1-[2-(4-benzyl-4-hydroxypiperidin-1-yl)-ethyl]-3-(2-methylquinolin-4-yl)-urea in crystalline sulphate form

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline 1-[2-(4-benzyl-4-hydroxypiperidin-1-yl)-ethyl]-3-(2-methylquinolin-4-yl)-urea of formula I

,

in monosulphate trihydrate form. The invention also relates to a composition based on the said compound which has antagonistic effect on urotensin.

EFFECT: obtaining a novel compound and compositions based on said compound, which can be used in medicine as neurohormonal antagonists.

8 cl, 3 dwg, 5 tbl, 5 ex

 

The present invention relates to 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea in the form of crystalline, stoichiometric specific and nephroscopes sulfate and to a method thereof. In addition, the present invention relates to the use of the specified 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea in the form of crystalline, stoichiometric specific and nephroscopes sulfate alone or in combination with other compounds. The present invention also relates to compositions comprising specified 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea in the form of crystalline, stoichiometric specific and nephroscopes sulfate and an inert carrier, which is applicable as an antagonist of urotensin II.

1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of formula I, as well as how you can get it in the form of a free base is known from WO-2004026836. It is shown that 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of formula I is active antagonist of the receptor urotensin II [Martine Clozel et al., in J. Pharmcol. Exp. Ther., 2004, 311, 204-212].

1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of free the th Foundation has the disadvantages, she is hygroscopic at high temperature and high humidity changes its color, and under these conditions it aglomerated into a ball. So the compound of the formula I in the form of a free base is unsuitable for use as a pharmaceutical product, because it is difficult to include in pharmaceutical preparations. In addition, due to the above characteristics of large-scale production and storage of the specified compounds of formula I is difficult.

The object of the present invention is to obtain 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in stoichiometric specific and nephroscopes crystalline form, which has improved characteristics suitable for use as a pharmaceutical product, pharmaceutical product, large-scale production and storage.

The present invention relates to 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of a three-hydrate sulfate. Sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I described in the publication [Martine Clozel et al., J. Pharmacol Exp. Ther., 2004; DOI: 10.1124/jpet.104.068320], but methods not described.

The present invention also relates to 1-[2-(4-benzo is l-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of sulfate dihydrate.

The present invention also relates to a method for producing 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of specific and stoichiometric nephroscopes sulfate, which includes

a) mixing 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of formula I and an organic solvent and adding an aqueous solution of sulfuric acid or sulfuric acid in a mixture of water and an organic solvent and stirring the mixture; or

b) mixing 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I and mixtures of organic solvent and water and adding an aqueous solution of sulfuric acid or sulfuric acid in a mixture of water and an organic solvent and stirring the mixture; or

c) the addition of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of solids or dissolved in a mixture of organic solvent and water to aqueous solution of sulfuric acid or sulfuric acid in a mixture of water and an organic solvent and stirring the mixture; or

d) the addition of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of solids or dissolved in an organic solvent to aqueous solution of sulfuric KIS is the notes or to the sulfuric acid solution in a mixture of water and an organic solvent and stirring the mixture; or

e) hydrating with uncertain composition of the hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea by mixing in water a mixture of water and an organic solvent, or by exposure to the atmosphere having a controlled relative humidity.

In the preferred embodiment, this method sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of formula I is a sulfate trihydrate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea.

In addition, the present invention relates to 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of specific and stoichiometric nephroscopes sulfate obtained as indicated above.

In addition, the present invention relates to pharmaceutical compositions comprising 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of specific and stoichiometric nephroscopes sulfate specified above, and an inert carrier.

In addition, the present invention relates to the salts of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea, above, and to their use as pharmaceuticals.

Due to their str is oblasti to inhibit the effects of urotensin II salt of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea, described above can be used to treat diseases that are associated with increased narrowing of the blood vessels, proliferation, or other pathological conditions associated with the effects of urotensin II. Examples of such diseases are hypertension, atherosclerosis, angina, or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, shock, spasm of cerebral vessels, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, diabetes, diabetic arteriopathy, diabetic nephropathy, diseases of the connective tissue, cirrhosis, asthma, chronic obstructive pulmonary disease, pulmonary edema at high altitude, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension and pulmonary fibrosis. They can also be used to prevent restenosis after balloon or Stanovoy angioplasty for the treatment of cancer, prostate hypertrophy, erectile dysfunction, hearing loss, blindness, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, sickle cell acute syndrome of breast cancer, glomerulonephritis, renal colic, glaucoma, treatment and prevention of Oslo the developments in diabetes, complications after surgery on the blood vessels or heart, or after organ transplantation, complications after treatment with cyclosporine, pain, substance abuse, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, different types of dementia, neuromuscular disorders, neurodegenerative diseases, and other diseases associated with dysregulation of urotensin II or receptors urotensin II.

These compositions can be entered in the enteral or oral form, for example, in the form of tablets, pills, capsules made of gelatin, emulsions, solutions or suspensions, nasal form, such as sprays, aerosols, or rectally in the form of suppositories. Salt of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea, as noted above, you can also type in the form of intramuscular, parenteral or intravenous form, for example in the form of solutions for injection.

These pharmaceutical compositions may contain salts of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea, above, in combination with inorganic and/or organic inert fillers, normal for the pharmaceutical industry, such as lactose, corn starch or its derivatives, talc, stearic acid or salts of these compounds.

In addition to the preservative composition may contain substances that increase the stability of the substance that increases or regulating the viscosity, substances that enhance solubility, sweeteners, dyes, chemicals, improves taste, salts for modifying the osmotic pressure, buffer substances, antioxidants, etc.

