Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid, and use thereof and methods for preparing

FIELD: medicine.

SUBSTANCE: invention refers to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid (formula I), pharmaceutical compositions and dosage forms containing these crystalline forms, as well as to methods for preparing such crystalline forms and methods for using them for treating, preventing a disease or a disorder associated with premature terminating codon. There are prepared new crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid which are non-absorbent and which can find application in medicine for treating or preventing such diseases or disorders as type III mucopolysaccharidosis, hemophilia A, hemophilia B, neurofibromatosis 1, neurofibromatosis 2, Parkinson's disease, cystic fibrosis, macular degeneration, cephalooculocutaneous telangiectasis, retinitis pigmentosa, tuberous sclerosis, Duchenne muscular dystrophy and Marfan's syndrome, cancer.

EFFECT: higher effectiveness of using the compounds and a method of treating.

46 cl, 11 dwg, 9 tbl

 

This application claims priority from provisional patent application U.S. No. 60/847326, filed September 25, 2006, which is fully incorporated into the present description by reference.

1. The technical field

The present invention relates to crystalline forms of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, pharmaceutical dosage forms and compositions containing crystalline forms, methods of producing crystalline forms and methods of use thereof for the treatment, prevention and management of diseases, facilitated by modulation of premature termination of translation or nonsense-mediated mRNA decay.

2. Prior art

1,2,4-oxadiazole compounds used for the treatment, prevention or management of diseases, facilitated by modulation of premature termination of translation or nonsense-mediated mRNA decay, described in U.S. patent No. 6992096 B2, issued January 31, 2006, which is fully incorporated into the present description by reference. One such compound is 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

In the pharmaceutical field it is known that solid forms, such as salts, crystalline forms, for example, polymorphic forms of compounds that affect, for example, the solubility, ustoichivosti, fluidity, brittle and compressibility compounds, as well as the safety and efficacy of medicinal products based on the compound (see, for example, Knapman, K. Modern Drug Discoveries, 2000: 53). The potential impact of solid forms in one medicinal product on the safety and effectiveness of the relevant medicinal product is so considerable that the Administration of food and drugs U.S. requires the identification and monitoring of solid forms, for example, crystalline forms of each of the compounds used in each drug product marketed in the United States. Accordingly, a new crystalline form of 1,2,4-oxadiazolidine acids can contribute to the development of a composition for the treatment, prevention or management of diseases, facilitated by modulation of premature termination of translation or nonsense-mediated mRNA decay. The present invention relates to new crystalline forms, for example, crystalline forms of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

The references listed in section 2 of this application should not be construed as an admission that such reference anticipates this application.

3. A brief description of the invention

The invention relates to new crystalline forms, for example, crystallizes is m the form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, which have the following chemical structure (I):

In particular, the crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid are used for treatment, prevention or management of diseases, facilitated by modulation of premature termination of translation or nonsense-mediated mRNA decay, as described in U.S. patent No. 6992096 B2, issued January 31, 2006, which is fully incorporated into the present description by reference. In addition, the present invention relates to a crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, which is essentially pure, i.e. the degree of its purity is more than about 90%.

Some embodiments of the invention relates to pharmaceutical dosage forms and compositions containing a crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid and pharmaceutically acceptable diluent, excipient or media. The invention also relates to methods of use thereof for the treatment, prevention or management of diseases, facilitated by modulation of premature termination of translation or nonsense-mediated mRNA decay. In some embodiments implementing the invention relates to a method of receiving, identifying and/or characteristics of ristalliceski forms according to the invention. The crystalline form according to the invention can be used as active pharmaceutical ingredients for obtaining compositions for use in animals or humans. Thus, the present invention encompasses the use of these crystalline forms in the quality of the final drug product. Crystalline forms and final drug products according to the invention can be applied, for example, for the treatment, prevention or management of diseases described in this application.

A detailed description of the invention

4.1. Brief description of drawings

Figure 1 shows x-ray powder diffractogram (XRPD) pattern of form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

Figure 2 shows thermograms obtained by differential scanning calorimetry (DSC) and thermogravimetrical analysis (TGA) of a sample of form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

Figure 3 shows the isotherm dynamic vapor sorption (DVS) of a sample of form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

Figure 4 shows13From the NMR spectrum of a sample of form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

Figure 5 shows the XRPD pattern of form 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

Figure 6 shows thermograms of DSC and TGA of a sample form 3-[5-(2-fluoro who enyl)-[1,2,4]oxadiazol-3-yl]benzoic acid.

7 shows DVS isotherm of sample form 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

On Fig presents the overlap of the experimental XRPD showing a characteristic set of peaks for form a (upper part) for several samples of the form (second down) 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, illustrating the shift of the peak among some samples form Century.

Figure 9 shows the packing of the crystal structure of form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid in the projection along the crystallographic b axis and the contour of the elementary cell.

Figure 10 shows the XRPD of form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, imitated by the crystal structure obtained by the method of x-ray diffraction on a single crystal.

Figure 11 shows a graph ORTEP asymmetric unit cell shapes And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained by the method of x-ray diffraction on a single crystal. The atoms are represented by 50% probability of anisotropic thermal ellipsoids.

4.2. Terminology

Crystalline forms, equivalent to crystalline forms described below and claimed in the present application, may exhibit similar, but not identical analytical characteristics within the allowable range is Altanbulag errors depending on test conditions, cleanliness, equipment and other normal variables, known to experts in the field or found in the literature. The term "crystalline" and related terms used in the present description, when used to describe a substance, component, product, means that the substance, component of the product is essentially crystalline, according to the definition of x-ray diffraction, microscopy, polarized microscopy, or other known analytical procedure known specialists in this field. See, for example, Remington''s Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA, 173 (1990);The United States Pharmacopeiathe 23rded., 1843-1844 (1995).

Accordingly, for specialists in this field will be obvious that the present invention can be made of various modifications and changes without departure from the scope and essence of the invention. Other embodiments of the invention will be obvious to specialists in this area from consideration of the description and it describes the embodiments of the invention. The applicants suggest that the description and examples should be considered illustrative, and not limiting the scope of invention.

Crystalline forms of the present invention can be characterized using the methods of diffraction of p is nenovsky rays on single crystals, powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). It should be understood that the described and claimed in the present description numeric values are approximate. Variation within units, along with other factors, can be attributed to calibration errors, equipment failures, purity of materials, size of the crystals and the size of the sample. In addition, the possible variations in obtaining the same result. For example, the value of the x-ray diffraction, which in General are accurate and are within ±0,2°, and intensity values (including the values of the relative intensity, the type of x-ray diffraction can vary depending on the measurement conditions. Similarly, the DSC results are usually accurate and are in the range of about 2°C. Therefore, it should be understood that the crystalline form of the present invention are not limited to crystalline forms, which provide the characteristic spectra (i.e. one or more of the PXRD, DSC and TGA), identical characteristic spectra, depicted in the accompanying drawings shown in this description. Any crystalline forms, which provide the characteristic spectra, essentially the same as those described in the accompanying drawings are included in the scope of the present invention. The average person skilled in the art can establish essentially the same characteristic spectra.

Presented in this description of embodiments of you can fully understand by reference to the following detailed description and illustrative examples, which are intended to illustrate a non-limiting embodiments.

Methods for the preparation of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is described in U.S. patent No. 6992096 B2, issued January 31, 2006, and in the application for U.S. patent No. 11/899813, filed September 9, 2007, which are fully included in the present description by reference.

4.3. Form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid

In one embodiment, the present invention relates to the form And crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid. In some embodiments, the implementation of the form And can be obtained by crystallization from various solvents, including, without limitation, methanol, tert-butyl alcohol (t-BuOH), 1-butyl alcohol (1-BuOH), acetonitrile, isopropyl alcohol (IPA), a simple isopropyl ether, dimethylformamide, heptane, isopropylacetate (IPOAc), toluene and/or water. Representative type XRPD of form a of 3-[5-(2-forfinal)-[1,2,4]oxadi the evil-3-yl]benzoic acid is shown in figure 1. In some embodiments, the implementation of the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is of type XRPD, which is essentially the same as the type depicted in figure 1.

Representative thermal characteristics of form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is shown in figure 2. Representative DSC thermogram, presented in figure 2, shows an endothermic phenomenon with a peak temperature at about 244°C. a Representative TGA thermogram, also presented in figure 2, shows a weight loss of less than about 1% of the total mass of the sample upon heating from about 33°to about 205°C. These thermal data indicate that the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid does not contain substantial amounts of either water or solvent in the crystal lattice. In some embodiments, the implementation of the form And manifests the phenomenon of mass loss starting at about 212°C, which corresponds to the sublimation before melting.

Crystal structure of single crystal form a of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid was obtained by the method of x-ray diffraction on a single crystal. Using data collected at about 150 K, were obtained the following unit cell parameters: a=24,2240(10) Å; b=3,74640(10) Å; C=27,4678(13) Å; α=90°; β=92,9938(15)° γ=90°; V=2489,38(17) Å3. Figure 9 shows the packing of the crystal structure XPD single crystal form And in projection on a crystallographic axis ofb. The simulated spectrum XPRD was generated for the irradiation of Cu using PowderCell for Windows Version 2.3 Kraus, W.; Nolze, G. Federal Institute for Materials Research and Testing, Berlin, Germany, EU, 1999) and the atomic coordinates, space group and unit cell parameters according to the single crystal. The simulated spectrum XPRD forms And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid are presented in figure 10.

In some embodiments, the implementation of the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is characterized by physical resistance when exposed to certain conditions. In some embodiments, the implementation of the form And is physically stable when stored for 6 days when exposed to one or more of the following conditions relative humidity (RH): RH 53% at 40°C; RH of 75% at 40°C; RH 50% at 60°C; RH 79% at 60°C. In other embodiments, the implementation of the form And is physically stable when grinding at ambient temperature or a temperature below ambient. In other embodiments, the implementation of the form And is physically stable when one or more of the following conditions: 1-BuOH for 4 days at ambient temperature; in chloroform for 2 days at 50°C; and in dichloromethane in t the value of 2 days at 50°C.

