Solid forms of n-(7-azabicyclo[2,2,1]heptan-7-yl-)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquiinoline-3-carboxamide

FIELD: chemistry.

SUBSTANCE: invention relates to form A of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl-)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, where said form A is characterised by peak at approximately 7.9 degree, peak at approximately 11.9 degree, peak at approximately 14.4 degree and peak at approximately 15.8 degree in powder X-ray. Invention also relates to pharmaceutical composition and set based on said form A, application of form A, method of CFTR modulation.

EFFECT: obtained is novel form of quinoline derivative, which is modulator of CFTR activity.

12 cl, 3 dwg, 2 tbl, 3 ex

 

RELATED APPLICATIONS

[001] This application claims the priority of Provisional Application US 61/107813, filed October 23, 2008, entitled "SOLID FORMS of N-(4-(7-AZABICYCLO[2.2.1]HEPTANE-7-YL)-2-(TRIFLUOROMETHYL)PHENYL)-4-OXO-5-(TRIFLUOROMETHYL)-1,4-DIHYDROQUINOLINE-3-CARBOXAMIDE”, the entire contents of which are incorporated here by reference.

The technical FIELD TO WHICH the INVENTION RELATES.

[002] This invention relates to solid forms of the condition, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, which is a modulator of transmembrane conductance regulator cystic fibrosis (cystic degeneration (pancreas) ("CFTR"). This invention relates also to pharmaceutical compositions comprising the crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide and related methods.

The LEVEL of TECHNOLOGY

[003] the Transporters ATP-cassette are a family of membrane Transporter proteins that regulate the transport of a large variety of pharmacological agents, potentially toxic drugs and xenobiotics, as well as anions. They are homologous membrane proteins that binding of the t and use of cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters have been found in proteins of resistance to multiple drugs (such as MDR1-P-glycoprotein or protein of resistance to multiple drugs, MRP1), which protects malignant cancer cells against chemotherapeutic agents. To date 48 of such transporters have been identified and grouped into 7 families on the basis of the identity of their sequences and functions.

[004] One member of the family of transporters ATP-cassette, usually associated with disease, is a camp/ATP-mediated anion channel CFTR. CFTR is expressed in various cell types, including suction cells and secretory epithelial cells, where it regulates the flow of anions through the membrane and the activity of other ion channels and proteins. In the epithelial cells of the normal functioning of CFTR is critical to maintain the transport of electrolytes through the body, including respiratory and digestive fabric. CFTR consists of approximately 1480 amino acids that encode a protein formed from a tandem repeat transmembrane domains, each of which contains six transmembrane helices and nucleotidase domain. These two transmembrane domain linked to a large, polar, regulatory (R)domain with many who promote sites of phosphorylation, that regulate channel activity and cell directional migration.

[005] the Gene encoding CFTR, was identified and sequenced (See. Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), Riordan, J. R. et al. (1989) Science 245:1066-1073). The defect in this gene causes mutations in CFTR, leading to cystic fibrosis ("CF"), the most life-threatening genetic disease in humans. Cystic fibrosis affects approximately one in every 2500 babies in the United States. In the General population of the United States, up to 10 million people carry a single copy of the defective gene without visible pathological effects. In contrast, individuals with two copies of the CF associated gene suffer from malnutrition and life-threatening actions CF, including chronic lung disease.

[006] In patients with cystic fibrosis mutations in CFTR, endogenous expressed in respiratory epithelium, leading to reduced apical secretion of anions, causing an imbalance in the transport of ions and fluids. The resulting reduction in the transport of anions contributes to the enhanced accumulation of mucus in the lung and associated microbial infections, which ultimately cause death in patients with CF. In addition to respiratory disease patients with CF suffer from gastrointestinal problems and pancreatic insufficiency, the which if untreated leads to death. In addition, most men with cystic fibrosis are infertile, and fertility is reduced among women with CF. In contrast to heavy action, two copies of the CF associated gene in individuals with a single copy of the CF associated gene detect increased resistance to cholera and dehydration originating from diarrhea, which may explain the relatively high frequency of CF gene in this population.

[007] the sequence Analysis of the CFTR gene CF-chromosomes revealed the diversity of causing this disease mutations (Cutting, G. R. Et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S, et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, were identified more than 1,000 causing disease mutations in the gene for CF (http://www.genet.sickkids.on.ca/cftr/). The most predominant mutation is a deletion of phenylalanine at position 508 amino acid sequence of CFTR, which is usually referred to as ΔF508-CFTR. This mutation is found in approximately 70% of cases of cystic fibrosis and is associated with severe disease.

[008] the Deletion of residue 508 in ΔF508-CFTR prevents accurate laying occurring protein. This leads to the inability of the mutant protein to exit the ER (endoplasmic reticulum) and directionally migrate to the plasma membrane. As a result, the number of channels present in the same membrane, is much smaller than the number of channels observed in cells expressing wild-type CFTR. In addition to impaired directional migration this mutation leads to a defective gate mechanism of ion channels. Together this reduced the number of channels in the membrane and the defective gate mechanism channels lead to reduced transport across the epithelium, leading to defective transport of ions and fluids (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown that reduced the number of ΔF508-CFTR in the membrane are functional, although to a lesser extent than wild-type CFTR (Dolmans et al. (1991), Nature Lond. 354: 526-528; Denning et at., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, R117H-CFTR and G551D-CFTR, other cause of disease mutations in CFTR that lead to defective directional migration, defective synthesis and/or gate the mechanism of ion channels could increase or decrease to adjusted for changes in the secretion of anions and modification of progression and/or severity of the disease.

[009] Although CFTR transports various molecules along with the anions, it is clear that this role (transport anions, chloride and bicarbonate) is one important element in the mechanism of transport of ions and water across the epithelium. Other elements include the epithelial Na+channel, ENaC, Na+/2Cl-K+-cotransporter, Na -K+ATP-azny pump and K+-channels basolateral membrane, which are responsible for absorption of chloride into the cell.

[0010] These elements work together to achieve directed transport through the epithelium by their selective expression and localization in the cell. Absorption of chloride occurs as a result of the coordinated activity of ENaC and CFTR present on the apical membrane, and Na+-K+ATP-asnago pump and Cl-channels expressed on basolateral the cell surface. Secondary active transport of chloride from the side of the lumen leads to accumulation of intracellular chloride, which can then passively leave cells through Cl-ion channels, leading to a vector transport. Accommodation Na+/2Cl-K+co-Transporter, Na+-K+ATP-asnago pump and+channels basolateral membrane on basolateral surface and CFTR on the side of the lumen coordinate the chloride secretion through CFTR on the side of the lumen. Since water may never transported itself, its flow through the epithelium depends on very small transepithelial osmotic gradients generated a massive influx of sodium and chloride.

[0011] it is Assumed that defective transport of bicarbonate due to mutations in CFTR cause the Def is you in some secretory functions. See, for example, "Cystic fibrosis: impaired secretion bicarbonate-heat and mucoviscidosis," Paul M. Quinton, Lancet 2008; 372: 415-417.

[0012] Mutations in CFTR associated with mild CFTR dysfunction, are also evident in patients with conditions that have certain common symptoms with CF, but do not meet diagnostic criteria for CF. They include congenital bilateral absence of the VAS duct, idiopathic chronic pancreatitis, chronic bronchitis and chronic rhinosinusitis. Other diseases that are considered, CFTR is a risk factor together with genes modifiers or environmental factors include primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, asthma.

[0013] it Was also demonstrated that cigarette smoke, hypoxia and environmental factors that induce hypoxic signaling, disrupt CFTR function and may contribute to certain forms of respiratory diseases such as chronic bronchitis. Diseases that can be caused by a defective CFTR function, but do not meet diagnostic criteria for CF, characterized as CFTR-related diseases.

[0014] in Addition to cystic fibrosis modulation of CFTR activity may be useful for other diseases that are not caused directly by mutations in CFTR, so is x as secretory disease and illness associated with the folding of other proteins, mediated by CFTR. CFTR regulates the flow of chloride and bicarbonate across the epithelium of many cells for regulation of the fluid, solubilization of proteins, the viscosity of the mucus and enzymes activity. Defects in CFTR can cause airway blockage or ducts in many organs, including the liver and pancreas. Potentiate equipment (amplifiers) are compounds that increase the activity of the gate mechanism of CFTR present in the cell membrane. Any disease that involves the thickening of mucus, impaired regulation of fluid, impaired clearance of mucus or blocked ducts, causing inflammation and destruction of tissue, could be a candidate to apply potentiation.

[0015] these include, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, smoke-induced COPD, chronic bronchitis, rhinosinusitis, the higher, dry eye disease, and Sjogren syndrome, gastroesophageal reflux, gall stones, prolapse of the rectum and inflammatory disease of the digestive tract. COPD is characterized by a lack of patency of the respiratory tract, which is progressive and not fully reversible. This lack of patency of the respiratory tract caused hypertec what ecia mucus, emphysema and bronchiolitis. Activators of mutant CFTR or CFTR wild type represent a potential treatment of mucus hypersecretion and impaired ciliary clearance, which is common in COPD. Specifically, an increase in the secretion of anions through CFTR may contribute to the transport of liquid in the liquid surface of the respiratory tract for the hydration of mucus and optimization of viscosity pricelearn fluid. This could lead to increased mucociliary clearance and reduce symptoms associated with COPD. In addition, by preventing emerging infection and inflammation due to enhanced clearance of airway CFTR modulators can prevent or slow down parenchymal destruction of the respiratory tract, which characterizes emphysema, and reduce or reverse the increase in the number and size of secreting mucus cells, which underlies the hypersecretion of mucus in the respiratory diseases. The disease is dry eye is characterized by a decrease in water production of tears and abnormal lipid profiles, protein and mucin tear film. There are many causes of dry eye, some of which include age, laser eye surgery, arthritis, medicines, chemical/thermal burns, allergies and diseases such as cystic fibrosis and the syndrome is Sjogren's syndrome. Increased secretion of anions through CFTR could enhance the transport of fluid from the endothelial cells of the cornea and secretory glands around the eye, to increase the hydration of the cornea. This would help to reduce the symptoms associated with dry eye disease. Sjogren syndrome is an autoimmune disease in which the immune system attacks producing liquid glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina and intestines. Symptoms include dry eyes, dry mouth, and vagina, as well as lung disease. This disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis/dermatomyositis. It is believed that the defective directional migration of proteins causes this disease, for which treatment options are limited. Modulators of CFTR activity can be hydrated various organs affected by the disease, and can contribute to the relief of associated symptoms. Individuals with cystic fibrosis have recurrent episodes of intestinal obstruction and a higher incidence of rectal polyps, biliary concretions, gastroesophageal reflux, gastrointestinal (GI) zlokacestvennosti and inflammatory diseases of the digestive tract that shows is that what is the function of CFTR may play an important role in the prevention of such diseases.