Salt of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea, as noted above, can also be used in combination with one or more therapeutically useful substances, for example with α - and β-blockers such as phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol, carvedilol, etc.; vasodilator means, such as hydralazine, Minoxidil, diazoxide, flosequinan etc.; with calcium antagonists such as diltiazem, nicardipine, nimodipine, verapamil, nifedipine and the like; inhibitors of angiotens convertervideo enzyme, such as cilazapril, captopril, enalapril, lisinopril, and the like; calcium channel activators, such as pinacidil, cromakalim and the like; angiotensin antagonists of the receptor, such as losartan, valsartan, candesartan, irbesartan, eprosartan, telmisartan and tasosartan and the like; diuretics, such as hydrochlorothiazide, chlorothiazide, acetamid, bumetanide, furosemide, metolazone, chlorthalidone, etc.; simpatolitiks, such as methyldopa, clonidine, guanabenz, reserpine and the like; with antagonists endothelioma receptor, such as bosentan, clazosentan, tezosentan, darusentan, atrasentan enrasentan or sitaxentan etc.; antihyperlipidemic means, such as lovastatin, pravastatin, fluvastatin, atorvastatin, tseriwastatina, simvastatin, and the like; and other therapeutic tools that are used to treat high blood pressure, cardiovascular disease or other disorders described above.

The dose can vary within wide limits, but should be chosen in accordance with the particular case. The usual dose, administered during the day in oral form, should be from about 3 mg to about 3 g, preferably from about 5 mg to about 1 g, particularly preferably from about 10 to about 300 mg for an adult with a body weight of approximately 70 kg The dose should preferably be introduced in the form of 1 to 3 doses of the same weight per day. Typically, children enter a smaller dose, appropriate body weight and age.

The present invention also relates to compositions containing amorphous part of the salts of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea, above.

The term "crystallinity" or "crystalline" is used to describe the crystalline part of the material, non-amorphous material, and it is determined, for example, in the form of a line and the background intensity on the x-ray.

When using these methods, the degree of crystallinity is equal to from 90 to 100%. In a more preferred embodiment, the degree of crystallinity is in the range from 92 to 100%. In the most preferred embodiment, the degree of crystallinity is in the range from 95 to 100%.

The term "organic solvent" when used in the present invention means a solvent or mixture of solvents, such as C1-C4-alkanols (CH3HE2H5HE, h3H7HE, I-C3H7HE, h4H9HE, i-C4H9OH, t-C4H9IT), ketones (acetone, ethylmethylketone, methyl isobutyl ketone), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, IU the Il-tert-butyl ether or acetonitrile. Preferred organic solvents are CH3HE2H5HE, h3H7HE, i-C3H7HE and acetone. The most preferred organic solvents are CH3HE2H5HE, i-C3H7HE and acetone.

The term "sulfuric acid" when used in the present invention means a solution of sulfuric acid in water or solutions of sulphuric acid in a mixture of water and an organic solvent, preferably aqueous solutions. The sulphuric acid solutions have concentrations in the range from 0.01 to 10 mol/l, more preferably a concentration in the range from 0.1 to 5 mol/l, most preferably a concentration in the range from 0.2 to 2 mol/L.

The term "stoichiometric certain crystalline form for use in the present invention means a crystalline compounds described above, which contains 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of formula I, sulphuric acid and water in a molecular ratio of X:Y:Z, where X and Y are equal to 1, and Z denotes a number equal to from 0 to 4. In a more preferred embodiment, Z represents a number equal to from 0 to 3. In the most preferred embodiment, Z represents a number equal to 2 or 3.

The above General description of us who Otsego of the invention will be further illustrated by the use of some non-limiting examples.

Examples according to the present invention

List of abbreviations:

DSP - dynamic vapor sorption

BB - high vacuum conditions

min - minutes

RH - relative humidity

CT room temperature

RGG - x ray powder diffraction, x-ray.

Radiographs (RGG) filmed on the instrument Bruker D5000, using radiation sialpha(1,5418 Ǻ), generator 40 kV - 30 mA, in the range from 3 to 40° (2-theta). Particleboard was investigated using gravimetric measurements (10-30 mg of sample) at a given temperature under controlled relative humidity. The measurements were carried out using SMS (Surface Measurement Sytems) DVS 1000. First, the sample was dried (0% RH) in a stream of dry nitrogen at the temperature of the experiment. Then the sample was subjected to cyclical effects of the atmosphere with different relative humidity (RH) (usually when speed increases, for example, 20, 40, 60 and 80% RH and at the same speed reduced to 0% RH). The duration of each stage S impact was sufficient to establish equilibrium mass.

Example 1

Trihydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea

1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (1 EQ.) dissolved in ethanol at a concentration equal to 25 wt./wt.%, and the mixture is heated at 50°C. Add water, R is the target of sulfuric acid (1M, 1.1 EQ.). Crystallization does not necessarily initiate a wet priming compound of example 1 (0,5%). The suspension is cooled to 0°C at a cooling rate of 15°C./h and maintained at this temperature for at least 1 h, and then filtered and washed with an aqueous solution of ethanol (50 wt.%/wt.). The solid is dried at 30°C in a stream of moist nitrogen (50% RH) and get the desired connection purity of 97.7% with a yield of about 90%.

Radiograph (RGG) three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea as described in example 1.

Figure 1 shows RGG compounds described in example 1. Table 1 shows the position of the peaks and their intensity.

