C-met/hgfr inhibitor polymorphs

FIELD: chemistry.

SUBSTANCE: invention relates to a free base (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)- ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine in crystalline form, having a powder X-ray diffraction pattern with peaks at diffraction angles (2θ) 15.7±0.1, 17.3±0.1 and 19.7±0.1. The invention also relates to a pharmaceutical composition, to methods of treating cancer in mammals, as well as to a method of treating abnormal cell growth in mammals in need of such treatment.

EFFECT: obtaining an novel biologically active compound having the said inhibitory activity.

12 cl, 1 ex, 3 tbl, 2 dwg

 

This application is based on provisional application U.S. No. 60/742676, filed December 5, 2005, the contents of which are incorporated herein by reference in full.

The scope of the invention

The present invention relates to polymorphs of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine, which are useful 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, especially humans.

Background of the invention

The compound (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine (which is here referred to as "compound 1"), represented by formula 1

a potent small molecule inhibitor of C-Met/HGFR (growth factor receptor of hepatocytes) kinase and ALK (kinase anaplastic lymphoma) activity. 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 wide variety of tumor types, and ALK, which is involved in the pathogenesis of ALCL (anaplastic both lymphoma). Soy is inania 1 described in international patent application number PCT/IB2005/002837 and the application for U.S. patent No. 11/212331, which are incorporated herein by reference in full. Additionally, the racemate of compound 1 is described in international patent application no PCT/IB05/002695 and the application for U.S. patent No. 11/213039, which is incorporated herein by reference in full.

Malignant neoplasms of the person include an extensive list of diseases, which in General are one of the leading causes of death in the developed world (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). The progression of malignant tumors caused by a complex series of multiple genetic and molecular events, including gene mutations, chromosomal translocations, and karyotypic abnormalities (Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying genetic causes of cancer are as varied and complex, each type of cancer, as noted, shows similarities and acquired features that facilitate its development. These acquired capabilities include unregulated cell growth, sustainable ability to involve blood vessels (i.e. angiogenesis) and the ability of tumor cells to spread locally and to metastasize to secondary target organs (Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70). Therefore, the ability to identify new therapeutic agents that 1) ingibiruet the molecular targets, that changed during the development of cancer, or 2) seek to multiple processes that are common to cancer in a variety of tumors, represents a significant unmet need.

In example 19 application for U.S. patent No. 11/212331 described the connection is1that is how it was discovered, is amorphous. Is privileged to have polymorphic forms having improved properties such as improved crystallinity, dissolution properties and/or reduced hygroscopicity, at the same time preserving the properties of chemical and enantiomeric stability.

Summary of the invention

In one embodiment of the present invention proposed a crystalline form of the free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine. In a specific embodiment the crystalline form of the free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine is anhydrous. In another embodiment, crystalline form of the free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine is a hydrate.

In an additional aspect, the crystalline form is a polymorph form 1 of free base. In additional the additional aspect, the crystalline form has a picture of the x-ray diffraction on the powder, contains a peak at diffraction angle (2θ) of 19.7±0,1. In an additional aspect, the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) of 17.3±0,1 and 19.7±0,1. In an additional aspect, the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) of 15.7±0,1, 17,3±0,1 and 19.7±0,1. In an additional aspect, the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) of 15.7±0,1, 17,3±0,1 and 19.7±0,1 and 26.8±0,1. In an additional aspect, the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) of 15.7±0,1, 17,3±0,1 and 19.7±0.1, the 21,0±0,1 and 26.8±0,1. In an additional aspect, the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) of 15.7±0,1, 17,3±0.1 and 19,7±0,1, 21,0±0,1, 21,7±0,1 and 26.8±0,1. In an additional aspect, the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) 12,8±0,1, 15,7±0,1, 17,3±0,1 and 19,7±0,1, 21,0±0,1, 21,7±0,1 and 26.8±0,1. In an additional aspect, the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ)essentially, such as shown in figure 1.

The present invention more the tion of the proposed pharmaceutical composition, contains a polymorphic form 1 of free base compounds1. The present invention additionally proposed capsule containing this pharmaceutical composition. In a particular aspect of this embodiment, the capsule contains from 0.1 to 200 mg of polymorphic form 1 of free base compounds1. In an additional aspect, the capsule contains from 25 to 150 mg of polymorphic form 1 of free base compounds1. In an additional aspect, the capsule contains from 50 to 100 mg of polymorphic form 1 of free base compounds1.

In yet another embodiment of the invention, a method for treating cancer in a mammal, including humans, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition of the present invention.

In yet another embodiment of the invention, a method for treating cancer in a mammal, comprising an introduction to the specified mammal, including humans, capsules of the present invention.

In yet another embodiment of the invention, a method for treating abnormal cell growth in need of such treatment of a mammal, including humans, comprising an introduction to the specified mammal a therapeutically effective amount of polymorphic form 1 of free base compounds1.

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

In yet another embodiment of the abnormal cell growth is a cancer. In yet another embodiment the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or 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 external female genital organs, Hodgkin's disease (Hodgkin's disease), cancer of the esophagus, 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, impolitically lymphoma, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasm Central nervous system (CN is), primary CNS lymphoma, spinal tumours, gliomas of the brain stem, pituitary adenomas and their combinations.

In yet another embodiment the cancer is selected from the group consisting of non-small-cell lung cancer (NSCLC), squamous cell cancer, hormonereceptor prostate cancer, papillary renal cell carcinoma, colorectal adenocarcinoma, for neuroblastoma, anaplastic both lymphoma (ALCL) and cancer of the stomach.

