Derivatives of 1-amino-alkylcyclohexane for treatment of diseases, mediated by mast cells

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and deals with medication for treatment or prevention of diseases, mediated by mast cells, including neramexane or its pharmaceutically acceptable salt.

EFFECT: medication has high efficiency with respect to treatment or prevention of diseases, mediated by mast cells.

28 cl, 1 dwg, 17 tbl, 1 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to the treatment of a patient suffering from diseases mediated by mast cells, comprising the administration to a patient an effective amount of a derivative of 1-amino-alkylcyclohexane.

The LEVEL of TECHNOLOGY

This invention relates to methods for treating patients suffering from diseases mediated by mast cells, including urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

Mast cells (MC) and blood basophils are the key components of acquired and hereditary human immune system. Different subtypes detected in almost all tissues, most abundantly in the skin and respiratory tract and gastrointestinal tract. Fat cells are the main effector cells in inflammatory reactions mediated by immunoglobulin E (IgE), and are involved in maintaining homeostasis of the skin and mucous membranes, and neurohumoral interactions associated with various inflammatory processes, such as allergic inflammation. Mast cells are involved in some inflammatory skin diseases such as urticaria, cutaneous mastocytosis, atopic dermatitis and psoriasis, and in itch polietiologic nature. That the data cells are also involved in waconah diseases, such as rhinitis, systemic mastocytosis, allergic and non-allergic bronchial asthma, conjunctivitis and keratoconjunctivitis. A key event in stimulated mast cells in inflammatory processes is the degranulation of mast cells, in which the surrounding tissue is delivered extensive mixture of various cytokines and neurotransmitters (such as serotonin and/or histamine).

Fat cells differentiate derived from bone marrow myeloid progenitor cells CD34+. After exiting the flow data precursors differentiate under the influence of local growth factors in the fat cells of the Mature tissue (Wedemeyer et al. 2000, Curr Opin Immunol. 2000;12(6):624-31). Fat cells are in close proximity to blood vessels, nerves and surface epithelium. In the skin of the person with the highest density of fat cells can be found around the hair follicles, sweat glands, sebaceous glands and capillaries in the papillary layer of the skin (Toruniowa, Jablonska 1988). It was also reported about the anatomical and functional relationship between mast cells and peripheral nerves (Bienenstock et al. 1987 lnt Arch Allergy Appl Immunol 82: 238-43; Naukkarinen et al. 1996. J Pathol. 1996;180(2):200-5).

Fat cells have a diameter equal to 9-11 microns, and characterized by the presence of numerous basophilic granules. Mast cells are important effectors of allergic reactions. the research cells play an important role in many physiological and pathological processes due to their sensitivity to numerous triggering factors and their ability to release the excess of various mediators. Mast cells are involved in numerous diseases of the skin and mucous membranes, including inflammation, hypersensitivity, and tissue healing (Benoist and Mathis, 2002; Nature. 2002;420(6917):875-8). Fat cells are associated with sensitive nerves and blood vessels through the release of histamine, thereby regulating neurogenic inflammation and pruritus (Steinhoff et al., 2003, Arch Dermatol. 2003;139(11):1479-88).

Urticaria is a skin disease that involves the pathological process of activated mast cells. When urticarnae lesions fat cells degranulate, and the dominant clinical symptoms are the effects of such vasoactive components of fat cells, as histamine. From urticaria, itching and swelling of the soft tissues suffer many patients. The causes of urticaria are numerous and, indeed, there are various States, ranging from acute urticaria as a symptom of allergic anaphylaxis, for example, after eating peanuts in patients with peanut Allergy. Type I allergies are unique, as to induce this action requires a specific mechanism and specific agent. In other forms of urticaria, specific triggers either unknown or do not exist (Maurer, et al., Hautarzt. 2003;54(2): 138-43). Hives also can occur due to a viral or bacterial infection. It is also known that neuroendocrine factors involved in the attack, for example, adrenergic or cholinergic urticaria, which are observed after exercise (Maurer et al., Hautarzt. 2004;55(4):350-6; Mtynek et al., Curr Opin Allergy Clin Immunol. 2008;8(5):433-7).

Typical treatment for urticaria involve blockade of histamine receptors H1 and, less often, H2 subtypes. It is reported that other pharmacological agents (such as, for example, cromoglicate acid or montelukast) "stabilize" the membranes of the fat cells; however, it was also reported that in the treatment of urticaria, these agents are less effective. Moreover, in severe cases to prevent attack of anaphylaxis requires the introduction of steroids.

One of the main obstacles to the treatment of urticaria presently is the low efficiency of antihistamines for severe, life-threatening form of acute urticaria and chronic forms of urticaria that are not prescribed reasons, and therefore belong to idiopathic. Some patients suffer from idiopathic forms of urticaria for several years and have significantly reduced quality of life (Mtynek et al., Curr Opin Allergy Clin Immunol. 2008;8(5):433-7).

Psoriasis is a polygenic multifactorial hereditary inflammatory skin disease complex pathogenesis of the, which can be influenced by several environmental factors. Despite considerable progress in terms of pathogenetic mechanisms involved in this disease, many factors still remain unexplored. Mast cells and macrophages are important in starting and developing psoriatic lesions, but also found in stable lesions. Despite the fact that the latter phenomenon, leading to the clinical phenotype, are well understood (e.g., involvement of cytokine-activated Th1, leading to the model of psoriatic epidermal reactions), an early phenomenon, which could help to unravel the genetic changes and key pathogenetic control points remain unclear.

The involvement of the cholinergic system in the pathogenesis of psoriasis confirm several lines of evidence. More than 50 years ago, the Hungarian research group was treated patients suffering from psoriasis, anticholinergic substance atropine, based on the assumption that the parasympathetic nervous system should be responsible for elevated levels of acetylcholine in psoriatic lesions, thus initiating the start and Uporaba disease (Helmeczi, Dermatologica, 1955 110: 439-48). A thorough examination of the patients represented in the study Helmeczi, revealed that the and oral treatment with atropine reacted almost exclusively patients with "spotted psoriasis", while patients with chronic plaque psoriasis type in General did not respond. According to several histological studies are the first cells that arrive in psoriatic lesions are fat cells and neutrophilic granulocytes. Indeed, it was found that the amount of fat cells significantly increased, especially when guttate psoriasis and palmoplantar psoriasis (Schubert and Christophers, Arch Dermatol Res 1985; 277:352-8; Brody, J Invest Dermatol. 1984 May;82(5):460-4; Naukkarinen et al., J Pathol. 1996 Oct;180(2):200-5; Ashenagar et al., Arch Dermatol Res. 2007 Feb;298(9):421-6), whereas chronic lesions domainroot lymphocytes and macrophages (Ghoreschi K and Rocken M; J Dtsch Dermatol Ges 2003; 1: 524-32).

One study shows a significant increase only the fat cells in chronic psoriatic lesions in patients who complain of itching (Nakamura et al. 2003 Br J Dermatol; 149(4):718-30.), whereas in respect of other immune cells and cytokines was not demonstrated any difference. In addition, it was shown that the degranulation of mast cells induces the expression of ICAM-1 in psoriatic epidermis, triggering, thus, the cascade of inflammation (Ackermann and Harvima, Arch Dermatol Res. 1998 Jul;290(7):353-9). There is additional evidence of the role of mast cells in psoriasis in mice. The so-called scaly mouse (kangana fsn/fsn) demonstrates diffuse epidermal orthocare otecheskii hyperkeratosis, much like psoriasis. This mouse numerous fat cells line up under the epidermis (Sundberg et al., Eur J Immunol 1998 Apr;28(4): 1379-88). Close "synaptopathies" neighborhood of fat cells from free nerve endings containing an excess of proinflammatory neurotransmitters, along with their well-proven susceptibility to stress hormones such as CRH and urocortin, makes fat cells are an ideal target for stress-mediated and neurogenic inflammation (Arck et al., J Mol Med. 2005; 83(5):386-96), which is in good clinical communication psoriasis with emotional stress (Singh et al., J Pharmacol Exp Ther. 1999 Mar;288(3): 1349-56). The physiological function of fat cells is being actively discussed (Maurer et al., Exp Dermatol. 2003 Dec;12(6):886-910); however, it has been demonstrated that mast cells are key cells of the neuroendocrine and inflammatory processes (Arck et al., J Mol Med. 2005; 83(5):386-96; Siebenhaar, et al., J Allergy Clin Immunol. 2008;121(4):955-61), which can be caused by a large variety of different stimuli, and among them, acetylcholine (Fantozzi et al. 1978, Nature 273: 473-4).

There are several protocols for the treatment of psoriasis, aimed at the products selection of fat cells, in particular histamine. The use of blockers H1-R H2-R was proposed and confirmed in the few studies (Kristensen et al., Br J Dermatol. 1995 Dec;133(6):905-8; Petersen et al., Acta Derm Venereol. 1998 May;7(3): 190-3); however, randomized controlled studies have not shown significant therapeutic effects. These results/lack of effect may arise from the use as a factor stratification scale PASI, not subtypes of psoriasis or acuity (Zonneveld et al., J Am Acad Dermatol. 1997 Jun;36(6 Pt 1):932-4. 7-103).