[0016] As discussed above, it is considered that the deletion of residue 508 in ΔF508-CFTR prevents the accurate folding occurring protein, leading to the inability of this mutant protein to exit the ER (endoplasmic reticulum) and directionally migrate to the plasma membrane. As a result, in the plasma membrane there are an insufficient number of this Mature protein, and chloride transport in epithelial tissues is significantly reduced. Indeed, it was shown that the cellular phenomenon of defective ER-CFTR processing apparatus ER underlies not only the disease of CF, but also a wide range of other isolated and hereditary diseases. Two ways that may not be very useful in the apparatus of the ER are either loss of binding to ER-export of proteins, leading to degradation or ER-accumulation of these defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B.S., et al, Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al., Swiss Med WkIy, 132, pp 211-222 (2002); Morello, JP et al., TIPS, 21, pp. 466-469 (2000); Bross, P., et al., Human Mut, 14, pp. 186-198 (1999)]. Diseases associated with the first class malfunction ER, are cystic fibrosis (due to misfolded ΔF508-CFTR described above), hereditary emphysema (due to α-1-antari the Shin; not Piz variants), hereditary hemochromatosis, deficiency of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema Type 1 (disease Quincke), failure of processing of lipids, such as hereditary hypercholesterolemia, chylomicronemia Type 1, abetalipoproteinemia, disease, lysosomal accumulation, such as disease cellular inclusions (mucolipidoses)/pseudo-Hurler syndrome, mucopolysaccharidosis (due to lysosomal enzymes processing), a disease Sandhoff/Tea-Sachs (due to β-hexosaminidase), disease criglernajjar Najjar syndrome type II (due UDF-glucuronyl-sialyltransferase), polyendocrinopathy/hyperinsulemia, diabetes mellitus (due to insulin receptor), dwarfism saranovskogo type (caused by hormone receptor growth), myeloperoxidase deficiency, primary hypoparathyroidism (due to preproparathyroid hormone), melanoma (due to tyrosinase). Diseases associated with the latter class of impaired function of the ER, are glycans CDG type 1, hereditary emphysema (due to α-1-antitripsin (PiZ variant)), congenital hyperthyroidism, imperfect osteogenesis (due procollagen Type I, II, IV), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (Bukovina α-1-antichymotrypsin), diabetes insipidus (DI), neurophysiology DI (caused by the hormone vasopressin/V2-receptor), nephrogenic DI (due to aquaporin II), hereditary neural amyotrophy Charcot-Marie-Toot (due to peripheral myelin protein 22), Sodankyla leukodystrophy disease Pelizaeus-Merzbacher), neurodegenerative diseases such as Alzheimer's disease (due to β-ARR and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, a disease of the Peak, a few polyglutamine neurological disorders such as Huntington's disease (HD), spinocerebellar (related to the spinal cord and cerebellum ataxia type I, related to the spinal cord and medulla muscular atrophy, dentatorubral pallidoluysian and myotonica dystrophy, as well as spongiform encephalopathies, such as hereditary disease Creutzfeldt-Jakob disease (due to defect processing Pranovich proteins), Fabry disease (due to defective lysosomal α-galactosidase A), the syndrome of Straussler-Sheinker (caused by the defect processing Prp), pancreatitis infertility, pancreas failure, osteoporosis, osteopenia, syndrome Gorham, chloride of kalapati, congenital myotonia form (Thomson and Becker), the syndrome Bartter type III, dent disease who, congenital pathologically enhanced reaction of fright epilepsy, the disease liposomal accumulation, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as syndrome Addition, PCD without situs inversus and ciliary aplasia, and liver disease.

[0017] Other diseases supposedly caused by a mutation in the CFTR include male infertility caused by congenital bilateral absence of vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA). See, work "CFTR-opathies: disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations," Peader G. Noone and Michael R. Knowles, Respir. Res. 2001, 2: 328-332 (incorporated herein by reference).

[0018] Along with the increasing regulation of CFTR activity decreases the secretion of anions CFTR-modulators may be useful for the treatment of secretory diarrhea, in which the epithelial transport of water striking increases in the activated amplifying secretion agent (secretagogues) transport of chloride. This mechanism includes an increase of camp and stimulation of CFTR.

[0019] Although there are many causes of diarrhea, the main consequences of diarrhoeal diseases originating from excessive transport of chloride, are common to all and include dehydration, acidosis, impaired growth and death. Acute and chronic d is area are a major problem in medicine in many areas of the world. Diarrhea is a significant factor in the depletion, and the leading cause of death (5000000 deaths a year in children aged less than five years.

[0020] Secretory diarrhea are also dangerous condition in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory disease of the digestive tract (IBD). Sixteen million travelers visiting developing countries from industrialized Nations each year develop diarrhea, weight and number of cases of diarrhoea, varying depending on the specific countries and regions of the journey.

[0021] Thus, there is a need for potent and selective CFTR-potentiator (CFTR-amps) forms of wild-type and mutant forms of CFTR person. These mutant forms of CFTR include, but are not limited to, ΔF508del, G551D, R117H, 2789+5G->A.

[0022] There is also a need for modulators of CFTR activity and their compositions, which can be used to modulate the activity of the CFTR in the cell membrane of mammals.

[0023] There is a need for methods of treatment of diseases caused by mutations in CFTR, using such modulators of CFTR activity.

[0024] There is a need for methods of modulating the activity of the CFTR in the cell membrane ex vivo mammals.

[0025] in Addition, there is a need for stability in the s solid forms of the compounds, which can easily be used in pharmaceutical compositions suitable for use as a therapeutic substance.

The INVENTION

[0026] the present invention relates to solid forms of N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (hereinafter referred to as "Compound 1"), which has the following structure:

Connection 1

[0027] the Compound 1 and its pharmaceutically acceptable composition suitable for treating or attenuating the severity of various diseases, disorders or conditions, including, but not limited to, cystic fibrosis, pancreatitis, sinusitis, hereditary emphysema, hereditary hemochromatosis, deficiency of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema Type 1 (disease Quincke), failure of processing of lipids, such as hereditary hypercholesterolemia, chylomicronemia, abetalipoproteinemia, diseases, lysosomal accumulation (or deposition), such as disease cellular inclusions (mucolipidoses)/the pseudo Hurler syndrome, mucopolysacharides, disease Sandhoff/Tea-Sachs disease criglernajjar Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, dwarfism, leonovs the type, the myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycans CDG type 1, hereditary emphysema, congenital hyperthyroidism, imperfect osteogenesis, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI, hereditary neural amyotrophy Charcot-Marie-Toot, adamopolou the leukodystrophy disease Pelizaeus-Merzbacher), neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, a disease of the Peak, a few polyglutamine neurological disorders such as Huntington's disease (HD), spinocerebellar (related to spinal brain and cerebellum ataxia type I, related to the spinal cord and medulla muscle atrophy, dentatorubral pallidoluysian and myotonias dystrophy, as well as spongiform encephalopathies, such as hereditary disease Creutzfeldt-Jakob disease, Fabry disease, syndrome Straussler-Sheinker, COPD, dry eye disease, pancreas failure, osteoporosis, osteopenia, syndrome Gorham, chloride of kalapati, congenital myotonia form (Thomson and Becker), the syndrome Bartter type III, dent disease, congenital pathologically enhanced reaction of fright epilepsy, the disease liposomal however, the population, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as syndrome Addition, PCD without situs inversus and ciliary aplasia, and sjögren's disease.

[0028] In one aspect, Compound 1 is essentially crystalline, pure form, Form A.

[0029] the Described processes can be used to prepare compositions of this invention containing the Form A. Number and characteristics of the components used in these processes are the same as described here.

BRIEF DESCRIPTION of FIGURES

[0030] Figure 1 is a powder x-ray Form A.

[0031] Figure 2 is a conformational image of the form And on the basis of individual x-ray analysis.

[0032] Figure 3 provides the FTIR spectrum of Form A.

DETAILED description of the INVENTION

[0033]Definitions

[0034] In this invention will be used in the following definitions, unless otherwise indicated.

[0035] the Term "ABC-Transporter" means in this context, ABC-Transporter protein or its fragment that contains at least one binding domain, where this protein or its fragment is present in vivo or in vitro. The term "binding domain" refers in this context on the domain ABC-Transporter, which can communicate with the modulator. See, for example, Hwang, T. C. et al, J. Gen. Physiol. (1998): 111(3), 47790.

[0036] the Term "CFTR" means in this context transmembrane conductance regulator cystic fibrosis, or a mutation that has a regulatory activity, including, but not limited to, ΔF508, CFTR, R117H CFTR and G551D CFTR (see, for example, http://www.genet.sickkids.on.ca/cftr/, in respect of CFTR mutations).

[0037] the Term "modulation" means in this context, the increase or decrease of the measured value.

[0038] the Term "normal CFTR" or "normal CFTR function" means in this context is similar to the wild type CFTR without any disturbance due to environmental factors, such as Smoking, pollution or anything that produces inflammation in the lungs.

[0039] the Term "reduced CFTR" or "reduced CFTR function" means in this context less active CFTR than normal CFTR or less function than normal CFTR function.

[0040] In this context, a “crystalline" refers to compounds or compositions, in which the structural units are located in fixed geometric crystal structures or arrays, so that crystalline solids have a hard long-range order (structure). The structural units that constitute the crystal structure may be atoms, molecules or ions. Crystalline solids discover distinct melting point.

[0041] In this it is nexte the phrase "essentially crystalline” refers to a solid material, located in a fixed geometric structures or arrays that have hard long-range order. For example, essentially crystalline materials have greater than approximately 85% crystallinity (for example, greater than about 90% crystallinity, or greater than about 95% crystallinity). It should also be noted that the term “essentially crystalline” includes the descriptor 'crystal', which is defined in the previous paragraph.

[0042] In one aspect of this invention describes the shape of N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, characterized as a Form of A.