Upon receipt of these results used the following parameter values:

Example 1. Type: 2-Theta/theta vary smoothly - Start: 3,000° - End: 40,000° - Step: At 0.020° - step Duration: 1 - Temperature: 25°C (room temperature) - start Time: 2 s - 2-theta: 3,000° - theta: 1,500° - Phi: 0,00° DIF - Y: 77,31% - d x by: 1. WL: 1,54056 - 0-

Table 1
Angles 2-theta and intensity of the peaks on the x-ray (RGG) of the compound described in example 1
Angle 2-thetaIs d IntensityIntensity
[°][angstroms][pulses][%]
7,21412,2441015710,3
8,23210,7315131152,2
9,0139,8031275313
10,3178,5672523025,7
10,8998,1115260of 5.4
11,8547,461339813,6
12,2767,2045804559,1
12,3857,14148973to 49.9
13,5596,5252286913,6556,4793626736,9
13,8326,3974227443
13,9246,3556732668,5
14,2676,2031570816
14,3796,15513167the 13.4
14,8945,9431178112
15,0225,8931362913,9
15,3125,7821270512,9
15,45,7492309223,5
15,7625,6181617016,5
16,195 5,4685985160,9
16,75,3041366013,9
17,155,16675807,7
17,2425,1391178112
17,3225,1151570816
17,884,9575508156,1
17,9984,9252517925,6
MT 18 : 344,8332294323,4
18,4814,7971293613,2
19,0764,6491822218,6
19,6814,50724880 to 25.3
20,084,4181482415,1
20,8294.2613820338,9
one-21.324,16453945,5
21,8364,06780448,2
22,6143,9291339813,6
22,8913,8824077541,5
23,483there are 3,7851617016,5
23,7063,7559467of 60.5
24,0463,6981894219,3
24,63,61698226100
25,011 3,5572102121,4
25,43,5042525725,7
25,763,4562323123,7
25,8633,4421524615,5
26,2173,3961039510,6
26,3843,3752520925,7
27,4493,2471311013,3
28,1913,1631842318,8
29,1443,0622263823
29,3053,0453234032,9
29,92,98612317 12,5
30,082,96896319,8
30,562,9231986620,2
30,9972,8832028920,7
31,1552,86812474a 12.7
31,8092,81168657
32,4442,7571486315,1
33,5682,66774447,6
35,8042,50665756,7
36,4842,46171207,2
37,2412,4121232512,5
39,54 2,27756765,8

It should be understood that, due to small changes in the conditions of the experiment can be observed small changes of the values of the 2-theta characteristic peaks in the powder x-ray.

Information about the crystal structure of three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea as described in example 1:

Formula C25H38N4O9S1

Crystal classMonoclinicSpace group P 1 21/C 1
and9,90180 (10)alpha90,02
b11,62120 (10)beta92,1147 (5)
24,4348 (2)gamma90,02

