C-met/hgfr inhibitor polymorphs

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to polymorph of 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazol-1-yl]ethanol, particularly to a new crystalline phosphate salt of 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazol-1-yl]ethanol.

EFFECT: preparing the pharmaceutical composition and using the new salt in treating cell growth abnormalities, such as cancer in mammals.

10 cl, 10 dwg, 6 tbl, 5 ex

 

This application claims priority from provisional patent application U.S. Provisional Application No. 60/991169, issued November 29, 2007, the contents of which is given here by reference in full.

The technical field to which the invention relates.

The invention relates to salts and polymorphs of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazole-1-yl]ethanol used in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to compositions including such salts and polymorphs, and methods of using such compositions in the treatment of abnormal cell growth in mammals, particularly in humans.

The level of technology

The compound 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo-[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol (referred to here as "compound 1"), represented by formula 1

a potent synthetic inhibitor of the activity of c-Met/HGFR (growth factor receptor of hepatocytes) kinase and ALK activity (kinase anaplastic lymphoma). Compound 1 possesses antitumor properties, which are pharmacologically mediated through inhibition of c-Met/HGFR, which is involved in the regulation of growth and metastatic development of a large variety of tumor types, and ALK, which is obleceni in the pathogenesis of ALCL (anaplastic both lymphoma). Compound 1 is disclosed in international application No. PCT/IB2007/001142 and in the patent application US No. 11/745921, the content of which is given here by reference in full.

Cancer in humans include a variety of many diseases, which together are one of the leading causes of mortality in developed countries around the world (American society of cancer control, Cancer. The facts and figures. 2005. Atlanta: American society of cancer; 2005). The development of cancer is caused by a number of comprehensive variety of genetic and molecular events, including gene mutation, chromosomal translocation and karyotypic abnormalities (Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying cancer genetic causes are varied and complex, we discovered that each type of cancer shows similarities and acquired features that contribute to its development. These acquired capabilities include uncontrollable cell growth, stable ability to form blood vessels (i.e., the ability to angiogenesis) and the ability of tumor cells to spread locally and to metastasize into secondary organs (Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70). Therefore, the ability to identify new tera is efticiency funds which 1) inhibit molecular targets that are changed in the process of cancer development, or 2) focus on the many processes that are common in the development of cancer in various tumors, is of great importance.

In example 209 patent application US No. 11/745921 described getting mesilate salt of compound 1, which was discovered, is a crystalline polymorphs. It is important to have salt and polymorphic salt having improved properties such as improved crystallinity, dissolution characteristics and/or reduced hygroscopicity, while maintaining the properties of the chemical and enantiomeric stability.

The invention

In one embodiment, the present invention provides a compound comprising a salt selected from the group consisting of cleaners containing hydrochloride salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol, maleate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol the phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol and tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In specific aspects of this invention the salt is anhydrous. In the l is an additional aspect the salt is crystalline. In an additional aspect, the salt is a crystalline anhydrous salt. In an additional aspect, the salt is almost pure polymorphs. In an additional aspect, the salt is a compound comprising cleaners containing hydrochloride salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the salt is a compound comprising maleato salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the salt is a compound comprising a phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the salt is a compound comprising a sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the salt is a compound comprising tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

In yet another embodiment, the present invention provides pharmaceutically acceptable salt of the compounds of formula 1.

provided that the pharmaceutically acceptable salt is not mesilate salt. In an additional aspect, the pharmaceutically acceptable salt is crystalline. In an additional aspect, the pharmaceutically acceptable salt is one the Xia crystalline anhydrous salt. In an additional aspect, the pharmaceutically acceptable salt is almost pure polymorphs. In an additional aspect, the pharmaceutically acceptable salt is a cleaners containing hydrochloride salt. In an additional aspect, the pharmaceutically acceptable salt is maleate salt. In an additional aspect, the pharmaceutically acceptable salt is a phosphate salt. In an additional aspect, the pharmaceutically acceptable salt is a sulfate salt. In an additional aspect, the pharmaceutically acceptable salt is toileta salt.

In an additional aspect, the present invention provides a connection representing cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol, which is characterized by a powder x-ray that includes a peak at the next value of the diffraction angle (2θ): 27,6±0,2. In an additional aspect of cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,7±0,2 and 27.6±0,2. In an additional aspect of cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes the peaks in the trace of the actual operation values of the angle (2θ): 17,7±0,2, 24,5±0,2 and 27.6±0,2. In an additional aspect of cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,7±0,2, 24,5±0,2, 26,5±0,2 and 27.6±0,2. In an additional aspect of cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,7±0,2, 24,5±0,2, 25,6±0,2, 26,5±0,2 and 27.6±0,2. In an additional aspect of cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 11,6±0,2, 17,7±0,2, 24,5±0,2, 25,6±0,2, 26,5±0,2 and 27.6±0,2. In an additional aspect of cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 11,6±0,2, 17,7±0,2, 20,3±0,2, 24,5±0,2, 25,6±0,2, 26,5±0,2 and 27.6±0,2. In an additional aspect of cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): the practice is logically the same, as shown in figure 1.