Definitions

As used here, unless otherwise indicated, the term "abnormal cell growth" refers to cell growth that is independent of normal regulatory mechanisms (e.g., lack of contact inhibition).

As used here, unless otherwise indicated, the term "therapy" means the treatment, relief, suppression of development or preventing the disorder or condition to which such term applies, or one or more than one symptom of such disorder or condition. The term "treatment", as used here, unless otherwise specified, refers to the act of therapy, as defined directly above.

As used here, the term "essentially the same" in relation to the peak positions of the diffraction of x-rays means that is considered a typical position of the peak and the variability of the intensity. For example, the special is ialist in this area should be clear, the position of peaks (2θ) will demonstrate some variability between devices, usually such as 0.1°. Moreover, the person skilled in the art it should be clear that the relative intensity of the peaks show the variability between devices, as well as variability due to the degree of crystallinity, preferred orientation, the surface of the prepared sample and other factors known to the person skilled in the art, and should be taken only as qualitative measurements.

A brief description of graphic materials

Figure 1 shows a picture of the x-ray diffraction by the powder of the crystalline forms of the free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine, polymorphic form 1.

Figure 2 shows thermogram of differential scanning calorimetry (DSC) crystalline form of the free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine, polymorphic form 1.

A detailed description of the invention

Was prepared with clearly defined physical form of the free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine. Picture of x-ray diffraction on the powder (PXRD) of polymorphic form 1 of free base p is the cauldron in figure 1, the corresponding tabular data shown in table 1.

Table 1
PXRD data for form 1 free base (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine
2θ (°)The value of DThe intensity of the peak (pulse)The intensity of peak (%)
12,86,9166,6930,9
15,75,65812,6to 58.1
the 17.35,12915,973,3
19,74,51121,6100
21,04,2358,0037,0
21,74,1027,0332,5
26,8 3,326a 7.9236,6

DSC thermogram for the crystalline forms of the free base 1 shown in figure 2.

The present invention also relates to pharmaceutical compositions containing the polymorphic form 1 of free base of compound 1 described herein. The pharmaceutical compositions of the present invention may, for example, be in a form suitable for oral administration such as tablet, capsule, pill, powder, drugs slow release, solution, suspension, for parenteral injection such 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 a standard dosage forms, suitable for a single administration of precise dosages. The pharmaceutical composition should include a conventional pharmaceutical carrier or excipient and the connection of the present invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.

Exemplary forms of parenteral administration 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 suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions can, if desired, contain additional ingredients such as corrigentov, binders, excipients and the like. Thus, in tablets for oral administration containing various excipients, excipients such as citric acid, can be used together with various leavening agents, such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and Arabic gum. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. 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 glycols of high molecular weight. When oral administration is desirable aqueous suspensions or elixirs, the active compound can be combined with various sweetening or korrigentami, coloring matter or dyes and, if manual is, emulsifying agents 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 known or will be apparent to the person skilled in the art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15thEdition (1975).

Examples

Examples and supporting examples below, further illustrate and exemplify specific aspects of embodiments of the present invention. It should be understood that the scope of the present invention in any case is not limited to the scope of the following examples.

Methods and materials

Powder x-ray diffraction (PXRD): PXRD data, shown in figure 1, was obtained in accordance with the following Protocol. A sample (2 mg) was placed on a microscope slide with zero background. The sample is then placed in D8 Discover (Bruker AXS Instruments), equipped with a GADDS detector. The system employs a copper x-ray source supported at 40 kW and 40 mA, to ensure the issue CUα1 when 1,5406 angstroms. Data were collected from 4 to 40° 2θ using a step scan of 0.02°with a step time 60,1 seconds. Peaks of diffraction are usually measured with an error of ±0.1 degrees (2θ).

Differential scanning calorimetry (DSC): DC measurement, shown in figure 2, was performed using Q1000, Thermal Analysis Instruments. The sample weight of 1.6 mg were placed in hermetically sealed aluminum container with a small opening. The sample was balanced to 25°C and then chased up to 250°C at a scanning rate of 10°C/min Dry nitrogen was used as purge gas.

Synthesis of compounds 1

PLE is an enzyme produced by Roche and sold Biocatalytics Inc. in the form of the crude drug esterase from pig liver, traditionally known as PLE-AS (purchased from Biocatalytics as ICR-123, sold as a suspension of ammonium sulfate). This enzyme is classified (CAS(Chemical Abstracts Service) Abstract service chemistry) registry as "hydrolase esters of carboxylic acids", CAS 9016-18-6". The appropriate classification number of enzyme EC 3.1.1.1. It is known that this enzyme has a broad substrate specificity in relation to the hydrolysis of a wide range of esters. Lipase activity was determined using the method based on the hydrolysis of ethyl butyrate in pH titrator. 1 LU (lipase unit) is the amount of enzyme that releases 1 μmol of titratable butyric acid per minute at 22°C, pH of 8.2. The drug is reported here (PLE-AS in suspension), usually transported in the form of opaque brown-green liquid with the stated active is part of more than 45 LU/mg (protein content of about 40 mg/ml).

(1S)-1-(2,6-dichloro-3-forfinal)ethanol

(1S)-1-(2,6-dichloro-3-forfinal)ethanol, shown as compound (S-1) in the diagram below, was obtained by combination of enzymatic hydrolysis of racemic 1-(2,6-dichloro-3-forfinal)acetic acid ethyl ester, esterification and chemical hydrolysis with inversion according to Scheme B. Racemic 1-(2,6-dichloro-3-forfinal)ethyl acetate (compound A2) was obtained in accordance with Scheme A.