The form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid was evaluated on hygroscopicity. Analysis of dynamic vapor sorption (DVS) capture moisture and release moisture as a function of relative humidity (RH) were obtained after cyclic change in RH from 5% to 95%. The maximum capture approximately 0.06% of the total mass of the sample, as shown in a representative DVS isotherm shape And figure 3. Accordingly, in some embodiments, the implementation of the form And is non-hygroscopic.

Figure 4 shows representative13From the NMR spectrum in the solid state 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid. In some embodiments, the implementation of the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is characterized by a13With NMR signals CP/MAS solid state localized in one or more of the following approximate positions: 172,6, 167,0, 131,3, 128,4 and 117,1 ppm with external comparison with glycine at 176,5 ppm

In some embodiments, the implementation of the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid exhibits desirable characteristics for processing and/or receiving a drug product that contains the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid. For example, in some embodiments, the implementation of the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid has a relatively the high melting point which is an important feature, along with other aspects, for processing and production. In addition, it was found that in some embodiments, the implementation of the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is essentially non-hygroscopic. Hygroscopic solid form desirable for a variety of reasons, including, for example, problems of processing and storage. In addition, it was found that in some embodiments, the implementation of the form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is physically and chemically stable after micronisation, how to reduce the size of the particles. Physical stability is an important property of pharmaceutical materials during retrieval, processing and storage.

4.4. Form 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid

In one embodiment, the present invention relates to the form In the crystalline forms of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid. In some embodiments, the implementation of the form can be obtained by crystallization from various solvents, including, without limitation, tetrahydrofuran (THF), hexane, isopropyl alcohol (IPA), ethyl acetate (EtOAc), acetic acid, 1-butyl acetate, acetone, simple, dimethyl ether, simple, diethyl ether, dioxane, water, methyl isobutyl ketone (MBK), methyl ethyl ketone (MEK), nitromethane and/or water.

In some embodiments, the implementation form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid includes the solvent in the crystal lattice in an amount which depends on one or more conditions, such as, without limitation, crystallization, handling, processing, preparation, receiving or storing. In some embodiments of the invention, the form includes the solvent in the crystal lattice. In some embodiments, the implementation form In essentially does not contain the solvent in the crystal lattice. In some embodiments, the implementation of maximum combined molar equivalents of solvent per mole of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid in the sample form In less than 6 less than 5 less than 4 less than 3, less than 2, less than 1.5, less than 1, less than 0,75, less than 0.5 or less than 0.25 molar equivalents. Without intending to be limited by theory, believe that the characteristic variability of the solvent content of form arises from the existence of the channel grid, which can be of different types and/or quantity of the solvent and which provides the ability to add and/or remove solvents depending on specific conditions. In some embodiments, the implementation strukturformel In is the basis for the isostructural family of crystalline forms. In some embodiments, the implementation form is a non-MES solvate crystalline form.

A representative XRPD spectrum of form 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is shown in figure 5. In some embodiments, the implementation form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is characterized by XRPD peaks located at one or more of the following provisions: about 6.4 to about 8.0 to about 14.1 to about 15,9 about 17,2 and about 20,1 °2θ. The person skilled in the art it is clear that when the solvents and/or water are added or removed from the crystal lattice, the lattice slightly expand or shrink, resulting in small changes in the XRPD peak positions. In some embodiments, the implementation form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid is characterized by an XRPD spectrum substantially similar spectrum, depicted in figure 5. In some embodiments, the implementation of the form b shows the XRPD spectrum substantially similar spectrum, depicted in figure 5, but shows small shifts of the peak positions, resulting from the presence or absence of certain solvents or water in the crystal lattice. Certain representative XRPD spectra of the form In (second down) are compared with the form A (top) 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-eventing acid Fig. In some embodiments, the implementation of the form has the XRPD spectrum substantially similar to one or more of the XRPD spectra depicted in Fig.

Thermal characteristics of a sample form 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, crystallized from a mixture of 2.5:1 THF:hexane, shown in Fig.6. The TGA thermogram of the sample forms presented on Fig.6 shows two phenomena weight loss: one phenomenon of weight loss of approximately 5% of the total weight of the sample after heating from about 25°to about 165°C., and the second appearance of the mass loss starting at about 220°C. high-Temperature microscopy revealed that the first phenomenon of mass loss occurred due to loss of solvent and/or water from the crystal lattice, and the second is the phenomenon of mass loss occurred due to sublimation of form C. the XRPD Analysis of the obtained sublimate showed that the formed shape And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid. The DSC thermogram of the sample forms presented on Fig.6, shows a sharp endothermic phenomenon with a peak temperature at about 243°C corresponding to the melting of sublimate form A. DSC of the sample form also exhibits at least one other phenomenon at a temperature below about 220°C. These thermal data indicate that this sample form 3-[5-(2-forfinal)-[1,2,4]oxadiazol the-3-yl]benzoic acid contained water and/or solvent in the crystal lattice. Due to the variable content of water and/or water in some samples of the forms of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid in some embodiments the invention, thermal characteristics of the form will show a certain change. For example, in certain embodiments of the invention, samples of forms, which are essentially devoid of water and solvent, do not show significant weight loss, according to the TGA, or thermal phenomena, according to DSC, below a temperature of about 220°C. As the form In sublimates and crystallized as form a, figure 6 heat of fusion for endothermy is after the sample is turned into the form of A.

In one embodiment of the invention the sample form In which crystallized from IPA, was about 0.1 molar equivalents IPA and about 1 molar equivalent of water per mole of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, based on the analysis using TGA and1H NMR. In certain embodiments implement a sample form, which has approximately 1 molar equivalent of water per molar equivalent of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, referred to as the monohydrate. In another embodiment of the invention the sample form In which it was processed by vacuum drying at 105°C for 10 min, showed the total pot is th mass of 2% wt. sample for subsequent analysis TGA from about 25 to about 185°C. In some embodiments, the implementation characteristics of forms, depending on the amount and/or identity of the solvent and/or water in the crystal lattice (e.g., mass loss after heating or drying), will exhibit a change in relation to the total number or identity of the solvent and/or water in the crystal lattice. In some embodiments, implementation, regardless of the number and/or identity of the solvent and/or water in the crystal lattice, XRPD spectrum of form b contains peaks characteristic form, as described above, but with a slight shift of the peak arising from differences in the number and/or identity of the solvent and/or water in the crystal lattice of the form Century Representative XRPD spectra illustrating the shift of the peak among certain sample forms imposed on Fig (second from top to bottom).

In some embodiments of the invention, after grinding at ambient temperature or a temperature below ambient, there is a transformation of the form In the form of A. In other embodiments of the invention form physically stable after storage for 6 days at one of the following values of relative humidity (RH): RH 53% at 40°C, 75% RH at 40°C and RH 50% at 60°C. In other embodiments, implementation of the image is possible, the form is essentially non-hygroscopic, as illustrated by the DVS isotherm of a representative form In figure 7. In other embodiments of the invention form b shows a partial transformation in the form And after storage for 6 days in the condition RH 79% at 60°C. In other embodiments of the invention form is physically stable when compressed separately and under pressure, in the presence of a mixture of 1:1 tert-BuOH, and water. In other embodiments of the invention form is physically stable when suspendirovanie at ambient temperature in a mixture of 1:1 THF and heptane. In other embodiments, implementation of the transformation of the forms In form And occurs after suspension form or in mixture, or in 1:1-mixture of dioxane and water.

4.5. Applications

In the present description presents methods of treatment, prevention and management of diseases or disorders, facilitated by the suppression of premature termination of translation and/or nonsense-mediated mRNA decay in a patient, which include the introduction needs it to the patient an effective amount of a solid form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

In one embodiment, the present invention relates to methods for treatment, prevention or management of any disease that is associated with the gene exhibiting premature stun the group of broadcast and/or nonsense-mediated mRNA decay. In one embodiment, the disease is partly due to the absence of gene expression as a result of premature termination codon. Specific examples of genes that may show premature termination of translation and/or nonsense-mediated mRNA decay, and diseases associated with premature termination of translation and/or nonsense-mediated mRNA decay, can be found in the application for U.S. patent No. 2005-0233327, entitled "Methods of identifying small molecules that modulate premature termination of translation and/or nonsense-mediated mRNA decay", which is fully incorporated into the present description by reference.

Diseases or disorders associated with inhibition of premature termination of translation and/or nonsense-mediated mRNA decay, include, without limitation, genetic disease, cancer, autoimmune disease, blood disease, a collagen disease, diabetes, neurodegenerative disease, a proliferative disease, cardiovascular disease, pulmonary disease, inflammatory disease or disease of the Central nervous system.

Certain genetic diseases within the scope of the methods of the invention include, without limitation, multiple endocrine neoplasia (type 1, 2 and 3), s is logos, mucopolysaccharidosis (type I and III), congenital adrenal hypoplasia, adenomatous polyposis of the colon, the disease von Hippel-Landau, of Menkes syndrome, hemophilia A, hemophilia B, collagen VII, the syndrome of Alagille syndrome Townes-Broks, Rathenow tumor, the bubble bullosa syndrome Hurler syndrome Coffin-Lowry, aniridia, Lou Gehrig's disease-Maria-Tusa, myotubular myopathy, X-linked myotubular myopathy, X-linked chondroplasia, X-linked and-gamma globulinemia, polycystic kidney disease, spinal muscular atrophy, familial adenomatous polyposis the failure of pyruvaldehyde, phenylketonuria, neurofibromatosis 1, neurofibromatosis 2, Alzheimer's disease, and Tay-Sachs syndrome rett syndrome German-Pudlak syndrome ectodermal dysplasia/skin fragility, dyschondrosteosis Leri-Walla, rickets, hypophosphatemia, adrenoleukodystrophy, atrophy of the convolutions of the cerebral cortex, atherosclerosis, sensorineural deafness, dystonia, dent disease, acute alternating Porphyrios, Cowden's disease is, bullous bullosa of Charlize, Wilson's disease, syndrome Tricera-Collins, pyruvate kinase deficiency, giantism, dwarfism, hypothyroidism, hyperthyroidism, aging, obesity, Parkinson's disease With the Neumann-Peak, cystic fibrosis, degeneration yellow spots, heart illness is the W, kidney stone disease, ataxia-telangiectasia, familial hypercholesterolemia, pigments retinal disease lysosomal accumulation, tuberose sclerosis, muscular dystrophy DuChene and Marfan syndrome.