[0043] In some embodiments, the implementation of the Form And is characterized by one or more peaks from about 7.7 to about 8.1 degrees, for example, approximately 7.9 degrees; from about 11.7 to about 12.1 degrees, for example, approximately 11.9 degrees; from about 14.2 to about 14.6 degrees, for example, about 14.4 degrees; and from about 5.6 to about 16.0 degrees, for example, about 15.8 degrees; in the x-ray powder diffraction obtained using alpha-radiation Cu K

[0044] In some embodiments, the implementation of the Form And is characterized by one or more p is kami: from about 7.8 to about 8.0 degrees, for example, approximately 7.9 degrees; from about 11.8 to about 12.0 degrees, for example, approximately 11.9 degrees; from about 14,3 up to approximately 14.5 degrees, for example, about 14.4 degrees; and from about 15.7 to about 15.9 degrees, for example, about 15.8 degrees; in the x-ray powder diffraction obtained using alpha-radiation Cu K

[0045] In other embodiments, the implementation of the Form And is characterized by one or more peaks from about 7.7 to about 8.1 degrees, for example, approximately 7.9 degrees; from about 21.6 to about 22.0 degrees, for example, about 21.8 degrees; and from about 23,6 to approximately 24.0 degrees, for example, about 23.8 degrees; x-ray powder diffraction obtained using alpha-radiation Cu K

[0046] In other embodiments, the implementation of the Form And is characterized by one or more peaks from about 7.8 to about 8.0 degrees, for example, approximately 7.9 degrees; from about 21,7 to approximately 21.9 degrees, for example, about 21.8 degrees; and from approximately 23.7 to about 23.9 degrees, for example, about 23.8 degrees; x-ray powder diffraction obtained using alpha-radiation Cu K

[0047] In some which the option exercise Form And is characterized by one or more of the following peaks, measured in degrees in a powder x-ray: a peak from about 7.7 to about 8.1 degrees (for example, approximately 7.9 degrees); a peak from about 9.1 and about 9.5 degrees, (for example, approximately 9.3 degrees); a peak from about 11.7 to about 12.1 degrees, (for example, approximately 11.9 degrees); a peak from about 14.2 to about 14.6 degrees, (for example, approximately 14.4 degrees); a peak from about 14,9 to approximately 15.3 degrees, (for example, about 15.1 degrees); a peak from about 15.6 to about 16.0 degrees, (for example, approximately 15.8 degrees); a peak from about 16,8 to approximately 17.2 degrees, (for example, approximately 17.0 degrees); a peak from about 17.5 to about 17.9 degrees, (for example, approximately 17.7 degrees); a peak from about 19.1 to approximately 19.5 degrees (for example, approximately 19.3 degrees); a peak from about 19.9 to approximately 20.3 degrees, (for example, approximately 20.1 degrees); a peak from approximately 21.2 to approximately 21.6 degrees, (for example, approximately 21.4 degrees); a peak from about 21.6 to approximately 22,0 degrees, (for example, approximately 21.8 degrees); a peak from about 23,2 to approximately 23.6 degrees (for example, about 23.4 degrees); a peak from about 23,6 to approximately 24,0 g is dosa, (for example, approximately 23.8 degrees); a peak from about 25.4 to about 25.8 degrees (for example, approximately 25.6 degrees); a peak from about 26.6 to approximately of 27.0 degrees, (for example, approximately 26.8 degrees); a peak from about 29,2 to approximately 29.6 per degree (for example, approximately 29.4 degrees); a peak from about 29.5 to about 29.9 degrees, (for example, about 29.7 degrees); a peak from about 29,9 to approximately 30.3 degrees, (for example, approximately 30.1 degrees) and a peak from about 31,0 to approximately 31,4 degrees, (for example, approximately 31.2 degrees).

[0048] In some embodiments, the implementation of the Form And is characterized by one or more of the following peaks measured in degrees in a powder x-ray: a peak from about 7.8 to about 8.0 degrees (for example, approximately 7.9 degrees); a peak from about 9.2 to about 9.4 degrees (for example, approximately 9.3 degrees); a peak from about 11.8 to about 12.0 degrees, (for example, approximately 11.9 degrees); a peak from about 14,3 up to approximately 14.5 degrees, (for example, approximately 14.4 degrees); a peak from about 15.0 to about 15.2 degrees, (for example, about 15.1 degrees); a peak from about 15.7 to about 15.9 degrees, (for example, approximately 15,8 is Ragusa); peak from approximately 16.9% to approximately 17.1 degrees, (for example, approximately 17.0 degrees); a peak from about 17.6 to about 17.8 degrees, (for example, approximately 17.7 degrees); a peak from about 19,2 to approximately 19.4 degrees, (for example, approximately 19.3 degrees); a peak from about 20.0 to about 20.2 degrees, (for example, approximately 20.1 degrees); a peak from about 21,3 to about 21.5 degrees (for example, approximately 21.4 degrees); a peak from about 21,7 to approximately 21.9 degrees, (for example, approximately 21.8 degrees); a peak from about 23,3 to about 23.5 degrees, (for example, about 23.4 degrees); a peak from approximately 23.7 to about 23.9 degrees, (for example, approximately 23.8 degrees); a peak from about 25.5 to about 25.7 degrees, (for example, approximately 25.6 degrees); a peak from about 26.7 to approximately 26.9 degrees, (for example, approximately 26.8 degrees); a peak from about 29.3 to approximately 29.5 degrees (for example, approximately 29.4 degrees); a peak from about 29.6 to approximately 29.8 degrees, (for example, approximately 29.7 degrees); a peak from about 30.0 to about 30.2 degrees, (for example, approximately 30.1 degrees) and a peak from about 31,1 to approximately 31.3 degrees, (for example, approximately 31.2 degrees).

[0049] In some embodiments, the implementation of the Form And is characterized by the diffraction pattern provided in Figure 1.

[0050] In one aspect, this invention describes a pharmaceutical composition comprising Form a and a pharmaceutically acceptable adjuvant or carrier.

[0051] In one aspect, the invention describes a method of treating CFTR-mediated human disease involving the introduction of this person an effective amount of Form A.

[0052] In some embodiments, the implementation of this method requires the introduction of an additional therapeutic agent.

[0053] In some embodiments, the implementation of this disease is selected from cystic fibrosis, pancreatitis, sinusitis, hereditary emphysema, hereditary hemochromatosis, nedostatochnosty coagulation-fibrinolysis, such as protein deficiency, hereditary angionevroticheskogo edema Type 1 (disease Quincke), nedostatochnosty processing of lipids, such as hereditary hypercholesterolemia, chylomicronemia Type 1, abetalipoproteinemia, diseases, lysosomal accumulation (or deposition), such as a disease of cell inclusions (mucolipidoses)/pseudo-Hurler syndrome, mucopolysaccharidoses, disease Sandhoff/Tea-Sachs disease criglernajjar Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, dwarfism, Lara who's type, the myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanase CDG type 1, hereditary emphysema, congenital hyperthyroidism, imperfect osteogenesis, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurofisiologia DI, nephrogenic DI, hereditary neural disease Charcot-Marie-Toot, soudaniennes leukodystrophy (disease Pelizaeus-Merzbacher), neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, a disease Peak, several polyglutamine neurological disorders such as Huntington's disease (HD), spinocerebellar (related to the spinal cord and cerebellum ataxia type I, related to the spinal cord and medulla muscle atrophy, dentatorubral pallidoluysian and motonishi dystrophy, as well as spongiform encephalopathies, such as hereditary disease Creutzfeldt-Jakob disease, Fabry disease, syndrome Straussler-Sheinker, COPD, dry eye disease, pancreatic insufficiency, osteoporosis, osteopenia, syndrome Gorham, chloride kanaapali, congenital myotonia (forms Thomson and Becker), syndrome Bartter type III, dent disease, congenital pathologically enhanced reactions of fear, epilepsy, diseases of l is osanago accumulation, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as syndrome Addition, PCD without situs inversus and ciliary aplasia and disease Sjogren's syndrome.

[0054] In one embodiment, the invention describes a method of treating cystic fibrosis in man, introducing a specified person an effective amount of Form A.

[0055] In one aspect, the invention describes a pharmaceutical package or kit containing a Form and a pharmaceutically acceptable carrier.

[0056] In one aspect of this invention describes the crystallographic form N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, having a trigonal crystal the crystal system, space group R-3, and the following dimensions of the unit cell of the crystal: a=19,1670(4) Å (angstroms), b=19,1670(4) Å(angstroms), c=33,6572(12) Å (angstroms), α=90°, β=90° and γ=120°.

[0057] In one embodiment, this invention provides a crystal form of N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, having the dimensions of the unit cell of the crystal: a=19,1670(4) Å (angstroms), b=19,1670(4) Å (angstroms), c=33,6572(12) Å (angstroms).

[0058]Application preparation and introduction

[0059]Pharmaceutically priemel the statutory composition

[0060] In one aspect of the present invention are provided pharmaceutically acceptable compositions, where the compositions include a Form As described above, and optionally contain a pharmaceutically acceptable carrier, adjuvant or excipient. In some embodiments, the implementation of these compositions optionally additionally contain one or more additional pharmaceutical agents.

[0061] As described above, the pharmaceutically acceptable compositions of this invention optionally contain a pharmaceutically acceptable carrier, adjuvant or excipient, which, in this context, include any and all solvents, diluents, or other liquid filler, dispersant or suspendresume agents, surface-active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binding agents, lubricants, etc. that are appropriate for your desired dosage form. Remington''s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes the various media used in the preparation of pharmaceutically acceptable compositions, and known methods for their preparation. Except when any generally accepted the carrier medium is incompatible with the compounds of this invention, for example, by producing kako what about any undesirable biological effect or otherwise interacting harmful manner with any other component (all other components) of the pharmaceutically acceptable composition, it is considered that the carrier medium is in the framework of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as serum human albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, intrigejosa, kalogeropoulos, sodium chloride, zinc salts, colloidal silicon dioxide, magnificient, polyvinylpyrrolidone, polyacrylates, waxes, copolymers of polyethylene and polyoxypropylene, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients such as cocoa butter and waxes for suppositories; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as Atila is eat and tillaart; agar; bufferedio agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as in this composition could be other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and colouring agents that enhance the release agents, agents for coatings, sweeteners, flavours and flavouring agents, preservatives and antioxidants, in accordance with the opinion of the manufacturer.

[0062]Application of compounds and pharmaceutically acceptable compositions

[0063] in Another aspect, the invention provides a method of treating or attenuating the severity of the condition, illness or disorders, caused presumably by CFTR mutation. In some embodiments, the implementation of this invention provides a method of treating the condition, illness or disorders, caused presumably by the activity of CFTR, introducing a composition comprising form a of Compound 1, to a subject, preferably a mammal in need of it.

[0064] In some embodiments, the implementation of this invention provides a method of treating diseases associated with reduced CFTR function due to mutations in the gene encoding CFTR, or environmental factors (e.g., smoke). These diseases include cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male infertility caused by congenital bilateral absence of vas deferens (CBAVD), female infertility caused by congenital absence of uterus and vagina (CAUV), idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eyes, higher, allergic bronchopulmonary aspergillosis (ABPA), bone diseases (e.g. osteoporosis) and asthma.

[0065] In some embodiments, the implementation of this invention provides a method of treating diseases associated with normal CFTR function. These diseases include chronic obstructive pulmonary disease (COPD), chronic bronchitis, recurrent bronchitis, acute bronchitis, rhinosinusitis, higher, pancreatitis, including chronic pancreatitis, recurrent pancreatitis and acute pancreatitis, the pancreas failure, male infertility caused by congenital bilateral absence of vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, liver disease, nakeds the public emphysema, bile concrements, gastroesophageal reflux, gastrointestinal malignancy, inflammatory disease of the digestive tract, the higher, diabetes, arthritis, osteoporosis and osteopenia.

