Crystalline modification of para-methoxyanilide of 6-hydroxy-4-oxo-2,4-dihydro-1h-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline modification of para-methoxyanilide of 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid of formula: (I) , which is obtained by crystallisation from ethyl acetate, where values of interplanar distance (d) and relative reflection intensities (Irel) are given in claim 1.

EFFECT: novel crystalline modification exhibits a high diuretic effect.

2 dwg, 9 tbl, 6 ex

 

The invention relates to organic chemistry, in particular relates to a new crystalline modification of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid, and can be used in pharmaceutical industry and medicine.

A known method of obtaining possessing diuretic properties of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]-quinoline-5-carboxylic acid of formula I involves crystallization from DMF [1]. According to powder x-ray phase analysis, the thus obtained product is a pure polymorphic modification of anilide (I) light yellow color, conventionally called the α-form. It is characterized by a certain set of values of the interplanar spacings and relative intensities of the reflections (Table 1).

A disadvantage of the known crystalline modifications para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid is that it is a small needle crystals. It is this feature that creates a number of significant technological problems in large-scale production of finely crystalline precipitate the α-form is very difficult to filter, wash and dry. Moreover, additional difficulties are created by IP is use for crystallization DMF - because of the high boiling point it is difficult to remove from the crystalline end product, despite the fact that the high toxicity of this solvent causes very strict requirements for its content medicines (maximum residual quantity in the pharmaceutical substances is not more than 880 ppm [2]).

Table 1
Mejplanetnye distance (d) and relative intensities of the reflections (IRel.) known crystalline modifications para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid (α-form)
d, ÅIRel.d, ÅIRel.d, ÅIRel.
10.415672.89012.2271
8.897142.80912.1851
6.4421002.77312.151<1
5.926<12.73612.1041
5.64822.69012.0871
5.38252.61312.0711
5.256122.60312.0541
4.94942.57811.9881
4.758102.51611.9831
4.476<1 2.50611.9521
4.179292.48911.9391
4.03622.46311.8801
3.906<12.44811.8591
3.77312.44011.8241
3.66742.413<11.8101
3.401982.36911.758<1
3.252222.3611 1.7212
3.14772.34911.6981
2.96212.32911.6781
2.92312.276<11.673<1

The present invention is the task of obtaining a new crystalline modification of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid, with more favorable pharmaceutical and biological properties.

This object is achieved due to the fact that the new crystalline modification of anilide (I), conventionally called the β-form, characterized by different values of d-spacings and relative intensities of the reflections (Table 2), and also showing an increased diuretic effect.

td align="center"> <1
Table 2
Between Lacoste distance (d) and relative intensities of the reflections (I Rel.the new crystalline modification of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid (β-form)
d, ÅIRel.d, ÅIRel.d, ÅIRel.
15.18963.86812.776<1
11.176543.75342.740<1
7.91253.728102.7281
7.821103.694522.7181
7.750133.666102.6561
7.634 43.65042.6421
7.426283.60042.630<1
7.376393.57582.601<1
6.751183.546422.5851
6.674363.52072.576<1
6.027<13.475<12.494<1
5.86743.44212.4821
5.798113.417 <12.4751
5.718213,38822.446<1
5.648153.362242.412<1
5.609103.3391002.4021
5.56133.323312.312<1
5.08443.25722.301<1
4.90713.24032.295<1
4.856<13.22022.283
4.75123.16312.2731
4.71453.14522.267<1
4.68173.108172.247<1
4.66063.08322.2361
4.58913.071<12.227<1
4.56733.049<12.221<1
4.54852.966<12.166<1
<12.95512.113<1
4.22512.94412.1032
4.18742.933<12.095<1
4.16882.869<12.086<1
4.140132.854<12.072<1
4.10042.840<12.051<1
4.08322.83112.0431
4.0471 2.81312.037<1
3.99212.80612.021<1
3.97742.79321.880<1
3.946122.78311.874<1
3.9077

In contrast to the α-form, a new polymorphic modification of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid (β-form) is a easy filtering and washing large pale-yellow octahedral crystals. Does not cause β-form and problems during drying, since it is formed during crystallization of anilide (I) of boiling and low-toxic ethyl acetate (tolerable residual medicines is 000 ppm [2]).