In another embodiment, the genetic disease is an autoimmune disease. In a preferred embodiment, the autoimmune disease is a rheumatoid arthritis or disease graft-versus-host.

In another embodiment, the genetic disease is a disease of the blood. In a specific embodiment, the blood disorder is a hemophilia a, a disease von Willebrand's disease (type 3), ataxia-telangiectasia, b-thalassemia or renal disease.

In another embodiment, the genetic disease is a collagen disease. In a specific embodiment, collagen disease represents an imperfect osteogenesis or cirrhosis.

In another embodiment, the genetic disease is a diabetes.

In another embodiment, the genetic disease is an inflammatory disease. In a specific embodiment, the inflammatory disease is an arthritis.

In another VA who ianthe implementation of genetic disease is a disease of the Central nervous system. In one embodiment, a disease of the Central nervous system is a neurodegenerative disease. In a specific embodiment, the disease of the Central nervous system represents multiple sclerosis, muscular dystrophy, muscular dystrophy DuChene, Alzheimer's disease, and Tay-Sachs, late neuronal ceroid lipofuscinosis young children (LINCL) or Parkinson's disease.

In another embodiment, the genetic disease is a cancer. In a specific embodiment, the cancer is a cancer of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, lung, colon, sigmoid colon, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart or adrenal glands. Cancer can be primary or metastatic. Cancers include solid tumor, hematological malignancy and other neoplasms.

In another specific embodiment, the cancer associated genes tumor suppressor (see, for example, Gariniset al.2002, Hum Gen 111: 115-117; Meyerset al.1998, Proc. Natl. Acad. Sci. USA, 95: 15587-15591; Kunget al.2000, Nature Medicine 6(12): 1335-1340. Such genes tumor suppressors include, without limitation, APC, ATM, BRAC1, BRAC2, MSH1, pTEN, Rb, DKN2, NF1, NF2, WT1 and p53.

In a preferred embodiment, the gene is a tumor suppressor is a gene p53. Nonsense mutations have been identified in the gene p53 and were involved in cancer. Identified several nonsense mutations in the p53 gene (see, for example, Masudaet al.,2000, Tokai J. Exp. Clin. Med. 25(2): 69-77; Ohet al.,2000, Mol. Cells 10(3): 275-80; Liet al.,2000, Lab. Invest. 80(4): 493-9; Yanget al.,1999, Zhonghua Zhong Liu Za Zhi 21(2): 114-8; Finkelsteinet al.,1998, Mol. Diagn. 3(1): 37-41; Kajiyamaet al.,1998, Dis Esophagus. 11(4): 279-83; Kawamuraet al.,1999, Leuk Res. 23(2): 115-26; Radiget al,1998, Hum. Pathol. 29(11): 1310-6; Schuyeret al.,1998, Int. J. Cancer 76(3): 299-303; Wang-Gohrkeet al.,1998, Oncol. Rep. 5(1): 65-8; Fulopet al.,1998, J. Reprod. Med. 43(2): 119-27; Ninomiyaet al.,1997, J. Dermatol. Sci. 14(3): 173-8; Hsiehet al.,1996, Cancer Lett. 100(1-2): 107-13; Railet al.,1996, Pancreas. 12(1): 10-7; Fukutomiet al.,1995, Nippon Rinsho. 53(11): 2764-8; Frebourg et al., 1995, Am. J. Hum. Genet. 56(3): 608-15; Doveet al.,1995, Cancer Surv. 25: 335-55; Adamsonet al.,1995, Br. J. Haematol. 89(l): 61-6; Grayson et al., 1994, Am. J. Pediatr. Hematol. Oncol. 16(4): 341-7; Lepelleyet al.,1994, Leukemia. 8(8): 1342-9; McIntyreet al.,1994, J. Clin. Oncol. 12(5): 925-30; Horioet al.,1994, Oncogene. 9(4): 1231-5; Nakamuraet al.,1992, Jpn. J. Cancer Res. 83(12): 1293-8; Davidoff et al., 1992, Oncogene. 7(l): 127-33; and Ishiokaet al.,1991, Biochem. Biophys. Res. Commun. 177(3): 901-6; the descriptions of which are fully incorporated into the present description by reference).

In other embodiments, implementation of the disease under treatment, prevention or management by introducing in need of treatment, the patient is effectively the effective amount of a solid form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, include, without limitation, a solid tumor, a sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordomas, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, abnormal Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, carcinoma of the sebaceous glands, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, pochernkletocny carcinoma, hepatoma, carcinoma of the gall ducts, horiokartsinoma, seminoma, embryonal carcinoma, Wilms ' tumor, cervical cancer, a tumor of the testes, lung carcinoma, small cell carcinoma of the lung, carcinoma of the bladder, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, the auditory nerve neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, a tumor of the blood cells, acute lymphoblastic leukemia, acute lymphoblastic b-cell leukemia, acute lymphoblastic T-cell leukemia, acute is Jablanicki leukemia, acute promyelocytic leukemia, acute monolithically leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nelimfocitarnyi leukemia, acute undifferentiated leukemia, chronic miliitary leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma. See, for example,Harrison''s Principles of Internal Medicine, Eugene Braunwald et al., eds., pp. 491-762 (15thed. 2001).

4.6 Pharmaceutical composition

Pharmaceutical compositions and unit standard dosage forms, containing a compound according to the invention, or its pharmaceutically acceptable polymorph, prodrug, salt, MES, hydrate, or clathrate also covered by the invention. Separate dosage forms according to the invention may be suitable for oral administration, injection through the mucous membranes (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intraarterial, or intravenous), transdermal or local injection.

Single standard dosage forms according to the invention suitable for oral administration, injection through the mucous membranes (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteralnogo (for example subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal injection for the patient.

The composition, shape, and type of dosage forms according to the invention will typically vary depending on their application. These and other signs by which certain dosage forms covered by the present invention, will be different from each other, will be obvious to specialists in this field. See, for example,Remington's Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA (1995).

Typical pharmaceutical compositions and dosage forms include one or more carriers, excipients or diluents. Suitable excipients are well known to experts in the field of pharmacy, and non-limiting examples of suitable excipients are presented in this description. Whether a particular excipient for inclusion in a pharmaceutical composition and dosage form, depends on a variety of factors well known in this field, including, without limitation, the way in which the dosage form will be administered to the patient. For example, oral dosage forms such as tablets may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on certain the active ingredients in the dosage form.

EXAMPLES

5.1. Synthesis of solid dosage forms 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid

The product 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained in the above synthesis may be crystallized or recrystallized in a variety of ways to obtain a solid form according to the invention. Below are a few non-limiting examples.

5.1.1 Synthesis of form And

5.1.1.1 Slow evaporation

The product 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as described in this application was led in the form And by the method of slow evaporation from each of the following solvents: acetonitrile; tert-butanol; isopropyl alcohol and simple isopropyl ether. A solution of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid was obtained in the specified solvent and treated by ultrasound between aliquot additions quantities to facilitate the dissolution. After reaching complete dissolution of the mixture, which was judged by visual observation, the solution was filtered through a filter with pore size 0.2 μm. The filtered solution was allowed to evaporate at 60°C (50°C in the case of tert-butanol) in a vial covered with aluminum foil containing the smallest hole(I). The resulting solids from the Yali and was characterized by XRPD as form A.

5.1.1.2 Rapid evaporation

The product 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as described in this application was led in a form And manner that rapidly evaporates from each of the following solvents or solvent system: 1-butanol; dimethoxyethan; tert-butanol; a mixture of dimethylformamide and water; simple isopropyl ether and the mixture of tert-butanol:water (in the ratio 3:2), 1 molar equivalent of methanol and 1 molar equivalent of sodium chloride. The solutions were received in the specified solvent or the solvent system and were treated by ultrasound between aliquot additions quantities to facilitate the dissolution. After reaching complete dissolution of the mixture, which was judged by visual observation, the solution was filtered through a filter with pore size 0.2 μm. The filtered solution was allowed to evaporate at 60°C (50°C in case of tert-butanol and simple isopropyl ether; 81°C in case of tert-butanol/water/methanol/NaCl) in an open vial. The resulting solids were isolated and characterized by XRPD as form A.

5.1.1.3 Transformation into suspension

The form of the free acid 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as described in this application was made in the form And manner of suspension in the solvent system is 1:1 dioxane:water. The suspension was obtained by adding a sufficient amount of solids form In this solvent, so that was attended by excess solids. Then the mixture was stirred in a sealed vial at 60°C. After 2 days, the solids were isolated by vacuum filtration and was characterized by XRPD as form And with a small amount of form C.

5.1.1.4 Sublimation and heat

Form 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as described in this application was made in the form And ways of sublimation and heat. In one experiment In the form sublimated when 160-208°C in vacuum for 35 min to obtain white needles, which were characterized by XRPD as form A. In another experiment In the form melted at 255°C, followed by immediate placement in liquid nitrogen to obtain a crystalline material, which was characterized by XRPD as form A. In another experiment In the form melted at 255°C and then slowly cooled to obtain a crystalline material, which was characterized by XRPD as form A.