[0066] In some embodiments, the implementation of this invention provides a method of treating diseases associated with normal CFTR function, including hereditary hemochromatosis, deficiency of coagulation/fibrinolysis, such as protein deficiency, hereditary angioedema Type 1 (disease Quincke), failure of processing of lipids, such as hereditary hypercholesterolemia, chylomicronemia Type 1, abetalipoproteinemia, disease, lysosomal accumulation, such as disease cellular inclusions (mucolipidoses)/pseudo-Hurler syndrome, mucopolysaccharidosis, disease Sandhoff/Tea-Sachs disease criglernajjar Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, dwarfism saranovskogo type, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroidism, imperfect osteogenesis, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI, hereditary neural amyotrophy Charcot-Marie-Toot, adamopolou the leukodystrophy disease Pelizaeus-Merza the EPA), neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, a disease of the Peak, a few polyglutamine neurological disorders such as Huntington's disease (HD), spinocerebellar (related to the spinal cord and cerebellum ataxia type I, related to the spinal cord and medulla muscle atrophy, dentatorubral pallidoluysian and myotonias dystrophy, as well as spongiform encephalopathies, such as hereditary disease Creutzfeldt-Jakob disease (due to defect processing Pranovich proteins), Fabry disease, syndrome Straussler-Sheinker syndrome Gorham, chloride of kalapati, congenital myotonia (forms Thomson and Becker), the syndrome Bartter type III, dent disease, congenital pathologically enhanced reaction of fright epilepsy, the disease liposomal accumulation, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as syndrome Addition, PCD without situs inversus and ciliary aplasia, or sjögren's disease, providing a stage of introduction of a given mammal an effective amount of the composition containing the Form As described here.

[0067] According to an alternative preferred variant implementation of the invention provides a method L. the treatment of cystic fibrosis, providing a stage of introduction of a given mammal an effective amount of the composition containing the Form As described here.

[0068] According to this invention, an "effective amount" of the Form a or its pharmaceutically acceptable composition is that amount effective for treating or attenuating the severity of one or more of the diseases, disorders or conditions described above.

[0069] the Shape And or its pharmaceutically acceptable composition can be administered using any amount and any route of administration effective for treating or attenuating the severity of one or more of the diseases, disorders or conditions described above.

[0070] In some embodiments, the implementation of the Form a or its pharmaceutically acceptable composition suitable for treating or attenuating the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and nerespectarea epithelium. The presence of residual CFTR activity in the epithelial surface can be easily detected using methods known in this field, such as standard electrophysiological, biochemical or histochemical methods. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological method is in, measurements of Cl--concentrations of sweat or saliva or ex vivo biochemical or histochemical methods for monitoring the density of the cell surface. Using such methods, residual CFTR activity can be easily detected in patients heterozygous or homozygous for many different mutations, including patients homozygous or heterozygous in respect of the most common mutation, ΔF508.

[0071] In another embodiment, Form As described herein, or its pharmaceutically acceptable composition suitable for treating or attenuating the severity of cystic fibrosis in patients who have residual CFTR activity is induced or increased with the use of pharmacological methods or gene therapy. Such methods increase the number of CFTR present on the cell surface inducyruya still missing CFTR activity in a patient or increasing the existing level of residual CFTR activity in a patient.

[0072] In one embodiment, the Form As described herein, or its pharmaceutically acceptable composition suitable for treating or attenuating the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, such as class III mutations (impaired regulation or broken gate mechanism channels), is atalah class IV (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis Transmembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6:521-529, 2000). Other genotypes of patients that detect residual CFTR activity, include patients homozygous for one of these classes or heterozygous with any other class of mutations, including mutations of class I, class II mutations or mutations, who are deprived of the classification.

[0073] In one embodiment, the Form As described herein, or its pharmaceutically acceptable composition suitable for treating or attenuating the severity of cystic fibrosis in patients within certain clinical phenotypes, such as moderate - mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of the epithelium. Such phenotypes include patients exhibiting pancreatic insufficiency, or patients diagnosed as having idiopathic pancreatitis and congenital bilateral absence of the vas deferens or moderate (erased) from a lung disease.

[0074] the Exact required amount will vary from subject to subject, depending on the species, age and General condition of the subject, the severity of the infection, the particular agent, its method of administration, etc. of the Compounds of this invention are preferably prepared in a standard four the e doses for ease of administration and uniformity of dosage. The expression "standard dose" refers in this context to a physically discrete unit of the agent, be suitable for the treatment of the patient. However, it will be clear that taking the total daily dose of the compounds and compositions of this invention will be determined by the attending physician within a framework of sound medical judgment. The specific effective dose for any particular patient or organism will depend on various factors, including the subject of the treatment of the violation and the severity of the disorder; activity of the specific compound; the specific composition; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of this specific connection; the duration of the treatment; drugs used in combination or coincident with the specific compound, and similar factors well known in the medical fields. The term "patient" refers, in this context, an animal, preferably a mammal, and most preferably human.

[0075] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally (inside the cavity), intrawaginalno, intraperitoneally, m is local, (in the form of powders, ointments, drops or patch), buccal, for example in the form of oral or nasal spray, or the like, depending on the severity of the treatment to be infection. In some embodiments, the implementation of the compounds of this invention can be administered orally or parenterally at dose levels of approximately 0.01 mg/kg to about 50 mg/kg and preferably from about 0.5 mg/kg to about 25 mg/kg of body weight of the subject per day, once or several times a day, to obtain the desired therapeutic effect.

[0076] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in this field, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, olive, castor and sesame oils), glycerol, tetrahydrofuranyl alcohol, glycols and ethers sorbitan and fatty acids and mixtures thereof. Along the inert diluents, the oral compositions can also include adjuvants, such as moistening agents, emulsifying and suspendresume agents, sweeteners, flavoring and aromatic agents.

[0077] Injectable preparations, for example sterile injectable aqueous or oily suspensions may be prepared in accordance with the prior art using suitable dispersing or wetting agents and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently used as the solvent or suspendida environment. For this purpose, can be used easy non-volatile oil, which includes mono - or diglycerides. In addition, in the preparation of injection solutions use fatty acids such as oleic acid.

[0078] These injectable form can be sterilized, for example, by filtration through a retaining bacteria filter, or by incorporating sterilizing agents in the form of sterile solid compositions of substances, which may dissolve or dispergirujutsja in sterile water or other sterile injectable medium prior to use.

[0079] For prolonging the activity of a compound of this invention it is often desirable to slow the absorption of this compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. After that, the speed of absorption of this compound depends on its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral entered the connection is carried out by dissolving or suspendirovanie of this compound in an oil carrier. Injectable depot forms are prepared by education microencapsulated of matrices of this compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the relationship of connection to polymer and the nature of the particular polymer used can be adjusted the speed of the released compounds. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Injectable depot preparations are also the conclusion of this compound in liposomes or microemulsions that are compatible with body tissues.

[0080] Compositions for rectal or vaginal injection are preferably suppositories which can the be prepared by mixing the compounds of this invention with suitable non-irritating with excipients or carriers, such as cocoa butter, polyethylene glycol or wax for suppositories, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0081] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and/or a) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binding agents, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (C) humectants, such as glycerol, d) dezinfeciruyuhimi agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) delaying the dissolution agents, such as paraffin, f) moisturizing agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite compounds, preventing clay, and i) lubricating agents such as tal is, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also contain bufferedio agents.

[0082] Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight glycols and other Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as intersolubility shell and other shell, are well known in the field of pharmaceutical preparation. They may not necessarily contain make them opaque agents and can also be a composition that releases the active ingredient (the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally detainees. Examples of the filled compositions, which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as Vysokomolekulyarnye the s glycols, etc.

[0083] These active compounds may also be in microencapsulating form with one or more excipients as noted above. Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as intersolubility coverage, regulating the release coatings and other coatings well known in the field of pharmaceutical preparation. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, for example tabletiruemye lubricants and other tabletiruemye additives such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, these dosage forms may also contain bufferedio agents. They may not necessarily contain the silencers (substances that make the material opaque) and can also be of such composition that they release the active ingredient (the active ingredients) only, or predominantly, in certain part of the intestinal tract, optionally detainees. Examples of the filled compositions that can be used is the Vanir, include polymeric substances and waxes.

[0084] Dosage forms for local or percutaneous introduction of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalant (inhalation substances) or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic form, ear drops are also considered within the scope of this invention. In addition, the invention considers the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or distribution of this compound in a suitable medium. Amplifiers absorption can also be used to increase the passage of this compound through the skin. This speed can be adjusted either by the provision regulating the speed of the membrane or by dispersing the compound in a polymer matrix or gel.

[0085] it Should be clear that the Form As described herein, or its pharmaceutically acceptable composition can be used in combination therapies, i.e. a Form As described herein, or its pharmaceutically acceptable whom I composition may be administered concomitantly with one or more other desired therapeutic substances or medical procedures, or before, or after them. The particular combination of therapies (therapeutic substances or procedures) for use in combined mode will take into account compatibility of the desired therapeutic substances and/or procedures and the desired therapeutic action, which should be achieved. It should also be clear that these are used therapy can provide the desired effect for the same disorder (for example, the compound of this invention can be administered concomitantly with another agent used to treat the same disorder), or they can provide other effects (for example, to monitor any harmful side effects). In this context, additional therapeutic agents, which are usually introduced for the treatment or prevention of a specific disease or condition, known as "suitable for a subject to treatment of a disease or condition."

[0086] In one embodiment, the additional agent selected from a mucolytic agent, bronhodilatator, antibiotic, anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, or nutritional (food) agent.

[0087] In one embodiment, the additional agent is an antibiotic. Examples of antibiotics that apply here include tobramycin, including inhalation powder tobramycin (TIP), azithromycin, aztreonam, including aerotolerance form aztreonam, amikacin, including its liposomal form, ciprofloxacin, including its form suitable for administration by inhalation, levofloxacin, including its aerotolerance forms, and combinations of two antibiotics, for example fosfomicin and tobramycin.

[0088] In another embodiment, the additional agent is a mucolytic agent. Approximate morality applicable here include Pulmozyme®.

[0089] In another embodiment, the additional agent is a bronchodilator. Examples of bronchodilators include albuterol sulphate metaproterenol, acetate pirbuterol, salmeterol or sulfate tetraline.

[0090] In another embodiment, the additional agent is effective in recovering the liquid surface of the lung Airways. These agents improve the movement of salt in the cells and from the cells, allowing the mucus in the lung airway to be more hydrated and, therefore, more easily cleanable. Examples of such agents include hypertonic saline, denufosol-tetranitro ([[(3S,5R)-5-(4-amino-2-oxopyrimidine-1-yl)-3-hydroxyhexane-2-yl]methoxyhydroquinone][[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidine-1-yl)-3,4-digitool oxolan-2-yl]methoxyhydroquinone]occipitotemporal]phosphate), or bronchitol (inhalation form of mannitol).

[0091] In another embodiment, the additional agent is an anti-inflammatory agent, i.e. an agent that can reduce inflammation in the lungs. Relevant examples of such agents include ibuprofen, docosahexaenoyl acid (DHA), sildenafil, inhalation glutathione, pioglitazone, hydroxychloroquine or simvastatin.

[0092] In another embodiment, the additional agent reduces the activity of the blocker of epithelial sodium channels (ENaC) or directly blocking the channel, or indirectly by modulation of proteases, which lead to an increase in ENaC activity (e.g., serine protease, activates channels proteases). Examples of such agents include chemostat (inhibitor of trypsin-like proteases), QAU145, 552-02, GS-9411, INQ-4995, Aerolitic and amiloride. Additional agents that reduce the activity of the blocker of epithelial sodium channels (ENaC), can be found, for example, in PCT Publication No. WO2009/074575, the entire contents of which are incorporated here in full.