Were confirmed by some changes of the cholinergic system in psoriatic lesions: SLURP-2 is a peptide modulator of nicotinic cholinergic receptors, which has been found in increased numbers in psoriatic lesions. It was shown that SLURP-2 inhibits caspase-3 and filaggrin and, in consequence, assumed to be involved in psoriasis through its role in hyperproliferative keratinocytes and/or differentiation/activation of T-cells (Tsuji et al., Genomics 2003;81(1):26-33).

Smoking increases the risk of psoriasis, at least in some patients. This, most likely, is connected with the main cigarette toxin, nicotine, nicotinic ligand acetylcholine receptors (nAChR) (Arathi et al., Am J Med, 2007, 120 (11): 953-959), also active against α10 nAChR present in the fat cells. In addition, a special form of psoriasis, pustular palmoplantar (PPP), is highly correlated with Smoking, and PPP lesions are particularly rich in mast cells expressing cetylpalmitate (AChE), and granulocytes expressing ChAT and α3 nAChR. (Hagforsen et al., Acta Derm Venereol 2002; 82(5):341-6).

Mast cells are key effector cells in bronchial asthma. Anticholinergic substances for the treatment of asthma, acting on muscarinic acetylcholine receptors (mAChR)are on sale (Tiotropium). It was assumed that when the inflammation of the mucous membrane in the lungs may occur involving both neuronal and non neuronal derivatives ACh, Cycling lymphocytes and macrophages, mast cells (Wessler and Kirkpatrick, Pulm Pharmacol Ther. 2001;14(6):423-34). This view has a direct impact on the question of action of nicotine derived from tobacco, and pulmonary diseases on the one hand, and application antimuskarinovoe act occurs medicines for chronic respiratory diseases, on the other hand.

Rhinitis is involved in the pathological process of inflammation and swelling of the mucous membrane of the nose, characterized by cold and lack of air and is usually caused by frequent colds or allergies.

Allergic rhinitis is the most common cause of rhinitis. He is a frequent pathological condition, affecting approximately 20% of the population. Although allergic rhinitis is not a life threatening condition, it can cause complications and is-being can significantly degrade the quality of life, which leads to a number of indirect costs. As it was recently estimated in the amount of direct and indirect costs of allergic rhinitis are 5.3 billion dollars a year.

Allergic rhinitis is involved in the pathological process of inflammation of mucous membranes of nose, eyes, Eustachian tubes, middle ear, sinuses and pharynx. The nose is invariably involved, and other organs are affected in some patients. Inflammation of mucous membranes characterized by a complex interaction of inflammatory mediators, but eventually it starts immunoglobulin E (IgE)-mediated reaction to a protein from the environment.

The tendency to develop allergic or IgE-mediated reactions to allergens in the environment (proteins that can cause allergic reaction) has a genetic component. In susceptible patients exposed to certain foreign proteins leads to allergic sensitization, which is characterized by the secretion of specific IgE directed against these proteins. Data specific IgE cover the surface of fat cells, which are present in the mucous membrane of the nose. When a particular protein (e.g., specific pollen grain) is inhaled into the nose, it can contact with IgE on mast cells, leading to immediate and delayed the release of several mediators.

The mediator is, which are released immediately, include histamine, tryptase, himizu, kinny and heparin. Fat cells quickly synthesize other mediators, including leukotrienes and prostaglandin D2. These mediators, through various interactions, ultimately leading to symptoms of rinorea (i.e. redness of the nose, sneezing, itching, redness, tearing, swelling, pressure in the eyes, the draining of mucus in the sinuses). Stimulates the mucous glands, which leads to increased secretion. Increased vascular permeability, leading to exudation of plasma. Is vasodilatation, leading to congestion and pressure. Stimulates sensory nerves, resulting in sneezing and itching. All these phenomena can occur within minutes; therefore, this reaction is called early or immediate phase reaction.

After 4-8 hours above mediators, due to the complex interaction phenomena that lead to entry into the mucous membrane of other cells of inflammation, such as neutrophils, eosinophils, lymphocytes and macrophages. This leads to ongoing inflammation, called the late phase response. Symptoms of late phase response similar to the symptoms of the early phase, but there is a tendency of occurrence of less sneezing and itching and greater congestion and the production of mucus. Late phase may last for hours or days.

<> Atopic dermatitis is a disease accompanied by itching, of unknown origin that usually starts in early childhood (recognized option appears in adults); it is characterized by itching, eczematous lesions, xerosis (dry skin) and lichenification (thickening of the skin and strengthening the skin of the figure). Atopic dermatitis may be associated with other atopic (immunoglobulin E [IgE]) disease (e.g. asthma, allergic rhinitis, urticaria, acute allergic reactions to foods). Atopic dermatitis has a high prevalence and morbidity and, it seems that the level of rasprostranennosti increases.

Substantial evidence shows that the development of atopic dermatitis (AD) are important genetic factors, but the pathophysiology is still poorly understood. Were offered two main hypotheses regarding the development of inflammatory lesions. The first puts the immune dysfunction leading to IgE sensitization and secondary damage of the epithelial barrier. The second suggests a defect in the epithelial cells, leading to the problem of the broken barrier, immunological aspects, representing side effects.

Itching is a frequent manifestation of the skin disease is, such as urticaria, atopic dermatitis and other allergic reactions. Effective treatment of itching can prevent excoriation caused complications, such as sclerosus simple chronic and impetigo.

Itching is triggered in the free nerve endings of the skin that are most heavily concentrated in the wrists and ankles. The itchy sensation is transmitted through C-fibers in the posterior horn of the spinal cord to the cerebral cortex through spinothalamic tract. Itching causes spinal reflex response, combing, which is both the innate and deep tendon reflex. Regardless of the reason, itching often accompanies inflammation of the skin, dry or hot ambient conditions, the vasodilatation of the skin and psychological stress factors.

Histamine, which is released fat cells in people with urticaria and other allergic reactions, is one of the factors usually associated with itching.

As noted above, there are various difficulties associated with conventional methods of treatment of diseases mediated by mast cells, such as urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis. Thus, there is a need for improved methods of treatment of urticaria, atopic dermati is a, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis and other diseases mediated by fat cells.

Derivatives of 1-amino-alkylcyclohexane, as for example, neramexane (also known as 1-amino-1,3,3,5,5-pentamethylchroman), as it was discovered, is suitable in the treatment of various diseases, especially certain neurological diseases, including Alzheimer's disease and neuropathic pain. Derivatives of 1-amino-alkylcyclohexane, as for example, neramexane, are described in detail in U.S. Patent No. 6034134 and 6071966, and the contents of these patents are included in this description by reference. I believe that therapeutic effect of 1-amino-alkylcyclohexanes, as for example, neramexane, associated with inhibition effects of excess glutamate at N-methyl-D-aspartate (NMDA)receptors of nerve cells, and therefore the compounds are also classified as NMDA antagonists or antagonists of the NMDA receptor.

Neramexane is also a blocker of nicotinic acetylcholine receptors α9α10. Neramexane acts as a noncompetitive antagonist. Since it was reported that the blockade neramexane in concentrations higher than 1 mm is only slightly dependent on the membrane potential and, as reported, does not change the level of desensitization can be achieved by using additional IU is aNISM. (Plazas, Paola V. et al., European Journal of Pharmacology 2007; 566: 11-19).

The INVENTION

The present invention relates to a method of treatment and/or prevention of diseases mediated by mast cells, such as urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis, in need thereof of a patient, comprising the administration to a patient an effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir).

The present invention also relates to a method of treatment and/or prevention of diseases mediated by mast cells, such as food allergies, we need in this patient, comprising the administration to a patient an effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir).

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is administered once a day, twice a day (b.i.d.) or three times a day.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkyltin is hexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is injected into the preparative form immediate release.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is injected into the preparative form of modified release.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is injected into the preparative for the local application form as, for example, the form for flushing or permanent application.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is administered in oral preparative form.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is administered systemically.

An additional aspect of the invention relates to a method of treatment is/or prevention of diseases, mediated fat cells, in need thereof of a patient, comprising the administration to a patient an effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir, and one or more additional pharmaceutical agents (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, Loratidine, Desloratadine, Meclizine, Quetiapine, Fexofenadine, Feniramina, Cetirizine, Prometazina, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Hyperemia, JNJ 7777120, Kromoglikatom, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen), which, as shown, are effective in the treatment or prevention of diseases, mediated fat cells.

Additionally the second aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered together.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (e.g. the, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered in a single preparative form.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin is h, Feniramin, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is injected into the preparative form for local application, such as a form for flushing or permanent application.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Not acromill), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered systemically.

An additional aspect of the invention relates to such method, in which the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast,pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered in oral preparative form.

An additional aspect of the invention relates to a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane the mesilate) for the treatment of a patient suffering from diseases mediated by mast cells, such as urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

An additional aspect of the invention relates to a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane the mesilate) for the treatment of a patient suffering from diseases mediated by mast cells, such as food allergies.