In an additional aspect, the present invention provides a compound comprising crystalline maleato salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes a peak at the next angle (2θ): 24,6±0,2. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 22,6±0.2 and 24,6±0,2. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo-[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 13,2±0,2, 22,6±0.2 and 24,6±0,2. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-yl-methyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 12,9±0,2, 13,2±0,2, 22,6±0,2 and 24.6±0,2. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray, comprising peaks at the following angles (2θ): 12,9±0,2, 13,2±0,2, 16,6±0,2, 22,6±0,2 and 24.6±0,2. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 12,9±0,2, 13,2±0,2, 16,1±0,2, 16,6±0,2, 22,6±0,2 and 24.6±0,2. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 12,9±0,2, 13,2±0,2, 16,1±0,2, 16,6±0,2, 22,6±0,2, 23,9±0,2 and 24.6±0,2. In an additional aspect, the crystalline malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): almost the same, as shown in figure 2.

In an additional aspect, the present invention provides a compound comprising a crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes a peak at the next angle (2θ): 17,0±0,2. In to anitelea aspect crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray, comprising peaks at the following angles (2θ): 17,0±0,2 and 20.9±0,2. In an additional aspect, the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2, 20,9±0.2 and 24,8±0,2. In an additional aspect, the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2, 20,9±0,2, 24,8±0,2 and 25.8±0,2. In an additional aspect, the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2, 20,9±0,2, 24,8±0,2, 25,8±0,2 and 28,4±0,2. In an additional aspect, the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2, 20,9±0,2, 24,8±0,2, 25,8±0,2, 27,0±0,2 and 28,4±0,2. In an additional aspect, the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2, 20,±0,2, 24,8±0,2, 25,8±0,2, 27,0±0,2, 28,4±0,2 and of 28.9±0,2. In an additional aspect, the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): almost the same, as shown in figure 3.

In an additional aspect, the present invention provides a compound comprising a crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes a peak at the next angle (2θ): 15,2±0,2. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 15,2±0.2 and 18,0±0.2. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 15,2±0,2, 18,0±0,2 and 25.0±0,2. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray, comprising peaks at the following angles (2θ): 15,2±0,2, 18,0±0,2, 25,0±0,2 and 27.2±0,2. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo-[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 15,2±0,2, 18,0±0,2, 25,0±0,2, 25,7±0,2 and 27.2±0,2. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 15,2±0,2, 18,0±0,2, 22,0±0,2, 25,0±0,2, 25,7±0,2 and 27.2±0,2. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 15,2±0,2, 18,0±0,2, 22,0±0,2, 25,0±0,2, 25,7±0,2, 27,2±0,2 and 27.8±0,2. In an additional aspect, the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): almost the same, as shown in figure 4.

In an additional aspect, the present invention provides a compound comprising a crystalline polymorphic form tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]three is gold[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes a peak at the next angle (2θ): 24,4±0,2. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 16,5±0,2 and 24.4±0,2. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 16,5±0,2, 17,2±0,2 and 24.4±0,2. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 14,9±0,2, 16,5±0,2, 17,2±0,2 and 24.4±0,2. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 10,7±0,2, 14,9±0,2, 16,5±0,2, 17,2±0,2 and 24.4±0,2. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray, comprising peaks at the following angles (2θ): 10,7±0,2, 14,9±0,2, 16,5±0,2, 17,2±0,2, 24,4±0,2 and 27.2±0,2. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): 10,7±0,2, 14,9±0,2, 16,5±0,2, 17,2±0,2, 24,4±0,2, 26,6±0,2 and 27.2±0,2. In an additional aspect, the crystalline toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is characterized by a powder x-ray that includes peaks at the following angles (2θ): almost the same, as shown in figure 5.

The present invention additionally provides a pharmaceutical composition comprising crystalline cleaners containing hydrochloride salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. The present invention additionally provides a pharmaceutical composition comprising crystalline maleato salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. The present invention additionally provides a pharmaceutical composition comprising a crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. The present invention additionally provides a pharmaceutical composition, including the expansion of the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. The present invention additionally provides a pharmaceutical composition comprising crystalline tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

The present invention additionally provides a capsule comprising the mentioned pharmaceutical composition. In a particular aspect of this alternative implementation, the capsule comprises from 0.2 to 200 mg cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the capsule comprises from 25 to 150 mg cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional embodiment, the capsule comprises from 50 to 100 mg of crystalline maleate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In a particular aspect of this alternative implementation, the capsule comprises from 0.2 to 200 mg of crystalline maleate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the capsule comprises from 25 to 150 mg of crystalline maleate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional embodiment, the capsule comprises from 50 to 100 mg of crystalline maleate salt of 2-[4-(3-quinoline-6-and the methyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In a particular aspect of this alternative implementation, the capsule comprises from 0.2 to 200 mg of crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the capsule comprises from 25 to 150 mg of the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional embodiment, the capsule comprises from 50 to 100 mg of the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In a particular aspect of this alternative implementation, the capsule comprises from 0.2 to 200 mg of the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the capsule comprises from 25 to 150 mg of the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional embodiment, the capsule comprises from 50 to 100 mg of the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In a particular aspect of this alternative implementation, the capsule comprises from 0.2 to 200 mg of crystalline tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional aspect, the capsule comprises from 25 to 150 mg of the crystal is esilalei salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo-[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In an additional embodiment, the capsule includes 50 to 100 mg of crystalline tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

In another embodiment, the invention provides a method of treating cancer in a mammal, including a human, which comprises administration to a mammal a therapeutically effective amount of the pharmaceutical composition of the present invention.