[0093] Among the other diseases described here, combinations of CFTR modulators, such as Form A, and agents that reduce the activity of ENaC are used to treat syndrome Liddle, inflammatory or allergic condition, which includes mu is ovicides, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung cancer, xerostomia and keratoconjunctivitis sicca, respiratory tract infections (acute and chronic; viral and bacterial) and lung cancer.

[0094] the Combinations of CFTR modulators, such as Form A, and agents that reduce the activity of ENaC are also applicable for the treatment of diseases mediated by blockade of the epithelial sodium channel, as well as diseases other than respiratory disease associated with aberrant regulation of fluid passing through the epithelium may include abnormal physiology protecting the surface of liquids on their surface, for example, in the case of xerostomia (dry mouth) and dry keratoconjunctivitis (dry eye). In addition, blockade of the epithelial sodium channel in the kidney could be used to stimulate diuresis and thereby to induce hypotensive effect.

[0095] Asthma involves both the innate (non-allergic)and external (caused by external factors (allergic) asthma, mild asthma, moderate asthma, severe asthma, asthma, asthma, stress, occupational asthma and asthma induced after bacterial infection. Treatment AST is s must also be understood as the treatment covering subjects such as age, less 4 or 5 years that detect the symptoms of wheezing and diagnosed or likely to be diagnosed as "babies with sibilant rale"set the category of patients the main medical concern and now often identified as asthmatics initial or early phase. (For convenience this specific asthmatic condition called "syndrome babies with a sibilant (strigosum) breathing"). Prophylactic efficacy in the treatment of asthma will be proved by reduced frequency or severity of symptomatic attacks, such as acute asthma or bronchoconstrictor attack, improved lung function and improved Hyper-reactive Airways. It can further be proved by the reduced need other symptomatic therapy, i.e. therapy for limiting or preventing or intended for limiting or preventing symptomatic attack when it appears, for example anti-inflammatory (e.g., corticosteroid) or banjoshua. Prophylactic benefit in the case of asthma may be particularly evident in subjects prone to “morning reduction” (maximum expiratory flow). "Morning decline" is recognized as asthmatic syndrome, common to the essential process is the asthmatics and characterized by asthma attack, for example, between approximately 4-6 hours before noon, i.e. in time, usually significantly distant from any previously entered therapy symptomatic asthma.

[0096] Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated with it, emphysema, and exazerbation (exacerbation) hyperresponsiveness of the Airways, after other drug therapy, in particular other therapy with inhalation drug. In some embodiments, the implementation of combinations of CFTR modulators, such as Form A, and agents that reduce the activity of ENaC applicable for the treatment of bronchitis of any type and origin, including, e.g., acute, arachidonic, catarrhal, lobar, or chronic purulent tuberculous bronchitis.

[0097] In another embodiment, the additional agent is a CFTR modulator other than the Form And compounds 1, i.e. the agent, which has the effect of modulating CFTR activity. Examples of such agents include, ataluren ("PTC124®"; 3-[5-(2-forfinal)-1,2,4-oxadiazol-3-yl]benzoic acid), sinapultide, lancemate, depeleted (recombinant ingredient elastase human neutrophils), cobiprostone (7-{(2R, 4aR, 5R, 7aR)-2-[(3S)-1,1-debtor-3-methylpentyl]-2-hydroxy-6-accountpaydayloan[b]Piran-5-yl}heptane acid) or (3-(6-(1-(2,2-debtorrent[d][1,3]dioxol-5-enciclopediadirepubblica)-3-methylpyridin-2-yl)benzoic acid.

[0098] In another embodiment, the additional agent is dietary (nutritional) agent. Examples of such agents include pancrelipase (substitute pancreatic enzyme), which includes Pancrease®, Pancrecarb®, Ultrase® or CREON®, Liposomes® (formerly Tracetek®), Aquadeks® or inhaled glutathione. In one embodiment, additional nutritional agent is pancrelipase.

[0099] In one embodiment, the additional agent is a CFTR modulator other than a compound of the present invention.

[00100] the Amount of additional therapeutic agent present in the compositions of this invention, is not more than the number that would normally introduced into the composition containing therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the compositions described herein will be in the range of about 50-100% of the amount normally present in a composition containing the agent as the sole therapeutically active agent.

[00101] A Shape described herein, or its pharmaceutically acceptable composition can also be incorporated into compositions for coating an implantable medical device, such as the prosthesis is, artificial valves, vascular grafts, stents and catheters. Thus, this invention, in another aspect, includes a composition for coating an implantable device containing the compound of this invention, broadly described above and in classes and subclasses here, and a carrier suitable for coating of specified implanted device. In another aspect, the invention includes an implantable device coated with a composition comprising a compound of this invention, broadly described above and in classes and subclasses here, and a carrier suitable for coating of specified implanted device. Suitable coatings and the General preparation of coated implantable devices are described in U.S. Patents numbers 6099562; 5886026 and 5304121. These coatings are typically biocompatible polymeric materials, such as polymer-hydrogel, polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. These coatings can be optionally coated with a suitable top coating Versiliana, polyethylene glycol, phospholipids or combinations thereof to impart properties of the regulated release of this composition.

[00102] Another aspect of this invention relates to the modulation of CFTR activity in a biological about the e or the patient (for example, in vitro or in vivo), which method provides for the introduction of this patient Forms As described herein, or contacting the specified biological sample to form a described herein, or its pharmaceutically acceptable composition. The term "biological sample" includes, in this context, without limitation, cell cultures or extracts; biopsy material obtained from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other biological fluids and extracts.

[00103] the Modulation of CFTR in a biological sample are applicable for a variety of purposes that are known to the skilled in this field specialist. Examples of such purposes include, but are not limited to, the study of CFTR in biological and pathological phenomena; and the comparative evaluation of new modulators of CFTR.

[00104] in Another embodiment is provided a method of modulating the activity of anion channel in vitro or in vivo, providing a stage of contacting the specified channel with the Form As described herein, or its pharmaceutically acceptable composition. In preferred embodiments, the implementation of this anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, the implementation of this anion channel is a chloride channel.

[00105] According alters the active variant implementation of the invention provides a method of increasing the number of functional CFTR in the cell membrane, providing a stage of contacting the specified cell with the Form As described herein, or its pharmaceutically acceptable composition.

[00106] in another preferred variant implementation of the CFTR activity is measured by measuring the transmembrane voltage potential. Methods for measuring the voltage potential in a biological sample can be any of the known in the field of methods, such as optical analysis of membrane potential or other electrophysiological methods.

[00107] the Optical analysis of the membrane potential uses potentialcustomers FRET sensors described by Gonzalez and Tsien (See. Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells." Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997); "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77)in combination with the equipment (devices) for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (Cm. Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439).

[00108] These potentialcustomers analyses based on the change of the resonant transfer of energy fluorescence (FRET) between the membrane-soluble, potentialcustomers dye, DiSBAC2(3), and fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts to the operation of the FRET donor. Changes in membrane potential (Vm) force negatively charged DiSBAC2(S) be distributed across plasma membrane, and the amount of energy transfer from CC2-DMPE is changed accordingly. Changes in the emission of fluorescence can be monitored using VIPR™ II, which is integrated liquid manipulator and a fluorescent detector, designed to conduct scans on the basis of cells in 96-384 microtiter plates.

[00109] In another aspect, the invention provides a kit for use in measuring the activity of CFTR or a fragment in a biological sample in vitro or in vivo, containing (i) a composition comprising Form a or any of the above options; and (ii) instructions for a) contacting the composition with this biological sample and b) measuring activity of the specified CFTR or fragment. In one embodiment, this kit further comprises instructions for a) contacting an additional composition with the biological breakdown; and (C) comparing the activity of the CFTR in the presence of the additional compound with the density of CFTR in the presence of described here Form A. In preferred embodiments, the implementation of this set is used to measure the density of CFTR.

[00110] For a more complete understanding described here the invention presents the following examples. It should be clear that these examples are for illustrative purposes only and should not be construed as limiting in any way the invention.

EXAMPLES

[00111]Methods and materials

[00112]X-ray powder diffraction (XRPD)

[00113] the Data of x-ray powder diffraction (XRPD) were recorded at room temperature using x-ray powder diffractometer Rigaku/MSC MiniFlex Desktop (Rigaku, The Woodlands, TX). X-rays were generated using a Cu tube operated at 30 kV and 15 mA with locking filter (filter-tube) β. The divergence slit was variable with gaps, scattering and reception at 4.2 degrees and a gap of 0.3 mm, respectively. Scan mode was fixed time (FT) width of stage of 0.02 degrees and a time account of 2.0 seconds. This powder x-ray diffractometer was calibrated using a reference standard: 75% Sodalite (Na3Al4Si4O12Cl) and 25% silicon (Rigaku, Cat# 2100/ALS). Used platform with six sample holders sample with 0-background (SH-LBSI511-RNDB). The powder sample was placed on the pressed area and leveled the slide.

[00114]FTIR (infrared spectroscopy with Fourier transform)

[00115] FTIR spectra were collected from the spectrophotometer Thermo Scientific Nicolet 6700 FT-IR, with compartment for taking about the harsh orbit (trajectory), diamond-shaped window, using the Program: Omnic, 7.4. The powder sample was placed directly on the diamond crystal and added pressure to the conformation of the surface of the sample relative to the surface of the diamond-shaped crystal. Collected a range of background and then collected a range of samples. Installation of the collection were the following:

Detector: DTGS KBr;

The beam splitter: KBr;

Source: IR;

Scanning range: 4000-400 cm-1;

Gain: 8,0;

Optical speed: 0,6329 cm/sec;

Aperture: 100;

Number of scans: 32; and

Resolution: 4 cm-1.

[00116]Example 1:Getting 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (7).

[00117] 2-chloro-5-(trifluoromethyl)aniline 2 (200 g, 1,023 mol), diethyl-2-(ethoxymethylene)malonate 3 (276 g, 1.3 mol) and toluene (100 ml) were combined under nitrogen atmosphere in a three-neck round bottom flask of 1 l equipped with a trap (condenser) Dean-stark. This solution was heated with stirring to 140°C. and this temperature was maintained for 4 hours, the Reaction mixture was cooled to 70°C and slowly added hexane (600 ml). The resulting suspension was stirred and allowed it to warm to room temperature. The solid is collected by filtration, washed with 10% ethyl acetate in hexane (2×400 ml) and then dried in vacuum to obtain a white solid (350 g, o is d 94%) as the desired product of the condensation of diethyl-2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate 4. 1H NMR (400 MHz, DMSO-d6) δ 11,28 (d, J=13,0 Hz, 1H), 8,63 (d, J=13,0 Hz, 1H), 8,10 (s, 1H), 7,80 (d, J=8,3 Hz, 1H), 7,50 (DD, J=1,5, and 8.4 Hz, 1H), 4,24 (kV, J=7,1 Hz, 2H), 4,17 (kV, J=7,1 Hz, 2H), 1.27mm (m, 6N).