An additional aspect of the invention relates to the use of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir) for the manufacture of a medicinal product for the treatment of a patient suffering from diseases mediated by mast cells, such as urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

Additional the SPECT invention relates to the use of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir) for the manufacture of a medicinal product for the treatment of a patient suffering from diseases mediated by mast cells, such as food allergies.

An additional aspect of the invention relates to the above derivative or use wherein neramexane mesilate enter in the range from about 5 mg to about 150 mg/day, or neramexane mesilate enter in the range from approximately 5 mg to approximately 100 mg/day, or neramexane mesilate enter in the range from about 5 mg to about 75 mg/day, or in which neramexane mesilate injected approximately 50 mg/day, or in which neramexane mesilate injected approximately 75 mg/day, for example, in oral preparative form.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is administered once a day, twice a day (b.i.d.) or three times a day.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, nerome the San or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is injected into the preparative form an immediate release or preparative form of modified release.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is injected into the preparative form for local application, such as, for example, the form for flushing or permanent application.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is administered in oral preparative form.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) is administered systemically.

An additional aspect of the invention relates to the above derivative or use wherein introducing at least one additional pharmaceutical agent (e.g., anticholinergic agents (for example, MEK is melamin, kynurenic acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen), which, as shown, is effective in the treatment or prevention of diseases mediated by fat cells.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticol ergicheskie substances (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered together.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, who according to, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered in a single preparative form.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), the anti-Christ. histamine drugs (for example, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (eg, theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is injected into the preparative form for local application, such as a form for flushing or permanent application.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Prometa is in, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered in oral preparative form.

An additional aspect of the invention relates to the above derivative or use wherein the derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, as for example, neramexane mesilate) and the additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydroco Tyson), glucocorticoids (for example, ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) is administered systemically.

An additional aspect of the invention relates to pharmaceutical compositions for treating diseases mediated by mast cells, comprising a therapeutically effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir), and optionally at least one pharmaceutically acceptable carrier or excipient.

An additional aspect of the invention relates to pharmaceutical compositions for treating diseases mediated by mast cells, comprising a therapeutically effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir) in the preparative form of immediate or modified release.

An additional aspect of the invention relates to pharmaceutical compositions for treating diseases mediated by mast cells, comprising therapeutically effective the effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir) in the preparative form for local application.

An additional aspect of the invention relates to pharmaceutical compositions for treating diseases mediated by mast cells, comprising a therapeutically effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir) in oral preparative form.

An additional aspect of the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir) in combination with at least one additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubokurarinom, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadine, Feniramina, Cetirizine, Prometazina, Cimetidine, The famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, T is Piramida, JNJ 7777120, Kromoglikatom, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen), which, as shown, are effective in the treatment of diseases mediated by fat cells, and, optionally, at least one pharmaceutically acceptable carrier or excipient.

An additional aspect of the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salts, as for example, neramexane nelfinavir) in combination with at least one additional pharmaceutical agent (e.g., anticholinergic agents (for example, mecamylamine, kynurenine acid, d-tubokurarinom, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine, Fexofen the other, The feniramina, Cetirizine, Prometazina, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Theoperation, JNJ 7777120, Kromoglikatom, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen), which, as was shown are effective in the treatment of diseases mediated by fat cells, and, optionally, at least one pharmaceutically acceptable carrier or excipient in the form of an oral formulation or form for local application.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the impact neramexane by degranulation of mast cells in vitro.

DETAILED description of the INVENTION

As used herein, the term “disease-mediated fat cells”includes urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

As used herein, the term “disease, incidental what these fat cells”, also includes food allergies.

As used herein, the term “urticaria” includes allergic non-allergic urticaria and hives.

As used herein, the term “atopic dermatitis” includes atopicescoy eczema.

As used herein, the term “psoriasis” includes the ordinary psoriasis, plaque psoriasis, psoriasis flexor surfaces, inverse psoriasis, guttate psoriasis, pustular psoriasis, nail psoriasis, erythrodermic psoriasis and psoriatic arthritis.

As used herein, the term “asthma” includes bronchial asthma, allergic and non-allergic asthma.

As used herein, the term “rhinitis” includes allergic rhinitis (e.g., seasonal, perennial and occupational rhinitis and non-allergic rhinitis (e.g., eosinophilic, autonomic, hormonal, rhinitis, is caused by the action of drugs, atrophic and gustatory rhinitis) and infectious rhinitis.

As used herein, the term “mastocytosis” includes cutaneous mastocytosis and systemic mastocytosis.

As used herein, the term “food Allergy” includes immune response to a food protein, such as allergies to dairy products allergic to eggs, peanut Allergy, and the device on nutmeg, allergic to seafood allergies shellfish allergic to soy and allergies to wheat or a combination thereof.

As used in this description, the terms “mecamylamine”, “kynurenic acid”, “d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium”, “Tiotropium, Diphenhydramine, loratadine, Desloratadine”, “Meclizine”, “Quetiapine”, “Fexofenadin”, “Veniamin”, “Cetirizine”, “Promethazine”, “Cimetidine, Famotidine, Ranitidine”, “Nizatidine”, “A-349821”, “ABT-239”, “Ciproxifan”, “Closedprofit”, “Typename”, “JNJ 7777120”, “Cromoglycate, Nedocromil, prednisone, cortisone, hydrocortisone, ciclesonide, beclomethasone, budesonide, flunisolide”, “fluticasone”, “mometazon, triamcinolone, montelukast, zafirlukast, pranlukast”, “zileuton, methylxanthines, theophylline, aminophylline”, “Omalizumab, Methotrexate and ketotifen include optical isomers, diastereomers, enantiomers, hydrates, pharmaceutically acceptable salts and their mixtures, respectively.

As used herein, the term "patient" includes mammals, including animals and people.

The term “derivative of 1-amino-alkylcyclohexane” is used in this application to describe the 1-amino-alkylcyclohexane or compounds derived from 1-amino-alkyl is clohexane, for example, pharmaceutically acceptable salts of 1-amino-alkylcyclohexanes.

Derivatives of 1-amino-alkylcyclohexane of the present invention can be represented by the General formula (I):

in which R*represents -(CH2)n-(CR6R7)m-NR8R9

in which n+m = 0, 1, or 2

in which R1-R7independently selected from the group consisting of hydrogen and C1-6the alkyl, in which R8and R9independently selected from the group consisting of hydrogen and C1-6the alkyl or together represent lower alkylene -(CH2)X-, in which x is from 2 to 5, inclusive, and optical isomers, enantiomers, hydrates and pharmaceutically acceptable salts.

Non-limiting examples of 1-amino-alkylcyclohexane used according to the present invention, include:

1-amino-1,3,5-trimethylcyclohexane,

1-amino-1(TRANS),3(TRANS),5-trimethylcyclohexane,

1-amino-1(CIS),3(CIS),5-trimethylcyclohexane,

1-amino-1,3,3,5-tetramethylcyclobutane,

1-amino-1,3,3,5,5-pentamethyldisiloxane (neramexane),

1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,

1-amino-1,5,5-trimethyl-3,3-diethylsiloxane,

1-amino-1,5,5-trimethyl-CIS-3-ethylcyclohexane,

1-amino-(1S,5S)CIS-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1,5,5-trimethyl-TRANS-3-ethylcyclohexyl is h,

1-amino-(1R,5S)TRANS-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1-ethyl-3,3,5,5-tetramethylcyclobutane,