Scheme And

1-(2,6-dichloro-3-forfinal)ethanol (A1): sodium borohydride (90 mg, 2.4 mmol) was added to a solution of 2',6'-dichloro-3'-fluoro-acetophenone (Aldrich, catalogue number 52294-5) (207 mg, 1 mmol) in 2 ml anhydrous CH3HE. The reaction mixture was stirred at room temperature for 1 hour, then evaporated to obtain a colorless oily residue. The residue was purified using flash chromatography (elwira 0→10% EtOAc in hexano), with compound A1 as a colourless oil (180 mg; 0.88 mmol; 86,5% yield); MS (APCI (mass spectrometry with chemical ionization at atmospheric pressure)) (M-N)-208;1H NMR (400 MHz, chloroform-D) δ million-11.64 (d, J=PC 6.82 Hz, 3H), 3.02 (d, J=9,85 Hz, 1H), 6.97-7.07 (m, 1H), 7.19-7.33 (m, 1H).

1-(2,6-dichloro-3-forfinal)in ethyl acetate (A2): acetic anhydride (1,42 ml, 15 mmol) and pyridine (1.7 ml, 21 mmol) was sequentially added to a solution of compound A1 (2.2 g, 10.5 mmol) in 20 ml of CH2Cl2. The reaction mixture is PE is amasyali at room temperature for 12 hours, and then was evaporated to obtain yellow oily residue. The residue was purified using flash chromatography (elwira 7→9% EtOAc in hexano), with compound A2 in the form of a colorless oil (of 2.26 g; 9.0 mmol; for 85.6% yield);1H NMR (400 MHz, chloroform-D) δ million-11.88 (d, J=PC 6.82 Hz, 3H), 2.31 (s, 3H), 6.62 (q, J=6,82 Hz, 1H), 7.25 (t, J=8,46 Hz, 1H), 7.49 (dd, J=8,84; of 5.05 Hz, 1H).

Scheme B

Into the flask with a shirt on 50 ml, equipped with a pH electrode, the upper stirrer and a supply line of the base (1M NaOH)was added to 1.2 ml of 100 mm phosphate potassium buffer pH 7.0 and 0.13 ml of suspension PLE AS. Then was added dropwise compound A2 (of 0.13 g, 0.5 mmol, 1.00 equiv.) and the resulting mixture was stirred at room temperature for 20 hours, maintaining the pH of the reaction constant of 7.0 using 1 M NaOH. As for the conversion and enantiomeric excess of the reaction was observed by HPLC with reversed phase and stopped after 50% of the original material has trashdolls (approximately 17 hours in these conditions). This mixture then was extracted three times with 10 ml ethyl acetate for separation of ester and alcohol in the form of a mixture of R-1 and S-2.

Methanesulfonate (0.06 ml, 0.6 mmol) was added to a solution mixture of R-1 and S-2 (0.48 mmol) in 4 ml of pyridine in a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h the owls, then evaporated to obtain oil. To the mixture was added water (20 ml) and then EtOAc (20 ml×2) for the extraction of aqueous solution. The organic layers were combined, dried, filtered and evaporated to obtain a mixture of R-3 and S-2. This mixture was used in the next stage of the reaction without additional purification. 1H NMR (400 MHz, chloroform-D) δ million-11.66 (d, J=7,1 Hz, 3H), 1.84 (d, J=7,1 Hz, 3H), 2.09 (s, 3H), of 2.92 (s, 3H), 6.39 (q, J=7,0 Hz, 1H), 6.46 (q, J=6,8 Hz, 1H), 6.98-7.07 (m, 1H), 7.07-7.17 (m, 1H), 7.23-7.30 (M, 1H), 7.34 (dd, J=8,8; 4,80 Hz, 1H).

Potassium acetate (0,027 g, 0.26 mmol) was added to a mixture of R-3 and S-2 (0.48 mmol) in 4 ml of DMF under nitrogen atmosphere. The reaction mixture was heated to 100°C for 12 hours. To the reaction mixture were added water (20 ml) and extraction of the aqueous solution was added EtOAc (20 ml×2). The combined organic layer was dried, filtered and evaporated to obtain oil S-2 (72 mg, 61% yield in two steps). Chirality: the enantiomeric excess of 97.6%.1H NMR (400 MHz, chloroform-D) δ million-11.66 (d, J=7,1 Hz, 3H), 2.09 (s, 3H), 6.39 (q, J=6,8 Hz, 1H), 7.02 (t, J=8.5 Hz, 1H), 7.22-7.30 (m, 1H).

The sodium methoxide (19 mmol; 0.5 M in methanol) was slowly added to the compound S-2 (with 4.64 g of 18.8 mmol) under nitrogen atmosphere at 0°C. the resulting mixture was stirred at room temperature for 4 hours. The solvent is evaporated and added H2O (100 ml). The cooled reaction mixture was neutralized buffer solution of sodium acetate - acetic acid to p-7. Ethyl acetate (100 ml×2) was added for extraction of the aqueous solution. The combined organic layers were dried over Na2SO4, filtered and evaporated to obtain oil S-1 in the form of a white solid (4,36 g of 94.9% yield); SFC-MS (mass spectrometry-supercritical fluid chromatography): the enantiomeric excess of 97%. 1H NMR (400 MHz, chloroform-D) δ million-11.65 (d, J=6.8 Hz, 3H), 5.58 (q, J=6,9 Hz, 1H), 6.96-7.10 (m, 1H), 7.22-7.36 (m, 1H).