In another embodiment, the invention provides a method of treating cancer in a mammal which comprises the administration to a mammal, including humans, capsules of the present invention.

In another embodiment, the present invention provides a method of treating abnormal cell growth in a mammal, including humans, if there is a need for such treatment, including the introduction of a given mammal a therapeutically effective amount of crystalline cleaners containing hydrochloride salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In another embodiment, the present invention provides a method of treating abnormal cell growth in a mammal, including humans, if there is a need for such treatment, including the introduction of a given mammal a therapeutically effective amount crystallizability salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In another embodiment, the present invention provides a method of treating abnormal cell growth in a mammal, including humans, if there is a need for such treatment, including the introduction of a given mammal a therapeutically effective amount of a crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In another embodiment, the present invention provides a method of treating abnormal cell growth in a mammal, including humans, if there is a need for such treatment, including the introduction of a given mammal a therapeutically effective amount of a crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. In another embodiment, the present invention provides a method of treating abnormal cell growth in a mammal, including humans, if there is a need for such treatment, including the introduction of a given mammal a therapeutically effective amount of crystalline tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

In another embodiment, the abnormal cell growth is mediated by at least one genetically modified receptor. In another embodiment is sushestvennee abnormal cell growth is mediated by growth factor receptor of hepatocytes (c-Met/HGFR) kinase or kinase anaplastic lymphoma (ALK). In another embodiment, the abnormal cell growth is mediated by growth factor receptor of hepatocytes (c-Met/HGFR) kinase. In another embodiment, the abnormal cell growth is mediated by a kinase anaplastic lymphoma (ALK).

In another embodiment, the abnormal cell growth is cancer. In another embodiment, the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, hypernephroid kidney tumors, carcinoma of the renal pelvis, neoplasms of the Central nervous system (CNS), primary CNS lymphoma, tumors of the axis of the spine, glioma of the brain stem, pituitary adenomas and their combinations.

In yet another embodiment, the wasp is estline cancer selected from the group consisting of non-small cell lung cancer (NSCLC), squamous cell carcinoma, hormone-refractory prostate cancer, papillary hypernephromas kidney tumors, colorectal adenocarcinoma, for neuroblastoma, anaplastic both lymphoma (ALCL) and cancer of the gastrointestinal tract.

Definitions

Used herein, the term "abnormal cell growth", unless otherwise specified, means that it is independent of normal regulatory mechanisms (e.g., lack of contact inhibition).

Used herein, the term "almost pure" in respect of a particular polymorphic or amorphous forms means that polymorphic or amorphous form comprises less than 10%, preferably less than 5%, preferably less than 3%, preferably less than 1% by weight of any other physical forms of connection.

Used herein, the term "treatment", if not indicated otherwise, means a reverse flow, relief, suspension of development or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. Used herein, the term "treatment", if not specified otherwise, refers to the act of "treatment"as defined just above.

Used herein, the term "virtually the same" relative locations of the ICA radiographs means, that accounted for the variability typical location of the peak and its intensity. For example, for a specialist in this field is obvious that the locations of the peaks (2θ) will be characterized by a certain degree of variability inherent to the x-ray machine, which usually has a value of up to 0.2°. In addition, for the specialist in this field is obvious that the relative intensity of the peaks will be characterised by the variability inherent to x-ray machines, as well as variability associated with the degree of crystallinity, preferred orientation, the surface of the prepared sample and other factors known to practitioners in this area that should be considered only as qualitative indicators.

Brief description of drawings

Figure 1 shows powder x-ray crystal cleaners containing hydrochloride salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 2 shows powder x-ray crystal maleate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 3 shows powder x-ray crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 4 shows powder rent anogramma crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 5 shows the powder x-ray crystal tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 6 shows thermogravimetric curve of differential scanning calorimetry (DSC) for cleaners containing hydrochloride crystalline salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 7 shows thermogravimetric curve of differential scanning calorimetry (DSC) for crystalline maleate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

On Fig shows thermogravimetric curve of differential scanning calorimetry (DSC) for crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 9 shows a thermogravimetric curve of differential scanning calorimetry (DSC) for crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Figure 10 shows a thermogravimetric curve of differential scanning calorimetry (DSC) for crystalline tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol.

Detailed description of the invention

Received several individual KRISTALLIChESKAYa 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol. The compound 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol in free base form may be obtained in accordance with the methods described in patent document United States Patent Application No. 11/745921, the content of which is given here by reference thereto.

Salts of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo-[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol can be obtained by treating compound in free base form with a suitable amount of the chosen mineral or organic acid in an aqueous solvent or in an environment suitable organic solvent, such as methanol, acetonitrile, ethanol or ethyl acetate. The desired solid salt obtained when careful evaporation of the solvent. The desired salt of the acid can be precipitated from a solution of the free base in an organic solvent by adding to a solution of the appropriate mineral or organic acid.