Coordinates

S1 5 0,61225 0,30855 0,69926 1,00000 0,02322 0,02464 0,02313 0,00167 0,00063 0,00177

O2 4 0,75650 0,31402 0,71730 1,00000 0,02586 0,03254 0,02979 0,00278-0,00447 0,00256

O3 4 0,58955 0,38261 0,65118 1,00000 0,03122 0,04462 0,03211 0,01219-0,00409 0,00430

O4 4 0,57966 0,18851 0,68588 1,00000 0,03488 0,02929 ,04629 -0,00599 0,00578-0,00161

O5 4 0,52793 0,35026 0,74402 1,00000 0,03548 0,03517 0,03507 -0,00384 0,01084-0,00025

C6 1 1,06055 0,14970 0,64896 1,00000 0,02454 0,02130 0,02257 0,00206 0,00058-0,00056

C7 1 1,12232 0,24424 0,61313 1,00000 0,03172 0,02449 0,02891 0,00194 0,00403-0,00495

C8 1 1,11753 0,21849 0,55275 1,00000 0,02995 0,02402 0,02877 0,00430 0,00426-0,00571

C9 1 1,21317 0,14730 0,52949 1,00000 0,03226 0,02742 0,03788 0,00418 0,00723-0,00204

C10 1 1,20706 0,12488 0,47335 1,00000 0,05040 0,02742 0,04308 -0,00375 0,01655-0,00362

C11 1 1,10561 0,17362 0,44020 1,00000 0,05518 0,03689 0,03007-0,00216 0,00308-0,01324

C12 1 1,01004 0,24365 0,46248 1,00000 0,03887 0,03909 0,03499 0,00696-0,00108-0,00786

C13 1 1,01638 0,26594 0,51861 1,00000 0,03167 0,03385 0,03080 0,00592 0,00465-0,00114

C14 1 1,06064 0,19260 0,70839 1,00000 0,02371 0,02675 0,02450-0,00049-0,00073-0,00262

C15 1 0,99245 0,10870 0,74596 1,00000 0,02345 0,02899 0,02040 0,00092-0,00158 0,00013

N16 3 0,84909 0,08816 0,72582 1,00000 0,02198 0,02239 0,02046 0,00057 0,00103-0,00159

C17 1 0,84692 0,03907 0,66903 1,00000 0,02489 0,02614 0,02038-0,00248 0,00158-0,00282

C18 1 0,91619 0,12027 0,62983 1,00000 0,02443 0,02694 0,02117 0,00136 0,00007-0,00088

C19 1 0,77287 0,01423 0,76410 1,00000 0,02965 0,02321 0,02425 0,00293 0,00416-0,00174

C20 1 0,72630 0,08309 0,81299 1,00000 0,03694 0,02660 0,02164 0,00124 0,00755-0,00374

N21 3 0,65520 0,00988 0,84999 1,00000 0,03150 0,03283 0,01998 0,00113 0,00270-0,00819

C22 1 0,70082-0,00650 0,90231 1,00000 0,02529 0,02356 0,02126-0,00087 0,00274-0,00165

N23 3 0,61239-0,07503 0,93170 1,00000 0,02335 0,02555 0,02022 0,00053 0,00116-0,00338

C24 1 0,62202 -0,09992 0,98648 1,00000 0,02275 0,02173 0,02082-0,00006 0,00294 0,00242

C25 1 0,52400-0,17760 1,00846 1,00000 0,02295 0,02371 0,02385 0,00080 0,00346 0,00286

S 1 0,53177-0,20051 1,06518 1,00000 0,02457 0,02575 0,02287 0,00108 0,00249 0,00319

N27 3 0,63200-0,14985 1,09755 1,00000 0,02772 0,03166 0,01952 0,00063 0,00208 0,00192

S 1 0,72600-0,08148 1,07716 1,00000 0,02478 0,03071 0,02230-0,00180 0,00144 0,00249

S 1 0,72175-0,05396 1,02179 1,00000 0,02536 0,02706 0,02325 0,00002 0,00233-0,00077

C30 1 0,83455-0,03727 1,11567 1,0000 0,03160 0,04595 0,02380-0,00433-0,00394-0,00283

A31 1 0,44021-0,27599 1,08943 1,00000 0,03315 0,03296 0,02721 0,00431 0,00675 0,00116

C32 1 0,34335-0,33018 1,05725 1,00000 0,03354 0,03358 0,03909 0,00468 0,00903-0,00618

S 1 0,33499-0,30941 1,00057 1,00000 0,03129 0,03472 0,03698 0,00074 0,00063-0,00758

S 1 0,42228-0,23517 0,97654 1,00000 0,02790 0,02945 0,02830 0,00056 0,00076-0,00283

O35 4 0,80651 0,03300 0,92140 1,00000 0,03090 0,04063 0,02968 0,00500 0,00135-0,01196

O36 4 1,13670 0,04565 0,64500 1,00000 0,02594 0,02489 0,02898 0,00159 0,00165 0,00240

O37 4 0,35801 0,20143 0,79365 1,00000 0,04596 0,05690 0,02594 0,00553 0,00357-0,01359

O38 4 0,62759 0,54632 0,79414 1,00000 0,03006 0,03907 0,05616-0,01265-0,00524 0,00291

O39 4 0,90339 0,32234 0,81772 1,00000 0,05421 0,02870 0,04454-0,00971-0,015120,00371

DSP 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of three-hydrate sulfate described in example 1

Table 2 shows the results for two cycles (relative humidity 0-85%) in the measurement of particle Board (40°C) three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea as described in example 1.

Table 2
Data chipboard for the connection described in example 1
The target valueThe change in mass (%)
S (%)SorptionDesorptionHysteresis
Cycle 10,00,00-0,02
20,09,71becomes 9.970,26
40,010,2310,260,03
60,010,42the 10.40-0,02
85,0for 10.68for 10.68
Cycle 20,0-0,02-0,02
20,09,819,980,17
40,010,2610,280,02
60,010,420,01
85,0for 10.68for 10.68

Example 2

Trihydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea

To a suspension of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (21,36 kg) in CH3HE (178 l) for 10 min was added an aqueous solution of N2SO4(6 l, to 9.91%), a clear solution is filtered and the additional amount of an aqueous solution of H2SO4(33,8 l 1,07 M) was added during 45 minutes the Solution is cooled at -2°C for 1.5 h and stirred at a temperature of from -5 to -9°C for 1 h the precipitate is filtered off, washed with chilled CH3HE (-5°C 54 l), dried in a stream of nitrogen and receive sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form with uncertain composition of the hydrate. The suspension thus obtained salt in N2On (16,2% wt./wt.) stirred for 3 days at 25°C. Filtration and drying (30°C) in a stream of moist nitrogen (50% RH) to give the desired compound.

Radiograph (RGG) three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea, episunago example 2

Figure 2 shows RGG compounds described in example 2.

Table 3 shows the position of peaks and their intensity.

Upon receipt of these results used the following parameter values:

Example 2. Type: 2-Theta/theta vary smoothly - Start: 3,000° - End: 40,000° - Step: At 0.020° - step Duration: 1 - Temperature: 30°C - Time started: 2 s - 2-theta: 3,000° - theta: 1,500° - Phi: 0.00 to° - Aux1: 0,0 DIF - Y: 77,08% - d x by: 1. WL: 1,54056 - 0-

Table 3
Angles 2-theta and the intensity of the bands on the radiograph (RGG) of the compound described in example 2
Angle 2-thetaIs dIntensityIntensity
[°][angstroms][pulses][%]
6,40513,7882083116
8,503accounted for 10.39108168,3
8,75510,09224436 18,7
8,9849,8356048946,3
9,1379,671130592100
9,4619,342683920,6
9,7849,0332483619
9,9748,8616609750,6
10,158,7081762613,5
10,6278,31868105,2
11,8977,433124189,5
12,2147,2496147,4
12,3167,181120189,2
12,70484126,4
12,9076,85392147,1
13,8666,38176115,8
14,126,2673405026,1
14,8215,972128199,8
15,2595,80240063,1
16,6865,309116178,9
17,4345,0821562312
17,679USD 5,0131722513,2
17,9644,9342643920,2
18,1624,8876112 58,3
18,4024,8174927237,7
18,6174,762120189,2
19,0454,65652084
19,983of 4.441682512,9
20,094,4163445126,4
20,3714,35613219the 10.1
20,7174,2843284825,2
20,8224,2635047438,7
21,1054,2063044523,3
21,414,1472083116
21,777 4,0781522211,7
22,1574,0093845629,4

Angle 2-thetaIs dIntensityIntensity
[°][angstroms][pulses][%]
22,5013,9481602412,3
23,1213,8446409a 4.9
23,8173,73396147,4
23,9593,7111362010,4
24,2863,662116178,9
24,435of 3.642363518,1
24,6533,608112168,6
25,4923,4914005930,7
25,7333,4592203216,9
26,0393,4191442111
26,8553,3172002915,3
27,1043,2872403518,4
27,4463,2472203216,9
27,657AZN 3.223 bn3164624,2
27,8743,1981482211,3
28,1193,1711722513,2
28,5183,127 104158
29,4443,03172115,5
29,7223,0031602412,3
30,2242,9551442111
30,8982,8926409a 4.9
31,2622,85944063,4
33,9032,64276115,8
34,338to 2.60956084,3
34,9022,5696409a 4.9
36,092,487116178,9
37,5462,39488136,7
37,7032,3846409a 4.9
38,5612,33344063,4
39,4362,28332052,5
39,8232,26236052,8

Particleboard three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea as described in example 2

Table 4 shows the results for three cycles (relative humidity 0-85%) measurements chipboard (25°C) for three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea as described in example 2.

