properties of compounds and pharmaceutical compositions.

17 cl, 1 tbl, 6 ex

FIELD: chemistry of metalloorganic compounds, agriculture.

SUBSTANCE: invention describes derivatives of mepiquate borate of the general formula (I): wherein DMP means N,N-dimethylpiperidinium (mepiquate); M means metal cation acceptable for agriculture and chosen from a series comprising sodium, potassium, magnesium, calcium, zinc, manganese or copper, hydrogen atom or NH4+; O means oxygen atom; A means chelate of complex-forming fragment bound with one boron atom and representing (lower)-alkylglycols or sugars; n and m mean similar whole numbers in the range from 1 to 6; x means a whole or fraction number in the range from 0 to 10; y means a whole or fraction number in the range from 1 to 48; z means a whole or fraction number in the range from 0 to 48; v means a whole or fraction number in the range from 0 to 24, and w means a whole or fraction number in the range from 0 to 24. Also, invention describes methods for preparing compound of the formula (I) by interaction of N,N-dimethylpiperidinium hydroxide with boric acid and/or boron-containing oxides and optionally with metal hydroxides acceptable for agriculture indicated above or electrochemical method involving interaction of N,N-dimethylpiperidinium halide in the presence of water and boric acid and in the presence metal hydroxides acceptable for agriculture by bipolar electrodialysis. Invention describes electrochemical method for preparing N,N-dimethylpiperidinium hydroxide and a suspension concentrate possessing the plant growth-regulating effect prepared by mixing N,N-dimethylpiperidinium hydroxide, boron-containing compound chosen from boric acid and borate salt with a thickening agent and water, or by mixing compound of the formula (I) with Na2B8O13 x 4 H2O, a thickening agent and water. Prepared derivatives of mepiquate borate possess the improved indices of hygroscopicity and corrosion activity.

EFFECT: improved preparing methods, valuable properties of derivatives.

22 cl, 7 tbl, 16 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a new biologically active compound. Invention describes quaternary ammonium derivative of lidocaine of the formula:

eliciting anti-arrhythmic activity. Also, invention describes a method for preparing quaternary ammonium derivative of lidocaine of the formula (1). Method involves interaction of N-(2,6-dimethylphenylaminocarbonylmethyl)-morpholine with allyl bromide in isopropyl alcohol medium at temperature 58-62°C followed by cooling the reaction mixture to room temperature and isolation of N-allyl-(2,6-dimethylphenylaminocarbonylmethyl)-morpholinium bromide. Invention provides preparing new compound eliciting useful biological properties.

EFFECT: improved preparing method.

2 cl, 4 tbl, 4 ex

The invention relates to the field of organic chemistry and relates to new triiodide 1,2,3-substituted benzimidazole with antimicrobial and anti-tumor activity, which may find application in medicine, as well as methods for their preparation

The invention relates to the production technology of heterocyclic substances, in particular to the production technology, morpholine 3-methyl-1,2,4-triazolyl-5-thioacetate used in medicine and veterinary medicine

The invention relates to an improved method of obtaining a known regulator of growth - meekatharra, N,N-dimethylpiperidinium

The invention relates to medicine, specifically to medicines used in the treatment of ischemic heart disease, and arrhythmias complicating it

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns cat allergen fused proteins and application thereof. Substance of the invention involves a compositions containing a virus-like particle (VLP) or a viral particle and at least, one antigen, first of all at least, one cat antigen, and more specifically at least one cat antigen which is human allergen. In specific versions of the invention, said antigen represents cat antigen Fel d1 or its fragment covalently bound with the VLP.

EFFECT: invention can be applied for preparing vaccines first of all aimed at treatment and/or prevention of cat dander allergy and other cat antigens and allergens responses.

25 cl, 20 ex, 5 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: daily in morning hours nasal passages are washed with physiological solution, 10% oil solution of vitamin E in dose 3 drops into each passage is dropped into both nasal passages. After 2 hours transcutaneous impact with constant magnetic field and low-intensity laser irradiation with power 30-80 mW, wavelength 0.85-0.89 mcm, pulse repetition rate 50-80 Hz is carried out on region of projection of thymus, maxillary sinuses, submandibular lymph nodes, spinous process of the third cervical vertebra, mastoid process. Time of impact is 60 seconds per each region. Ozonised olive oil is dropped into each nasal passage in dose 3 drops. After that, by means of light-conducting nozzle performed is impact on anterior parts of inferior nasal conchas with pulse red irradiation with wavelength 0.63-0.65 mcm, pulse power of irradiation at outlet not less than 5 W, pulse repetition rate 50-80 Hz, frequency of light diode modulation - 4-8 Hz. Impact time is 60-120 seconds. Total treatment course is 7 days with 4 month interval, 3 times per year. During the first interval between courses bacterial immunomodulator IRS-19 is introduced in age dose in therapeutic regimen. During the second interval antihomotoxic therapy with drugs Luffel and Lymphomyosot is administered.

EFFECT: method makes it possible to increase treatment efficiency, reduce frequency of disease recurrences, reduce medication load in case of allergic rhinites, which usually require long treatment.

2 tbl, 2 ex

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