Cleaners containing hydrochloride salt

HCl salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol can be obtained with good crystallinity, for example, by stirring the compound in free base form in any suitable solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl the initial alcohol or their mixture, with 2 M HCl at elevated temperature (for example, ~68°C, then cooling to room temperature. After cooling, the solution is precipitated in crystalline form of the resulting HCl salt, which can be selected by filtering.

Powder x-ray (PXRD) of the crystalline HCl salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol are shown in table 1. Thermogravimetric curve of DSC for HCl salt is shown in Fig.6.

Table 1:PXRD tabular data for crystalline polymorph form 1 of the hydrochloride of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol (Example 1)

Table 1
2θ (°)Intensity, %2θ (°)Intensity, %
6,524,224,579,1
8,721,325,669,3
the 11.664,126,569,4
13,017 27,6100
13,732,629,929,2
17,136,230,641,3
17,797,731,525,9
19,840,732,820,4
20,355,934,227,1
22,533,135,517
23,345,836,913,5

Malata salt

Malata salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol can be obtained with good crystallinity, for example, by placing maleic acid and 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol in a test tube and rastvoreniya in any suitable solvent including, but not limited to, CH2Cl2ACE is he, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture, then add a suitable co-solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture, and then crystallization from any suitable solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture.

Powder x-ray (PXRD) crystal maleate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol are shown in table 2. Thermogravimetric curve of DSC for maleate salt is shown in Fig.7.

td align="center"> 50,1
Table 2
2θ (°)Intensity, %2θ (°)Intensity, %
6,5of 31.420,849,5
12,962,522,662,8
13,262,823,9
15,048,124,6100
16,153,926,149,8
16,656,727,047,7
17,24528,143
18,448,429,634,2
19,640,7

Phosphate salt

The phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol can be obtained with good crystallinity, for example, by mixing 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol with H3PO4in an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture, and then stirring the obtained solid substance in an appropriate solvent, including, what about this is not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture, and then crystallization from an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture.

Powder x-ray (PXRD) of the crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol are shown in table 3. Thermogravimetric DSC curve for phosphate salt is shown in Fig.

Table 3
2θ (°)Intensity, %2θ (°)Intensity, %
6,014,720,9of 97.8
6,923,423,149,8
8,422,324,894,9
the 9.719,425,881,5
10,32527,064,5
11,438,728,475
13,828,228,951,1
16,346,630,619,8
of 17.010031,922,3
18,07134,816,8
19,746,937,413,3

Sulfate salt

Sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol can be obtained with good crystallinity, for example, by mixing 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol with H2SO4in an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture, the ATEM stirring the obtained solid substance in an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture, and then crystallization from an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture.

Powder x-ray (PXRD) of the crystalline sulfate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol is shown in table 4. Thermogravimetric DSC curve for sulfate salt is shown in Fig.9.

Table 4
2θ (°)Intensity, %2θ (°)Intensity, %
8,931,622,0of 56.4
the 9.7of 21.923,7to 45.4
15,210025,085
17,127,525,718,094,327,273,8
19,536,327,853,2
20,131,2

Toiletry salt

Toiletry salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol can be obtained with good crystallinity, for example, by mixing 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol with steam-toluensulfonate acid in an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl alcohol, or their mixture, and then stirring the obtained solid substance in an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methyl tert-butyl ether, methanol, ethanol, water, isopropyl alcohol, or their mixture, and then crystallization from an appropriate solvent, including, but not limited to, CH2Cl2, acetone, THF, acetonitrile, ethyl acetate, methanol, ethanol, water, isopropyl JV is RT or their mixture.

Powder x-ray (PXRD) crystal tosylate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol are given in table 5. Thermogravimetric curve of DSC for tosylate salt is shown in figure 10.

Table 5
2θ (°)Intensity, %2θ (°)Intensity, %
10,7to 49.324,4100
14,967,325,434,1
16,596,926,641,5
17,280,827,247
19,323,728,232,3
20,333,931,026
22,528,2

The present invention also relates to pharmaceutical compositions comprising the described here, the crystalline polymorph salt of salt of compound 1. The pharmaceutical compositions of the present invention may, for example, be in a form suitable for oral administration in the form of tablets, capsules, pills, powder, compositions with delayed release, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration in the form of ointment or cream or for rectal administration in the form of a suppository. The pharmaceutical composition may be in the form of standard dosage forms, suitable for a single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, may include other medicinal or pharmaceutical agents, carriers, auxiliary medicinal substances and so on.

Examples of parenteral injection include solutions or suspensions of the active compounds in sterile aqueous solutions, for example aqueous solutions of propylene glycol or dextrose. Such dosage forms can be if there is neobhodimosti, appropriately buffered.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions can, if necessary, contain additional ingredients such as substances, correcting the taste and smell of medicines, binders, excipients, and other similar substances. Thus, for oral administration, tablets containing various excipients such as citric acid, can be used together with various loosening substances such as starch, alginic acid and certain complex silicates, and with a binder, such as sucrose, gelatin and Arabic gum. In addition, to facilitate tabletting often use lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be used in soft and hard filled gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight glycols. When oral administration is required aqueous suspensions or elixirs, the active compound can be incorporated in them with different sweeteners or flavorings, paint is their matter or dyes and, if necessary, emulsifiers or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of obtaining various pharmaceutical compositions with a specific number of active compounds are known, or they are obvious to experts in this field. Examples can be found in the monograph Remington''s Pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 15th Edition (1975).