Table 4
Data chipboard for the connection described in example 2
The target value S (%)The change in mass (%)
SorptionDesorptionHysteresis
Cycle 10,00,00-0,01
20,011,3811,940,57
40,012,0012,310,32
60,012,4112,490,08
85,012,7012,70
Cycle 20,0-0,010,00
20,0to 11.5211,950,43
40,012,0612,320,25
60,012,41 12,490,07
85,012,7012,70
Cycle 30,00,000,08
20,011,55
40,012,07
60,012,40
85,012,6912,69

Example 3

The sulfate dihydrate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea

To a suspension of 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (21,36 kg) in CH3HE (178 l) for 10 min was added an aqueous solution of N2SO4(6 l, to 9.91%). A clear solution is filtered and the additional amount of water rest is RA H 2SO4(33,8 l 1,07 M) was added during 45 minutes the Solution is cooled at -2°C for 1.5 h and stirred at a temperature of from -5 to -9°C for 1 h the precipitate is filtered off, washed with chilled CH3HE (-5°C 54 l), dried in a stream of nitrogen and receive sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form with uncertain composition of the hydrate. Thus obtained salt is exposed to a moist atmosphere (>70% RH) at 25°C and receive the desired connection.

Radiograph (RGG) three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea as described in example 3

Figure 3 shows RGG compounds described in example 3. Table 5 shows the position of peaks and their intensity.

Upon receipt of these results used the following parameter values:

Example 3. Type: 2-Theta/theta vary smoothly - Start: 4,010° - End: 40,010° - Step: At 0.020° - step Duration: 1 - Temperature: 25°C (room temperature) - Time started: 0 s - 2-theta: 4,010° DIF - Y: 79,17% - d x by: 1. WL: 1,54056 - 0-

Table 5
Angles 2-theta and the intensity of the bands on the radiograph (RGG) of the compound described in example 3
Angle 2-thetaIs dIntensityIntensity
[°][angstroms][pulses][%]
6,46613,65979185,9
7,19712,27333292,5
9,1669,641133099100
9,6969,11510293977,3
9,9978,84141811of 31.4
10,2388,6341861114
10,3698,5241871214,1
11,6937,562125589,4
12,3077,18669105,2
12,7366,94545903,4
12,9076,85473135,5
13,6446,4855195a 3.9
14,0446,301116008,7
14,1886,2372390618
14,5546,0816546549,2
15,4495,73135812,7
16,3095,4316506a 4.9
16,6215,329108948,2
17,3645,103 3964229,8
18,1644,8810087175,8
18,3684,8267237554,4
18,949to 4.684756135,7
19,2474,6085900944,3
19,484,55311015182,8
20,094,4163475026,1
20,4514,3393898729,3
20,84,2675855644
21,0654,2144846836,4
21,3554,1583197624
22,1264,0144115530,9

Angle 2-thetaIs dIntensityIntensity
[°][angstroms][pulses][%]
22,5113,9473268224,6
22,6553,9223757428,2
23,9443,7131442510,8
24,3733,6493243024,4
25,1793,5344196231,5
25,453,4973934029,6
25,9023,43733287 25
26,8593,3175341140,1
27,163,2815512641,4
27,3653,2576359947,8
27,7023,2184216431,7
27,9913,1852491518,7
28,5213,1272108215,8
28,8343,0941613912,1
29,4483,0311649212,4
29,6233,0132264617
30,2432,953124589,4
30,7 2,91101887,7
31,1072,873108448,1
31,8632,80648423,6
32,2112,77754474,1
33,2792,6912962the 9.7
33,8482,6461351710,2
34,8672,571100377,5
35,632 Yes2,51859514,5
35,9272,49887766,6
36,6092,453104407,8
37,1422,4198070 6,1
37,4762,3981447510,9
38,7482,322125089,4
39,2012,29612962the 9.7
39,6072,2746456a 4.9

Example 4

Trihydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea

1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (15,4 kg, 1 EQ.) dissolved in ethanol (78 l) and the mixture is heated at 50°C. an Aqueous solution of sulfuric acid (1 M, 1.1 EQ.) added over 35 minutes initiate Crystallization wet priming compound of example 1 (1%), as described below. The suspension is cooled to 1°C at a cooling rate equal to 14°C./h and maintained at this temperature for at least 11 h, and then filtered and washed with an aqueous solution of ethanol (50% wt./wt., 50 l). The solid is dried at 30°C in a stream of moist nitrogen (33-40% RH) and get the desired connection purity of 99.4% with a yield of about 79%.

Wet the seed used in the above method, the floor is with a mix of three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (example 1, 104 g) saturated solution (421 g) three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (example 1, 73,9 g) in aqueous ethanol (50% wt./wt., 810 g).

Example 5

Trihydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea

1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (1,01 kg, 1 EQ.) under stirring (200±20 rpm) was dissolved in ethanol (3,05 kg) and the mixture is heated at 50°C. an Aqueous solution of sulfuric acid (1 M, 1.1 EQ.) add within 20 minutes after Crystallization initiate wet priming compound of example 1 (1%), as described below. The mixture was incubated at 50°C for about 15 min, then cooled to 0°C at a cooling rate of 15°C./h and maintained at this temperature for at least 1 h, and then filtered and washed with an aqueous solution of ethanol (50% wt./wt., 3 kg). The solid is dried in a conductive dryer with stirring at a temperature of 35±3°C in a stream of moist nitrogen (45±5% RH), optionally under stirring (to a maximum of 70 rpm) in case the cake moisture below 25%, and get the desired connection purity 99.8% with a yield of about 94%.