5.1.2 Synthesis of form

5.1.2.1 Slow evaporation

The product 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as In the method of slow evaporation from each of the following solvents: acetone; simple dimethyl ether and METI ethylketone. A solution of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid was obtained in the specified solvent and treated by ultrasound between aliquot additions quantities to facilitate the dissolution. After reaching complete dissolution of the mixture, which was judged by visual observation, the solution was filtered through a filter with pore size 0.2 μm. The filtered solution was allowed to evaporate at a temperature of 50°C (60°C in the case of methyl ethyl ketone) in a vial covered with aluminum foil containing the smallest hole(s).

In one embodiment, 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid was dissolved in dimethoxyethane. The solution was poured into a clean vial. The contents of the vial were filtered through a filter with pore size 0.2 μm, covered with aluminum foil perforated with tiny hole(s), and the solvent was allowed to evaporate. The resulting solids were isolated and characterized by XRPD as form C. the XRPD Analysis is illustrated in table 8 (R.O.)

5.1.2.2 Rapid evaporation

The product 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as described in this application was led in a form In a way that rapidly evaporates from each of the following solvents or solvent system: acetone, acetic acid, 1-butyl acetate; a simple dime levy ether; THF and simple diethyl ether; dioxane; ethyl ketone; nitromethane; methyl isobutyl ketone; THF:hexane (2,5:1) and dioxane:water (3:2). The solutions were received in the specified solvent or the solvent system and were treated by ultrasound between aliquot additions quantities to facilitate the dissolution. After the complete dissolution of the mixture, which was judged by visual observation, the solution was filtered through a filter with pore size 0.2 μm. The filtered solution was allowed to evaporate at an elevated temperature in an open vial. The resulting solids were isolated and characterized by XRPD as form C.

5.1.2.3 Transformation into suspension

The form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as described in this application was made in the form In the way of suspension in each of the following solvents: acetic acid; 1-butyl acetate and nitromethane. In one embodiment, 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid suspended on an orbital shaker in 1-butyl acetate (13 ml) at room temperature for 3 days. After 3 days the solvent was removed by pipette, dried and was characterized by XRPD as form In (table 5).

5.1.2.4 the transformation of the orbital vibrator

The form And 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid obtained as described in the present application, transformed into the form by heating on an orbital shaker in 1-propanol (10 ml) at 60°C for 1 day. The resulting solution was filtered through a filter with pore size 0.2 μm in a clean bottle. After 1 day, the solvent was removed and the sample was dried in nitrogen atmosphere. Analysis of the XRPD as form is illustrated in table 4.

5.1.2.5 Other embodiments of

3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid (20 mg, form) suspended in a mixture of tetrahydrofuran/heptane 1/1 (2 ml) at ambient temperature for 1 day. After 1 day in the suspension was made of the seed of the form A (10 mg) and form (9 mg) and suspended for one day after which was added an additional amount of form a (30 mg). After suspension of the sample within 7 days added an extra number of the form A (30 mg) and the temperature was increased to 50°C. the Solids were collected after the suspension at 50°C for one day. The resulting solids were isolated and characterized by XRPD as form C. the XRPD Analysis is illustrated in table 6.

3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid (UNMEASURED QUANTITY, FORM) resulted in stress state at a relative humidity of 75% at 40°C for 6 days. The resulting solids were isolated and characterized by XRPD as form C. the XRPD Analysis of illustri is : in table 7.

5.2 Analytical procedures

The following methods of analysis in the solid state provide examples of how to characterize the solid forms of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid according to the present invention. Certain methods described below were used to obtain the data described here, characterizing the solid state.

5.2.1 Powder x-ray diffraction (XRPD)

Certain types of XRPD analysis was performed using powder x-ray diffractometer Shimatzu XRD-6000, using Cu-α radiation. The device is equipped with long-precision x-ray tube. The voltage and amperage were set respectively at 40 kV and 40 mA. Crack deflection and dispersion were set to 1°, receiving slit was set at 0.15 mm, Subjected to diffraction radiation was detected with a scintillation detector NaI. Used continuous scanθ-2θat 3°/min (0.4 with step/0,02°) from 2.5 to 40° 2θ. A silicon standard was analyzed to check the alignment of the instrument. Data were acquired and analyzed using XRD-6100/7000 v.5.0. The samples were received for analysis by placing them in the sample holder.

Some XRPD analyses were performed using a diffractometer XRG-3000, equipped with a detector CPS (sensitive to curved position) dia is an azone 2 θ120°. Data in real-time were obtained using Cu-α radiation at a resolution of 0.03° 2θ. The voltage and amperage were set respectively at 40 kV and 30 mA. The slit of the monochromator was set to 5 mm by 160 mm. Type presents with 2.5-40° 2θ. Used holder aluminum sample with a silicone liner /or/ samples received for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted on a goniometer head, which was set in motion to enable rotation of the capillary during data collection. The samples were analyzed within 300 C. Calibration was performed using a silicon reference standard.

Some types XRPD received by the diffractometer Bruker D-8 Dicover and devices identify the General area diffraction Bruker's General Area Diffraction Detection System (GADDS, v.4.1.20). An incident beam of Cu-α radiation was obtained with the use of just-focus tube (40 kV, 40 mA), mirrors Gőbel and collimator with double the smallest hole of 0.5 mm Sample of the sample was Packed in a capillary and recorded in the floating stand. The camera and the laser used for the location area of concern with the intersection of the incident beam in transmission geometry. The incident beam is scanned to optimize statistical orientation. The stop beam used for the mini is Itachi scattering of the incident beam in the air at low angles. Spectra diffraction were obtained using the detector field of Hi-Star, located 15 cm from the sample, and processed using GADDS. The intensity in the image GADDS diffraction spectrum was integrated using a step size of 0.04° 2θ. Integrated spectra show the diffraction intensity as a function of 2θ. Prior to analysis, a silicon standard was analyzed to verify the position of the peak of Si 111.

Some files XRPD, obtained devices Intel XRPD, was turned into the file Shimadzu.raw using version 3.0.4 File Monkey. File Shimadzu.raw were processed using software version 2.6 Shimadzu XRD-6000 to automatically search for the peak positions. "The position of the peak" means the maximum intensity profile of the maximum intensity. The parameters used to select the peaks shown in the lower half of each set of parameter data. The following processes were used with the application of the algorithm of the software version 2.6 Shimadzu XRD-6000 "Basic Process"

The smoothing was performed on all spectra.

The background was subtracted to find the accurate relative intensities of the peaks.

Peak of the wavelength of Cu K A2 (1,5444 Å) subtracted from the peak generated by Cu K alpha (1,5406 Å) at 50% intensity for all spectra.

5.2.2 Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) you shall anjali, using a differential scanning calorimeter (TA Instruments 2920. The sample was placed in an aluminum Chan DSC and the exact weight was registered. The tub was covered with a lid and then folded. The cell sample was balanced at 25°C and was heated by blowing with nitrogen at a rate of 10°C/min to a final temperature of 350°C. indium Metal was used as the calibration standard. Observed temperatures are maximum levels of the transition.

5.2.3 Thermogravimetric analysis (TGA)

Thermogravimetric (TGA) analyses were performed using thermogravimetric analyzer, TA Instruments 2950. Each sample was placed in an aluminum tub for samples and inserted into the furnace TG. Oven (first grooved at 35°C, then heated in nitrogen atmosphere at a rate of 10°C/min to a final temperature of 350°C. Nickel and AlumelTMused as calibration standards.

5.2.4 Dynamic sorption/desorption pair (DVS)

The data of sorption/desorption of moisture collected on the sorption analyzer pair VTI SGA-100 Vapor Sorption Analyzer. The data of sorption and desorption were collected in the range of relative humidity (RH) 5% to 95% intervals RH 10% nitrogen purging. The samples were not dried before analysis. Criteria of equilibrium used for analysis was less than 0,0100% wt. after 5 min at maximum time of equilibrium 3 hours in locatedoutside criterion by weight. Data are not corrected for the initial moisture content in the samples. As the calibration standards used NaCl and PVP (polyvinylpyrrolidone).

5.2.5 Analysis of Karl Fischer

Calorimetric analysis of the Karl Fischer (KF) for determination of water was performed using the titrator Mettler Toledo DL39 Karl Fischer. Approximately 21 mg of sample was placed in tetrapody vessel KF containing Hydranal - Coulomat AD and mixed within 42-50 with to ensure dissolution. Then the sample was titrated electrode of the generator, which produces iodine by electrochemical oxidation: 2 I- => I2+ 2e. To ensure reproducibility received three repetitions.

5.2.6 high Temperature microscopy

High temperature microscopy was performed using a high-temperature microscope Linkam FTIR 600 controller TMS93 mounted on microscope Leica DM LP, equipped with a color camera Spot Insight, to receive images. Until otherwise noted, images were obtained using version 4.5.9 software Spot Advance, the creation date of June 9, 2005, Before using the camera was balanced in white. The samples were examined and images were obtained using a lens with a long working distance 20×0,40 N.A. with crossed poles and the compensator red of the first order. The samples were placed on top of the tape. Each is th sample was examined visually with the heating stage. Hot stage was calibrated using standards of melting points according to Pharmacopeia of the United States.