1-amino-1-propyl-3,3,5,5-tetramethylcyclobutane,

N-methyl-1-amino-1,3,3,5,5-pentamethyldisiloxane,

N-ethyl-1-amino-1,3,3,5,5-pentamethyldisiloxane,

N-(1,3,3,5,5-pentamethylbenzyl)pyrrolidin,

3,3,5,5-tetramethylcyclopentadienyl,

1-amino-1-propyl-3,3,5,5-tetramethylcyclobutane,

1-amino-1,3,3,5(TRANS)-tetramethyldisiloxane (axial amino group),

3-propyl-1,3,5,5-tetramethylcyclopentadiene hemihydrate,

1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,

1-amino-1,3,5-trimethylcyclohexane,

1-amino-1,3-dimethyl-3-propylcyclohexane,

1-amino-1,3(TRANS),5(TRANS)-trimethyl-3(CIS)-propylcyclohexane,

1-amino-1,3-dimethyl-3-ethylcyclohexane,

1-amino-1,3 .3m-trimethylcyclohexane,

CIS-3-ethyl-1(TRANS)-3(TRANS)-5-trimethylcyclohexane,

1-amino-1,3(TRANS)-dimethylcyclohexane,

1,3 .3m-trimethyl-5,5-dipropylenetriamine,

1-amino-1-methyl-3(TRANS)-propylcyclohexane,

1-methyl-3(CIS)-propylcyclohexyl,

1-amino-1-methyl-3(TRANS)-ethylcyclohexane,

1-amino-1,3 .3m-trimethyl-5(CIS)-ethylcyclohexane,

1-amino-1,3 .3m-trimethyl-5(TRANS)-ethylcyclohexane,

CIS-3-propyl-1,5,5-trimethylcyclohexylamine,

TRANS-3-propyl-1,5,5-trimethylcyclohexylamine,

N-ethyl-1,3,3,5,5-pentamethylcyclopentadiene,

N-methyl-1-amino-1,3,3,5,5-pentamethyl clohexane,

1-amino-1-methylcyclohexane,

N,N-dimethyl-1-amino-1,3,3,5,5-pentamethyldisiloxane,

2-(3,3,5,5-tetramethylsilane)ethylamine,

2-methyl-1-(3,3,5,5-tetramethylsilane)propyl-2-amine,

2-(1,3,3,5,5-pentamethylene-1)-ethylamine hemihydrate,

N-(1,3,3,5,5-pentamethylbenzyl)pyrrolidin,

1-amino-1,3(TRANS),5(TRANS)-trimethylcyclohexane,

1-amino-1,3(CIS),5(CIS)-trimethylcyclohexane,

1-amino-(1R,5S)TRANS-5-ethyl-1,3 .3m-trimethylcyclohexane,

1-amino-(1S,5S)CIS-5-ethyl-1,3 .3m-trimethylcyclohexane,

1-amino-1,5,5-trimethyl-3(CIS)-isopropylcyclohexane,

1-amino-1,5,5-trimethyl-3(TRANS)-isopropylcyclohexane,

1-amino-1-methyl-3(CIS)-ethylcyclohexane,

1-amino-1-methyl-3(CIS)-methyl-cyclohexane,

1-amino-5,5-diethyl-1,3 .3m-trimethyl-cyclohexane,

1-amino-1,3,3,5,5-pentamethyldisiloxane,

1-amino-1,5,5-trimethyl-3,3-diethylsiloxane,

1-amino-1-ethyl-3,3,5,5-tetramethylcyclobutane,

N-ethyl-1-amino-1,3,3,5,5-pentamethyldisiloxane,

N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine,

N-[1,3(TRANS),5(TRANS)-trimethylcyclohexyl]pyrrolidine or piperidine,

N-[1,3(CIS),5(CIS)-trimethylcyclohexyl]pyrrolidine or piperidine,

N-(1,3,3,5-tetramethylsilane)pyrrolidine or piperidine,

N-(1,3,3,5,5-pentamethylbenzyl)pyrrolidine or piperidine,

N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,

N-(1,5,5-trimethyl-3,3-dietitics the hexyl)pyrrolidine or piperidine,

N-(1,3 .3m-trimethyl-CIS-5-ethylcyclohexyl)pyrrolidine or piperidine,

N-[(1S,5S)CIS-5-ethyl-1,3 .3m-trimethylcyclohexyl]pyrrolidine or piperidine,

N-(1,3 .3m-trimethyl-TRANS-5-ethylcyclohexyl)pyrrolidine or piperidine,

N-[(1R,5S)TRANS-5-ethyl,3,3-trimethylcyclohexyl]pyrrolidine or piperidine,

N-(1-ethyl-3,3,5,5-tetramethylsilane)pyrrolidine or piperidine,

N-(1-propyl-3,3,5,5-tetramethylsilane)pyrrolidine or piperidine,

N-(1,3,3,5,5-pentamethylbenzyl)pyrrolidin

and optical isomers, diastereomers, enantiomers, hydrates, their pharmaceutically acceptable salts and mixtures thereof.

Derivatives of 1-amino-alkylcyclohexane (for example, neramexane, 1-amino-1,3,3,5,5-pentamethylchroman) are disclosed in U.S. Patent No. 6034134 and 6071966. Derivatives of 1-amino-alkylcyclohexane (for example, neramexane) can be used according to the invention in the form of any pharmaceutically acceptable salt, solvate, isomers, conjugates and prodrugs, and any reference to derivatives of 1-amino-alkylcyclohexane (for example, neramexane) in this description should be understood as references to such of salt, solvate, isomers, conjugates and prodrugs.

Pharmaceutically acceptable salts include, but without limitation, acid additive salts, such as salts derived from hydrochloric, methylsulfonate, Hydrobromic, itestosterone chlorine, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic, carbonic, cinnamic, almond, methansulfonate, econsultancy, hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, cyclohexanesulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic and 2-acetoxybenzoic acid. All data salt (or other salt) can be obtained by traditional methods. The origin of the salt is not critical, provided that it is non-toxic and essentially no detrimental desired pharmacological activity.

The term "analog" or "derivative" is used in this description in a recognized pharmaceutical value, indicating the molecule, which has structural similarities with the original molecule (such as neramexane), but was modified planned and controlled manner to replace one or more specific alternate atoms of the original molecule alternative rollover atom, creating due to this molecule, which structure is similar to the parent molecule. Synthesis and screening of analogs (for example, the use of structural and/or biochemical analysis) to identify slightly modified varieties known compounds, is the quiet can be improved or different features (such as improved efficiency and/or selectivity of the intended specific type of receptor, increased ability to overcome barriers mammals, such as cell membranes, reduced side effects, and so on) is an approach to drug development, are well known in pharmaceutical chemistry.

The term "curing" is used in this description, implying assistance or relief, at least one symptom of a disease in a patient. In understanding the present invention, the term "treat" also means stopping, slowing the onset (i.e., the period prior to clinical manifestation of the disease) and/or reducing the risk of occurrence or worsening of the disease.

The term "therapeutically effective"applied to dose or amount refers to that amount of a compound or pharmaceutical composition that is sufficient to entail the necessary activity, with the introduction of the needy in the mammal.

The phrase "pharmaceutically acceptable", which is used in connection with compositions of the invention, refers to molecular substances and other component parts of such compositions that are physiologically tolerable and usually do not cause adverse reactions when administered to a mammal (n is an example, person). The term "pharmaceutically acceptable" can also mean approved by a regulatory Agency of the Federal government or the state government or listed in the U.S. Pharmacopoeia or other generally accepted Pharmacopoeia in order to apply for mammals, and more specifically to the people.

The term "carrier"applied to pharmaceutical compositions of the invention refers to a diluent, excipient or environment with which enter the active connection (for example, neramexane). Such pharmaceutical carriers can be a sterile liquid such as water, saline solutions, aqueous dextrose, aqueous solutions of glycerin and oils, including oils of mineral, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described, for example, in "Remington''s Pharmaceutical Sciences" by A.R. Gennaro, 20thEdition.

The term "about" or "approximately" usually means within 20%, alternatively in the range of 10%, including 5%from set value or range. Alternatively, especially in biological systems, the term "about" means within about logarithm (i.e., magnitude), including in p is adalah twice the specified value.

PHARMACEUTICAL FORMULATION AND INTRODUCTION

In connection with the methods of the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane). Compositions of the invention can further include a carrier or excipient (all pharmaceutically acceptable). The compositions can be formulated for administration once a day injection twice a day or administration three times a day.

Active ingredient (for example, neramexane, as for example, neramexane mesilate) or composition of the present invention can be used for the treatment of at least one of the disorders, and the treatment fit or appropriately prepared for a specific administration, which is disclosed in this specification (e.g. once a day, twice a day or three times a day). To this end, the leaflet and/or information for a patient contains the relevant information.

Active ingredient (for example, neramexane, as for example, neramexane mesilate) or composition of the present invention may be used for the manufacture of a medicinal product for the treatment of at least one of the above disorders, in which the drug is lighting cableway or appropriately prepared for a specific administration, which is disclosed in this specification (e.g. once a day, twice a day or three times a day). To this end, the leaflet and/or information for a patient contains the relevant information.

According to the present invention the dosage form of a derivative of 1-amino-alkylcyclohexane (for example, neramexane) can be a solid, semi-solid or liquid preparative form as set forth below.

Derivatives of 1-amino-alkylcyclohexane of the present invention (for example, neramexane) can be administered orally, topically, parenterally or through mucous membranes (for example, transbukkalno, by inhalation, or rectally in the form of dosage units preparative forms containing conventional non-toxic pharmaceutically acceptable carriers. In yet another embodiment, for the introduction of pediatric patients, a derivative of 1-amino-alkylcyclohexane can be prepared in the form of a flavored liquid (for example, with the taste of peppermint). Derivatives of 1-amino-alkylcyclohexane of the present invention can be administered orally in the form of capsules, tablets and the like, or in the form of a liquid formulation or topically in the form of a semi-preparative forms such as ointment, cream, gel or hydrogel (see Remington's Pharmaceutical Sciences, 20thEdition, by A.R. Gennaro).

For oral administration in the form of tablets or capsules derivatives of 1-amino-alkylcyclohexane of the present invention (for example, neramexane) can be combined with non-toxic, pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hypromellose); fillers (e.g. lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non sugar, microcrystalline cellulose, calcium sulfate or secondary acidic calcium phosphate); lubricants (e.g. magnesium stearate, talc or silicon dioxide, stearic acid, sodium stearyl fumarate, glycerinated, calcium stearate and the like); disintegrating agents (e.g., potato starch or sodium starch glycolate); or hydrating agents (e.g., sodium laurylsulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as gum Arabic, tragacanth gum or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes and the like.