To characterize the two polymorphic modifications para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid used a range of different physico-chemical and biological methods of analysis carried out in the same conditions.

Example 1. Powder x-ray phase analysis. Confirmation that the known and the new product are different pure polymorphic modifications of anilide (I) obtained by using powder x-ray phase analysis not only for the individual α - and β-forms, but also their mixtures formed by recrystallization from solvents. Studies performed on the diffractometer Siemens D500 (CuKα radiation, graphite monochromator). The obtained radiographs processed using PowderX and WinPLOTR [3, 4] and shown in figure 1.

Presented on Fig.1 data clearly indicate that x-rays, α - and β-forms have nothing in common. Therefore, these samples are pure polymorphic modifications of anilide (I). At the same time, samples obtained by crystallization from dioxane and ethanol, are mixtures of these two polymorphs in different proportions, as the observed x-ray lines characteristic of α - and β-forms. Samples 3 and 4 were obtained from different solvents, so it is possible is to say, they are not christallerian. This same statement applies to the sample 2 (α-form). Attempt to decipher the structure of the α-form by powder x-ray proved unsuccessful due to the fact that the line on the radiograph significantly broadened and reliably determine the unit cell parameters failed. To obtain crystals of the α-form, suitable for single crystal x-ray study also failed. It should be noted that it is likely that this polymorphic modification has a unit cell volume of about 9000 Å3and in this case, the structure determination by powder x-ray is hardly possible. However, for reliable identification of α - and β-polymorphs of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid can be used as themselves powder x-ray (Figure 1), and data specific to each of them interplanar distances and relative intensities of the reflections (table 1 and 2).

Figure 1 shows the powder diffraction pattern samples anilide (I), obtained by crystallization from ethyl acetate (1 - β-form), DMF (2 - α-form), dioxane (3 - a mixture of α - and β-forms with a predominance of β-form) and ethanol (4 - mixture mixture of α - and β-forms with a predominance of α-form).

Example 2. Single crystal x-ray diffraction study. Crystals of a new β-form pair-who of ethoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid were suitable for single crystal x-ray diffraction analysis, that allowed us to clearly identify the features of its spatial structure. Thus, in particular, it was found that in the independent part of the unit cell contains two molecules (a and b)differing in orientation metoxygroup and degree of OBLASTNOI (Figure 2, tables 3 and 4). Tricyclic fragment, the atoms O(1), O(2) and urea group in both molecules lie in the same plane with an accuracy of 0.04 Å, which is probably due to the presence of two strong intramolecular hydrogen bond O(2)-H(2O)...O(3) [H...O 1.30 Å, O-H...O 171° in molecule A and H...O 1.56 Å, O-H...O 151° in molecule B] and N(2)-H(2N)...O(1) [H...O 1.61 Å, N-H...O 144° in A and H...O 1.80 Å, N-H...O 147°, B]. The formation of hydrogen bonds leads to a significant lengthening of the communication is O(1)-C(9) 1.244(1) Å in A and to 1.252(2) Å B, and communication O(3)-C(12) - to 1.268(2) Å in A and 1.255(2) Å in B compared to their average value [5] 1.210 Å. Communication O(2)-C(7), on the contrary, shortened to 1.359(2) Å in A and to 1.329(2) Å in B (mean 1.362 Å). Connection C(7)-C(8) extended to 1.372(2) Å in A and 1.391(2) Å in B (mean 1.326 Å), which is characteristic of quinolone compounds. Pair-metoksifenilny Deputy is ap-conformation of C(8)-C(12) in the molecule and A slightly expanded relative to the plane urea fragment, and the molecule B coplanar this plane (torsion angles C(13)-N(2)-C(12)-C(8) 176.3(1)° in A and-178.5(2)°, B, C(12)-N(2)-C(13)-(14) 22.4(2)° in a and 0.6(3)° in (B). On the mutual position of the carb is midney group and the aromatic cycle is affected by two opposing factors: the intramolecular hydrogen bond C(14)-H(14)...O(3) [H...O 2.38 Å C-H...O 117° in molecule A and H...O 2.28 Å C-H...O 121° in molecule B] stabilizing coplanar arrangement of the fragments and the repulsion between the hydrogen atoms H(18)H(2N) 2.36 Å in A and 2.30 Å in B (sum of van der Waals radii [6] 2.34 Å), contributing to the spread of the fragments relative to each other. We can assume that the more pronounced coplanarity urea group and an aromatic cycle in the molecule B is determined by the stronger influence of hydrogen bonds.