5.2.713Nuclear magnetic resonance spectroscopy in the solid state with cross-polarized rotation under the "magic" angle (13With CP/MAS ssNMR)

The received samples for NMR spectroscopy in the solid state packing them in Zirconia rotors type PENCIL size 4 mm Scans were collected at ambient temperature with a delay of relaxation 120,000 C, pulse width of 2.2 µs (90,0°), the processing time 0,030 with and spectral width 44994,4 Hz (447,520 ppm). In total we collected 100 scans. Cross-polarization was achieved by the use of13With the quality of the observed nucleus and1N as fission with a contact time of 10.0 MS. Used speed magic angle 12000 Hz. The spectra are compared with the external reference glycine at 176,5 ppm

Specialists in this field will be clear, or they can be installed with no more than ordinary experimentation, many equivalents to the specific embodiments described in this application of the invention. Such equivalents are intended to cover by the following claims. All publications, patents and patent applications mentioned in the present description, are included in the description by reference to the same with epine, as if each individual publication, patent or patent application was specifically and individually indicated as included in the present description by reference.

5.2.8 x-ray Diffraction on single crystal

The crystals used for structure determination of form a was obtained by sublimation of form A. the Crystals were removed from the cold finger after heating the sample to a temperature of from 155 to 206°C for about 90 min (experimental table 3).

Data collection

Colorless needle C15H9FN2O3having the approximate size of 0.44×0,13×0.03 mm, were mounted on glass finger in a random orientation. Preliminary examination and data collection were performed by irradiation of Mo Kα(λ=0,71073 Å) diffractometer Nonius KappaCCD. Refinement was performed on a personal computer LINUX PC using SHELX97 (Sheldrick, G.M.SHELX97, A Program for Crystal Structure Refinement,University of Gottingen, Germany, 1997).

The cell constant and the matrix orientation for data collection was obtained by the minimum quadratic refinement using angles 13862 reflections in the range2°<θ<24°. The refined mosaicity on the program DENZO/SCALEPACK (Otwinowski, Z.; Minor, W.Methods Enzymol. 1997, 276, 307) was 0.33°, indicating good crystal quality. The space group was determined by the program (Bruker, XPREP in SHELXTL v.6.12., Bruker AXS In., Madison, WI, USE, 2002). On the systematic presence of the following conditions: h Olh+l=2n;0k0k=2nand subsequent minimum quadratic specification, it was determined that the space group P2 representsl/n (No. 14).

Data were collected up to a maximum value of 2θ2469° at a temperature of 150±1 K.

Reducing data

The frames were integrated with the program DENZO-SMN (Otwinowski, Z.; Minor, W.Methods Enzymol. 1997, 276, 307). There were collected 13862 reflection, of which 3201 were unusual. Data used for the correction of the Lorentz and polarization. The coefficient of linear absorption is 0,110 mm-1for irradiation of MoKα. Applied an empirical correction for absorption using the program SCALEPACK (Otwinowski, Z.; Minor, W.Methods Enzymol.1997, 276, 307). The transmission coefficients ranged from 0,951 to 0,997. Applied correction secondary attenuation (Sheldrick, G.M.SHELX97, A Program for Cristal Structure Refinement,University of Gottingen, Germany, 1997). The final factor, the adjusted minimum square method, amounted to 0,0046 (in absolute units). The intensities of equivalent reflections were averaged. The coincidence factor for averaging 10.1 percent on the basis of intensity.

Establishment and structure refinement

The structure was determined by direct methods using SIR2004 (Burla, M.C., et al., J. Appl. Cryst. 2005, 38, 381). The locale is the situation of the remaining atoms were determined by Fourier syntheses consistent differences. Hydrogen atoms were included in the refinement, but was limited by the atom with which they were associated. The structure was refined in the minimum standard full matrix by minimizing the function:

Weightwis defined aswhereP=(F,o2+2Fc2)/3.

The dispersion factors were taken from International Tables for Cristallography" (International Tables for Cristallography, Vol. C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.1.4).From 3201 reflections used in the refinement, only reflections with Fo2>2σ(Fo2) were used in the calculation of R. When calculating the used 2010 reflections. The final cycle of refinement included 382 variable parameters and converged (largest shift parameter was 0.01 times less than the defined standard deviation) with unweighted and weighted factors matches:

The standard deviation of the data unit mass was 1,01. The highest peak in the final difference Fourier had a height 0,63 e/Å3. The minimum negative peak had a height -0,33 e/Å3.

Spectrum was calculated powder x-ray diffraction (XRPD)

The calculated XRPD spectrum generated for the irradiation of Cu using the program PowderCell 2.3 (PowderCell for Windows Versin 2.3 Kraus, W.; Nolze, G. Federal Institute for Materials Research and Testing, Berlin, Germany, EU, 1999) and of atomic coordinates, space group and unit cell parameters according to the single crystal.

Graphics ORTEP and packaging

Schedule ORTEP received using ORTEP III (Johnson, C.K. ORTEPIII, Report ORNL-6895, Oak Ridge National Laboratory, TN, U.S.A. 1996, and OPTEP-3 for Windows V1.05, Farrugia, L.J.,J. Appl. Cryst.1997,30,565). The atoms are anisotropic thermal ellipsoids with 50%probability. Graphic packaging has been using modeling CAMERON (Watkin, D.J.et al.,CAMERON, Chemical Crystallography Laboratory, University of Oxford, Oxford, 1996).

Results and discussion

Monoclinically cell parameters and calculated volume form And representα=24,2240(10) Å;b=3,74640(10) Å;with=27,4678(13) Å;α=90,00°; β=92,9938(15)°; γ=90,00°;V=2489,38(17) Å3. Molecular weight is 284,25 g/mol-1and Z=8 (where Z represents the number of drug molecules in the asymmetric unit), resulting in calculated density (dcalc., g·cm-3) 1,517 g·cm-3for this crystal structure. Space group determination wasP2l/n (No. 14), which represents an achiral space group. The result data of the crystal and the acquisition parameters crystallographic data are presented below:

C15H9FN2O3
Formula
weight according to the formula284,25
space groupP 1 2l/n 1 (No. 14)
α, Å24,2240(10)
b, Å3,74640(10)
c, Å27,4678(13)
b, C92,9938(15)
V, Å2489,38(17)
Z8
dcalc., g·cm-31,517
the size of the crystal, mm0,44×0,13×0,03
temperature, K150
radiation (wavelength, Å)Moand(0,71073)
the monochromatorgraphite
linear absolute coefficient, mm-10,110

applied to recce absorption empirical
the transmission factors: min, max0,951-997
diffractometerNonius KappaCCD
the rangeh, k, l0 to 28, 0 to 4, -32 to 32
the range 2q, C4,45-49,38
mosaicism, C0,33
used programsCHELXTL
F0001168,0
Weighing 1/[s2(Fo2)+(0,0975P)2+0,0000P],
whereP=(Fo2+2Fc2)/3
the collected data13862
unusual data3201
Rint0,101
the data used in the refinement3201
cutoff used in the calculations of the tah RfactorFo2>2,0s(Fo2)
data withI>2,0s(I)2010
the adjusted attenuation factor0,0046
variables382
the biggest shift that is installed in the final cycle0,00
R(Fo)0,062
Rw(Fo2)0,152
the quality of the match1,006

The quality of the resulting patterns is from high to moderate, as indicated by the value ofR0,062 (6,2%). Usually the value ofRin the range from 0.02 to 0.06 quotesource for most reliably defined structures. Although the quality of the crystal structure slightly beyond the accepted range for most reliably defined structures, the data are of sufficient quality to ensure proper localization of the position of the atoms in the molecular structure.

Schedule ORTEP form As shown figure 11. Asymmetric unit, shown in IG, contains a dimer of two molecules located for the formation of possible hydrogen bonds through neighboring group of carboxylic acids. Since the localization of the protons of the acid was not determined by Fourier map, it is assumed that the molecules are neutral. Graph packing forms And in projection down the a crystallographic axis ofbshown in Fig.9.

Simulated XRPD spectrum of form a is shown in figure 10 was generated according to the single crystal, and it agrees well with the experimental XRPD spectrum of form a (see, for example, Fig 1). Differences in intensity can result from the preferred orientation. The preferred orientation is the tendency of a crystal, usually of plates or needles, be combined with each other with some degree of order. Preferred orientation can affect the intensity of the peaks, but not on the position of the peaks in the XRPD spectra. Small changes in the localization of the peaks can arise from the fact that the experimental powder spectrum was obtained at ambient temperature, and data on a single crystal was obtained at 150 K. the Low temperature used for the analysis of single crystals to improve the quality of the structure.

Table 1 shows the fractional coordinates of the atoms of the asymmetric unit of form A.

Table 1
The parameters of the situation and their standard deviation for the forms And obtained estimates

The hydrogen atoms included in the calculation of structure factors, but not updated.

Table 2
The position of peaks forms And calculated XRPD spectrum generated according to the single crystal

A. I/Iabout= relative intensity.
b. Peaks having I/Iabout= relative intensity of less than 1 and the position of peaks more than 36,6 °2θnot represented.

Table 3
The position of peaks of the experimental XRPD spectrum of form a

A. I/Iabout= relative intensity.
b. Bold characteristic set of peaks in the range of 0.2 °2θrelatively files RTS form In 169490, 172972, 172973, 170901, 169284 and 168717.

Table 4
The position of the peaks in the XRPD spectrum of form (file 169490)

A. I/Iabout= relative intensity.
b. Bold characteristic set of peaks in comparison with form A.

Table 5
The position of the peaks in the XRPD spectrum of form (offset 1) (file 168717)
A. I/Iabout= relative intensity.
b. Bold characteristic set of peaks in comparison with form A.

Table 6
The position of the peaks in the XRPD spectrum of form (offset 2) (file 172972)
A. I/Iabout= relative intensity.
b. Bold characteristic set of peaks in comparison with form A.

Table 7
The position of the peaks in the XRPD spectrum of form (offset 3) (file 172173)
A. I/Iabout= relative intensity.
b. Bold characteristic set of peaks in comparison with form A.

Table 8
The position of the peaks in the XRPD spectrum of form B (RO) (file 170901)
A. I/Iabout= relative intensity.
b. Bold features the ing a set of peaks in comparison with form A.