Tablets can be coated with a concentrated sugar solution which may contain, for example, gum Arabic, gelatin, talc, titanium dioxide and so podobn the E. Alternatively, tablets can be coated with polymer, which is soluble in a volatile organic solvent or mixture of organic solvents. In particular embodiments, the implementation neramexane receive in the form of dosage forms, immediate release (IR) or modified release (MR). Solid dosage forms for immediate release provide the ability to release most or all of the active component over a short period of time, such as 60 minutes or less, and allow rapid absorption of the medicinal product (formulation immediate-release 1-amino-alkylcyclohexanes, as for example, neramexane, disclosed in Published Application U.S. No. 2006/0002999 and 2006/0198884, the contents of which are incorporated in this description by reference). Solid oral dosage forms of the modified release provide prolonged release of the active ingredient over an extended period of time in an attempt to maintain therapeutically effective plasma levels over the same extended time intervals and/or modify other pharmacokinetic properties of the active ingredient (formulation of modified release Nera is Aksana disclosed in Published Application U.S. No. 2007/0141148, the contents of which are incorporated in this description by reference).

To obtain the preparative form soft gelatin capsules, derivatives of 1-amino-alkylcyclohexane of the present invention (for example, neramexane) can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substances, using either of the above excipients for tablets, for example, lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Hard gelatin capsules may be filled with liquid or semi-liquid medicines.

Derivatives of 1-amino-alkylcyclohexane of the present invention (for example, neramexane) can also be entered in microspheres or microcapsules, e.g., made of polyglycolic acid/lactic acid (PGLA) (see, for example, U.S. Patent No. 5814344; 5100669 and 4849222; PCT Publication no WO 95/11010 and WO 93/07861). Biocompatible polymers that can be used to achieve controlled release of drugs include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polishlanguage, polyhydroxyalkane KIS the GTC, poliorcetes, Polyacetals, polyhydraminos, polycyanoacrylate and Poperechnaya or amphipatic block copolymers of hydrogels.

Can also be used preparative form derivatives of 1-amino-alkylcyclohexane of the present invention in semi-solid or liquid form. Derivative of 1-amino-alkylcyclohexane (for example, neramexane) may constitute between 0.1 and 99% by weight of the formulation, more specifically between 0.5 and 20% by weight for preparative forms intended for injection and between 0.2 and 50% by weight for preparative forms suitable for oral administration.

Can also be used preparative form derivatives of 1-amino-alkylcyclohexane of the present invention in semi-solid or liquid form for local use. Such preparative forms include gels, creams, creams, hydrogels, pastes, emulsions, aerosols, solutions, lotions, etc. Derived 1-amino-alkylcyclohexane (for example, neramexane) may constitute between 0.1 and 99% by weight of the formulation, more specifically between 0.5% and 50% by weight of the formulation, or between 1% and 25% by weight of the formulation, or between 2% and 20% by weight of the preparative form.

In one embodiment of the invention a derivative of 1-amino-alkylcyclohexane (for example, neramexane) is injected into the preparative form of modified release. Lech is the only form of modified release provide a means to improve patient compliance regime and treatment and to ensure efficient and safe therapy by reducing the proportion of adverse reactions on the drug. Compared to dosage forms for immediate release pharmaceutical form modified-release can be used for prolonged pharmacological action after injection and to reduce the variability of concentration of drug in plasma throughout the interval between doses of a medicinal product, eliminating due to this or slimming sharp peaks.

Pharmaceutical form modified-release may include core or covered with, or containing a drug. The core is then coated with modifying the release of a polymer which dispersed drug. Modifying the release of the polymer gradually decomposes, releasing over time drug. Thus, the most extreme layer of the composition effectively slows down and regulates the diffusion of the drug through the covering layer when the composition is exposed to water environments, i.e. in the gastrointestinal tract. Clean the diffusion coefficient of the drug depends mainly on the ability of the gastric juice to overcome the covering layer or matrix and the solubility of the drug.

In another one the m variant of the invention, the derivative of 1-amino-alkylcyclohexane (for example, neramexane) are obtained in the form of an oral liquid formulation. Liquid preparations for oral administration can take the form, for example, solutions, syrups, emulsions or suspensions, or they can be presented as a dry product for restore before applying water or other suitable medium. Preparations for oral administration can be obtained accordingly in the form of a formulation to impart a controlled or delayed release of the active compounds. Oral liquid formulations of 1-amino-alkylcyclohexanes, as for example, neramexane described in the International PCT Application no PCT/US2004/037026, the contents of which are incorporated in this description by reference.

For oral administration in liquid form derivatives of 1-amino-alkylcyclohexane of the present invention (for example, neramexane) can be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspendresume means (for example, orbitalum syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or gum Arabic), anhydrous environments (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable by weight of the AMI), preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid) and the like. Stabilizing agents, such as antioxidants (for example, butylacetamide, equivalent, propylgallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms. For example, the solutions may contain from about 0.2% to about 20% by weight neramexane, with balanced sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such a liquid formulation may contain colouring agents, flavouring agents, substances, sweeteners and thickeners, such as carboxymethylcellulose, or other excipients.

In yet another embodiment, a therapeutically effective amount of a derivative of 1-amino-alkylcyclohexane (for example, neramexane) administered in the oral solution containing a preservative, a sweetener, a solubilizer and a solvent. The oral solution can include one or more buffers, flavors or additional excipients. In an additional embodiment, for oral liquid formulations form neramexane derived add peppermint or other flavoring.

For administration by inhalation, proizvodnye 1-amino-alkylcyclohexane (for example, neramexane) of the present invention can be conveniently delivered in the form of feed spray spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dosage can be determined by providing a valve to deliver a measured quantity. Recipe for capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator, can be made with the contents of a powder mix of the compound and a suitable powder base, such as lactose or starch.

Solutions for parenteral applications by injection can be obtained in the form of an aqueous solution of water-soluble pharmaceutically acceptable salts of the active substances, for example in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffer substances, and can easily be provided in capsules with different dosage units.

Formulations of the invention can be delivered parenterally, i.e. by intravenous (IV), intracerebroventricular (i.c..), subcutaneous (s/C), intraperitoneal (I.P. Pavlova.), intramuscular (I/m), subdermal (s.d.) or intradermal () administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulation for injection may be presented in a standard dosage form, e.g., in ampoules or in containers containing multiple doses, with added preservative. Alternatively, the active ingredient may be in powder form for recovery before using a suitable vehicle, e.g. sterile, containing pyrogens water.

The invention also provides a pharmaceutical pack or kit comprising one or more containers containing a derivative of 1-amino-alkylcyclohexane (for example, neramexane) and, optionally, more complex parts of the preparative form. In a particular embodiment, neramexane provided in the form of oral solution (2 mg/ml) for injection using a syringe with a capacity of 2 teaspoons (dosage KORC®). Each oral syringe has a barcode label for the dimension, and the line on the right side of the syringe (tip down) denote units in teaspoons, and the lines on the left indicate the units in ml.

Optimal therapeutically effective amount can be set experimentally, taking into account the om exact mode of administration, in which injected the drug, symptom, in respect of which directed the introduction involved with the patient (e.g., body weight, condition, age, sex, etc) and the preference and experience of the responsible physician or veterinarian.

Unit dosing for rectal application can be a solution or suspension, or may be prepared in the form of suppositories or retention enemas, containing neramexane in a mixture with a neutral fat base, or gelatin rectal capsules comprising the active substance with the addition of vegetable oil or paraffin oil.

Toxicity and therapeutic efficacy of the compositions of the invention can be installed using standard pharmaceutical procedures in experimental animals, for example, by identifying LD50(the dose lethal to 50% of the population) and ED50(the dose therapeutically effective in 50% of the population). The relationship between therapeutic and toxic actions of the dose represents therapeutic index, which can be expressed as the ratio LD50/ED50. Preferred are compositions which show large therapeutic indices.

Suitable daily doses of the active compounds of the invention in therapeutic treatment of humans are about 0.01 to 10 the g/kg body weight by oral administration and 0.001-10 mg/kg body weight at parenteral administration. For example, for adults suitable daily dose neramexane (for example, neramexane nelfinavir) are within the range of from about 5 mg to about 150 mg per day, such as from about 5 mg to about 120 mg, about 5 mg to about 100 mg, or from about 5 mg to about 75 mg, or from about 5 mg to about 50 mg, such as 25 mg or 37.5 mg or 50 mg per day. For example, the daily dose can be adjusted depending on body mass, as for example, 50 mg/day if body weight of 90 kg or 75 mg/day for patients with body weight, component ≥ 90 kg Also suitable equimolar amount of another pharmaceutically acceptable salt, MES, isomer, conjugate, prodrug or derivative, such as, for example, neramexane hydrochloride. For pediatric patients aged 4-14 years neramexane (for example, neramexane mesilate) may be in the form of oral liquid dosage forms, approximately 0.5 mg/day, up to the maximum dose, containing 10 mg/day.

Daily dose specified in this description can be entered, for example, as one or two dosage units once, twice or three times a day. The appropriate dose per unit dosage may therefore be a daily dose, divided (e.g., equally) between the number of dosage units, enter per day, and thus will generally be approximately equal to a daily dose or one second, one third, one fourth or one-sixth. Dosing unit dosing can thus be calculated from each daily dosage specified in this description. The daily dose, component 5 mg, for example, can be seen as providing a dose of a dosing unit equal to, for example, about 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and 0,83 mg, depending on the selected mode of treatment. Accordingly, the dosage of 150 mg per day, corresponds to the dosage per unit dosage equal to, for example, about 150 mg, 75 mg, 50 mg, 37.5 mg and 25 mg for the respective modes of treatment.