Fig.2 shows the structure of molecules A and B β-form pair-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid numbering of atoms.

The methoxy group in the molecule A is in the CIS-position relative to the connection C(15)-C(16), and in the molecule In the TRANS-position relative to the same context (torsion angle C(15)-(16)-0(4)-C(19) 1.6(2)° and-172.7(1)° in (B) and almost coplanar the plane of the aromatic cycle, despite the strong repulsion between the atoms of the loop and metal band (short intramolecular contacts H(15)C...(19) 2.56 Å (2.87 Å), H(19a)...C(15) 2.78 Å (2.87 Å), H(19s)...C(15) 2.77 Å (2.87 Å in molecule A and N(17)...(19) 2.56 Å (2.87 Å), H(17)H(19d) 2.32 Å (2.34 Å), H(19d)...C(17) 2.78 Å (2.87 Å), N(19th)...(17) 2.77 Å (2.87 Å) in the molecule).

In the crystal, molecules A and B form layers parallel to the crystallographic plane (-1 -1 2). Molecules of adjacent layers are arranged relative to each other according to the type of "head to tail", and the degree of their overlap and R is sloanie between layers (3.37 Å) suggest the existence of stacking interaction.

Table 3
The bond length (l) in the structure of the β-form pair-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid
Linkl, ÅLinkl, Å
O(1A)-C(9A)1.244(1)O(2A)-C(7A)1.359(2)
O(3A)-C(12A)1.268(2)O(4A)-C(16A)1.376(2)
O(4A)-C(19A)1.410(2)N(1A)-C(1A)1.366(2)
N(1A)-C(9A)1.370(2)N(1A)-C(10A)1.484(2)
N(2A)-C(12A)1.322(2)N(2A)-C(13A)1.419(2)
From(1A)-C(6A)1.365(2)From(1A)-(2A)1.398(2)
(2A)-(3A)1.348(2) (2A)-C(11A)1.501(2)
(3A)-C(4A)1.410(2)C(4A)-C(5A)1.373(2)
(5A) (6A)1.406(2)From(6A)-C(7A)1.415(2)
C(7A)-C(8A)1.372(2)From(8A)-C(9A)1.469(2)
From(8A)-C(12A)1.481(2)(10A) (11A)1.547(2)
(13A) (14A)1.369(2)(13A)-C(18A)1.388(2)
(14A) (15A)1.398(2)(15A) (16A)1.371(2)
(16A) (17A)1.379(2)(17A) (18A)1.374(2)
O(1B)-C(9B)1.252(2)O(2B)-C(7B)1.329(2)
O(3B)-WITH(12V)1.255(2)O(4B)-C(16B)1.368(2)/td>
O(4B)-(19C)1.422(2)N(1B)-C(9B)1.358(2)
N(1B)-C(1B)1.365(2)N(1B)-C(10B)1.466(1)
N(2B)-C(12B)1.345(2)N(2B)-C(13B)1.408(2)
(1B)-C(6B)1.372(2)(1B)-(2B)1.389(2)
With(2B)-C(3V)1.364(2)With(2B)-C(11B)1.504(2)
With(3B)-C(4V)1.396(2)(4B) (5B)1.380(2)
(5B) (6B)1.409(2)(6B)-C(7B)1.424(2)
C(7B)-C(8B)1.391(2)(8B) (9B)1.460(2)
(8B)-WITH(12V)1.478(2)With(10B) (11B)1.551(2)
C(13B)-C(18V) 1.380(2)C(13B)-C(14B)1.385(2)
With(14C)-(15)1.377(2)With(15)-C(16B)1.381(2)
From(16B) (17B)1.372(2)With(17B) (18B)1.378(2)