Table 9
The position of peaks shifted XRPD spectrum of form (file 169284)
A. I/Iabout= relative intensity.
b. Bold characteristic set of peaks in comparison with form A.

1. Crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, characterized by at least one of the following conditions:
(a) the unit cell parameters, measured at 150 K:=24,220 Å; b=3,74640 Å; C=27,4678 Å; α=90°; β=92,9938°; γ=90°; V=2489,38 (17) Å3; Z=8; calculated density (dcalc, g·cm-3) is 1,517 g·cm-3; and the space group is P21/n (No. 14);
(b) x-ray powder diffraction pattern containing at least three peaks (°2θ±0,2)obtained when measured using cu-Kα radiation, selected from the group consisting of:

4.69, 6.39, 10.10, 11.54, 12.62, 12.81, at 13.92, 14.16, 14.55, at 14.88, 15.07, 15.58, 16.27, 16.61, 18.74, 18.94, 19.28, 19.94, 20.27, 20.74, 20.97, 21.22, 21.93, 22.58, 22.80, 23.00, 23.79, 24.14, 24.46, 25.44, 25.64, 26.07,26.34, 26.74, 27.06, 27.79, 28.42, 29.09 and 30.48;
(c) mass loss on thermogram, obtained by means of thermogravimetric analysis, is less than 1% of the total mass of the sample after heating from 33°C to 205°C;
(d) thermogram of differential scanning calorimetry contains the endotherm with a peak in temperature at the level of 244°C and
(e) functional coordinates of atoms equal presents

-0.09772(17)/tr>
AtomXYzU (Å2)
P(122)0.43198(12)0.7655(8)-0.17546(10)0.0487(10)
F(222)-0.20343(15)0.7129(10)0.06378(14)0.0781(14)
O(13)0.42977(13)0.4875(8)-0.08927(11)0,0324(10)
O(23)-0.12941(13)0.4507(9)0.12653(12)0.040(10)
O(151)0.25519(13)0.4795(9)0.10765(12)0.0382(10)
O(152)0.29215(13)0.2155(9)0.17515(12)0.0403(10)
O(251)0.16226(13)0.4813(9)0.15012(12)0.0385(10)
O(252)0.19645(13)0.1939(9)0.21659(12)0.0393(10)
N(11)0.35817(15)0.5856(9)-0.04386(14)0.0279(10)
N(14)0.44373(16)0.3409(10)-0.04263(14)0.0327(12)
N(21)-0.04134(16)0.5165(9)0.11065(14)0.0305(12)
N(24)0.3201(11)0.16787(15)0.0388(14)
C(12)0.37827(18)0.6256(11)-0.08637(17)0.0266(14)
C(15)0.40019(19)0.4091(11)-0.01823(17)0.0261(14)
C(22)-0.0926(2)0.5601(12)0.09502(18)0.0319(15)
C(25)-0.0471(2)0.3690(11)0.15580(17)0.0302(15)
C(121)0.35225(19)0.7961(11)-0.12930(17)0.0291(14)
C(122)0.3784(2)0.8567(12)-0.17244(18)0.0345(15)
C(123)0.3519(2)1.011712) -0.21257(19)0.0407(17)
C(124)0.2973(2)1.1101(13)-0.21014(19)0.0416(17)
C(125)0.2694(2)1.0543(12)-0.1677(2)0.0409(17)
C(126)0.2966(2)0.8996(12)-0.12784(18)0.0349(15)
C(151)0.39702(19)0.3013(11)0.03319(16)0.0260(14)
C(152)0.34897(19)0.3623(11)0.05704(16)0.0261(15)
C(153)0.34631(18)0.2594(11)0.10554(16)0.0253(14)
C(154)0.39150(19)0.0970(11) 0.13029(17)0.0279(14)
C(155)0.43977(19)0.0412(11)0.10614(17)0,0291(15)
C(156)0.44250(19)0.1421(11)0.05765(17)0.0292(15)
C(157)0.2955(2)0.3188(12)0.13209(18)0.0312(15)
C(221)-0.1109(2)0.7083(12)0.04727(19)0,0388(17)
C(222)-0.1643(3)0.7823(15)0.0331(2)0.053(2)
C(223)-0.1825(3)0.9272(15)-0.0122(3)0.064(2)
C(224)-0.1415(4)0.9930(16)-0,0433 (3)0.068(3)
C(225)-0.0870(3)0,9202(15)-0.0316(2)0.066(2)
C(226)-0.0678(3)0.7766(12)0.01365(17)0.0543(19)
C(251)0.00110(19)0.2695(11)0.18877(17)0.0300(15)
C(252)0.05426(19)0.3352(11)0.17481(17)0.0289(15)
C(253)0.09949(19)0.2449(11)0.20524(17)0.0277(15)
C(254)0.0919(2)0.0940(11)0.25087(17)0.0296(15)
C(255)0.0389(2)0.0335(11)0.26491(17)0.0300(15)
(256) -0.0064(2)0.1185(12)0.23430(17)0,0322(15)
(257)0.1559(2)0.3165(12)0.18902(17)0.0305(15)
N(123)0.3711,050-0.2410,048
H(124)0.2781,217-0.2380.050
H(125)0.2321.123-0.1660.049
H(126)0.2780.862-0.0990.042
H(151)0.2270.4910.1250.057
N(152)0.3180.4730.041 0.031
H(154)0.3890.0250.1630.033
N(155)0.471-0.0660.1230.035
N(156)0.4750.1030,0410.035
N(223)-0.2200.975-0.0200.077
N(224)-0.1511.094-0.0740.082
N(225)-0.0610.969-0.0550.080
N(226)-0.0300.7290.0210.065
N(252)0.2260.213 0.2020.059
H(254)0.1230.0340.2720.035
N(255)0.033-0.0680.2960.036
H(256)-0.0430.0740.2440.039
N(25A)0.0600.4430,1440.035

2. The crystalline form according to claim 1, which has the following unit cell parameters, measured at 150 K:=24,220 Å; b=3,74640 Å; C=27,4678 Å; α=90°; β=92,9938°; γ=90°; V=2489,38 (17) Å3; Z=8; calculated density (dcalc, g·cm-3) is 1,517 g·cm-3; and the space group is P21/n (No. 14).

3. The crystalline form according to claim 1, the x-ray powder diffraction pattern which contains at least three peaks (°2θ±0,2)obtained when measured using cu-Kα radiation, selected from the group consisting of:

4.96, 6.39, 10.10, 11.54, 12.62, 12.81, at 13.92, 14.16, 14.55, at 14.88, 15.07,15.58, 16.27, 16.61, 18.74, 18.94, 19.28, 19.94, 20.27, 20.74, 20.97, 21.22, 21.93, 22.58, 22.80, 23.00, 23.79, 24.14, 24.46, 25.44, 25.64, 26.07, 26.34, 26.74, 27.06, 27.79, 28.42, 29.09 and 30.48.

4. The crystalline form according to claim 3, the x-ray powder diffraction pattern which contains at least one peak (°2θ±0,2) when measured using cu-Kα radiation, selected from the group consisting of peaks in the area 10,10, 11,54, 14,55, 14,88 and 15,07.

5. The crystalline form according to claim 1, characterized13With NMR signals CP/MAS solid state localized in one or more of the following provisions: 172,6, 167,0, 131,3, 128,4 and 117,1 ppm with external comparison with glycine at 176,5 ppm

6. The crystalline form according to any one of claims 1 to 5, which is a thermogram of differential scanning calorimetry, containing the endotherm with a peak in temperature at the level of 244°C.

7. The crystalline form according to any one of claims 1 to 5, which has a thermogram obtained by means of thermogravimetric analysis, according to which the mass loss is less than 1% of the total mass of the sample after heating from 33°C to 205°C.

8. The crystalline form according to any one of claims 1 to 5, which is not hygroscopic.

9. The crystalline form according to any one of claims 1 to 5, which is clean.

10. Crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, characterized by at least one of the following conditions:
(a) rent is anouska powder diffraction pattern contains at least three peaks (°2θ±0,2), obtained when measured using Cu-Kα radiation, selected from the group consisting of:

6.14, 6.39, 6.96, 7.92, 10.78, 12.44, 12.61, 12.88, 13.52, 13.78, 13.97, 14.30, 15.46, 15.68, 15.89, 16.33, 16.76, 17.03, 20.10, 21.03, 23.34, 23.86, 24.18, at 24.42, 24.64, 26.62, 26.96, 27.29, 27.64, 27.96, 28.81, 31.05, 32.38, 32.58, 36.23, 37.81, 38.28, 38.44 and 39.16;
(b) mass loss on thermogram of differential scanning calorimetry is less than 5% of the total mass of the sample after heating from 25°C to 165°C;
(c) thermogram of differential scanning calorimetry contains the endotherm with a peak in temperature at the level of 243°C.

11. The crystalline form of claim 10, which includes the solvent in the crystal lattice.

12. The crystalline form of claim 10, which contains water in the crystal lattice.

13. The crystalline form according to item 12, which contains 1 molar equivalent of water in the crystal lattice per mole of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

14. The pharmaceutical composition intended for treating or preventing diseases or disorders associated with premature termination-codon containing a crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid described in any one of claims 1 to 9, and one or more carriers, excipients or diluents.

15. The pharmaceutical composition according to 14, intended for oral administration of insertion through the mucous membranes, parenteral, transdermal or local injection.

16. The pharmaceutical composition according to 14 or 15 represents a single standard dosage form.

17. The use of crystalline forms of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid described in any one of claims 1 to 13, for modulation of suppression of a premature termination codon in the cell by contacting the cell with a crystalline form.

18. The use of crystalline forms of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid described in any one of claims 1 to 13, for preparing a medicinal product for treating or preventing diseases or disorders associated with premature termination of the codon, the need in this patient.