EXAMPLES

The following examples and preparations additionally illustrate and explain certain aspects of the embodiments of the invention. It should be borne in mind that the scope of the present invention is not limited in any way by the scope of the following examples.

Methods and materials

Salt PF-04217903 characterized by their powder x-ray. So, powder x-ray salts were removed by powder x-ray diffractometer brand Bruker D8 Discover with GADDS detector (detector system for the registration of diffraction in the full angular range) CS operating in reflection mode using Cu Ka radiation (1.54 Å). The voltage and current of the tube was set to 40 kV and 40 mA, respectively. Scans were collected when the distance between the sample and the detector, which is mounted 15.0 see Samples were scanned for 60 seconds, cover the th range from 4.5 to 38.7° in 2θ. The diffractometer was calibrated for peak positions in 2θ with corundum standard. The samples were moved into the Nickel holders for samples, specially manufactured by the company Gasser & Sons, Inc. (Commack, NY). All analyses were carried out at room temperature, which is usually 20-30°C. Data were collected and integrated using the software product GADDS for WNT version 4.1.14T. Pattern cheated by using DiffracPlus software product, software release 2003, with Eva version 9.0.0.2.

To withdraw for powder x-ray diffractometer brand Bruker D8 Discover with GADDS detector CS sample is usually placed in the recess in the middle of Nickel holder for samples. A powder sample of the press slide or the like to provide an arbitrary surface and the corresponding height of the sample. The holder for the sample is then placed in a Bruker instrument and remove the powder x-ray when using the above device parameters. The difference in measurements associated with the same powder x-ray analysis, is the result of several factors, including (a) errors in the preparation of the sample (for example, the height of the sample), (b) errors of the instrument, (c) errors of calibration (d) operator error (including errors that are present when determining the provisions of the peak) and (e) the nature of the material (for example, errors are preferably the orientation). Errors and calibration errors of the height of the sample often lead to a shift of all peaks in the same direction. Small differences in the height of the sample using a flat holder can lead to large displacements of the positions of the peaks in powder x-ray. A systematic study showed that the difference in the height of the sample in a 1 mm can cause peak shifts up to 1° 2θ (Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001; 26, 63). These shifts can be identified in the diffraction pattern and can be eliminated by introducing amendments to the peak (applying a systematic correction factor for all values of the position of peaks) or by re-calibrating the instrument. As mentioned above, it is possible to correct differences in measurements on different devices, by applying a systematic correction factor to match the peak positions. Typically, this correction factor may result in compliance with the provisions of the measured peaks with the expected peak positions and may be located in areas expected 2θ values is ±0,2° 2θ. Angle (°2θ) and the intensities (in % of the value of the highest peak) for each form solids are given in tables 1-6.

Differential scanning calorimetry (DSC) was performed on the device brand DSC Q1000 V9.1 Build 296 company TA Instruments. The instrument gauge the Wali to determine the constant of the cell and the heat capacity using indium and sapphire, respectively. Samples were prepared by weighing 1-3 mg of sample in an aluminum crucible, which was then covered with perforated aluminum cover (TA Instruments' part nos. 900786.901 (bottoms) and 900779.901 (top)). Data were analyzed using the software product Universal Analysis 2000 for Windows 2000/XP version 4.3A Build 4.3.0.6. The experiments were started at ambient temperature and heated the sample at a rate of 10°C/min to 350°C by blowing nitrogen gas (flow rate was 50 ml/min). Characteristics of thermal phenomena for each salt are shown in table 6.

Table 6
SolThe beginning of the transition
(°C)
The prospective nature
transition
HCl214-215Decomposition
Maleate220-221Melting
Phosphate224-225Melting/Decomposition
Sulfate185-186Melting/Decomposition
Toilet180-181 Melting/Decomposition

Example 1: obtain the HCl salt

29,5 mg of compound 1 was weighed in a glass scintillation vial with a volume of 20 ml was Added to 1 ml of MeOH and the solution was stirred. Was added to the solution from the pipette of 38.4 μl of 2 M HCl. Covered with a lid and stir the solution was heated to ~68°C in a module heater-stirrer. The heater was switched off and the solution continued to stir. Visually observed precipitation by cooling the solution to approximately 48°C. was Added 500 μl of MeOH and the solution continued to stir overnight. The solid was isolated by filtration under vacuum membrane filter made of polytetrafluoroethylene (PTFE) with a pore size of 0.45 μm. The solid was dried in a vacuum drying Cabinet at 60°C for ~30 minutes.