Table 4
The bond angles (ω) in the structure of the β-form pair-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid
The valence angleω deg.The valence angleω deg.
(16A)-O(4A)-C(19A)117.9(1)C(1A)-N(1A)-C(9A)123.9(1)
C(1A)-N(1A)-C(10A)111.1(1)C(9A)-N(1A)-C(10A)125.0(1)
C(12A)-N(2A)-C(13A)128.6(2)C(6A)-C(1A)-N(1A)123.5(2)
From(6A)-C(1A)-(2A)125.1(2)/td> N(1A)-C(1A)-C(2A)111.4(2)
(3A)-C(2A)-C(1A)117.5(2)C(3A)-C(2A)-C(11A)133.6(2)
From(1A)-(2A)-C(11A)108.9(1)C(2A)C(3A)-C(4A)119.7(2)
From(5A)-C(4A)-C(3A)121.7(2)C(4A)-C(5A)C(6A)119.5(2)
From(1A)-C(6A)-C(5A)116.5(2)C(1A)-C(6A)C(7A)115.2(2)
From(5A)-C(6A)-C(7A)128.3(2)O(2A)-C(7A)-C(8A)120.4(2)
O(2A)-C(7A)-C(6A)116.8(2)C(8A)-C(7A)-C(6A)122.8(2)
C(7A)-C(8A)-C(9A)120.5(2)C(7A)-C(8A)-C(12A)119.9(2)
From(9A)-C(8A)-C(12A)119.7(2)O(1A)-C(9A)-N(1A)119.7(2)
O(1A)-C(9A)-C(8A)126.2(2) N(1A)-C(9A)-C(8A)114.1(1)
N(1A)-C(10A)-C(11A)103.9(1)C(2A)-C(11A)C(10A)104.6(1)
O(3A)-C(12A)-N(2A)122.6(2)O(3A)-C(12A)-C(8A)119.6(2)
N(2A)-C(12A)-C(8A)117.8(2)C(14A)-C(13A)-C(18A)118.4(2)
C(14A)-C(13A)-N(2A)125.7(2)C(18A)-C(13A)-N(2A)115.9(2)
C(13A)-C(14A)-C(15A)120.9(2)C(16A)-C(15A)-C(14A)119.9(2)
C(15A)-C(16A)-O(4A)125.8(2)C(15A)-C(16A)-C(17A)119.6(2)
O(4A)-C(16A)-C(17A)114.6(2)C(18A)-C(17A)-C(16A)120.2(2)
C(17A)-C(18A)-C(13A)121.1(2)C(16B)-O(4B)-C(19B)117.5(1)
C(9B)-N(1B)-C(1B)123.3(2) C(9B)-N(1B)-C(10B)125.1(1)
C(1B)-N(1B)-C(10B)111.7(1)C(12B)-N(2B)-C(13B)129.7(2)
N(1B)-C(1B)-C(6B)123.6(2)N(1B)-C(1B)C(2B)111.8(2)
C(6B)-C(1B)C(2B)124.6(2)C(3B)-C(2B)-C(1B)117.5(2)
C(3B)-C(2B)-C(11B)134.3(2)C(1B)C(2B)-C(11B)108.2(2)
C(2B)C(3B)C(4B)120.4(2)C(5B)-C(4B)-C(3B)121.0(2)
C(4B)-C(5B)-C(6B)119.8(2)C(1B)-C(6B)-C(5B)116.7(2)
C(1B)-C(6B)-C(7B)115.7(2)C(5B)-C(6B)-C(7B)127.6(2)
O(2B)-C(7B)-C(8B)120.9(2)O(2B)-C(7B)-C(6B)117.7(2)
C(8B)-C(7B)-C(6B)121.4(2)C(7B)-C(8B)-C(9B) 120.3(2)
C(7B)-C(8B)-C(12B)118.7(2)C(9B)-C(8B)-C(12B)121.0(2)
O(1B)-C(9B)-N{1B)119.7(2)O(1B)-C(9B)-C(8B)124.6(2)
N(1B)-C(9B)-C(8B)115.6(2)N(1B)-C(10B)-C(11B)103.5(1)
C(2B)-C(11B)-C(10B)104.9(1)O(3B)-C(12B)-N(2B)122.0(2)
O(3B)-C(12B)-C(8B)120.4(2)N(2B)-C(12B)-C(8B)117.6(2)
C(18B)-C(13B)-C(14B)118.2(2)C(18B)-C(13B)-N(2B)117.2(2)
C(14B)-C(13B)-N(2B)124.7(2)C(15B)-C(14B)-C(13B)119.5(2)
C(14B)-C(15B)-C(16B)122.3(2)O(4B)-C(16B)-C(17B)126.0(2)
O(4B)-C(16B)-C(15B)116.0(2)C(17B)-C(16B)-C(15B)118.0(2)
C(16B)-C(17B)-C(18B)120.3(2)C(17B)-C(18)-C(13B)121.8(2)