5-bromo-3-[1-(2,6-dichloro-3-forfinal)-ethoxy-pyridine-2-ylamine (racemate)

1. 2,6-Dichloro-3-peracetate (15 g, 0,072 mol) was stirred in THF (150 ml, 0.5 M) at 0°C using an ice-water bath for 10 minutes. Alumoweld lithium (2,75 g, 0,072 mol) was slowly added. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was cooled in an ice bath, was added dropwise water (3 ml) followed by slow addition of 15% NaOH (3 ml). The mixture was stirred at ambient temperature for 30 minutes. Added 15% NaOH (9 ml), MgSO4and the mixture was filtered to remove solids. The solids washed with THF (50 ml) and the filtrate was concentrated to obtain 1-(2,6-dichloro-3-forfinal)-ethanol (14,8 mg, 95% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 1.45 (d, 3H), 5.42 (m, 2H), 7.32 (m, 1H), 7.42 (m, 1H).

2. To a stirred solution of triphenylphosphine (8,2 g, 0.03 in the ol) and DEAD (diethylazodicarboxylate, 13,65 ml of 40% solution in toluene) in THF (tetrahydrofuran, 200 ml) at 0°C was added to a solution of 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (4,55 g, 0,021 mol) and 3-hydroxy-nitropyridine (3,35 g, is 0.023 mol) in THF (200 ml). Received a bright orange solution was stirred in nitrogen atmosphere at ambient temperature for 4 hours, the time by which all the raw materials were consumed. The solvent was removed and the crude material was loaded dry silica gel and was suirable a mixture of ethyl acetate and hexanol in a ratio of 20:80 to obtain 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (6,21 g 0,021 mol, 98%) as a pink solid.1H NMR (CDCl3, 300 MHz) δ 1.8-1.85 (d, 3H), 6.0-6.15 (q, 1H), 7.0-7.1 (t, 1H), 7.2-7.21 (d, 1H), 7.25-7.5 (m, 2H), 8.0-8.05 (d, 1H).

3. In the mixed mixture Asón (650 ml) and EtOH (500 ml) was added 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (9,43 g 0,028 mol) and iron filings (15.7 g, 0.28 mol). The reaction mixture was heated slowly to a temperature of phlegmy and left to mix for 1 hour. The reaction mixture was cooled to room temperature, then added diethyl ether (500 ml) and water (500 ml). The solution is carefully neutralized by adding sodium carbonate. The combined organic extracts were washed with saturated NaHCO3(2×100 ml), H2O (2×100 ml) and brine (1×100 ml), then dried (Na2SO4), filtered is concentrated to dryness under vacuum to obtain 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridine-2-ylamine (9,04 g, or 0.027 mol, 99%) as a light pink solid.1H NMR (CDCl3, 300 MHz) δ 1.8-1.85 (d, 3H), 4.9-5.2 (brs, 2H), 6.7-6.84 (q, 1H), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 1H), 7.6-7.7 (m, 1H).

4. The mixed solution of 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridine-2-ylamine (9,07 g, 0.03 mol) in acetonitrile was cooled to 0°C using an ice bath. To this solution portions were added N-bromosuccinimide (NBS) (5,33 g, 0.03 mol). The reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was concentrated to dryness under vacuum. The obtained dark oil was dissolved in EtOAc (500 ml) and was purified by chromatography on silica gel. The solvents were then removed in vacuo to obtain 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridine-2-ylamine (5.8 g, 0.015 mol, 51%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ 1.85-1.95 (d, 3H), 4.7-5.0 (brs, 2H), 5.9-6.01 (q, 1H), 6.8-6.95 (d, 1H), 7.01-7.2 (t, 1H), 7.4-7.45 (m, 1H), 7.8-7.85 (d, 1H).

5-bromo-3-[1(R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy-pyridine-2-ylamine

Enantiomerically pure R isomer was obtained as described above for the racemate, but using enantiomerically pure starting materials described above.1H NMR (400 MHz, DMSO-d6) δ 1.74 (d, 3H), 6.40 (m, 1H), 6.52 (br s, 2H), 7.30 (m, 1H), 7.48 (m, 1H), 7.56 (s, 1H); MS m/z 382 M+1).

4 methansulfonate-piperidine-1-carboxylic acid tert-butyl ester (2)

To parmesano is the solution tinder-butyl ester 4-hydroxy-piperidine-1-carboxylic acid (7,94 g, 39,45 mmol) in CH2Cl2(100 ml), cooled to 0°C., was slowly added NEt3(5,54 ml, 39,45 mmol), and then methanesulfonanilide (a 3.06 ml, 39,45 mmol) and DMAP (4-dimethylaminopyridine, 48 mg, 0,39 mmol). The mixture was stirred at room temperature overnight. To the mixture was added water (30 ml). Extraction of CH2Cl2(3×30 ml), followed by drying (Na2SO4) and removal of solvent in vacuo gave 4-methanesulfonate-piperidine-1-carboxylic acid tert-butyl ester as a white solid (11,00 g, yield 99%).1H NMR (CDCl3, 400 MHz) δ 4.89 (m, 1H), 3.69 (m, 2H), 3.31 (m, 2H), 3.04 (s, 3H), 1.95 (m, 2H), 1.46 (s, N).

Tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl]piperidine-1-carboxylate

Tert-butyl 4-(4-iodine-1H-pyrazole-1-yl)piperidine-1-carboxylate (3)

NaH (1.2 EQ., of 0.68 mmol) was added in portions to a stirred solution of 4-iodopyrazine (or 0.57 mmol) in DMF (dimethylformamide, 2 l) at 4°C and then added tert-butyl ether 4-methanesulfonate-piperidine-1-carboxylic acid, compound 2 (1.1 EQ., to 0.63 mmol). The resulting mixture was heated to 100°C for 12 hours. The reaction was suppressed by using H2O and was extracted with EtOAc several times. The combined organic layers were dried, filtered and concentrated to obtain an orange oil. The residue was purified with the help of the chromatography on silica gel (elwira 5% EtOAc in pentane) to give compound 3 as a white solid (140 g, 66%).

Tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl]piperidine-1-carboxylate (4)

Bis(pinacolato)LIBOR (1.4 EQ., 134 g, 0.52 mol) and potassium acetate (4 EQ., 145 g, 1.48 mol) were added sequentially to a solution of compound 3 (140 g, and 0.37 mol) in 1.5 l of DMSO (dimethylsulfoxide). The mixture was purged with nitrogen several times and then added dichlorobis(triphenylphosphine)palladium (II) (0,05 EQ., 12,9 g, 0.018 mol). The resulting mixture was heated at 80°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a substrate celite and washed with EtOAc. The filtrate was washed with saturated NaCl (500 ml×2), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (elwira 5% EtOAc in hexano) to obtain compound 4 as a white solid (55 g, 40%).

3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine (1)

To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-ylamine (15,22 g values 35,64 mmol) and tert-butyl ester 4-(4-bromo-pyrazole-1-yl)-piperidine-1-carboxylic acid (14,12 g, 42,77 mmol) in DME (1,2-dimethoxyethane, 143 ml) was added a solution of Na2CO3(11,33 g, 10692 mmol) in water (36 ml). The solution was degirolami and cleared with nitrogen three times. To Yes the resultant solution was added Pd(PPh 3)2Cl2(1.25 g, 1,782 mmol). The reaction solution was degirolami and purified using the nitrogen again three times. The reaction solution was stirred at 87°C oil bath for about 16 hours (or until until expended bramptonbuy ether), was cooled to ambient temperature and diluted with EtOAc (600 ml). The reaction mixture was filtered through a substrate cellite and washed with EtOAc. The EtOAc solution was washed with saline, dried over Na2SO4and concentrated. The crude product was purified on a column of silica gel, elwira by the system of EtOAc/hexane (Biotage 90+ Column: balance 600 ml of 100% hexanol, segment 1: 2250 ml of 50% EtOAc/hexane linear segment 2: 4500 ml of 75% EtOAc/hexane line, segment 3: 4500 ml 100% EtOAc), to obtain tert-butyl ester 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridine-3-yl}-pyrazole-1-yl)-piperidine-1-carboxylic acid (11.8 g, 60% yield, purity approximately 95%) with Rf Of 0.15 (50% EtOAc/hexane). MS m/e 550 (M+1)+.

To a solution of tert-butyl ester 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridine-3-yl}-pyrazole-1-yl)-piperidine-1-carboxylic acid (11.8 g, 21,45 mmol) in CH2Cl2(59 ml, 0.2 M) was added to a mixture of 4 N. HCl/dioxane (21 ml). The solution was stirred over night with the formation of solids. This solid is thoroughly crushed using a glass pestle is treated with ultrasound to release the source material, the prisoner in this solid. Added an additional amount of a mixture of 4 N. HCl/dioxane (21 ml) and stirred for 2 hours at room temperature, in which LCMS (liquid chromatography-mass spectrometry) showed the absence of starting material. The suspension was filtered in BONEROWSKI funnel lined with filter paper. The mother liquor was kept because it contains less than 5% of the product. The solid was transferred into a beaker of 500 ml HPLC water was added to until the solid did not dissolve completely. the pH was brought to 10 by adding solid Na2CO3. The aqueous solution was extracted with CH2Cl2(5×200 ml) or up until LCMS showed the absence of product in the aqueous layer. CH2Cl2the solution was dried over Na2SO4and concentrated. The crude product was re-dissolved in CH2Cl2(10 ml) and Meon (1 ml), was purified on silikagelevye column, elwira using system CH2Cl2/MeOH/NEt3. (Biotage 40+ Column: balance 600 ml of CH2Cl2100%, giving a byproduct segment 1: 1200 ml of 10% MeOH/CH2Cl2line, segment 2: 2400 ml of 10% MeOH/CH2Cl2speed, segment 3: 2400 ml of 9% Meon/1% NEt3/CH2Cl2). The desired fractions were collected to obtain 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin the-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine (7,19 g, 75% combined yield, white solid). MS m/e 450 (M+1)+.1H NMR (DMSO-d6, 400 MHz) δ 7.92 (s, 1H), 7.76 (s, 1H), 7.58 (m, 1H), 7.53 (s, 1H), 7.45 (m, 1H), 6.90 (s, 1H), 6.10 (m, 1H), 5.55 (bs, 2H), 4.14 (m, 1H), 3.05 (m, 2H), 2.58 (m, 2H), 1.94 (m, 2H), 1.80 (d, 3H), 1.76 (m, 2H).

Solid product, 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine was dissolved in dichloromethane and the solvent slowly evaporated to obtain a crystalline solid. After drying under high vacuum the uniqueness of the crystalline polymorph form 1 of this sample was confirmed by melting point 194°C.

For the recrystallization of the solid substances were used the following solvents: isopropanol, Isobutanol, ethanol, ethyl acetate, toluene, tetrahydrofuran and dioxane. All seven of the solvents gave the same polymorphic form 1 crystalline solid, the original crystalline solid from dichloromethane.

Polymorph (Compound 1) according to the present invention was tested on patients, people with non-small cell lung cancer (NSCLC).