Example 2: Getting maleate salt

6,95 mg of maleic acid and 22.3 mg of compound 1 was weighed in a glass scintillation vial with a volume of 20 ml was Added to ~2 ml ACN and 20 µl of water. The vial was closed and was carried out by stirring for ~20 minutes. The solvent was evaporated by passing a gentle stream of N2. Added ~3 ml of EtOAc and 1 ml of IPA and a bottle of solution was covered with a lid and stirred over night. The solid is removed from the solution by filtering under vacuum membrane filter made of PTFE with a pore size of 0.45 μm. The solid was dried in VA is yumnam desiccator for ~30 minutes. The solid was placed in a glass scintillation vial with a volume of 20 ml was Added to ~2 ml of acetone and the solution was covered with a lid and stirred at 50°C for ~1 hour. The solid is removed from the solution by filtering under vacuum membrane filter made of PTFE with a pore size of 0.45 μm. The solid was dried in a vacuum dessicator for ~30 minutes.

Example 3: Obtaining phosphate salt

21,12 mg of compound 1 was added in a glass vial for HPLC with screw cap. Using the pipette was added into the vial 1 ml MeOH, closed the lid and carried out the mixing. With a pipette and added to a solution 28,357 μl 2M H3PO4. Added 500 μl of MeOH, closed bottle with a lid and was carried out by stirring at 60°C for ~2 hours. Heating was stopped and the solution continued to stir overnight. Observed sedimentation of solids, and it was removed from the solution by filtering under vacuum membrane filter made of PTFE with a pore size of 0.45 μm. The solid was dried in a vacuum drying Cabinet at 60°C for 30-60 minutes. The solid was placed in a glass scintillation vial with a volume of 20 ml and add 5-15 ml of IPA, and then the vial was closed with a lid and was carried out by stirring overnight. A solid substance was separated by filtration under vacuum on the membranes of the nd filter made of PTFE with a pore size of 0.45 μm and dried in a vacuum dessicator for ~30 minutes. The solid was placed in a glass scintillation vial with a volume of 20 ml was Added ~10 ml ACN and the vial containing the solution was placed in a casing and stirred not closed within ~48 hours. The solid is removed from the remaining solution by filtration under vacuum membrane filter made of nylon with a pore size of 0.45 μm. The solid was dried in a vacuum dessicator for ~30 minutes.

Example 4: obtaining the sulfate salt

20,92 mg of compound 1 were placed in a glass vial for HPLC with screw cap. Using the pipette was added into the vial 1 ml MeOH, closed the lid and carried out the mixing. With a pipette and added to a solution 28,169 ál of 2 M H2SO4. Then with a pipette and added to a solution of 500 μl of MeOH. The solution was heated to 60°C and stirred at this temperature for ~2 hours. Heating was stopped and the solution continued to stir overnight. Observed sedimentation of solids, and it was removed from the solution by filtering under vacuum membrane filter made of PTFE with a pore size of 0.45 μm. The solid was dried in a vacuum drying Cabinet at 60°C for 30-60 minutes. The solid was placed in a glass scintillation vial with a volume of 20 ml was Added 5-15 ml IPA, then the bottle of solution closed with a lid and was carried out by stirring overnight. the solid substance was separated by filtration under vacuum membrane filter made of PTFE with a pore size of 0.45 μm and then dried in a vacuum dessicator for ~30 minutes. The solid was placed in a glass scintillation vial with a volume of 20 ml was Added ~10 ml ACN and the vial containing the solution was covered with the lid and stirred over night. The solid was removed by filtration under vacuum membrane filter made of nylon with a pore size of 0.45 μm. The solid was dried in a vacuum dessicator for ~30 minutes.

Example 5: Receiving tosylate salt

23,79 mg of compound 1 were placed in a glass vial for HPLC with screw cap. Added 1 ml of MeOH, closed bottle with a solution of cap and subjected to mixing. Was added into the solution with a pipette and 31,912 ál of 2 M pair-toluensulfonate acid. The solution was stirred at 60°C for ~2 hours. The lid of the vial was opened and the vial was placed in a stream of N2up until the solution volume was reduced to ~500 ál. Added aliquots of MTBE 100 ál up until not started the precipitation total was added 300 μl). The vial containing the solution was covered with the lid, stirred and heated to 45°C and then heating was stopped. Continued to stir the solution during the night. The solution was transferred to a glass scintillation vial with a volume of 20 ml was Added ~15 ml IPA and a bottle of solution closed with a lid and was carried out by stirring for ~72 hours. The solution was placed in a stream of N2until then, until the solvent was removed. obavljale 5-10 ml of acetone. We observed formation of light brown gel which adheres to the walls of the glass vial. The solution was transferred into a new glass scintillation vial with a volume of 20 ml (brownish resin remained in the old bottle). Added ~5 ml of acetone and ~1 ml of MeOH and the solution was stirred in an open flask in the casing. The solid was separated from the solution by filtering under vacuum membrane filter made of PTFE with a pore size of 0.45 μm. The solid was dried in a vacuum dessicator for ~2 hours.

1. Crystalline phosphate salt of 2-[4-(3-quinoline-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazole-1-yl]ethanol, characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2 and 20.9±0,2.

2. The crystalline salt according to claim 1, characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2, 20,9±0.2 and 24,8±0,2.

3. The crystalline salt according to claim 1, characterized by a powder x-ray that includes peaks at the following angles (2θ): 17,0±0,2, 20,9±0,2, 24,8±0,2 and 25.8±0,2.

4. The pharmaceutical composition intended for the treatment of abnormal cell growth in a mammal, comprising a compound according to claim 1.