Crystals of β-form pair-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid monoclinic (ethyl acetate), at 20°Ca=16.381(2), b=8.459(1), c=23.630(2) Å, β=108.61(1)°, V=3103.1(4) Å3, Mr=336.34, Z=8, space group P21/n, dthe calc=1.440 g/cm3, µ(MoKα)=0.103 mm-1F(000)=1408. The unit cell parameters and intensity 33430 reflections (8993 independent, Rint=0.095) measured on the diffractometer Xcalibur-3 (MoKαradiation, CCD detector graphite monochromator, ω-scan, 2θmax=60°).

Structure deciphered by the direct method on complex programs SHELXTL [7]. Position of hydrogen atoms detected from the differential synthesis of the electron density and refined model of the rider" Uout=nUEQnon-hydrogen atoms associated with hydrogen (n=1.5 for the metal group and n=1.2 for all other hydrogen atoms). The hydrogen atoms involved in the formation of hydrogen bonds, refined in isotropic approximation. The structure is specified by F2total matrix MNK in anisotropic approximation for non-hydrogen atoms to wR2=0.032 for 8873 reflections (R1=0.032 in 1951 reflections with F > 4σ(F), S=0.465). Interatomic distances and the shaft is ntie angles are presented in tables 3 and 4, respectively.

Example 3. NMR spectroscopy in solution. For the qualitative analysis of known α-form and a new β-form pair-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid used NMR spectroscopy1H and13With the solution.

The NMR spectra of1H and13With registered spectrometer Varian Mercury-400 (400 MHz for1H and 100 MHz for13(C) in a solution of DMSO-d6, internal standard TMS.

Shown in table 5 and 6 suggests that both the sample have the same chemical formula, i.e. they are para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid. As expected, after the dissolution characteristic of crystals differences polymorphic modifications disappear - known result for the α-form and a new β-form obtained almost identical NMR spectra1H and13C.

Table 5
The chemical shifts of nuclei1N source of α-form and a new β-form anilide (I) in NMR spectra1H in a solution of DMSO-d6
Functional groupThe original α-formNew β-form
HE (1H, s)16.5616.48
NH (1H, s)12.4312.35
H-7 (1H, d)7.677.58
N-9,2',6' (3H, m)7.547.48
H-8 (1H, t)7.237.16
H-3',5' (2H, d)6.956.90
CH2-2 (2H, t)4.304.23
OCH3(3H, s)3.773.75
CH2-1 (2H, t)3.383.30

6-WITH-IT
Table 6
The chemical shifts of nuclei13Source α-form and a new β-form anilide (I) in NMR spectra13With the solution, DMSO-d6
The carbon atomThe original α-formNew β-form
172.66172.57
CONH169.58169.50
4-C=O161.29161.21
4'-Soma157.29157.24
9b-142.73142.63
9-132.42132.24
1'-130.68130.72
7-129.21129.04
8124.27124.14
2',6'-123.02122.94
6a-C121.02120.97
3',5'-115.14115.10
9a-C112.82112.79
5-98.23 98.17
OCH356.1056.07
2-CH247.7847.68
1-CH227.2927.25

Example 4. High-performance liquid chromatography. The purity of the α - and β-forms of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid was determined by high performance liquid chromatography (HPLC). The study is performed on a liquid chromatograph Waters Alliance 2695, the detector is a Waters 2998 PDA (diagramaticly in the UV and visible regions of the spectrum), the wavelength detector 235 nm, analytical column Agilent Bond SB-CN of size 250×4.6 mm, particle diameter 5 μm, the temperature of the column thermostat 30°C, mobile phase: a mixture of M phosphate buffer solution with pH 3.0 and acetonitrile (55:45), the flow rate of the mobile phase 1.0 ml/min, the analyzed solution: 0.5 mg/ml in acetonitrile, the volume of the sample test solution and 20 µl.