19. Use p, where the disease or disorder associated with premature termination-codon, is a mucopolysaccharidosis type III, hemophilia A, hemophilia, neurofibromatosis 1, neurofibromatosis 2, Parkinson's disease, cystic fibrosis, degeneration yellow spots, ataxia-telangiectasia, pigments retina, tuberose sclerosis, muscular dystrophy DuChene and Marfan syndrome.

20. Use p, where the disease or disorder associated with premature termination-codon, is a disease of the blood, pigments is atchade, disease of the Central nervous system or muscular dystrophy.

21. Use p, where the disease or disorder associated with premature termination-codon, is a cancer that is associated with the premature termination codon in the gene for the tumor suppressor gene p53.

22. Crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid characterized by x-ray powder diffraction pattern containing at least three peaks (°2θ±0,2)obtained when measured using Cu-Kα radiation, selected from the group consisting of:

6.42, 7.00, 7.89, 10.85, 12.61, 12.92, 13.47, 13.97, 15.81, 16.45, 17.12, 20.05, 21.05, 23.92, 24.28, 27.00, 27.39, at 27.84, 28.04, 28.94, 31.10, 32.58, 36.11, 37.71, at 38.15 and 38.61.

23. The crystalline form according to item 22, which contains the solvent in the crystal lattice, where the specified solvent is a 1-butyl acetate.

24. Crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid characterized by x-ray powder diffraction pattern containing at least three peaks (°2θ±0,2),
obtained by measurement using Cu-α radiation selected from the group consisting of: 6.10, 6.38, 6.54, 7.10, 8.02, 10.91, 12.71, 13.50, 13.62, at 13.86, 14.10, 15.56, 15.70, 15.91, 16.55, 16.96, 17.22, 17.50, 19.82, 20.08, 20.34, 21.15, 23.78, 23.93, 24.38, 24.56, 26.88, 27.16, 27.48, 27.88, 28.04, 28.78, 29.02, 32.71, 36.01, 38.10, 38.56 and 39.38.

25. The crystalline form according to paragraph 24, which contains dissolve the spruce in the crystal lattice, where the specified solvent is a mixture of 1:1 tetrahydrofuran and heptane.

26. Crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid characterized by x-ray powder diffraction pattern containing at least three peaks (°2θ±0,2)obtained when measured using Cu-Kα radiation, selected from the group consisting of: 1.79, 2.30, 2.57, 2.78, 3.29, 3.59, 3.89, 4.07, 4.34, 4.49, 4.76, 5.06, 6.47, 6.91, 7.96, at 10.89, 12.87, 13.58, 13.99, at 15.97, 16.48, 17.10, 20.00, 20.36, 21.04, 23.40, 24.29, 24.89, at 26.87, 27.49, 27.80, 28.07, 29.08 and 38.61.

27. Crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid characterized by x-ray powder diffraction pattern containing at least three peaks (°2θ±0,2), obtained by measurement using Cu-α radiation selected from the group consisting of: 6.22, 6.51, 7.13, 8.17, 10.91, 12.87, 13.80, 14.12, 14.28, 15.78, 16.23, 16.54, 17.15, 20.33, 21.22, 21.36, is at 23.94, 24.30, 27.30, 27.58, 28.00, 28.74, 28.96, 32.70, 36.74, 38.18, 38.38, 38.52 and 39.31.

28. The crystalline form according to item 27, which contains the solvent in the crystal lattice, where the specified solvent is dimethoxyethan.

29. Crystalline form of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid characterized by x-ray powder diffraction pattern containing at least three peaks (°2θ±0,2)obtained when measured using Cu-Kα radiation, selected from the group consisting of the C: 6.04, 6.49, 7.91, 10.92, 12.61, 12.92, 13.10, 13.42, 13.82, 13.99, 15.40, 15.76, 16.51, 17.15, at 19.92, 20.04, 21.01, 23.92, 24.28, at 24.48, 26.77, 27.14, 27.40, 27.74, 28.09, 28.82, 28.99, 31.03, 32.58, 35.64, 35.85, 37.48, 37.66 and 38.62.

30. The crystalline form according to any one of p, 22, 24, 26, 27 or 29, which contains the crystal lattice is less than 6 molar equivalents of solvent per mole of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.

31. The crystalline form according to any one of p, 22, 24, 26, 27 or 29, which is capable of partial transformation into crystalline form, which nephroscopy.

32. The crystalline form according to any one of p, 22, 24, 26, 27 or 29, which is able to transform into a crystalline form, which nephroscopy.

33. The crystalline form according to any one of p, 22, 24, 26, 27 or 29, which can partially transform into a crystalline form according to any one of claims 1 to 9.

34. The crystalline form according to any one of p, 22, 24, 26, 27 or 29, which is able to transform into a crystalline form according to any one of claims 1 to 9.

35. A method of obtaining a crystalline form according to any one of claims 1 to 9, including: (1) grinding the crystalline form according to any one of p, 22, 24, 26, 27 or 29 when the ambient temperature or a temperature below ambient temperature, (2) the suspension of the crystalline form according to any one of p, 22, 24, 26, 27 or 29 in the solvent or the solvent system, (3) heating the crystalline form according to Liu the WMD from PP, 22, 24, 26, 27 or 29, (4) crystallization of the crystalline form according to any one of claims 1 to 9 of the solvent or solvent system, (5) evaporating the solvent or solvent system containing 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, at a temperature in the range from 50°C to 60°C, or (6) evaporation of the solvent or solvent system containing 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid, at a temperature in the range from 50°C to 81°C.

36. The method according to p, where the crystalline form according to any one of p, 22, 24, 26, 27 or 29, is suspended in the solvent or solvent system selected from the group consisting of isobutyl ketone or 1:1-mixture of dioxane and water.

37. The method according to p, where the crystalline form according to any one of p, 22, 24, 26, 27 or 29 sublimated after heating at a temperature in the range from 160°C to 208°C in vacuum, or after heating at 220°C, or after heating at a temperature of 255°C.

38. The method according to p, where the crystalline form according to any one of claims 1 to 9 were led from a solvent or solvent system selected from the group consisting of: methanol, tert-butyl alcohol, 1-butyl alcohol, acetonitrile, isopropyl alcohol, simple isopropyl ether, dimethylformamide, heptane, isopropylacetate, toluene, water or mixtures thereof.

39. The method according to p, where the solvent is a solvent system, which is evaporated at a temperature in the range from 50°C to 60°C, selected from the group consisting of: acetonitrile, tert-butyl alcohol, isopropyl alcohol, simple isopropyl ether, water or mixtures thereof.

40. The method according to p, where the solvent or solvent system, which is evaporated at a temperature in the range from 50°C to 81°C, selected from the group consisting of: methanol, 1-butyl alcohol, tert-butyl alcohol, dimethylformamide, dimethoxyethane, simple isopropyl ether, water or mixtures thereof, optionally in combination with sodium chloride.

41. The method according to p, where the system solvent, which is evaporated at a temperature in the range from 50°C to 81°C, selected from the group consisting of: dimethylformamide:water and systems containing tert-butyl alcohol:water (3:2) and methanol:sodium chloride (1:1).

42. The method of obtaining the crystalline form of claim 10, including: (1) crystallization of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid from a solvent selected from the group consisting of tetrahydrofuran, hexane, isopropyl alcohol, ethyl acetate, acetic acid, 1-butyl acetate, acetone, easy dimethyl ether, simple diethyl ether, dioxane, isobutyl ketone, methyl ethyl ketone, nitromethane, water, and mixtures thereof, (2) evaporation of the solvent, containing 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoi the second acid selected from the group consisting of acetone, easy dimethyl ether and methyl ethyl ketone, at a temperature in the range from 50°C to 60°C, (3) evaporation of the solvent or solvent system containing 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid and selected from the group consisting of acetone, acetic acid, 1-butyl acetate, easy dimethyl ether, tetrahydrofuran and simple diethyl ether; dioxane; ethyl ketone; nitromethane; isobutyl ketone; tetrahydrofuran:hexane (2,5:1) and dioxane: water (3:2), at elevated temperature, (4) the suspension of the crystalline form according to any one of claims 1 to 9 in a solvent selected from the group consisting of acetic acid, 1-butyl acetate and nitromethane, or (5) heating the crystalline form according to any one of claims 1 to 9 in 1-propanol at 60°C for one day in the vibrator.

43. A method of obtaining a crystalline form according to article 22, including suspension of 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid vibrator in 1-butyl acetate at room temperature for three days.

44. A method of obtaining a crystalline form according to paragraph 24, including the suspension of crystalline form according to any one of claims 1 to 9 in a mixture of tetrahydrofuran:heptane (1:1) at ambient temperature for one day, making diluted, for the first time, a mixture of crystalline form according to any one of claims 1 to 9 and ristalliceski form of claim 10, suspension for another day, introduction diluted, for the second time, the crystalline form according to any one of claims 1 to 9, and the suspension within seven days, and introducing the diluted, for the third time, the crystalline form according to any one of claims 1 to 9, suspension for one day at 50°C.

45. The method of obtaining crystalline form b, including maintaining the crystalline form of claim 10 under conditions of a relative humidity of 75% at 40°C for six days.

46. A method of obtaining a crystalline form according to item 27, which includes evaporation of the solvent dimethoxyethane or solvent system containing 3-[5-(2-forfinal)-[1,2,4]oxadiazol-3-yl]benzoic acid.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention offers compounds presented by general formula (I): or their pharmaceutically acceptable salts wherein R1, R2, R3 and R4 are presented in the description and exhibit substantial COMT inhobotory activity. Besides, the present invention described pharmaceutical compositions inhibiting catechol-O-transferase activity which contain the compound or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

EFFECT: there are declared pharmaceutical combinations for treatment or prevention of Parkinson's disease which contain (1) the pharmaceutical composition containing the compound under any cl 1-8 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier, and (2) at least one compound specified in L-dope or carbidole.