The treatment duration may be short, for example, a few weeks (for example, 8-14 weeks), or long term up until the attending physician decides that the additional injection is no longer required.

Derivatives of 1-amino-alkylcyclohexane of the present invention (for example, neramexane) can be administered as monotherapy or in combination with another agent prescribed for the treatment of diseases mediated by fat cells.

The term "combination"applied to active components, is used in this description to define a single pharmaceutical composition is (preparative form), includes two active agent (e.g., pharmaceutical compositions containing the derivative of 1-amino-alkylcyclohexane, as for example, neramexane, and another agent prescribed for the treatment of diseases mediated by mast cells, as for example, anticholinergic agents (for example, mecamylamine, kynurenic acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene Modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)or two separate pharmaceutical compositions, to be jointly introduction, each of which includes an active agent (e.g., pharmaceutical compositions containing derivative of 1-amino-alkylcyclohexane, as for example, neramexane and one pharmaceutical component is icii, containing another agent prescribed for the treatment of diseases mediated by mast cells, as for example, anticholinergic agents (for example, mecamylamine, kynurenic acid, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, loratadine, Desloratadine, Meclizine, Quetiapine, Fexofenadin, Pheniramine, Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349821, ABT-239, Ciproxifan, Closedprofit, Typename, JNJ 7777120, Cromoglycate, Nedocromil), corticosteroids (e.g., prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometazon and triamcinolone), leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen).

In understanding the present invention, the term "co-administration" is used to denote the introduction of a derivative of 1-amino-alkylcyclohexane, as for example, neramexane, and one or more additional active agents (e.g., another agent prescribed for the treatment of diseases mediated by mast cells, as for example, anticholinergic agents (for example, mecamylamine, kynurenine KIS is the notes, d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium and Tiotropium), antihistamines (eg, Diphenhydramine, Loratidine, Desloratadine, Meclizine, Quetiapine, Fexofenadine, Feniramina, Cetirizine, Prometazina, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan, Closedprofit, Hyperemia, JNJ 7777120, Kromoglikatom, Nedocromil), corticosteroids (such as prednisone, cortisone, hydrocortisone), glucocorticoids (e.g., ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone), modifiers leukotrienes (e.g., montelukast, zafirlukast, pranlukast and zileuton), methylxanthines (such as theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen) simultaneously in one composition, or simultaneously in different compositions, or sequentially. However, for sequential injection, which can be considered "joint", a derivative of 1-amino-alkylcyclohexane, as for example, neramexane and one or more additional agents, should be entered separately with a time interval, which also provides the resulting beneficial effect for the treatment in mammals of diseases mediated by fat cells.

EXAMPLES of TYPICAL PREPARATIVE FORMS

Using Shiro what about the used solvents, auxiliary agents and carriers active constituent parts can be processed into tablets, pills, coated, capsule, solution for intravenous drip infusions, suppositories, injection and infusion preparations, gels, creams, ointments and the like and can be used for therapeutic purposes by oral, rectal, parenteral, local, and additional paths. Tablets suitable for oral administration can be obtained by conventional tabletting technology. The following example is given solely for illustration purposes and should not be construed as limitations.

EXAMPLE FORMULATION 1: Tablets Neramexane Nelfinavir Immediate Release

The following table provides the composition of the tablets neramexane immediate release at doses of 12.5, to 25.0, 37.5 and 50.0 mg, including active components, covering agents, and other excipients.

Table 1
Neramexane mesilate, 12.5 mg tablet, film-coated
ComponentAmount (mg)Function
Neramexane Mesilate12,50 Active pharmaceutical ingredient
Microcrystalline cellulose103,25Binder
Croscarmellose sodium6,25Causing the disintegration agent
Silicon dioxide, colloidal1,25Activator yield
Talc1,25Glidant
Magnesium stearate0,50Grease
The mass of the core125,00
Floor (HPMC), Opadry or Sepifilm5,00Floor
Coating weight5,00
The total mass of the coated tablets130,00

Table 2
Neramexane mesilate, 25.0 mg tablets is, film-coated
ComponentAmount (mg)Function
Neramexane Mesilate25,00Active pharmaceutical ingredient
Microcrystalline cellulose206,50Binder
Croscarmellose sodium12,5Causing the disintegration agent
Silicon dioxide, colloidal2,50Activator yield
Talc2,50Glidant
Magnesium stearate1,00Grease
The mass of the core250,00
Floor (HPMC), Opadry or Sepifilm10,00Floor
Coating weight10,00
The total mass of the coated tablets260,00

Table 3
Neramexane mesilate, 37.5 mg tablets, film-coated
ComponentAmount (mg)Function
Neramexane Mesilate37,50Active pharmaceutical ingredient
Microcrystalline cellulose309,75Binder
Croscarmellose sodiumof 18.75Causing the disintegration agent
Silicon dioxide, colloidal3,75Activator yield
Talc3,75Glidant
Magnesium stearate1,5Grease
The mass of the core375,00
Floor (HPMC), Opadry or Sepifilm15,00Floor
Coating weight15,00
The total mass of the coated tablets390,00

Table 4
Neramexane mesilate, 50.0 mg tablets, film-coated
ComponentAmount (mg)Function
Neramexane Mesilate50,00Active pharmaceutical ingredient
Microcrystalline cellulose413,00Binder
Croscarmellose sodium25,00Causing the disintegration agent
Silicon dioxide, colloidal5,00Activator yield
Talc5,00Glidant
Magnesium stearate2,00Grease
The mass of the core500,00
Floor (HPMC), Opadry or Sepifilm20,00Floor
Coating weight20,00
The total mass of the coated tablets520,00

The following tables provide the local preparative forms neramexane.

The PREPARATIVE EXAMPLE FORM 2:

Table 5
"Unguentum emulsificans"
DescriptionNumber
Alcohol cetylicus et sterilicus emulsificans30.0 g
Paraffinum subliquidum35,0 g
Vaselinum album35,0 g

Table 6
"Unguentum emulsificans aquosum containing 1% Neramexane
Number
Neramexane mesilate1.0 g
Unguentum emulsificans30.0 g
Aqua purificata69,0 g

Table 7
"Unguentum emulsificans aquosum", containing 20% Neramexane
DescriptionNumber
Neramexane mesilate20,0 g
Unguentum emulsificans30.0 g
Aqua purificata50.0 g

EXAMPLE FORMULATION 3:

Table 8
"Cremor nonionicus emulsificans aquosum"
DescriptionNumber
Alcohol cetylicus et sterilicus emulsificans nonionicum21,0 g
2-Ethylhexylis lauras10.0 g
Glycerolum 85%5.0 g
Kalium sorbinicum 0.14 g
Acidum citricum, anhydricum0.07 g
Aqua purificata63,79 g

Table 9
"Cremor nonionicus emulsificans aquosum containing 1% Neramexane
DescriptionNumber
Neramexane Mesilate1.0 g
Cremor nonionicus emulsificans aquosum99,0 g

Table 10
"Cremor nonionicus emulsificans aquosum containing 10 % Neramexane
DescriptionNumber
Neramexane Mesilate10.0 g
Cremor nonionicus emulsificans aquosum90.0 g

The PREPARATIVE EXAMPLE FORM 4:

Table 11
"Macrogoli unguentum"
DescriptionNumber
Macrogolum 30050.0 g
Macrogolum 150050.0 g

Table 12
"Macrogoli unguentum"containing 2 % Neramexane
DescriptionNumber
Neramexane Mesilate2.0 g
Macrogoli unguentum98,0 g

Table 13
"Macrogoli unguentum"containing 15 % Neramexane
DescriptionNumber
Neramexane Mesilate15.0 g
Macrogoli unguentum85,0 g

EXAMPLE FORMULATIONS of 5:

Table 14
"Linimentum nonionicum aquosum"
DescriptionNumber
Alcohol cetylicus et sterilicus emulsificans nonionicum10,5 g
2-Ethylhexylis lauras5.0 g
Glycerolum 85%2.5 g
Kalium sorbinicum0.14 g
Acidum citricum, anhydricum0.07 g
Aqua purificata81,79 g

Table 15
"Linimentum nonionicum aquosum"containing 3 % Neramexane
DescriptionNumber
Neramexane Mesilate3.0 g
Linimentum nonionicum aquosum97,0 g

Table 16
"Linimentum nonionicum aquosum"containing 12 % Neramexane
DescriptionNumber
Neramexane Mesilate12.0 g
Linimentum nonionicum aquosum88.0 g

Table 17
"Linimentum nonionicum aquosum", containing 25% Neramexane
DescriptionNumber
Meramecs is as Mesilate 25,0 g
Linimentum nonionicum aquosum75,0 g

EXAMPLES

The following examples illustrate the invention without limiting the scope of its legal claims.

EXAMPLE 1: Action neramexane on induced acetylcholine activation of mast cells

Neramexane investigated for its ability to inhibit mast cell degranulation in vitro.