Wet the seed used in the method described above, added in two portions and is produced by mixing the three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (example 1, 6.5 g) with a saturated solution of 13.9 g for the first portion with the addition of 15.6 g for subsequent washing and second portions) of the three-hydrate sulfate 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (example 1, 7.0 g) in aqueous ethanol (50% wt./wt., 50.0 g) for about 2 minutes the First portion of the wet seed cook at least 5 minutes before use, so that it was properly soaked.

1. Crystalline 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I

in the form of sulfate, which is a trihydrate monosulfata.

2. 1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of sulfate in crystalline form according to claim 1, having a powder x-ray shown in figure 1, where x-rays are taken using a radiation source sialpha(1,5418 Å).

3. 1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of sulfate in crystalline form according to claim 1, having a powder x-ray shown in figure 2, where x-rays are taken using a radiation source sialpha(1,5418 Å).

4. 1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of sulfate in crystalline form according to claim 1, to ora in its powder x-ray shows the following peaks at angles of deflection of diffraction (2-theta), where x-rays are taken using a radiation source sialpha(1,5418 Å):
7,214 (10,3%); 8,232 (52,2%); 9,013 (13%); 10,317 (25,7%); 10,899 (5,4%); 11,854 (13,6%); 12,276 (59,1%); 12,385 (49,9%); 13,559 (23,3%); 13,655 (36,9%); 13,832 (43%); 13,924 (68,5%); 14,267 (16%); 14,379 (13,4%); 14,894 (12%); 15,022 (13,9%); 15,312 (12,9%); 15,4 (23,5%); 15,762 (16,5%); 16,195 (60,9%); 16,7 (13.9%); 17,15 (7,7%); 17,242 (12%); 17,322 (16%); 17,88 (56,1%); 17,998 (25,6%); 18,34 (23,4%); 18,481 (13,2%); 19,076 (18,6%); 19,681 (25,3%); 20,08 (15,1%); 20,829 (38,9%); 21,32 (5,5%); 21,836 (8,2%); 22,614 (13,6%); 22,891 (41,5%); 23,483 (16,5%); 23,706 (60,5%); 24,046 (19,3%); 24,6 (100%); 25,011 (21,4%); 25,4 (25,7%); 25,76 (23,7%); 25,863 (15,5%); 26,217 (10,6%); 26,384 (25,7%); 27,449 (13,3%); 28,191 (18,8%); 29,144 (23%); 29,305 (32,9%); 29,9 (12,5%); 30,08 (9,8%); 30,56 (20,2%); 30,997 (20,7%); 31,155 (12,7%); 31,809 (7%); 32,444 (15,1%); 33,568 (7,6%); 35,804 (6,7%); 36,484 (7,2%); 37,241 (12,5%); 39,54 (5,8%).

5. 1-[2(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3(2-methylinosine-4-yl)-urea of the formula I in the form of sulfate in crystalline form according to claim 1, which at its powder x-ray shows the following peaks at angles of deflection of diffraction (2-theta), where x-rays are taken using a radiation source sialpha(1,5418 Å):
6,405 (16%); 8,503 (8,3%); 8,755 (18,7%); 8,984 (46,3%); 9,137 (100%); 9,461 (20,6%); 9,784 (19%); 9,974(50,6%); 10,15 (13,5%); 10,627 (5,2%); 11,897 (9,5%); 12,214 (7,4%); 12,316 (9,2%); 12,704 (6,4%); 12,907 (7,1%); 13,866 (5,8%); 14,12 (26,1%); 14,821 (9,8%); 15,259 (3,1%); 16,686 (8,9%); 17,434 (12%); 17,679 (13,2%); 17,964 (20,2%); 18,162 (58,3%); 18,402 (37,7%); 18,617 (9,2%); 19,045 (4%); 19,983(12,9%); 20,09 (26,4%); 20,371 (10,1%); 20,717 (25,2%); 20,822 (38,7%); 21,105 (23,3%); 21,41 (16%); 21,777 (11,7%); 22,157 (29,4%); 22,501 (12,3%); 23,121 (4,9%); 23,817 (7,4%); 23,959 (10,4%); 24,286 (8,9%); 24,435 (18,1%); 24,653 (8,6%); 25,492 (30,7%); 25,733 (6,9%); 26,039 (11%); 26,855 (15,3%); 27,104 (18,4%); 27,446 (16,9%); 27,657 (24,2%); 27,874 (11,3%); 28,119 (13,2%); 28,518 (8%); 29,444 (5,5%); 29,722 (12,3%); 30,224 (11%); 30,898 (4,9%); 31,262 (3,4%); 33,903 (5,8%); 34,338 (4,3%); 34,902 (4,9%); 36,09 (8,9%); 37,546 (6,7%); 37,703 (4,9%); 38,561 (3,4%); 39,436 (2,5%); 39,823 (2,8%).

6. 1-[2-(4-Benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea of the formula I in the form of sulfate in crystalline form according to claim 1, having a spatial group and coordinates below:
Formula C25 N N4 O9 S1

Crystal classMonoclinicSpace group P 1 21/c 1
a9,90180(10)alpha90,02
b11,62120(10)beta92,1147(5)
c24,4348(2)gamma90,02