5. Capsule comprising a pharmaceutical composition according to claim 4.

6. The use of a crystalline salt according to claim 1 for obtaining medicinal cf is DSTV, used for the treatment of abnormal cell growth in a mammal, which need such treatment.

7. The use according to claim 6, where the abnormal cell growth is mediated, at least one genetically modified receptor.

8. The use according to claim 6, where the abnormal cell growth is cancer.

9. The use of claim 8, where the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, hypernephroid kidney tumors, carcinoma of the renal pelvis, neoplasms of the Central nervous system (CNS), primary CNS lymphoma, tumors of the axis of the spine, glioma of the brain stem, pituitary adenomas and their combinations.

10. The use of claim 8, where the cancer the choice is up from the group, consisting of non-small cell lung cancer (NSCLC), squamous cell carcinoma, hormone-refractory prostate cancer, papillary hypernephromas kidney tumors, colorectal adenocarcinoma, for neuroblastoma, anaplastic both lymphoma (ALCL) and cancer of the gastrointestinal tract.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I in which: X8 denotes N, and X5 and X6 denote CH; R7 denotes phenyl or C5-6-heteroaryl group which is optionally substituted with one or more groups selected from halogen, hydroxy group, nitro group, cyano group, carboxy group and thiol, or phenyl or a methoxy group -C(=O)CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)N(CH2CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -N(CH2CH3)2 or C1-4-alkyl, optionally substituted with a hydroxy group; RN3 and RN4, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperidinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; R2 denotes NRN5RN6, where RN5 and RN6, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperdinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; or a pharmaceutically acceptable salt thereof, and where "C5-6-heteroaryl" denotes a heteroaryl group selected from furan, thiophene, pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole, octatriazole, isoxazine, pyridine, pyridazine, pyrimidine, pyrazine and triazine; and where "C3-5-heterocyclyl", as used here, relates to a univalent structure obtained by removing a hydrogen atom from the ring of the heterocyclic compound, where that structure contains 5 or 6 ring atoms, 1-4 of which are ring heteroatoms selected from oxygen, nitrogen and sulphur; and under the condition that when R2 denotes an unsubstituted morpholine group, RN3 and RN4, together with the nitrogen atom with which they are bonded, form a morpholine group, R7 does not denote an unsubstituted phenyl, and when R2 denotes an unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom with which they are bonded, form an unsubstituted piperidinyl, R7 does not denote unsubstituted phenyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having mTOR inhibiting activity.

EFFECT: novel compound which can be suitable for treating malignant growths is obtained and described.

10 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, particularly to application of an antiviral agent - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-7-one dehydrate sodium salt (hereinafter - the Agent) for preventing and treating viral diseases caused by a tick-borne encephalitis virus. Also, there is described method for preventing and treating conditions caused by the tick-borne encephalitis virus in humans and animals involving introduction of the Agent presented above to humans and animals.

EFFECT: extended range of the drug preparations possessing a wide spectrum of action and used for treating and preventing tick-borne encephalitis.

20 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolo-[1,2-a]benzimidazole derivatives of formula I , where NR2 assumes morpholino or diethylamino values, and Ar is 4-methoxyphenyl or 4-chlorophenyl, having antioxidant and antiradical properties.

EFFECT: obtaining novel sulphates possessing useful biological properties.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: pharmachology.

SUBSTANCE: invention describes new compounds with general formula (I-c) Where R1 is a radical (d-1) or (d-2) (radical values are given in the invention formula) and pharmaceutical composition containing them. The described compounds are the hepatitis C inhibitors and can be used in medicine.

EFFECT: enhanced hepatitis C inhibition.

5 cl, 1 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

Kinase inhibitors // 2440352

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula : a pharmaceutically acceptable salt or solvate thereof, having Syk kinase inhibiting properties. The invention also relates to a pharmaceutical composition containing said compound, methods of treating diseases whose development is aided by c-kit receptor activity, such as arthritis, rheumatoid arthritis, tumours, mantle cell lymphoma, as well as a method of inhibiting angiogenesis.

EFFECT: improved method.

13 cl, 4 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula in which is or (values of radicals are given in the claim), a method of producing said compounds, a pharmaceutical composition containing said compounds and therapeutic application thereof.

EFFECT: compounds are cysteine protease inhibitors and can be used in medicine.

25 cl, 1 tbl, 41 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, and may be used for organ-preserving treatment of the patients with initial carcinoma of vulva. That is ensured by sequential intravenous introduction of radachlorine and per os administration of alasensl Then the patient is exposed to distant surface laser light of wave length 662 nm, power density 80-150 J/cm2 and wave length 630 nm of the same power density with using a quartz light guide. The quartz light guide is provided with a microlens.

EFFECT: method provides an adequate anticancer effect, single-step photodynamic exposure, an organ-preserving effect in women of reproductive age, reduced basic dose within the tumour location, the absence of destructive tissue changes within a photodynamic exposure coverage, reduced length of wound epithelisation, shorter rehabilitation and extended indications in women of various ages.