[00118] the Receiving ethyl-8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate (5). 3-necked flask of 1 l was downloaded Dowtherm® (200 ml, 8 ml/g), which was degirolami at 200°C for 1 h the Solvent was heated to 260°C and loaded in portions over 10 minutes diethyl-2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate 4 (25 g, 0.07 mol). The resulting mixture was stirred at 260°C for 6.5 hours (h) and the resulting ethanol by-product was removed by distillation. This mixture was let to cool slowly to 80°C. was Slowly added hexane (150 ml) for 30 minutes (min) and then adding an additional 200 ml of hexane in a single portion. This suspension was stirred until reaching room temperature. The solid was filtered, washed with hexane (3×150 ml) and then dried in vacuo to obtain ethyl-8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 5 in the form of a yellowish-brown solid (13,9 g, yield 65%).1H NMR (400 MHz, DMSO-d6) δ 11,91 (s, 1H), 8,39 (s, 1H), of 8.06 (d, J=8,3 Hz, 1H), 7,81 (d, J=8,4 Hz, 1H), 4,24 (kV, J=7,1 Hz, 2H), 1,29 (t, J=7,1 Hz, 3H).

[00119] to Obtain ethyl-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylate (6). 3-necked flask of 5 l was downloaded ethyl-8-chloro-4-oxo-5-trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 5 (100 g, 0.3 mol), ethanol (1250 ml, 12.5 ml/g) and triethylamine (220 ml, 1.6 mol). Then the vessel was loaded 10 g of 10% Pd/C (50% wet) at 5°C. This reaction was strongly stirred in a hydrogen atmosphere for 20 h at 5°C, and then this reaction mixture was concentrated to a volume of approximately 150 ml This product, ethyl-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylate 6, in the form of a suspension with Pd/C, was taken directly to the next stage.

[00120] Getting 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (7). Ethyl-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylate 6 (58 g, 0.2 mol, the crude reaction slurry containing Pd/C) suspended in NaOH (814 ml of 5 M, 4.1 mol) in a flask of 1 l with a partial condenser hot irrigation and heated at 80°C for 18 hours, then further heated at 100°C for 5 h the reaction was filtered warm through Packed Celite to remove Pd/C and the Celite was washed 2 N. NaOH. The filtrate was acidified to approximately pH 1 with obtaining a thick, white precipitate. This precipitate was filtered, then washed with water and cold acetonitrile. Then, this solid was dried in vacuum to obtain 4-oxo-5-(trifluoromethyl)-1,4-dehydrocholic-3-carboxylic acid 7 as a white solid (48 g, yield 92%).1H NMR (400 MHz, DMSO-d6) δ 15,26 (s, 1H), 13,66 (s, 1H), 8,98 (s, 1H), 8,13 (DD, J=1,6 7,8 Hz, 1H), 8,06-to 7.99 (m, 2 is).

[00121]Example 2:Getting 4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)aniline

[00122] Obtaining 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (20).Into the flask containing the hydrochloride of 7-azabicyclo[2.2.1]heptane 9 (4.6 g, 34,43 mmol)obtained in nitrogen atmosphere, was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene 8 (6.0 g, 28,69 mmol and triethylamine (8.7 g, 12,00 ml, 86,07 mmol) in acetonitrile (50 ml). The reaction flask was heated at 80°C in nitrogen atmosphere for 16 hours. The reaction mixture was allowed to cool and then distributed between water and dichloromethane. The organic layer washed with 1 M HCl, dried over Na2SO4, filtered and concentrated to dryness. Purification by chromatography on silica gel (0-10% ethyl acetate in hexane) gave 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane 10 (7.2 g, yield 88%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8,03 (d, J=9.1 Hz, 1H), 7,31 (d, J=2.4 Hz, 1H), 7,25 (DD, J=2,6, and 9.1 Hz, 1H), 4,59 (s, 2H), 1,69-to 1.67 (m, 4H), 1,50 (d, J=7,0 Hz, 4H).

[00123] Obtain 4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)aniline (11). In the flask, downloaded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane 10 (7,07 g, 24,70 mmol) and 10% Pd/C (0.71 g, only 6.64 mmol), created a vacuum and then the flask was purged with nitrogen. Added ethanol (22 ml) and the reaction flask was connected to a balloon with hydrogen. After strong is th stirring for 12 hours, this reaction mixture was purged with nitrogen and Pd/C was removed by filtration. The filtrate was concentrated to a dark oil under reduced pressure and the residue was purified by chromatography on silica gel (0-15% ethyl acetate in hexane) to give 4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)aniline 11 in the form of a purple solid (USD 5.76 g, yield 91%).1H NMR (400 MHz, DMSO-d6) δ to 6.95 (DD, J=2,3 8,8 Hz, 1H), 6,79 (d, J=2.6 Hz, 1H), 6,72 ( d, J=8,8 Hz, 1H), 4,89 (s, 1H), 4.09 to (s, 2H), 1,61-to 1.59 (m, 4H) and 1.35 (d, J=6,8 Hz, 4H).

[00124]Example 3:Obtaining N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (Compound 1).

[00125] To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid 7 (9,1 g, 35,39 mmol) and 4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)aniline 11 (9.2 grams, 35,74 mmol) in 2-methyltetrahydrofuran (91,00 ml) was added cyclic anhydride propylphosphonic acid (50% solution in ethyl acetate, 52,68 ml, 88,48 mmol) and pyridine (5.6 g, 5,73 ml, 70,78 mmol) at room temperature. The reaction flask was heated at 65°C for 10 h under nitrogen atmosphere. Then after cooling to room temperature the reaction mixture was diluted with ethyl acetate and extinguished a saturated solution of Na2CO3(50 ml). The layers were separated and the aqueous layer was extracted twice additional ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4and conc is believed to yellowish-brown solid. This crude solid product is suspended in a mixture of ethyl acetate/diethyl ether (2:1), collected by filtration under vacuum and washed twice additionally, the mixture of ethyl acetate/diethyl ether (2:1) to give the product as a pale yellow crystalline powder. This powder was dissolved in warm ethyl acetate and absorbed on Celite. Purification by chromatography on silica gel (0-50% ethyl acetate in dichloromethane) gave N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (Compound 1) as a white crystalline solid (Form A) (13.5 g, yield 76%). LC/MS m/z 496,0 [M+H]+the retention time of 1.48 min (RP-C18,10-99% CH3CN/0.05% of TFU for 3 min).1H NMR (400 MHz, DMSO-d6) δ 13,08 (s, 1H), 12,16 (s, 1H), 8,88 (s, 1H), 8,04 (DD, J=2.1 a, 7,4 Hz, 1H), 7.95 is-7,88 (m, 3H), 7,22 (DD, 2,5, an 8.9 Hz, 1H), 7,16 (d, J=2.5 Hz, 1H), 4,33 (s, 2H), 1,67 (d, J=6,9 Hz, 4H), of 1.44 (d, J=6,9 Hz, 4H).

[00126] Powder diffraction pattern of Form a is shown in Figure 1.

[00127] table 1 below provides a representative XRPD-peaks Form A.

Table 1
XRPD-peaks Form And
2-theta (degrees)Intensity (%)
of 7.90100,0
928 10,8
11,9012,8
14,3835,2
15,0812,6
15,8034,1
16,9625,2
17,6613,8
19,2839,4
grade of 20.0620,2
21,3614,5
21,80a 94.2
23,4030,0
23,8092,0
25,648,9
26,826,4
29, 36 the8,1
29,7218,1
30,1414,2
31,209,9

[00128] a Conformational image of the Form And on the basis of x-ray diffraction analysis of individual p is th crystal is shown in Figure 2. These diffraction were obtained on a diffractometer Broker Apex II, equipped with a sealed tube source CuK-alpha and detector Apex II CCD. The structure was determined and refined using SHELX (Sheldrick, G.M., Acta Cryst. A64, pp.112-122 (2008)). On the basis of intensities, statistics and symmetry of this structure was determined and refined in the trigonal system crystal and space group R-3. Form And has the following dimensions of the unit cell of the crystal: a=19,1670(4) Å (angstroms), b=19,1670(4) Å (angstroms), c=33,6572(12) Å (angstroms), α=90°, β=90° and γ=120°.

[00129] the FTIR spectrum of Form a is shown in Figure 3.

[00130] table 2 below provides a representative FTIR peaks Form A.

Table 2
FTIR peaks Form And
Position (cm-1)Intensity
407,446,07
436,772,55
471,561,17
497,863,61
505,760,34
532,961,14
567,854,31
590,755,23
614,464,01
649,750,74
661,049,82
686,851,43
726,153,80
751,435,60
798,148,21
808,848,47
824,842,25
875,552,89
898,671,77
918,768,93
977,742,31
1008,164,09
1047,335.70 barm
1072,553,76
1091,243,79
1113,428,46
1131,430,00
1153,034,61
1168,340,13
1199,374,26
1221,848,07
1253,147,84
1277,636,67
1291,748,07
1310,855,99
1329,163,21
1352,842,30
1433,2ø 42.45
1463,063,68
1526,035,86
1574,060,60
1607,560,30
1662,655,12
1740,986,74
2870,081,63
2947,775,12
2963,875,30
3092,784,58

[00131]Assays for detecting and measuring the properties of the potentiation ΔF508-CFTR compounds

[00132]Optical measurements of membrane potential for the analysis of modulation of ΔF508-CFTR connection properties

[00133] This analysis uses fluorescent potentialcustomers dyes to measure changes in membrane potential using fluorescent tablet reader (e.g., FLIPR III, Molecular Devices, Inc.) in the form of readings readings increase functional ΔF508-CFTR in cells NIH 3T3. The driving force for this reaction is the creation of a gradient of chloride ions together with the activation of channels through a single stage of adding liquid, after these cells were pretreated with compounds and then loaded potentialcustomers dye.

[00134]Identification potentiating connections

[00135] To identify potentiators ΔF508-CFTR was developed format HTS-analysis of double add. This HTS analysis uses fluorescent potentialcustomers dyes to measure changes in membrane potential on FLBPR DI as a measure for the increase in the gate mechanism (conductivity) ΔF508 CFTR in the temperature-corrected ΔF508 CFTR cells NIH 3T3. The driving force for this reaction is Gras is ient Cl -ions together with the activation of channels by Forskolin in a single stage addition of liquid using fluorescent tablet reader, such as FLIPR III, after these cells were pre-treated potentiators connections and then loaded redistributive dye.

[00136]Solutions

The solution bath No. 1: (in mm) NaCl 160, KCl 4.5 Is, CaCl22, MgCl21, HEPES 10, pH of 7.4 with NaOH.

Does not contain chloride baths: chloride salt bath No. 1 replaced gluconate salts.

[00137]Cell culture

[00138] the optical measurement of membrane potential used murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR. These cells were maintained at 37°C in 5% CO2and 90% humidity in a modified method of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 X NEAA, β-mercaptoethanol, 1 X pen/strap (penicillin/streptomycin) and 25 mm HEPES in the culture flasks 175 cm2. For all optical analysis, these cells were sown at approximately 20,000 cells per well in 384-well coated with Matrigel tablets and were cultured for 2 hours at 37°C before cultivation at 27°C for 24 hours for analysis of potentiator. For corrective analyses these cells were cultured at 27°C or 37°C with connections or no connections within 16-24 hours.

p> [00139] Electrophysiological analyses to analyze modulating ΔF508-CFTR connection properties.