Coordinates
S1 5 0,61225 0,30855 0,69926 1,00000 0,02322 0,02464 0,02313 0,00167 0,00063 0,00177
O2 4 0,75650 0,31402 0,71730 1,00000 0,02586 0,03254 0,02979 0,00278 - 0,00447 0,00256
O3 4 0,58955 0,38261 0,65118 1,00000 0,03122 0,04462 0,03211 0,01219-0,00409 0,00430
O4 4 0,57966 0,18851 0,68588 1,00000 0,03488 0,02929 0,04629-0,00599 0,00578-0,00161
O5 4 0,52793 0,35026 0,74402 1,00000 0,03548 0,03517 0,03507-0,00384 0,01084-0,00025
C6 1 1,06055 0,14970 0,64896 1,00000 0,0254 0,02130 0,02257 0,00206 0,00058-0,00056
C7 1 1,12232 0,24424 0,61313 1,00000 0,03172 0,02449 0,02891 0,00194 0,00403-0,00495
C8 1 1,11753 0,21849 0,55275 1,00000 0,02995 0,02402 0,02877 0,00430 0,00426-0,00571
C9 1 1,21317 0,14730 0,52949 1,00000 0,03226 0,02742 0,03788 0,00418 0,00723-0,00204
C10 1 1,20706 0,12488 0,47335 1,00000 0,05040 0,02742 0,04308-0,00375 0,01655-0,00362
C11 1 1,10561 0,17362 0,44020 1,00000 0,05518 0,03689 0,03007-0,00216 0,00308-0,01324
C12 1 1,01004 0,24365 0,46248 1,00000 0,03887 0,03909 0,03499 0,00696-0,00108-0,00786
C13 1 1,01638 0,26594 0,51861 1,00000 0,03167 0,03385 0,03080 0,00592 0,00465-0,00114
C14 1 1,06064 0,19260 0,70839 1,00000 0,02371 0,02675 0,02450-0,00049-0,00073-0,00262
With 15 1 0,99245 0,10870 0,74596 1,00000 0,02345 0,02899 0,02040 0,00092-0,001580 0,00013
N16 3 0,84909 0,08816 0,72582 1,00000 0,02198 0,02239 0,02046 0,00057 0,00103-0,00159
C17 1 0,84692 0,03907 0,66903 1,00000 0,02489 0,02614 0,02038-0,00248 0,00158-0,00282
C18 1 0,91619 0,12027 0,62983 1,00000 0,02443 0,02694 0,02117 0,00136 0,00007-0,00088
C19 1 0,77287 0,01423 0,76410 1,00000 0,02965 0,02321 0,02425 0,00293 0,00416-0,00174
C20 1 0,72630 0,08309 0,81299 1,00000 0,03694 0,02660 0,02164 0,00124 0,00755-0,00374
N21 3 0,65520 0,00988 0,84999 1,00000 0,03150 0,03283 0,01998 0,00113 0,00270-0,00819
C22 1 0,70082-0,00650 0,90231 1,00000 0,02529 0,02356 0,02126-0,00087 0,00274-0,00165
N23 3 0,61239-0,07503 0,93170 1,00000 0,02335 0,02555 0,02022 0,00053 0,00116-0,00338
C24 1 0,62202-0,09992 0,98648 1,00000 0,02275 0,02173 0,02082-0,00006 0,00294 0,00242
C25 1 0,52400-0,17760 1,00846 1,00000 0,02295 0,02371 0,02385 0,00080 0,00346 0,00286
S 1 0,53177-0,20051 1,06518 1,00000 0,02457 0,02575 0,02287 0,00108 0,00249 0,00319
N27 3 0,63200-0,14985 1,09755 1,00000 0,02772 0,03166 0,01952 0,00063 0,00208 0,00192
S 1 0,72600-0,08148 1,07716 1,00000 0,02478 0,03071 0,02230-0,00180 0,00144 0,00249
S 1 0,72175-0,05396 1,02179 1,00000 0,02536 0,02706 0,02325 0,00002 0,00233-0,00077
C30 1 0,83455-0,03727 1,11567 1,00000 0,03160 0,04595 0,02380-0,00433-0,00394-0,00283
A31 1 0,44021-0,27599 1,08943 1,00000 0,03315 0,03296 0,02721 0,00431 0,00675 0,00116
C32 1 0,34335-0,33018 1,05725 1,00000 0,03354 0,03358 0,03909 0,00468 0,00903-0,00618
S 1 0,33499-,30941 1,00057 1,00000 0,03129 0,03472 0,03698 0,00074 0,00063-0,00758
S 1 0,42228-0,23517 0,97654 1,00000 0,02790 0,02945 0,02830 0,00056 0,00076-0,00283
A 4 0,80651 0,03300 0,92140 1,00000 0,03090 0,04063 0,02968 0,00500 0,00135-0,01196
A 4 1,13670 0,04565 0,64500 1,00000 0,02594 0,02489 0,02898 0,00159 0,00165 0,00240
A 4 0,35801 0,20143 0,79365 1,00000 0,04596 0,05690 0,02594 0,00553 0,00357-0,01359
A 4 0,62759 0,54632 0,79414 1,00000 0,03006 0,03907 0,05616-0,01265-0,00524 0,00291
A 4 0,90339 0,32234 0,81772 1,00000 0,05421 0,02870 0,04454-0,00971-0,01512 0,00371.

7. Crystalline trihydrate monosulfata 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea according to any one of claims 1, 2, 4 or 6, obtained through the
a) dissolving 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea (1 EQ.) in ethanol at a concentration of 25% wt./wt.;
b) heating the mixture at 50°C;
b) adding an aqueous solution of sulfuric acid (1M, 1.1 EQ.);
g) optionally initiating crystallization using the wet salt (0,5%) crystalline three-hydrate monosulfata 1-[2-(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3-(2-methylinosine-4-yl)-urea according to any one of claim 2, 4 or 6;
d) cooling the suspension to 0°C at a cooling rate of 15°C/h;
e) maintaining the suspension at 0°C for at least 1 h;
g) filtering and washing with an aqueous solution of ethanol (50% wt./wt.) and
C) drying the solids at 30°C in a stream of moist nitrogen (50% RH).