2 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is using a prostaglandin compound for general formula (II) for making a pharmaceutical composition for treating inflammatory intestinal diseases, cancer, gastroesophageal reflux disease or Barrett's syndrome in a mammal subject (versions), related methods of treating (versions) and pharmaceutical compositions (versions). It has been shown that the compound of formula induces the conformational alteration in close contact which enables functional recovery of the mucosal barrier. What is shown as treating the injured mucosa with the compound: colon inflammation, colon cancer (prevented tumour growth).

EFFECT: preparing the compounds enabling the functional recovery of mucosal barrier.

25 cl, 6 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to the use of pyrimidylaminobenzamide derivatives, particularly 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide of formula

, or its pharmaceutically acceptable salt for preparing drugs applicable for treating and preventing systemic mastocytosis. The invention refers to a drug, a method of treating or preventing systemic mastocytosis. The invention also refers to a combination to be used for treating systemic mastocytosis containing the compound of formula (II) and imanitib taken in a therapeutically efficient amount.

EFFECT: compound (II) and combination are applicable in treating systemic mastocytosis which is characterised by resistance to imanitib and preferentially bound with FIPlLl-PDGFRa hybrid gene.

12 cl, 1 ex

FIELD: medicine.

SUBSTANCE: there are presented versions of antibodies specific to claudin 18A2 produced by immunisation by a related amino acid sequence or a nucleic acid or a host cell expressing said peptide. The antibodies possess an ability to mediate elimination of cancer cells expressing claudin 18A2. There are disclosed versions of antibody-producing hybridomas. What is described is a conjugate or a pharmaceutical composition on the basis of antibodies or conjugates for elimination and/or inhibition of a cancer cell expressing claudin 18A2. There are disclosed versions of the method for growth inhibition and/or elimination of the cancer cell, as well as for treating or preventing a disease or a disorder involving cancer cells expressing claudin 18A2 with using the antibodies, conjugate and pharmaceutical composition under the invention.

EFFECT: use of the invention can find further application in medicine for treating cancer cells expressing claudin 18A2.

39 cl, 33 dwg, 5 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: what is offered is an antibody or its antigen-binding fragment which specifically coupling hlL-4R with KD less than 200-pM measured with using surface plasmon resonance. What is described is a recovered nucleic acid molecule coding the antibody, and a based vector for producing the antibody. There are disclosed a host-vector system for producing the antibody or its antigen-binding fragment, and a method for producing the substances stated above with using such system. What is disclosed is using the antibody or antigen-binding fragment for preparing a drug for relieving (inhibiting) hlL-4R mediated diseases. What is disclosed is a composition on the basis of the antibody or antigen-binding fragment to be used in a method for treating a hlL-4R mediated disease or disorder in humans.

EFFECT: inventions can find application in therapy of the hlL-4R mediated diseases.

15 cl, 3 dwg, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel chemical compound and specifically to N-ethylpiperazylamide of betulinic acid of formula (I): which can be used in medicine as a medicinal agent with antitumour activity.

EFFECT: high efficiency of the compounds.

1 cl, 6 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I in which: X8 denotes N, and X5 and X6 denote CH; R7 denotes phenyl or C5-6-heteroaryl group which is optionally substituted with one or more groups selected from halogen, hydroxy group, nitro group, cyano group, carboxy group and thiol, or phenyl or a methoxy group -C(=O)CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)N(CH2CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -N(CH2CH3)2 or C1-4-alkyl, optionally substituted with a hydroxy group; RN3 and RN4, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperidinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; R2 denotes NRN5RN6, where RN5 and RN6, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperdinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; or a pharmaceutically acceptable salt thereof, and where "C5-6-heteroaryl" denotes a heteroaryl group selected from furan, thiophene, pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole, octatriazole, isoxazine, pyridine, pyridazine, pyrimidine, pyrazine and triazine; and where "C3-5-heterocyclyl", as used here, relates to a univalent structure obtained by removing a hydrogen atom from the ring of the heterocyclic compound, where that structure contains 5 or 6 ring atoms, 1-4 of which are ring heteroatoms selected from oxygen, nitrogen and sulphur; and under the condition that when R2 denotes an unsubstituted morpholine group, RN3 and RN4, together with the nitrogen atom with which they are bonded, form a morpholine group, R7 does not denote an unsubstituted phenyl, and when R2 denotes an unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom with which they are bonded, form an unsubstituted piperidinyl, R7 does not denote unsubstituted phenyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having mTOR inhibiting activity.

EFFECT: novel compound which can be suitable for treating malignant growths is obtained and described.

10 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I), treating a disease related to proteinkinase activity inhibition, specifically cancer, particularly leukaemia, a method of treating such disease and a method of producing such compounds. In formula (I) R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl; R2 represents lower alkyl substituted by one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzcyclopentyl(indane), benzcyclohexyl, penta-, hexa- or heptamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen and oxygen which can be unsaturated or completely saturated, and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl which is unsubstituted or substituted by one or two substituted specified in a group consisting of lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl, lower alkylcarbamoyl, amino mono- or disubstituted lower alkyl, morpholino, lower alkylsulphonyl, halogen and benzoyl; and the value R3 is specified in the patent claim, or R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl; hexamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen which can be unsaturated or completely saturated, and is unsubstituted or substituted according to the patent claim, R4 represents hydrogen or lower alkyl.

EFFECT: preparing the composition for treating a disease related to proteinkinase activity inhibition.

5 cl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

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