[00140] the Analysis chamber Ussing

[00141] the Experiments with the Ussing chamber were performed on polarized epithelial respiratory cells expressing ΔF508-CFTR to further characterize the modulators ΔF508-CFTR identified in the optical assays. The epithelium of the respiratory tract of non-CF (without cystic fibrosis) and CF (cystic fibrosis) was isolated from bronchial tissue, cultured, as described previously (Galietta, L.J.V., Lantero, S., Gazzolo, A., Sacco, A., Romano, L., Rossi, G.A., & Zegarra-Moran, O. (1998) In Vitro Cell. Dev. Biol. 34, 478-481), and were sown on filters Costar® Snapwell™, which previously covered NIH3T3-conditioned medium. Four days later, this apical medium was removed and the cells were grown at the interface of the air-liquid for >14 days before use. This led to a monolayer of fully differentiated cylindrical prismatic cells, which were ciliated, i.e. there were signs characteristic of the epithelium of the respiratory tract. Non-CF HBE was isolated from non-smokers who had no known lung disease. CF-HBE were isolated from patients homozygous in respect of ΔF508-CFTR.

[00142] HBE grown on inserts cell culture Costar® Snapwell™, was placed in the Ussing chamber (Physiologic Instruments, Inc., San Diego, CA) and transepithelial resistance is the short circuit current in the presence of basolateral - apical CF--gradient (Isc) was measured using a fixation system potentials (Department of Bioengineering, University of Iowa, IA). Briefly, HBE felt when registering conditions of fixed potential (Vhold=0 mV) at 37°C. Basolateral solution contained (in mm) 145 NaCl, 0,83 K2HPO4, 3,3 KH2PO4that 1.2 MgCl2, 1,2 CaCl2, 10 glucose, 10 HEPES (pH brought up to 7.35 using NaOH) and the apical solution contained (in mm) 145 Na-gluconate, 1,2 MgCl2, 1,2 CaCl2, 10 glucose, 10 HEPES (pH brought up to 7.35 using NaOH).

[00143]Identification of compounds-potentiation

[00144] a Typical Protocol used basolateral - apical membrane gradient of Cl-the gradient. To apply this gradient used conventional koleobrazovaniya on basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 using NaOH) to give a large gradient of concentration of Cl-across the epithelium. Forskolin (10 μm) and all test compounds were added to the apical side of these inserts cell cultures. The estimated efficiency of potentiation ΔF508-CFTR was compared with the effectiveness of the known potentiator, genistein (inhibitor proteincontaining).

[00145]Check the patch-clamav

[00146] the Total current Cl-in the Δ508 cells-NIH3T3 were subjected to monitoring by using the registration of the perforated-patch configuration, described previously (Rae, J., Cooper, K., Gates, P., & Watsky, M. (1991) J. Neurosci. Methods 37, 15-26). Registration of potential fixation was performed at 22°C using the amp patch-clamp Axopatch 200B (Axon Instruments Inc., Foster City, CA). The pipette solution contained (in mm) 150 N-methyl-D-glucamine (NMDG)-Cl, 2MgCl2, 2CaCl210 EGTA, 10 HEPES, and 240 μg/ml amphotericin-B (pH brought up to 7.35 using HCl). Extracellular medium contained (in mm) 150 NMDG-Cl, 2MgCl2, 2CaCl2, 10 HEPES (pH brought up to 7.35 using HCl). Generating pulses, the data acquisition and analysis were performed using a PC equipped with a surface section Digidata 1320 A/D together with Clampex 8 (Axon Instruments Inc.). To activate ΔF508-CFTR to the bath was added 10 μm Forskolin and 20 μm genistein and the response of the current - potential were monitored every 30 seconds.

[00147]Identification of compounds-potentiation

[00148] the Ability of potentiation ΔF508-CFTR to increase the macroscopic current ΔF508-CFTR Cl-(IΔF508) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using the registration perforated-patches (foci) means. Potentiator identified from the optical analysis, induced a dose-dependent increase of IΔF508with power and efficiency, with similar power and efficiency in the optical assays. In all tested cells facing potential before and during application is intiator was equal to approximately -30 mV, which is equal to the calculated ECl(-28 mV).

[00149]Cell culture

[00150] For registrations of whole cells used murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR. These cells were maintained at 37°C in 5% CO2and 90% humidity in a modified method of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 X NEAA, β-mercaptoethanol, 1 X pen/strap (penicillin/streptomycin) and 25 mm HEPES in the culture flasks 175 cm2. For registration of whole cells 2500-5000 cells were sown on covered with poly-L-lysine glass cover glass and were cultured for 24-48 hours at 27°C before use to test the activity of potentiation; and incubated with corrective connection or without corrective compounds at 37°C for measuring the activity of the correctors.

[00151] the registration of individual channels

[00152] the Activity of the gate mechanism of wt-CFTR and adjustable temperature ΔF508-CFTR expressed in NIH3T3 cells, was observed using the registration cut-out patches (foci) turned inside out membrane as described previously (Dalemans, W., Barbry, P., Champigny, G., Jallat, S., Dott, K., Dreyer, D., Crystal, R.G., Pavirani, A., Lecocq, J-P., Lazdunski, M. (1991) Nature 354, 526-528) using amp patch-clamp Axopatch 200B (Axon Instruments Inc.). The pipette contained (in mm): 150 NMDG, 150 aspartic acid, 5CaCl2, 2MgClsub> 2and 10 HEPES (pH brought up to 7.35 Tris-base). Bath contained (in mm): 150 NMDG-Cl, 2MgCl25 EGTA, 10 TES and 14 Tris-base (pH brought up to 7.35 using HCl). After cutting, both wt-CFTR and ΔF508-CFTR was activated by adding 1 mm Mg-ATP, 75 nm catalytic subunit of camp-dependent protein kinase (PKA; Promega Corp. Madison, WI) and 10 mm NaF to inhibit proteinopathies, which prevented the decrease in current. The pipette potential was maintained at 80 mV. Channel activity was analyzed from membrane patches (foci), containing < 2 active channels. The maximum number of simultaneous opening was determined by the number of active channels during the course of the experiment. To determine the amplitude of single-channel current these data, recorded from 120-second activity of ΔF508-CFTR, were filtered offline at 100 Hz and then used to build the histograms of the amplitudes of all points that are customized using multihousing functions using Bio-Patch Analysis (Bio-Logic Comp. France). General microscopic current and the open probability (Po) was determined from 120 seconds of active channels. This Powas determined using the Bio-Patch or relationship of P0=I/i(N), where I=average current, i=the current amplitude of single-channel and N=number of active channels in the patch (ocache).

[00153]Cell culture

[00154] the La registrations cut out membrane patch-clamav used mouse fibroblast NIH3T3, stably expressing ΔF508-CFTR. These cells were maintained at 37°C in 5% CO2and 90% humidity in a modified method of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 X NEAA, β-mercaptoethanol, 1 X pen/strap (penicillin/streptomycin) and 25 mm HEPES in the culture flasks 175 cm2. To register individual channels 2500-5000 cells were sown on covered with poly-L-lysine glass cover glass and were cultured for 24-48 hours at 27°C before use.

[00155] the Shape And the Connection 1 is applicable as a modulator of transporters ATP-binding cassette. It was measured that EC50(μm) of Form a of Compound 1 is less than 2.0 μm. It was estimated that the efficiency of the Forms And the Connection 1 is equal to 100%-25%. It should be noted that 100% efficiency is the maximum response obtained with 4-methyl-2-(5-phenyl-1H-pyrazole-3-yl)phenol.

1. N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide characterized as Form And, where this Form And is characterized by a peak at approximately 7.9 degrees, a peak at approximately 11.9 degrees, a peak at about 14.4 degrees and a peak at about 15.8 degrees in a powder x-ray.

2. Form a according to claim 1, where this Form And is characterized by the following peaks in the powder x-ray is: approximately 7.9, approximately 9.3, approximately 11,9, approximately 14.4V, approximately 15,1, approximately 15,8, approximately 17,0, approximately 17,7, approximately 19,3, approximately 20,1, approximately 21.4, approximately 21,8, approximately 23,4, approximately 23,8, approximately 25,6, approximately 26,8, approximately 29,4, approximately 29,7, approximately 30,1, and approximately 31.2 degrees.

3. Form a according to claim 1, where this Form And is characterized by the diffraction pattern, shown in Figure 1.

4. Pharmaceutical composition for treating or attenuating the severity of CFTR-mediated disease that contains the Form And according to any one of claims 1 to 3 and a pharmaceutically acceptable adjuvant or carrier.

5. Application Forms And in accordance with paragraph 1 to obtain drugs to cure or ameliorate disease severity of a patient, where the disease is selected from cystic fibrosis, smoke-induced COPD, pancreatitis, pancreatic insufficiency, hereditary emphysema, chronic obstructive pulmonary disease (COPD) and dry eye disease.

6. The use according to claim 5, where the specified disease is cystic fibrosis.

7. A kit for use in measuring the activity of CFTR or a fragment in a biological sample in vitro or in vivo, comprising:
(i) a composition containing a Form And in any one of claims 1-3;
(ii) instructions for:
a) Comtat the tests of this composition with this biological breakdown;
b) measuring the activity of the specified CFTR or fragment.

8. The kit according to claim 7, further containing instructions for:
a) contacting an additional compound with the biological breakdown;
b) measuring the activity of the specified CFTR or fragment in the presence of the specified additional connections, and
c) comparing the activity of CFTR or fragment in the presence of the additional compound with the activity of CFTR or fragment in the presence of the Forms And according to any one of claims 1 to 3.

9. The set of claim 8, where the phase comparison activity specified CFTR or fragment provides a measure of the density specified CFTR or fragment.

10. A method of modulating CFTR activity in a biological sample to which the stages of contact specified CFTR with the Form And according to any one of claims 1 to 3.

11. Form a according to claim 1, having the following dimensions of the unit cell of the crystal:
a=19,2 Å (angstroms);
b=19,2 Å (angstroms) and
C=33,7 Å (angstroms).

12. Crystalline form of N-(4-(7-azabicyclo[2.2.1]heptane-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, having a trigonal crystal system, space group R-3 and the following dimensions of the unit cell:
a=19,2 Å (angstroms);
b=19,2 Å (angstroms);
C=33,7 Å (angstroms);
α=90°;
β=90° and
γ=120°.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to piperidine compounds of formula and their pharmaceutically acceptable salts, based on them pharmaceutical composition, treatment method with therein application and therein application for treatment of gastrointestinal diseases. In formula (I) m represents integer number 1 or 2; n represents integer number from 0 to 2, A is selected from phenyl group and benzimidazole group, where phenyl group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, aminogroup and halogen, and benzimidazole group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, aminogroup, halogen and oxogroup; X represents hydroxyl or OCONR1R2, where R1 and R2 are independently selected from hydrogen and C1-C6 linear or branched alkyl group, or R1 and R2 form 5-7-membered heterocyclic ring or 3,5-dimethylpiperidine ring, together with nitrogen atom, to which they are attached, and B is selected from phenyl group, phenoxygroup, thienyl group and naphthyl group, where phenyl group, phenoxygroup, thienyl group or naphthyl group is substituted with one or more groups, independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 linear or branched alkyl group and C1-C6 linear or branched alkoxygroup.