10 cl, 9 ex, 17 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine of formula (I) in which R1 denotes a methyl group, R2 denotes a R21NR22 group, where R21 denotes an ethyl group which is substituted with an ethoxycarbonyl group, and R22 denotes a pyridin-2-yl group, R3 denotes an n-hexyloxycarbonyl group, where at step (a) phenyldiamine of formula (II) where R1 and R2 assume values given for formula (I), which reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, to obtain a product of formula (III) where R1 and R2 assume values given for formula (I), which is hydrogenated at temperature from 30 to 60°C at hydrogen pressure from 1 to 10 bar, over palladium on activated charcoal (Pd/C) in a mixture of tetrahydrofuran and water, and then, without any preliminary extraction of the hydrogenation product, the obtained compound of formula (I), in which R3 denotes hydrogen, in the presence of potassium carbonate reacts with a compound of formula (IV) R3-X (IV), where R3 assumes values given for formula (I), and X denotes a suitable splitting group.

EFFECT: simple method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine.

3 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new phenyl derivatives with the formula (I) where # symbol indicates two carbon atoms of the phenyl ring bearing R1, R2 and R3; to each of the latter components the A group can be linked; and where A represents or where asterisks indicate the link through which the formula (I) is linked to the phenyl ring bearing R1, R2 and R3; R1 represents hyndrogen or C1-3-alkyl; R2 represents C2-5-alkyl or C1-4-alkoxy group; R3 represents hydrogen, and in case when the A group is linked in the para-position in relation to the phenyl ring of the formula (I) bearing R1, R2 and R3, R3 can additionally represent the methyl group; R4 represents hydrogen; R5 represents C1-3-alkyl; R6 represents a hydroxy group, di-(hydroxy-C1-4-alkyl)-C1-4-alkoxy group, 2,3-dihydroxypropoxy group, -OCH2-CH(OH)-CH2-NR61R62 or -OCH2-CH(OH)-CH2-NHCOR64; R61 represents hydrogen; R62 represents hydrogen; R64 represents hydroxymethyl; and R7 represents C1-3-alkyl; and to its salt. The invention also refers to the pharmaceutical composition that is agonistic in relation to S1P1/EDG1 receptor on the basis of the mentioned compounds.

EFFECT: new compounds and the pharmaceutical composition based on them that may find their application in medicine as immunomodulating agents.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: medicine.

SUBSTANCE: there is described application of 1-hetaryl-2-nitro-2-(3-phenyl-1,2,4-oxadiazole-5-yl)ethanes of general formula I a-m 1a, e, and R1=NO2, R2=H; 1b, f, to R1=NO2, R2=Me; 1c, g, l R1=CO2Et, R2=H; 1d, h, m R1 =CO2Et, R2 =Me; 1a-d R2 =piperidino; 1e-h R3 =1-pyrrolidinyl, 1j-m R3=morpholino as psychotropic substances.

EFFECT: substances are low-toxic and have an evident psychotropic effect on rats.

4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to sulphonic 2-nitro-2-(3-aryl-1,2,4-oxadiazole-5-yl)ethane derivatives of formula I a-g la R=3-NO2C6H4, R1=NO2, R2=H; b R=3-NO2C6H4, R1=NO2, R2=CH3; c R=4-CH3OC6H4, R1=NO2, R2=H; d R=4-CH3OC6H4, R1=NO2, R2=CH3; e R=4-CH3OC6H4, R1=CO2Et, R2=H; f R=4-CH3OC6H4, R1=CO2Et, R2=CH3; g R=4-CH3C6H4, R1=CO2Et, R2=H.

EFFECT: preparation of the compound exhibiting antileprous and antituberculous activity.

1 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to nanotechnology of new materials applicable in biology, veterinary science and medicine, particularly for laser hyperthermia of new growths. What is presented is a method differing from known ones by agent concentrations, pH values of a reaction mixture, and particle surface functionalisation. At the first stage, gold spherical particles of the diameter of 1-3 nm used as a templates for the further growth of non-spherical particles are synthetised. At the second stage, gold is additionally reduced by ascorbic acid on the particles in cetyl trimethyl ammonium bromide in an acid medium (pH=1). At the third stage, cetyl trimethyl ammonium bromide molecules on the particle surface are substituted by polyethylene glycol for reducing biotoxicity of gold nanorods. The method uses the ingredients taken in specific molar ratios. What is also presented is a thermal sensitiser which is produced by the method above and representing a gold nanorod suspension. The rods are 30-45 nm long, 9-12 nm wide and coated by polyethylene glycol molecules.

EFFECT: invention provides higher stability and reproducibility of the gold nanorod synthesis with biotissue infrared absorption, as well as reduced toxicity of the thermal sensitiser.

2 cl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered: use of the tri-substituted glycerol compounds of formula (I) in preparing a therapeutic agent with said therapeutic agent applied with at least one other therapeutic agent containing one or more additional active ingredients specified in a group consisting of antimetabolites, herbal alkaloids, topoisomerase II inhibitors, proteasome inhibitors; related combination and an in vitro method for determining sensitivity of hematological malignant tumours to a combination of the therapeutic agents as specified in the present invention.

EFFECT: what is presented is a synergic cytotoxic effect of the compound of formula (I) of edelfosine in a combination with the proteasome inhibitor Bortezomib, with the antimetabolite fludarabine, cytarabine, the topoisomerase II inhibitor edelfosine.

11 cl, 10 dwg, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and may be used for treating liver metastases. That is ensured by introducing the hydrophobic suspension Teraftal® containing a radiopaque substance into a hepatic artery. The introduction is aided by X-ray. It is followed by the introduction of ascorbic acid started one day after the arterial embolisation and continued for seven days daily. A single dose of ascorbic acid makes 100 mg.

EFFECT: invention provides partial metastasis regression in limited hepatic metastatic involvement that leads to prolonging average-expectancy life.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology and radiology, and concerns prevention of complications in treating the patients with lung cancer. For this purpose, a complex of radiation and antioxidant therapy involves antioxidant preparations containing derinat - conducting radiation therapy, antioxidant and drug-induced therapy differing by the fact that the antioxidant drug-induced therapy involves the prescribed per os derinat-containing preparations - Coletex-gel-DNA and Coletex-gel-DNA-D. The antioxidants are administered in the following regimen: for 10-15 days before the beginning of the radiation therapy Coletex-gel-DNA 15-20 g 1-3 times a day; during the entire course of the radiation therapy, Coletex-gel-DNA-L 25-30 g 15 minutes before a session; after the termination of the radiation therapy for 10-15 days Coletex-gel-DNA-L 25-30 g before and after each meal.

EFFECT: such regimen of the introduction of the preparations provides reduced side effects and higher clinical effectiveness ensured by conducting the radiation therapy in full thereby with no pauses caused by complications.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology and concerns treating oesophageal cancer. That is ensured by the intravenous introduction of 5-fluoruracil twice a week, 300 mg/m in one introduction every 2-3 days in a combination with the oral introduction of Coletex-gel-DNA-L 10-15 ml 3 times a day. On the other days of week, the hydrogel material Hydrogel Tissue Coletex-5-ftur is introduced in a dose 5 ml once a day; 10-15 min before the introduction of the gel material, Coletex-gel-DNA-L 10-15 ml is additionally introduced. Length of the therapeutic course is 4 weeks.

EFFECT: method provides higher effectiveness of the treatment ensured by a higher dose of cytostatic with reduced general toxicity and side effects.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is presented is an antibody produced of hybridoma ATCC No. PTA-7580 specific to human protein tyrosine phosphatase beta (HPTPβ). What is described is a Fab version of said antibody, as well as versions of method of treating and pharmaceutical compositions based on the use of the antibodies. Binding the antibody and HPTPβ intensifies Tie-2 signal transmission, and thereby increases angiogenesis, whereas binding the Fab antigen-binding antibody fragment and HPTPβ inhibits Tie-2 signal transmission, and thereby reduces angiogenesis.

EFFECT: use of the invention can find application in medicine for treating the diseases related to disturbed angiogenesis.

21 cl, 12 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to conjugates of Disorazol with cell adhesion molecules, such as peptides, proteins, hormones, blood proteins, and methods for preparing conjugates.

EFFECT: conjugates of Disorazol may be used as drug preparations for treating various tumours.

19 cl, 17 dwg, 2 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology and medicine, more specifically to the use of EGFRvIII in a combination with temozolomide, and may be used for treating a tumour in an individual. A method of treating the tumour in the individual provides introducing into the individual an amount of temozolomide effectively inducing lymphopenia; monitoring of white blood cell count after introducing temozolomide; and introducing into the individual an effective amount of the EGFRvIII peptide for white blood cell count recovery in a point of the least white blood cell count. Introducing the EGFRvIII peptide into the individual may be combined with introducing the effective amount of GM-CSF as an adjuvant.

EFFECT: invention enables the combined chemotherapy and immunotherapy without downing the immunotherapeutic effects with temozolomide-induced lymphopenia being able to intensify action of a peptide vaccine.

19 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compound presented by Formula

or Formula ,

wherein A and B optionally represent CH2, CO; D represent S; the values R1, R2, R4, R4 are specified in cl. 1 of the patent claim, as well as to their pharmacologically acceptable salts or hydrates and methods for preparing them.

EFFECT: compounds are able to inhibit TNF-α recovering cells.

19 cl, 71 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, specifically to 16-(1,2,4-oxadiazol-3-yl)-15,16-epoxilabdanoids of formula

wherein R=Me(Ia), Ph(1b), CH2Cl(lc) possessing an ability to inhibit human tumour cell growth. The compounds are produced of lambertianic acid contained in Siberian cedar gum and fir needles.

EFFECT: there are produced new compounds which possess considerable cytotoxic activity on human tumour cells.

1 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

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