Table 7
Times chromatographic retention (RT) and peak areas (%) on the chromatograms of the original α-form and a new β-form EN the Lede (I)
SampleRT, minThe peak area, %
the α-form16.91499.93
β-form17.375100.00

Presented in table 7, the results indicate a high degree of purity known as α-form, and a new β-form pair-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid - content of the basic substance is at least 99.93%.

Example 5. NMR spectroscopy in the solid. In contrast to NMR spectroscopy solutions, and solve problems to determine the phase composition (including polymorphism and structure of solid materials of any degree of orderliness allows the NMR method in the solid. Therefore, the study of polymorphic differences and polymorphic purity of the known α-form and a new β-form anilide (I) is carried out using the method of solid-state NMR spectroscopy on nuclei13C.

The NMR spectra of13Both crystal modifications anilide (I) were obtained in the NMR spectrometer AVANCE II 400 production (BRUKER) with an operating frequency of 100.4 MHz for nuclei13C. For registration of spectra used two-channel solid-state sensor the system VMF (rotation under magic angle) with an outer diameter of 4 mm rotor The sample in powder form was placed in VMF-rotors ceramic. The speed of rotation of the sample was equal to 12000 Hz. The NMR spectra of VMF on nuclei13With recorded using the technique of transfer of polarization (CP/MAS) with linearly decreasing momentum in nuclei1N during the polarization transfer and RF isolation high power SW-TPPM (τ=8 ľs, φ=15°) for protons during the registration of the spectrum. The contact time was 2 MS, time between scans - 2, 90-degree pulse and nuclei1H - 5 μs, the number of scans is 1024. As an external standard scale chemical shifts were used TMS (0 ppm).

Table 8
The chemical shifts of nuclei13Source α-form and a new β-form anilide (I) in solid-state NMR spectra13
The carbon atomThe original α-formNew β-form
6-WITH-IT172.4172.3
CONH167.6168.1 d
4-C=O160.2161.0
4'-Soma157.8156.3 d
9b-141.9142.2
9-131.7132.0 d
1'-130.7131.1 d
7-128.0129.9
8124.0128.1 d
2',6'-123.2124.8 d
121.9123.0
6A-C120.7121.6 d
3',5'-118.9116.6
112.5114.3 d

The carbon atomThe original α-formNew β-form
9a-C110.6110.8 d
5-96.298.3 d
OCH356.154.7 d
2-CH248.548.7 d
1-CH228.228.6 d

The analysis presented in Table 8 the data shows that the new β-form is a crystalline phase in which the molecules of the starting compound are two non-equivalent positions (this conclusion is fully consistent with the results described in example 2 single crystal x-ray study of β-form). This is indicated by the doubling of the majority of the NMR signals13For comparison with the spectrum of the NMR13With this substance, obtained in dissolved form. The high crystallinity indicates the small width of the spectral lines VMF NMR13C.

Known α-form, on the contrary, is polymorphic modification, in which there is only one type of molecules. This is evidenced by the total number of singlet NMR signals13C, equal to 19, which coincides with the number of carbon atoms in the molecule, and the absence of splitting a single signal, as it was observed for the β-form. In the profile is from an NMR spectrum 13With this substance, obtained in dissolved form, all the carbon atoms in the crystalline α-form equivalent as their inequality affects not only the location within the molecule, but also the position of the molecule relative to the neighboring molecules.

The position of the lines in NMR spectra13For α - and β-forms are not the same. Smaller line width of the NMR spectrum13With β-form indicates a higher degree of crystallinity compared to the α-form.

The study of known α-form and a new β-form by the method of solid-state NMR spectroscopy on nuclei13With demonstrated that they are fundamentally different polymorphic modifications para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid with almost complete polymorphic purity.

Example 6. Diuretic activity of the new crystal modification (β-form) para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid in comparison with the activity of known crystalline modifications (α-form) of the same compounds was studied on white rats weighing 180-200 g (12 animals per substance) by the standard method [8]. All experimental animals were given via a stomach tube water pressure at a rate of 5 ml per 100 g body weight. The control group of animals received only the analogue of the offered amount of water with tween-80. The tested substance was administered orally at a dose of 10 mg/kg (average effective dose of the known α-form) in the form of a thin water suspension, stabilized by tween-80. After that, the test animals were placed in metabolic cages". The intensity of the urinary tract was the amount of urine, the selected animals for 5 hours. Presented in table experimental data allow to conclude that the new crystal modification (β-form) para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]-quinoline-5-carboxylic acid strength diuretic effect on average 19% higher than the known α-form.