An example of the results of the study (22 patients who participated in this study, having NSCLC and event fusion gene EML4-ALK) below. In relation to one of the 22 patients, the study was interrupted for reasons not connected the m treatment; in five patients the study was discontinued due to disease progression; and in sixteen patients with either stable disease or significant partial responses to therapy a compound of the present invention, the study was continued. Sample results are presented in table (3). As shown below, tumor response all patients, except one, has led to 20-70%increase decrease in tumor size.

Additional data supporting the claimed invention are presented in table 2. The table shows that a number of patients for whom other anti-cancer therapy were unsuccessful, had a good response on connection 1, above.

In tables 1 and 2, Sz indicates stable disease, PZ means the progression of the disease and the Czech Republic means a partial response. The example results presented in table 2, it follows that a large proportion of patients whose best response to prior acts of other treatment agents for cancer treatment was Sz or BD, after treatment with compound 1 had the best reaction of the Czech Republic. Several other patients with the best response to prior acts of other treatment agents for cancer treatment Sz or BD) after treatment with compound 1 had the best reaction NW. And only a smaller part of clients is impressive even after treatment with compound 1 still had the reaction of PZ.

The above data is clinical evidence that the compounds of the present invention is useful and effective for the treatment of abnormal cell growth in humans.

1. The free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine in the form of a crystalline form having a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) of 15.7±0,1, 17,3±0,1 and 19.7±0,1.

2. Free base according to claim 1 where the crystalline form is a polymorph form 1 of free base.

3. Free base according to claim 1 or 2, where the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) 15,7±0,1, 17,3±0,1, 19,7±0,1 and 26.8±0,1.

4. Free base according to claim 1 or 2, where the crystalline form has a picture of the x-ray diffraction on powder containing peaks at angles of diffraction (2θ) 12.8±0,1, 15,7±0,1, 17,3±0,1, 19,7±0,1, 21,0±0,1, 21,7±0,1 and 26.8±0,1.

5. Pharmaceutical composition having activity of an inhibitor of c-Met/HGFR, containing the free base according to any one of claims 1 to 4.

6. Pharmaceutical composition in the form of capsules containing pharmaceutical composition according to claim 5.

7. The pharmaceutical composition according to claim 6, containing from 0.1 to 200 mg of polymorphic form 1 of (R)-3-[1-(2,6-is ALOR-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine.

8. The pharmaceutical composition according to claim 6, containing from 25 to 150 mg of polymorphic form 1 of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine.

9. The pharmaceutical composition according to claim 6, containing from 50 to 100 mg of polymorphic form 1 of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine.

10. A method of treating cancer in a mammal, including humans, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition according to claim 5.

11. A method of treating cancer in a mammal, comprising an introduction to the specified mammal a pharmaceutical composition according to any one of p-9.

12. A method of treating abnormal cell growth in need of such treatment of a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of a free base polymorphic form 1 of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidine-4-yl-1H-pyrazole-4-yl)-pyridine-2-ylamine.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a combined product containing compounds of formula (I): where: R1 and R2 represent CF3; R3 and R4 represent fluoro; R5 and R6 represent hydrogen; R7 presents Cl, X represents CR8, where R8 represents Cl; and R9 represents NH2; or its veterinary acceptable salt, and b) doramectin. The invention also relates to an antiparasitic veterinary composition based on the said combined product.

EFFECT: obtaining a combined product which can be used in veterinary for treating parasitic infections in mammals.

4 cl, 1 dwg, 1 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Novel insecticides // 2379301

FIELD: chemistry.

SUBSTANCE: compounds with formula I are described, where each of E and Z is oxygen; A is C1-C6alkylene or a 3-member monocyclic ring system, which can be monosubstituted; Y is C1-C6alkylene; p equals 0; q equals 0 or 1; B represents a 3- or 4-member ring system which is completely or partially saturated and can contain a heteroatom selected from oxygen, possibly substituted; each R1 independently represents halogen, nitro group, C1-C6alkyl; or each R1 independently represents an amino group; n equals 1, 2; each of R2 and R3 represents hydrogen; D represents a group and agronomically acceptable salts of said compounds. Also described is a method of producing formula I compounds, intermediate compounds, a pesticide composition containing a formula I compound, as well as an insect control method and a method of protecting plant propagation material.

EFFECT: novel anthranylamide derivatives have good insecticidal activity.