EFFECT: obtaining novel compounds.

25 cl, 3 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound, which contains pyridine ring, represented by formula (1) , where R0 represents C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxy-C1-6alkyl group, 1,3-dioxan-2-yl-C1-6alkyl group or group CR01C(=NOR02) (where each of R01 and R02 independently represents C1-6alkyl group), R1 represents C1-2 alkoxycarbonyl group, acetyl group or benzoyl group, which can be substituted with nitrogroup, X represents halogen atom, and n represents quantity of X substituents and equals integer number from 0 to 3, and when n equals 2 or more, X substituents can be similar or different from each other, which can be synthesised in industrially profitable way and used as intermediate compound for obtaining tetrazolyloxime derivatives which demonstrate fungicidal activity.

EFFECT: industrially profitable methods of obtaining tetrazolyloxime derivatives are described.

10 cl, 3 tbl, 13 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining activated ester of formula (I): where R stands for C1-C6 alkyl, linear or branched, 6-membered heteroaryl with one nitrogen atom as heteroatom; Alk stands for C1-C6 alkyl, linear or branched, consisting in interaction of dicyclohexylamine salt P1 and disuccinimidylcarbonate (DSC) in solvent which represents ketone, in which salt of dicyclohexylamine and N-hydroxycuccinimide P2 precipitates.

EFFECT: method makes it possible to obtain target product with high output and good degree of purity.

10 cl, 1 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: agriculture.

SUBSTANCE: agent for control of plant diseases comprises: at least one compound chosen from tetrazolyl oxime derivatives represented by the formula , and their salts: in the formula (I) X is C1-6-alkyl group, C1-6-alkoxy group, halogen atom, nitro group, cyano group, C6-10-aryl group or C1-6-alkyl-sulfonyl group; n is an integer from 0 to 5; Y is C1-6 alkyl group; Z is a hydrogen atom, an amino group or a group represented by the formula NHC(-O)-Q; Q is a hydrogen atom, C1-8-alkyl group, C1-6-haloalkyl group, C3-6-cycloalkyl group, C1-8-alkoxy group, C3-6-cycloalkoxy group, C7-20-aralkoxy group, C1-4-alkylthio-C1-8 alkyl group, C1-4-alkoxy-C1-2-alkyl group, C1-4-acylamino-C1-6-alkyl group, C1-4-acylamino-C1-6-alkoxy group, C1-8-alkylamino group, C2-6-alkenyl group, C7-20-aralkyl group or C6-10-aryl group; R is an halogen atom; m is an integer from 0 to 3; and at least one compound selected from the group consisting of triflumizole, hydroxyisoxazole, acetamiprid and their salts.

EFFECT: invention enables to improve the efficiency of disease control.

2 tbl

FIELD: biotechnologies.

SUBSTANCE: in general formula (I), R1 and R2 that have been taken jointly are a group of formula (II), R3 represents atom of hydrogen or F and R4 represents F; R1, R2, R3 and R4 are connected to 17, 16, 6 and 9 carbon atoms of steroid structure in position α or β; R represents (III) or (IV), and the rest values of radicals are given in the description.

EFFECT: improving use efficiency of compositions for curing of eye diseases, such as diabetic macular edema, diabetic retinopathy, macular degeneration, age-related macular degeneration and other macular and retina diseases.

11 cl, 4 dwg, 5 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular opthalmology, and may be used for treating the patients with a "dry" form of age-related macular degeneration. That is combined with using lutein-containing antioxidants and carotenoids for one year every 2-3 months. Fenofibrate (Tricor 145) is additionally used for a period of time long enough to normalise a lipid profile and to maintain the above values at the attained level. Vitrum vision forte and nutrof total are used as the above lutein-containing antioxidants and carotenoids.

EFFECT: invention provides arresting the progression of the "dry" form of age-related macular degeneration.

2 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, specifically to preparations inhibiting angiogenesis, and may be used in medicine. The method involves administering an EGFL8 antagonist to a subject suffering a pathological condition associated with angiogenesis.

EFFECT: invention enables inhibiting the vascular growth in pathological, eg tumour tissues.

14 cl, 4 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to ophthalmology, endocrinology and restorative medicine, and may be used to treat the patients with non-proliferative diabetic retinopathy. For this purpose, with underlying background individual antidiabetic therapy, endonasal electrophoresis with 0.1% Semax in a daily dose of 700 mcg is applied in a patient lying on his/her back. A bifurcated positive electrode is coated with cotton swabs each of which is moistened with 7 drops of Semax. These electrodes are introduced into the middle nasal passages. At the same time, a cathode spacer of the second negative electrode 8×10 cm is moistened with 2% aminophylline and placed in the back of the neck. The current intensity is 1.2 mA. The exposure length is 20-22 minutes. The therapeutic course is 8-10 sessions, daily or every second day.

EFFECT: provided therapeutic effect in the early stages of the disease, including in the patients with severe comorbidities, as well as slow progression of the retinal pathological process, and stabilised long-term result up to 6 months.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, in particular to neuroophthalmology, and may be used for treating the visual pathway disorders in the patients with multiple sclerosis. For this purpose, the preparation cortexin is introduced retrobulbar or parabulbar. Then 30 minutes after the introduction of cortexin, upper cervical and stellate ganglia of the sympathetic nervous system are percutaneously exposed to a rotating electric pulse field. This field is generated in a space between the left and right ganglia using two multiple electrodes. The electrodes consist of a number of partial galvanic isolated conductive elements functioning as cathodes and two anodes which are placed in a projection of the ganglia. While forming the electric current pulses, the partial elements of the multiple electrodes are switched; the exposure is paused. Thereafter, a zone of ganglia activity block is switched. It is followed by electrical stimulation of the visual pathway via an electrode applied on the eyelids. For this purpose, the rotating electric pulse field is generated in the space between this electrode which is as the anode, and the partial elements of the multiple electrodes.

EFFECT: method provides relieved demyeliniation, neurodegenerative processes within the visual pathway, improved visual function, including visual acuity and functional characteristics.

5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely neurology, otorhinolaryngology and orthopaedics, and may be used for treating cochleovestibular disorders in the patients with cervical osteochondrosis. That is ensured by daily injections of the drugs improving cerebral circulation; those are followed by three-stage exposure of head-to-lower extremities centrifugal force on the patient. At the first stage, the patient is exposed to one session a day of centrifugal force at 28 rpm for 5 minutes. The second stage involves 3 days of the exposure to centrifugal force at 30 rpm for 8 minutes, one session a day. The third stage involves 4 days of the daily exposure to centrifugal force at 30 rpm for 10 minutes.

EFFECT: implementing the method provides the higher therapeutic effect ensured by the traction exposure on the cervical spine, passive training of vestibular analyser stability, improved vertebrobasilar circulation ensured by vertebral artery spasmolysis under craniocaudal hypergravitation.

1 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to ophthalmology and can be used for treatment of glaucoma or higher intraocular pressure (IOP) in patient. For this purpose efficient amount of composition, containing preparation inhibiting PAI-1 binding with vitronectin, is introduced to patient. Also claimed is method of treating PAI-1-associated eye disease.

EFFECT: group of inventions ensures treatment of glaucoma and IOP due to reduction of separation of trabecular meshwork tissue and reduction of increased resistance to intraocular fluid outflow, and also due to increase of TM tissue cellularity and preservation of phagocytosis.

14 cl, 8 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology and physiotherapy, and may be used for treating vascular and dystrophic retinal and visual nerve diseases. That is ensured by the intravenous drop-by-drop infusion of the 2/3 amount of the medical solution made of cytoflavin 10 ml and 0.9% sodium chloride 200 ml. It is followed by 15-minite transverse halvanisation in the Potok-1 apparatus at current force making 0.5 mA. For this purpose 2 oval anode electrodes through a pad impregnated in distilled water are placed on skin of closed eyelids of both eyes and connected by a Y-wire with the anode of the apparatus. The third cathode electrode is placed transversally in relation to the two first anode electrodes on the area of upper cervical spines S2-S4 and connected with the cathode of the apparatus. The therapeutic course makes 10 daily procedures.

EFFECT: method provides high clinical effectiveness ensured by high functional effectiveness of cytoflavin electric accumulation in eye tissue with improving visual acuity by 0,15-0,3, prolonged action of the ensured therapeutic effect up to 5-6 months, eliminated risk of damaging an external eyeball capsule.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to suspension for visualisation of transparent tissue of eye, which contains finely dispersed particles of biodegradable macromolecular compound and salt, selected from salt of divalent metal in amount 0.1-1 wt/vol.% or salts of trivalent metal in amount 0.01-1 wt/vol.%. Said suspension is intended for pouring into eye to come in contact with transparent eye tissues with the purpose to improve their distinguishability. Invention also relates to ophthalmologic preparation which contains hard particles of biodegradable macromolecular compound and water medium, which contains said salts of divalent or trivalent metal, solid and water media being placed separately and without allowing contact with each other. Invention also relates to methods of obtaining suspension for eye visualisation, which include obtaining solid composition, containing finely dispersed particles of biodegradable macromolecular compound or finely dispersed particles of biodegradable macromolecular compound and 0.1-1 wt/vol.% of salt of divalent or 0.01-1 wt/vol.% of salt of trivalent metal, and suspending said solid composition in water solution.

EFFECT: invention ensures obtaining suspension for visualisation of transparent eye tissue, which can be applied as convenient and safe means for improvement of distinguishability of transparent eye tissues when performing surgical operation on them.

21 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology and is intended for treatment of optic nerve atrophy of vascular genesis. For this purpose pterygopalatine (PP) and submustoidal (SM) blockades are performed to patient with application of medicinal mixture, 7-9 blockades per course with time interval 22-24 hours. After that, discrete plasmapheresis in amount 3-5 procedures with time interval 48-72 hours is performed, with volume of exfusion for a procedure constituting 20-25% of circulating blood volume. Then extracorporal pharmacotherapy is carried out. Activation of cell mass, obtained in carrying out plasmapheresis, is performed with gliatilin in dose 500-1000 mg, with further reinfusion of activated cell mass intravenously, by drip infusion. To perform PP medicinal mixture, containing lidocaine 50-100 mg, gliatilin 250-500 mg, lidase 16-32 U, is used. To perform SM medicinal mixture, containing lidocaine 50-100 mg, cortexin 5-10 mg, lidase 16-32 U, is used.

EFFECT: invention ensures efficient treatment of disease with reduction of labour-consumption and simplification of method.

2 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gastroenterology, and may be used for treating pain syndrome accompanying pancreatitis in oesophagogastroduodenoscopy. That is ensured by an endoscopic gastric and duodenal pH-metry; and if the derived pH in a duodenal cap and outside is 5 or less, 4% sodium bicarbonate 20-60 ml is introduced intraduodenally, and if the pH value is more than 5, 0.25% novocaine 20-60 ml is introduced.

EFFECT: method enables reducing pain syndrome in 95% patients suffering pancreatitis.

2 ex, 3 dwg, 2 tbl

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