Materials and methods

Cell Culture

Line HMC-1 mast cells received from J. H. Butterfield (Minnesota, USA) and were cultured under standard conditions in RPMI 1640 Medium (GIBCO, Karlsruhe, Germany) at 37°C. For functional analysis of the calcium concentration of the medium was brought to 1 mm.

Functional tests

Mast cell degranulation was monitored by determining the concentration of histamine in the cultural environment, using sandwich ELISA from IBL (Hamburg, Germany). The concentration of histamine was found in untreated cells, the medium without cells, the cells HMC-1 treated calcimining (iodoform calcium, used as a positive control). Additional controls to test the ability of the cells were LPS (lipopolysaccharide) and PMA (phorbol 12-myristate 13-acetate). The concentration of histamine was determined 10 minutes after adding the appropriate substances. Nicotine and choline used in the when asked incentive for nAChR, muscarin as an incentive for mAChR, and a combination of acetylcholine and ezerin (acetylcholinesterase inhibitor) was used as a General cholinergic stimulus. Neramexane investigated at concentrations ranging from 10 E-6 M up to 10 E-16 M, and added to the culture medium for 5 minutes until the appropriate cholinergic stimulus. All experiments were performed twice in four identical repetition.

Assessment of data

Statistical analysis was performed using the criterion of Wilcoxon rank-sum (available on www.statpages.net).

In order to establish the sensitivity of fat cells to cholinergic signals, used a cell line HMC-1, kultivirovaniya under standard conditions either at low or at high calcium concentrations. When using a low concentration of calcium cells HMC-1 remain insensitive to ACH, nicotine and callimico. Increasing the calcium concentration up to 1 mm makes the cells HMC-1 is highly sensitive to cholinergic stimulation. ACh, choline and nicotine provides dose-dependent mast cell degranulation, as evidenced by the concentration of histamine in the culture supernatant. Nanomolar concentrations of ACh and nicotine are sufficient for full induction of degranulation. The specificity of the resulting actions can be demonstrated through prior the preliminary incubation of cells HMC-1 with anticholinergic substances. Neramexane-mesilate inhibits the observed action in ravnomernykh concentrations, and dose-dependent even in lower concentrations than the corresponding agonist. No allocation of histamine by adding in the cultural environment of muscarine. These results are shown in Figure 1.

Results

Neramexane demonstrates the effect of dose-dependent suppression of degranulation of mast cells. These results show that neramexane may be useful in the treatment of diseases mediated by mast cells, such as urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

These results additionally show that neramexane may be useful in the treatment of diseases mediated by mast cells, such as food Allergy.

The present invention should not be limited to special embodiments described in this application. Actually, from the above description specialists in this field in addition to those described in this application will become apparent, various modifications of the invention. It is assumed that such modifications fall within the scope of the claims appended claims.

All patents, patent applications, publications, test methods, literature and other materials described in this description included in this application by reference.

1. For the treatment or prevention of diseases mediated by mast cells, including neramexane or its pharmaceutically acceptable salt.

2. The tool according to claim 1 where the pharmaceutically acceptable salt neramexane is neramexane mesilate.

3. The tool according to claim 2, where neramexane mesilate enter in the range from about 5 mg to about 150 mg/day, or in the range from approximately 5 mg to approximately 100 mg/day, or in the range from about 5 mg to about 75 mg/day.

4. The tool according to claim 2, where neramexane mesilate injected approximately 50 mg/day.

5. The tool according to claim 2, where neramexane mesilate injected approximately 75 mg/day.

6. The tool according to claim 1, where neramexane or its pharmaceutically acceptable salt is administered once a day, twice a day (b.i.d.) or three times a day.

7. A tool according to any one of claims 1 to 3 or 6, where neramexane or its pharmaceutically acceptable salt is administered in the composition of preparative forms for local application.

8. The tool according to claim 7, where neramexane or its pharmaceutically acceptable salt is administered in an amount of from 0.1 to 99% by weight of the preparative form.

9. A tool according to any one of claims 1 to 6, where neramexane or its pharmaceutically acceptable salt is administered in the composition of oral drugs the active form.

10. A tool according to any one of claims 1 to 6, where a disease mediated by fat cells, is not psoriasis.

11. A tool according to any one of claims 1 to 6, where a disease mediated by mast cells, which are selected from urticaria, atopic dermatitis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

12. The tool in claim 11, where the disease mediated by fat cells, is atopic dermatitis.

13. A tool according to any one of claims 1 to 6, where a disease mediated by fat cells, is a food Allergy.

14. The tool according to claim 7, where the disease is mediated by mast cells, which are selected from urticaria, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

15. Application neramexane or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of diseases mediated by fat cells.

16. The application indicated in paragraph 15, where the pharmaceutically acceptable salt neramexane is neramexane mesilate.

17. The application of article 16, where neramexane mesilate enter in the range from about 5 mg to about 150 mg/day, or in the range from approximately 5 mg to approximately 100 mg/day, or in the range from about 5 mg to about 75 mg/day.

18. The application of article 16, where neramexane mesilate injected approximately 50 mg/day.

19. The application of article 16, where neramexane mesilate injected approximately 75 mg/day.

20. The application of clause 15, where neramexane or its pharmaceutically acceptable salt is administered once a day, twice a day (b.i.d.) or three times a day.

21. The use according to any one of p, 16 or 20, where neramexane or its pharmaceutically acceptable salt is administered in the composition of preparative forms for local application.

22. Use item 21, where neramexane or its pharmaceutically acceptable salt is administered in an amount of from 0.1 to 99% by weight of the preparative form.

23. The use according to any one of p-20, where neramexane or its pharmaceutically acceptable salt is administered in the composition of the oral formulation.

24. The use according to any one of PP-19, where the disease mediated by fat cells, is not psoriasis.

25. The use according to any one of PP-19, where the disease is mediated by mast cells, which are selected from urticaria, atopic dermatitis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.

26. Use A.25, where the disease mediated by fat cells, is atopic dermatitis.

27. The use according to any one of PP-19, where the disease mediated by fat cells, is a food Allergy.

28. The application of claim 20, where the disease is mediated by mast cells, which are selected from Krapivna is s, atopic dermatitis, psoriasis, itching, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.



 

Same patents:

FIELD: biotechnologies.

SUBSTANCE: cell lines of human melanoma, such as Mel-XYl, deposited in DSMZ under No. DSM ACC2830, Mel-XY2, deposited in DSMZ under No. DSM ACC2831, Mel-XY3, deposited in DSMZ under No. DSM ACC2832, and Mel-XX4, deposited in DSMZ under No. DSM ACC2829, are radiated to produce populations with apoptotic and necrotic phenotype. The produced cell lines are used in various combinations for treatment of malignant diseases, namely, for treatment of human melanoma. Also the specified populations of radiated cells are cocultivated with autological dendrite cells for further joint injection to a patient suffering from melanoma.

EFFECT: invention makes it possible to induce a resistant anti-cancer immune response in a mammal suffering from melanoma.

21 cl, 10 dwg, 4 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a method for preparing a pharmaceutical preparation for treating inflammatory intestinal diseases. The method for preparing a pharmaceutical preparation for oral administration for inflammatory intestinal diseases, particularly chronic inflammatory gastrointestinal diseases containing a storage-stable suspension of vital eggs of the parasitic, non-pathogenic to humans helminthes Trichuris suis, which involves preparing the suspension of helminth eggs in an acid at pH max. 2 at the first stage; at the following stage, the pH value is increased to min. 4, and a pharmacologically acceptable preserving agent is added. A pharmaceutical preparation for oral administration for inflammatory intestinal diseases, particularly chronic inflammatory intestinal diseases. The use of the pharmaceutical preparation for oral administration for inflammatory alimentary diseases, particularly chronic inflammatory alimentary diseases.

EFFECT: method enables more effective storage of the produced preparation of vital helminth eggs not accompanied by dangerous intergrowths of fungal spores and yeast propagation.

11 cl, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to introducing dairy fat or an analogue thereof, optionally with at least one additional therapeutic factor, preferentially with lactoferrin or lactoferrin containing a metal ion, preferentially lactoferrin containing iron, preferentially bovine lactoferrin containing iron or a functional version thereof containing metal ions or a functional fragment to inhibit the tumour formation or growth, to maintain or improve one or more parameters, such as leukocyte count, erythrocyte count, or myelocyte count, to reduce the manifestations of cachexia, mucositis and anemia, to stimulate the immune system and to treat or prevent a malignancy and malignant symptoms, and side effects of treating the malignant tumour. Methods and therapeutic use according to the invention may be implemented by the use of a diet (in the form of food products or food additives), nutrient or pharmaceutical composition. There are also presented compositions applicable in the methods according to the invention.

EFFECT: group of inventions provides the higher clinical effectiveness or prevention of the malignant tumour or its symptoms.