Table 9
Diuretic activity of known α-form and a new β-form anilide (I) in the dose of 10 mg/kg
ConnectionDiuresis after 5 h, mlDiuretic activity, %
Known α-form9,7±0,28226
New β-form10,5±0,27245
Control4,3±0,20100

Thus, as presented in the description of the complex physico-chemical methods of analysis confirms that the claimed new crystal modification (β-form) para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid. In contrast to the known α-form, the resulting substance possesses improved pharmaceutical properties and shows an increased diuretic effect, so it may find wide application in various fields of medicine.

Sources of information

1. Pat. Of Ukraine # 86883 / C07D 215/22, A61K 31/47, publ. 2009.

2. The European Pharmacopoeia, 6thEdition. - 2008, Vol.1. - P.601-610.

3. C.Dong / PowderX: Windows 95-based program for powder X-ray dif-fraction data processing. - J. Appl. Crystallogr. - 1999. - Vol.32. - P.838.

4. J.Rodriguez-Carvajal, T.Roisnel / FullProf.98 and WinPLOTR: New Windows 95/NT Applications for Diffraction. Commission for Powder Diffraction, International Union of Crystallography, Newsletter No. 20 (May-August) Summer 1998.

5. H.-B.Burgi, J.D.Dunitz / Structure Correlation, VCH, Weinheim, 1994, Vol.2. - P.741.

6. Yevzerov / Crystallography. - 1997. - V.42, №5. - S.

7. G..Sheldrick / Acta Crystallogr. - 2008. Vol. A64. - P.112.

8. Lnternal, Var / Elements of experimental pharmacology. - M.: Medicine, 2000. - S.

Crystalline modification of para-methoxyaniline 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid, characterized by the following interplanar distances (d) and relative intensities of reflections (IRel. ):

d, E-IRel.d, E-IRel.d, E-IRel.
15.189-63.868-12.776-<1
11.176-543.753-42.740-<1
7.912-53.728-102.728-1
7.821-103.694-522.718-1
7.750-133.666-102.656-1
7.634-43.650-42.642-1
7.426-283.600-42.630-<1
7.376-393.575-82.601-<1
6.751-183.546-422.585-1
6.674-363.520-72.576-<1
6.027-<13.475-<12.494-<1
5.867-4.442-1 2.482-1
5.798-113.417-<12.475-1
5.718-213.388-22.446-<1
5.648-153.362-242.412-<1
5.609-103.339-1002.402-1
5.561-33.323-312.312-<1
5.084-43.257-22.301-<1
4.907-13.240-32.295-<1
4.856-<13.220-22.283-<1
4.751-23.163-12.273-1
4.714-53.145-22.267-<1
4.681-73.108-172.247-<1
4.660-63.083-22.236-1
4.589-13.071-<12.227-<1
4.567-33.049-<12.221-<1
4.548-52.966-<12.166-<1
4.356-<12.955-12.113-<1
4.225-12.944-12.103-2
4.187-42.933-<12.095-<1
4.168-82.869-<12.086-<1
4.140-132.854-<12.072-<1
4.100-42.840-<12.051-<1
4.083-22.831-12.043-1
4.047-12.813-12.037-<1
3.992-12.806-12.021-<1
3.977-42.793-21.880-<1
3.946-122.783-11.874-<1
3.907-7

and showing diuretic activity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to complexes of lanthanides and organic ligands which are luminescent in the visible spectrum and are used in electroluminescent devices, means of protecting security paper and documents from falsification etc. Disclosed are novel luminescent coordination compounds of lanthanides of formula: where Ln is Eu3+, Tb3+, Dy3+, Sm3+, Gd3+.

EFFECT: said compounds have high luminescence intensity and considerable thermal tolerance of up to 400°C, which enables use thereof in modern production of light-emitting diodes.