16 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: novel isoquinoline derivatives are described by general formula I, where q equals zero; p equals zero or one; Ra is -COOH or WR8; under the condition that, if Ra is -COOH, then p equals zero, and if Ra is -WR8, then p equals one; W is selected from an oxygen atom and -NR9-, where R9 is selected from a group consisting of a hydrogen atom, acyl and alkyl; and R8 is selected from a group consisting of a hydrogen atom and alkyl; R1 is selected from a group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl substituted with alkyl, and -XR6, where X is an oxygen atom, -S(O)n- or -NR7, where n equals zero, one or two, R6 is selected from a group consisting of alkyl, aryl, aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamide, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, and R7 is a hydrogen atom or aryl; R2 and R3 are independently selected from a group consisting of a hydrogen atom, amino, amino substituted with alkoxy-substituted phenylsulfonyl, alkyl, alkyl substituted with up to three times by a halogen atom, aryl, halogen atom -NR6C(O)NR6R6, and -XR6, where X is an oxygen atom or -S(O)n-, where n equals zero, one or two, each of the substitutes R6 is independently selected from a group consisting of hydrogen, alkyl, alkyl substituted with aryl, aryl , aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with up to three times by a halogen, alkoxy, alkoxy substituted with up to three times by a halogen, aryloxy substituted with a halogen, nitro, alkylsulfonamide, arylsulfonamide and alkyl-substituted arylsulfonamide, cycloalkyl, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, under the condition that if X is -SO2-, R6 cannot be a hydrogen atom; or R2 and R3 together with carbon atoms to which they are bonded, are bonded with formation of an aryl group; R4 and R5 are independently selected from a hydrogen atom or aryl; R is selected from a group which includes a hydrogen atom, deuterium and methyl; R' is selected from a group consisting of a hydrogen atom, deuterium, alkyl or alkyl substituted with one group selected from hydroxyl, amino, carboxyl, aryl, aryl substituted with one hydroxyl and heteroaryl, containing up to five carbon atoms, two of which can be nitrogen; on the other hand, R and R' and the carbon atom to which they are bonded can be bonded with formation of cycloalkyl; R" is formed from a hydrogen atom and alkyl, or R" together with R' and the nitrogen atom to which they are bonded can be bonded with formation of a heterocyclic group containing up to six carbon atoms, one of which is nitrogen; R'" is selected from a group consisting of hydroxyl, alkoxy, alkoxy substituted with aryl, acyloxy, aryl, -S(O)n-R10, where R10 is hydrogen, and n is zero; or its pharmaceutically acceptable salts, esters or amides; under the condition that restrictive conditions given in paragraph 1 of the formula of invention are met. The invention also relates to specific produced and described compounds, a pharmaceutical composition based on compounds with general formula I, a method of treating, preventing and pretreatment using said pharmaceutical composition, a method of inhibiting activity of hydrolase enzyme, based on taking an effective amount of a formula I compound, a composition for preventing and pretreatment, based on formula I compound and erythropoietin.

EFFECT: new isoquinoline derivatives have useful biological properties.

53 cl, 4 tbl, 253 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an agent, which is in form of fluorinated 1,4-naphthoquinone derivatives of general formula (I) which have cytotoxic effect on human cancer cells in a culture. In general formula (I) 1) R1=NHC(CH3)3, R2, R3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH2)2, R2, R3=F; 4) R1=N(CH2CH2)2, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5R2, R3=F; 7) R1=H(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=OCH3, R2, R3=F; 12) R1=NH(CH2)2SS(CH2)2NH(2-pentafluoro-1,4-naphthoqunonyl), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O; R3=F; 15) R1=NHCH2CH2OH, R2,R3=F; 16)R1, R2=OCH3, R3=F.

EFFECT: proposed compounds can be used in medicine as a base for designing drug formulations of preparations used in malignant growth therapy.

2 dwg, 4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: testosterone is introduced intramuscularly and applied on the stomach and breast skin to ensure the steady high blood concentration. 6-8 hours prior to a session of gamma-ray teletherapy, a composite is introduced through rectum. The composite contains sodium alginate, dimethyl sulphoxide solution and testosterone. 6-8 hours later, the composite is removed from rectum. It is followed with gamma-ray teletherapy with "РОД" 5 Gy and local microwave hyperthermia.

EFFECT: method allows enhancing radio modifying treatment effect, inhibiting growth and metastasis of the tumour to the extent of regression, reducing number of by-effects and contraindications.

2 cl, 2 tbl, 1 ex

Oncotherapy // 2387456

FIELD: medicine.

SUBSTANCE: therapy involves introduction of sonicated human DNA combined with nonhistone protein to the patient with the length of human DNA fragments making 200-6000 pairs of bases, and the ratio of sonicated human DNA/nonhistone protein being 1/0.8. The complex is administered in a dose to ensure the blood concentration of sonicated human DNA 25 ng/ml - 1000 ng/ml.

EFFECT: application of the invention implies oncotherapy ensured by substitution of replacement oncolocus by a DNA fragment with nonmutant allele to form a nucleotide stable complex.

2 cl, 4 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and biotechnology and concerns an anticancer drug based on nanoparticles bearing recombinant human tumour necrosis factor alpha. Substance of the invention includes the anticancer drug representing nanoparticles each of which contains a nucleus consisting of polynucleotide complex representing double-helical RNA (dhRNA) - an interferonogenesis inducer, and coated with a layer of spermidine conjugate with polyglucin held by ionic interaction between negative polynucleotide complex and positive spermidine, while recombinant human tumour necrosis factor alpha is covalently bound with activated polyglucin. As double-helical RNA, the anticancer drug contains double-helical RNA of Saccharomyces cerevisiae yeast. Nanoparticles are ball shaped and sized about 50-70 nm; 60-80 molecules of recombinant human TNF-α of cytolytic activity 106 ME/mg of protein and higher, 60-80 molecules of polyglucin and 1000-1300 molecules of spermidine are necessary for one molecule of double-helical RNA of Saccharomyces cerevisiae yeast.

EFFECT: reduced dose of TNF-α and lower toxicity.

5 cl, 5 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to preparation of a plant drug for treating stomach cancer. The drug for treating stomach cancer contains cod-liver oil, badger fat, plant seed blood chosen from the group: pomegranate, hot pepper, fennel and activated coal in the following ratio, wt %: cod-liver oil 28; badger fat 28; seed blood 42; activated coal the rest.

EFFECT: treatment with the declared drug involves activating body defences, resistance ensured by improved functioning of an individual's organs and systems, and targeting the lesion focus.

2 ex

Cancer therapy // 2386442

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely oncology and can be used in mesothelioma treatment. The method consists in monthly subcutaneous introduction to the patient of powdered fibrin solution recovered from the donor's blood clot in a dose 100-600 mg of dry powder per one introduction session.

EFFECT: application of the invention allows for effective cancer therapy by fibrin preparation only without administration of cytostatic agents, radioactive drugs and radioisotopes that ensures reduced complications.