39 cl, 7 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: there are presented versions of the peptide (A) or (B) with the amino acid sequence of SEQ ID NO: 1 or 2 respectively presented in this description. The peptide has activity to induce a cytotoxic T-cell when an antigen-presenting cell carrying HLA-A2 (A*0201) presents it. There are described the versions of the peptide antibodies prepared by immunisation by the proper peptide. There are presented: an agent, methods for inducing: a cytotoxic (killer) T-cell, an antigen-presenting cell, CDH3 expressing cancer immunity; as well as a method of treating CDH3 expressing cancer on the basis of the peptide. What is presented is an isolated cytotoxic T-cell induced by said method on the basis of the peptide. There are described: the antigen-presenting cell and exosome presenting the complex containing the peptide and HLA-A2 (A*0201).

EFFECT: higher effectiveness of the use of the invention in treating CDH3 expressing cancer.

15 cl, 5 dwg, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an aminopropylidene derivative presented by formula wherein R1 and R2, which may be identical or different, represent hydrogen or a substitute specified in the following (a)-(c), provided the case of both representing hydrogen is excluded: (a) carbonyl substituted with hydroxy, alkoxy or hydroxy alkylamino, (b) carbonylalkyl substituted by hydroxy or alkoxy, and (c) acrylic acid including its alkyl ester, R3 and R4, which may be identical or different, represent hydrogen, alkyl which may be substituted by phenyl or cycloalkyl, or R3 and R4, which together form a heterocyclic ring with a nitrogen atom bound thereto, represent pyrrolidino, piperidino, which may be substituted by oxo or piperidino, piperazinyl substituted by alkyl or penyl, morpholino or thiomorpholino; A means oxo or is absento, B represents canbon or oxygen; one of X and Y represents carbon, while the other one represents sulphur, a part represented by a dash line represents a single bond or a double bond, and a wavy line represents a cys-form and/or a transform. Also, the invention refers to a pharmaceutical composition exhibiting histamine receptor antagonist activity on the basis of said compounds.

EFFECT: there are produced new compounds and pharmaceutical compositions thereof, which can be used in medicine for treating asthma, allergic rhinitis, pollen allergy, hives and atopic dermatitis.

10 cl, 12 tbl, 58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and concerns a pharmaceutical composition in the form of a capsule either acid-resistant, or with an acid-resistant coating containing recombinant interferon specified from alpha, beta, gamma recombinant interferon; a stabiliser of the biological, physical and chemical properties specified in low-molecular polyvinylpyrrolidone, macrogol 400-12000, propylene glycol, hydroxypropyl methylcellulose; a stabiliser of microbial contamination resistance specified in dexamethasone, diflorazone, boric acid, phospholipids, cyclodextrins, calcium stearate, and/or magnesium stearate, a thickly-forming base specified in hydrophilic, lipophilic, hydrophilic-lipophilic bases.

EFFECT: invention provides a higher therapeutic effect and prolonged shelf life.

3 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, particularly to an agent with immunocorrective action on the humoral component of the immunity system in cytostatic immunosuppression. The agent with immunocorrective action on the humoral component of the immunity system in cytostatic immunosuppression, which is a liquid extract of licorice root (Radices Glycyrrhizae) prepared by repercolation with 40% ethanol in certain ratio materials: extractant.

EFFECT: licorice extract exhibits the immunocorrective properties expressed in the effective enhancement of the cyclophosphamide-suppressed humoral immune response.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, particularly to an agent with immunocorrective action on the humoral component of the immunity system in cytostatic immunosuppression. The agent with immunocorrective action on the humoral component of the immunity system in cytostatic immunosuppression, which is a liquid extract of licorice root (Radices Glycyrrhizae) prepared by repercolation with 40% ethanol in certain ratio materials: extractant.

EFFECT: licorice extract exhibits the immunocorrective properties expressed in the effective enhancement of the cyclophosphamide-suppressed humoral immune response.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutical compositions containing synthetic oxidised lipids.

EFFECT: developing the method for using the oxidised lipids for treating and preventing the inflammation associated with the endogenous oxidised lipid.

39 cl, 11 tbl, 15 ex, 25 dwg

Antibodies // 2482131

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. There are presented the antibodies that bind to the P-selectin glycoprotein ligand-1 (PSGL-1), as well as methods for stimulating the death of activated T-cells and simulating T-cell immune response in a patient by the use of the antibodies under the invention, and pharmaceutical compositions containing the antibodies under the invention. There are also disclosed nucleic acids, expression vectors and host cells for producing the antibodies under the invention.

EFFECT: invention may can find further application in therapy of the PSGL-1 associated diseases.

35 cl, 4 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a multidose ophthalmic composition containing prostaglandin as a therapeutic ingredient, mannitol or sorbitol 0.15-0.5 wt/vol %, propylene glycol or glycerol 0.2-1.8, borate 0.25-0.5 wt/vol %, an antimicrobial preserving agent 0.0003-0.003 wt/vol % representing a polymer quaternary ammonium compound and water. Said composition has pH 6.4-7.2 and is benzalconium chloride free. Besides, the invention refers to the use of said ophthalmic composition for preparing a drug for treating glaucoma, eye infections, allergies and inflammations.

EFFECT: preparing the ophthalmic composition which exhibits improved antimicrobial preserving activity and improved buffer properties.

16 cl, 8 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a piperidine derivative of general formula (I)

,

where R1 denotes hydrogen or a substitute selected from the following (b)-(i): b) acrylic acid (including alkyl ester and hydroxyalkyl amide), (c) ureide, (d) alkenyl, (e) aminoalkyl which can be substituted with alkyl carbonyl or aminocarbonyl, (f) carbonyl alkyl, substituted with hydroxy, alkoxy or hydroxyalkylamino, (g) carbonyl, substituted with hydroxy, morpholino, alkoxy, hydroxyalkyl aminoalkoxy or cyclohexyloxy carbonyloxyalkoxy, (h) carbonylamino, substituted with alkyl or alkoxy, (i) aminocarbonyl which can be substituted with one or two substitutes selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which can be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or one or two hydroxy); R2 denotes hydrogen or a substitute selected from the following (j)-(r): (j) cyano, (k) acrylic acid, (l) alkyl, substituted with hydroxy or piperidino, (m) carbonyl alkyl, substituted with hydroxy, alkoxy (which can be substituted with cyclohexyloxy carbonyloxy) or hydroxyalkylamino, (n) carbonyl, substituted with hydroxy or alkoxy, (o) carbonyl alkoxy, substituted with alkoxy, (p) carbonyl alkyl sulphanyl, substituted with hydroxy or alkoxy, (q) alkoxy, (r) halogen; and R3 denotes hydrogen or a substitute selected from the following (s)-(w): (s) alkyl which can be substituted with carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkyl sulphanyl or one or two hydroxy, (t) carbonyl, substituted with alkyl or alkoxy, (u) carbonyl alkoxyalkyl, substituted with hydroxy or alkoxy, (v) carbonyl alkyl, substituted with alkyl, alkoxy or alkylphenyl, (w) aminoalkyl, substituted with aminocarbonyl or alkane sulphonyl, where one of said R1 and R2 denotes a substitute other than hydrogen, A is unsubstituted or is an oxo, B denotes carbon or oxygen, one of X and Y denotes carbon and the other denotes sulphur, the dotted line denotes a single bond or a double bond, under the condition that when R2 denotes halogen or alkoxy, A is unsubstituted, R1 denotes a substitute other than hydrogen and B denotes oxygen. The invention also relates to an antihistamine which contains a compound of formula I and use of the described compound for treatment and production of a medicinal agent.

EFFECT: novel compounds having antagonistic action on histamine receptors are obtained and described and can be suitable as active ingredients of a pharmaceutical composition, especially an antihistamine composition.

17 cl, 40 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining said salts, to pharmaceutical composition, containing said salts, and to application of salt for preparation of medication for treatment, prevention or relief of one or several symptoms of disease, mediated by CRTH2, associated with eosinophils, basophils, where disease is selected from asthma, allergic asthma, asthma of physical effort, allergic rhinitis, atopic dermatitis, contact hypersensitivity and hyper IgE syndrome.

EFFECT: invention relates to novel pharmaceutically acceptable salts, containing pharmaceutically acceptable amine, selected from ethylenediamine, piperazine, benzathine or choline and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidin-5yl}acetic acid.

43 cl, 21 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel crystalline forms I, II and amorphous form of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidin-5-yl}acetic acid.

EFFECT: invention relates to pharmaceutical composition, containing crystalline form I of compound and to application of crystalline form I for treatment, prevention or relief of one or more symptoms of disease, mediated by CRTH2, associated with eosinophils, basophils, where disease is selected from asthma, allergic asthma, asthma, induced by physical effort, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity.

16 cl, 11 dwg, 8 tbl,11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new acid dihydrogenphosphate of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyrimidine-4-yl}phenyl)-2-methylpropionic acid of formula optionally in a crystalline form exhibiting cAMP inhibitor properties. Also, the invention refers to a pharmaceutical composition.

EFFECT: compound can find application for treating the diseases associated with cell expression of prostaglandin D2 in such diseases, as allergic rhinitis, bronchial asthma, allergic conjunctivitis, etc.

3 cl, 12 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to enzymatic wound healing medication. Enzymatic wound healing medication, which contains enzyme ultra-lysine in form of liquid substance, antiseptic myristamide and auxiliary substances - emuksol-268 and polyethyleneglycol, taken with specified ratio.

EFFECT: medication has increased wound healing activity.

4 dwg, 7 ex

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