4 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of imidazo[4,5-c]chinoline of general formula or to its pharmaceutically acceptable salts, where R1 represents straight-chained C1-C6alkyl, possibly substituted with one substituent, selected from C1-C3alkoxy; Z1 represents C2-C6alkylene; X1 represents NR5 or >NCOR5; Y1 represents C1-C6alkylene; R3 represents C1-C6alkyl, possibly substituted with C1-C6alkoxy; R5 represents hydrogen, piperidinyl, possibly substituted by piperidinyl nitrogen with group R10, group C1-C6alkyl, where the last group is possibly substituted with one substituent, independently selected from NR7R8 or R9; or R5 represents C1-C6alkylene, which can be bound with carbon atom in C2-C6alkylene group Z1 with formation of piperidine ring; each of R7 and R8 independently represents tetrahydropyranyl, piperidinyl, possibly substituted by piperidinyl nitrogen atom with group R10a, C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR12; or R7 and R8 together with nitrogen atom, to which they are bound, form 4-7-membered saturated heterocyclic ring, selected from asetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-oxazepanyl and 1,4-diazepanyl, where heterocyclic ring is possibly substituted with one or two substituents, independently selected from S(O)qR15, OR15, CO2R15, COR15, CONR15R16, NR15CO2R16, pyrimidinyl and C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR18 and CO2R18; R9 represents S(O)qR20; R10 and R10a independently represent COR2 or group C1-C6alkyl; each of R12, R15, R16, R18, R20 and R24 independently represents hydrogen or C1-C6alkyl; q equals 2; m and n both equal 0; and A represents phenyl. Invention also relates to method of obtaining formula (I) compound, based on it pharmaceutical composition, and to method of treating said pathological conditions.

EFFECT: obtained are novel derivatives of imidazo[4,5-c]chinoline, useful modulation of TLR7 activity.

17 cl, 18 dwg, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine.

SUBSTANCE: invention refers to the use of reserpine as an agent possessing anti-inflammatory and antifibrotic action in pulmonary tissue, and cytostatic action.

EFFECT: extended range of products used for pharmacological correction of pulmonary inflammation and fibrosis accompanying cytostatics prescribed.

1 dwg, 6 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a selective antituberculosis agent representing 3-hydrazono-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine of general formula A

wherein R2 = hydrogen atom or methyl; R3 = methyl, aryl specified in optionally substituted phenyl, heteryl specified in furyl, pyridyl, 3-phenylallyl. The invention also refers to a method for preparing 3-hydrazono-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with the use of microwave radiation; the given method is implemented with high speed and selectivity.

EFFECT: invention provides higher activity and specificity of antimycobacterial action.

2 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and medicine and deals with application of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidaso[4,5-c]quinilin-1-yl)phenyl]propionitryl or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidaso[4,5-c]quinoline-2-on or its tautomer, pharmaceutically acceptable salt, hydrate or solvate for obtaining medication, intended for treatment of disease, connected with change or impairment of mTOR kinase regulation, selected from group, including glioma, disease transplant-against-host, for instance, after bone marrow transplantation, restenosis, tuberous sclerosis, lymphangioleimyomatosis, pigment retinitis, autoimmune diseases, including encephalomyelitis, insulin-dependent diabetes mellitus, dermatomyositis, rheumatoid diseases, steroid-resistant acute lymphoblastic leukemia, fibrous diseases, pulmonary hypertension, immunomodulation, Von Hippel-Lindau syndrome, Carney syndrome, familial adenomatous polyposis, juvenile polyposis syndrome, Birt-Hogg-Duke syndrome, familial hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, neurodegenerative disorders, wet and dry macular degeneration, muscle dystrophy (atrophy, cachexia) and myopathies, such as Danone disease, bacterial and viral infections, including military tuberculosis, group A streptococcus, virus of type I herpes simplex, HIV-infection, neurofibromatosis, including type 1 neurofibromatosis, Peutz-Jeghers syndrome, or any their combinations.

EFFECT: invention ensures high efficiency.

9 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical composition for local application, which possesses antibacterial properties.

EFFECT: invention represents pharmaceutical stable semi-hard compositions for local application, which contain from 0.2 to 5 wt % of desfluoroquinolone compound, suitable for ointment or cream production.

24 cl, 5 ex, 15 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly gastroenterology, and may be applied in treating secondary lactase deficiency. For this purpose, with underlying diet and drug-induced therapy, bifiform 1 tablet 2-3 times a day and No-spa 1-2 tablets 3 times a day are additionally administered. The therapeutic course makes 14 days.

EFFECT: method enables higher clinical effectiveness in secondary lactase deficiency.

3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

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