3 dwg, 1 ex

Biomarker // 2385944

FIELD: medicine.

SUBSTANCE: invention describes a biomarker intended for determining sensitivity of proliferative diseases, such as cancer, to mTORs inhibitor combined with a cytotoxic agent, first of all with a cytotoxic agent (CA) that damages or disturb DNA integrity. According to the invention, the biomarker designated as p21 represents cip/kip-family of cyclinkinase inhibitors. Sensitivity or response of the proliferative disease in an individual on treatment with mTOR inhibitor combined with CA is determined by the level of p21 expression after CA treatment and a combination therapy with using CA and mTOR inhibitor. Favorable treatment and sensitivity of disease to the combination therapy is predicted by the absence of expression induction reduced. Besides according to the invention, the biomarker can be used in the method to overcome the CA resistance in the patient treated with CA. That is ensured by evaluating p21 level in a sample, the increasing regulation of p21 expression following CA introduction to the patient, mTOR inhibitor is administered in combination with CA, while lowered expression regulation observed following the combination therapy ensures to continue treatment with mTOR inhibitor with simultaneous or consecutive CA introduction.

EFFECT: application of the invention allows for more accurate prediction of sensitivity of a proliferative diseases in an individual to the combination therapeutic treatment.

4 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted quinoline derivatives of general formula (I) in which: m is an integer from 0 to 3; R1 is selected from a group comprising an acylamino group, ester carboxylic group and an alkyl with 1-5 carbon atoms, an optionally substituted hydroxy and a halogen; R2 denotes hydrogen or an alkyl with 1-5 carbon atoms; R3 denotes - C(=X)-A, where A is selected from a group comprising aryl, heteroaryl, heterocyclyl and cycloalkyl, each of which can optionally contain from 1 to 4 substitutes selected from a group comprising an alkyl with 1-4 carbon atoms, an alkoxy with 1-4 carbon atoms, a halogen, hydroxy or nitro, and X denotes oxygen or sulphur; R4 denotes alkylene-heterocyclyl or alkylene-NR7R8, where alkylene is a linear alkylene with 1-4 carbon atoms; R7 and R8 are independently selected from a group comprising hydrogen, an alkyl with 1-4 carbon atoms, arylalkyl, heteroarylalkyl, cycloalkyl or cyclo-alkylalkyl; R5 is selected from a group comprising L-A1, where A1 is selected from a group comprising aryl, heteroaryl, heterocyclyl and cycloalkyl, each of which can optionally contain from 1 to 4 substitutes selected from a group comprising an alkyl with 1-4 carbon atoms, an alkoxy with 1-4 carbon atoms, a halogen, hydroxy and nitro, and where L is selected from a group consisting of oxygen, -NR9, where R9 denotes hydrogen or alkyl; -S(O)q-, where q equals 0, 1 or 2, and an alkylene with 1-5 carbon atoms, optionally substituted with a hydroxy, halogen or acylamino; and R6 is selected from a group comprising an alkyl with 1-5 carbon atoms, an alkenyl with 2-5 carbon atoms, an alkynyl with 2-5 carbon atoms, -CF3, an alkoxy with 1-5 carbon atoms, a halogen and a hydroxy; or its pharmaceutically acceptable salts or esters, as well as to a pharmaceutical composition having anticancer activity or inhibitory effect on mitotic kinesin based on the said compounds, to a method of treating disorders and use of these compounds for making a medicinal agent.

EFFECT: novel compounds which can be useful in treating cancer are obtained and described.

40 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes novel derivatives of 2,6-diaminopyridine of formula (I), where R1 is piperidine which is optionally substituted with up to four substitutes independently selected from a group comprising: (a) hydrogen, (b) lower alkyl, (c) lower alkyl substituted with an oxo group or aryl, (d) CO2R7, (e) COR12, (f) C(O)NR13R14, and (g) S(O)nR15; R2 is phenyl which can be substituted with up to four substitutes independently selected from a group comprising: (a) lower alkyl, (b) lower alkyl substituted with a halide or OR10, (c) halide, or (d) OR12; R5 and R6 are independently selected from a group comprising (a) hydrogen and (b) lower alkyl; R7 is selected from a group comprising (a) hydrogen and (b) lower alkyl; R10 is selected from a group comprising (a) lower alkyl, (b) aryl and (c) aryl substituted with a halide or NR5R6; R12 is selected from a group comprising (a) hydrogen and (b) lower alkyl; R13 and R14 are independently selected from a group comprising (a) hydrogen and (b) lower alkyl, R15 is selected from a group comprising (a) aryl, (b) aryl substituted with a halide, CO2R12, SO2R10, COR12, lower alkyl or lower alkyl substituted with a halide, OR12, oxo group, CO2R12, C(O)NR5R6 or NR5R6, (c) heteroaryl, (d) heteroaryl substituted with a halide, CO2R12, SO2R10, COR12, lower alkyl and lower alkyl substituted with a halide, OR12, oxo group, CO2R12, C(O)NR5R6 or NR5R6, (e) NR5R6, (f) lower alkyl, (g) lower alkyl substituted with a halogen, OR12, oxo group, CO2R12, C(O)NR5R6 or NR5R6, (h) a heterocycle and (i) a heterocycle substituted with CO2R12, COR12, SO2R10, lower alkyl, C(O)NR5R6 or NR5R6; n equals 0, 1 or 2; as well as a pharmaceutical composition having inhibitory effect on cyclin-dependant kinase and a method of producing the compound of formula I.

EFFECT: novel compounds which have antiproliferative activity and can be used for treating or curbing cancer are obtained and described.

28 cl, 58 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

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