8. The composition having antagonistic activity against receptor urotensin II, including crystalline trihydrate m is nonsulfate 1-[2(4-benzyl-4-hydroxypiperidine-1-yl)-ethyl]-3(2-methylinosine-4-yl)-urea according to any one of claims 1 to 6, and an inert carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids. The substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids of general formula 1 and their pharmaceutically acceptable salts and/or hydrates , where: R1 is an amino group substitute selected from hydrogen; optionally substituted C1-C5 alkyl; optionally substituted C1-C5 alkylsulphonyl, optionally substituted arylsulphonyl or optionally substituted heterocyclylsulphonyl; acyl; R2 is an alkyl substitute selected from hydrogen, substituted amino group, optionally substituted hydroxy group, substituted mercapto group, substituted alkylamino group; R3 is hydrogen, C1-C3 alkyl; R4 is a substitute selected from hydrogen, C1-C3 alkyl substituted with an amino group, optionally substituted with phenyl or heterocyclyl; R5 is one or more substitutes of the cyclic system selected from trifluoromethyl, carboxyl, alkyloxycarbonyl, possibly substituted aryl, heterocyclyl, substituted aminomethyl, cyano group, or R5 is hydrogen provided that when R1 is a substitute selected from hydroxy-substituted C1-C3 alkyl, amino-substituted C1-C3 alkyl, and R2, R3, R4 and R6 are as described above, or R2 is an alkyl substitute selected from substituted amino group, optionally substituted hydroxy group, substituted mercapto group, substituted alkylamino group, and R1, R3, R4 and R6 are as described above; or R5 is fluorine.

EFFECT: obtaining novel substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids which have antiviral activity, especially against the influenza virus and hepatitis C virus (HCV).

19 cl, 3 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1), their tautomers and pharmaceutically acceptable salts. The disclosed compounds have thromobopoietin receptor agonist properties. In formula (1) , A is a nitrogen atom or CH, when A is a nitrogen atom, B is NR9 (where R9 is a C1-10 alkyl group), and when A is CH, B is a sulphur atom, R1 is a phenyl group (the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10 alkyl groups and C1-10 alkoxy groups (C1-10 alkyl groups and C1-10 alkoxy groups are unsubstituted or substituted with one or more halogen atoms)), L1 is bond, X is OH, R2 is a C1-10 alkyl group, L2 is a bond, L3 is NH, L4 is a bond or NH, Y is a sulphur atom, and when L4 is a bond, R3 is a piperidinyl group, a piperazinyl group (the piperidinyl group and the piperazinyl group are substituted with substitutes selected from a group containing C1-10 alkoxycarbonyl groups, carboxyl group, hydroxyl groups, di-C1-10 alkylaminocarbonyl groups, C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups (C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups are substituted with a substitute selected from a group containing pyridyl groups, hydroxyl groups and carboxyl groups)), or when L4 is NH, R3 is a C1-10 alkyl group (C1-10 alkyl group is substituted with a substitute selected from a group containing C1-10 alkoxy groups, C1-10 alkoxycarbonyl groups or carboxyl groups).

EFFECT: obtaining a thrombopoietin receptor activator which is a formula (1) compound and a medicinal agent which contains the disclosed compound as an active ingredient.

10 cl, 3 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

Cytokine inhibitors // 2394029

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where D is pyrrolidine, X is a radical selected from a group containing C=O, SO2, (C=O)-NH, CH2, O-(C=O), (C=O)-O, (C=S)-NH, Y is a radical selected from a group containing - (CH2)n-E-(CH2)m-L-(CH2)k, where E is O, k, m and n are separately and independently equal to 0, 1, 2 and 3, Z is an alkyl, where the alkyl is CH2 or CH2CH2, A is a radical selected from a group containing benzyl, substituted benzyl, phenyl, substituted phenyl, alkyl and substituted alkyl, cycloalkyl, heterocyclyl, aryl, alkyloxyalkyl, substituted alkyloxyalkyl, alkyloxyaryl, B is a radical of formula (II) , where R1 is selected from a group containing H, alkyl and substituted alkyl, cycloalkyl, R2 is selected from a group containing H, benzyl, substituted benzyl, phenyl, substituted phenyl, alkyl and substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, substituted cycloalkylalkyl, G is an amino group which is substituted by a heteroaryl or substituted heteroaryl, and where Q and L each independently denotes a radical selected from a group containing (C=O)-NH, NH, CH2, NH-(C=O)-NH, NH-(C=O), NH-SO2, NRc, (C=O)-NRc, and where Ra, Rb, Rc and Rd each independently denotes a radical selected from a group containing H, alkyl, cycloalkyl, heterocyclyl, aryl, substituted aryl, as well as to use of these compounds as integrin inhibitor and for making a medicinal and a diagnostic agent, to a pharmaceutical composition based on these compounds and to methods of treating integrin-associated condition.

EFFECT: novel compounds which are integrin inhibitors and can be used to treat diseases where angiogenesis inhibition is necessary are obtained and described.

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: medicine.

SUBSTANCE: invention belongs to the field of medicine, notably to remedy for arterial hypertension and cardiac dysrhythmia treatment, which includes water-soluble complex of nifedipine (dimethyl ether of 2,6-dimethyl-4-(2ґ-nitrophenyl)-1,4-dihydropiridin-3,5-dicarboxylic acid) with polysaccharide, namely arabinogalactan, obtained as a result of mechanochemical activation of hard components mix with weight ratio nifedipine/arabinogalactan 1:(10-40) in a planetary mill at acceleration 60 g. Complex shows higher antihypertensive activity in tenfold lower dose of nifedipine, and high dysrhythmic activity in two hundredfold lower dose of nifedipine compared with dose, which brings hypotensive effect. Besides complex has higher water solubility.

EFFECT: remedy for arterial hypertension and cardiac dysrhythmia treatment is offered.

1 cl, 2 dwg, 3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to regenerative medicine, physiotherapy, reflexotherapy. The method involves daily extremely high frequencies puncture by extremely high frequencies electromagnetic radiation in a noise mode at frequency 59-63 GHz. There are involves acupuncture points (AP): E 36 (2), T 14, T 20, GI 4(2), TR 2(2), GI 11(2), RP 6(2), C 7(2), MC 6(2). In addition, the acupuncture points: C 9(2); VB 10(2), T 13, MC 3(2), MC 4(2), GI 10(2), RP 4(2), MC 5(2), C 8(2) are exposed. The exposure is carried out within 10-13 o'clock. Thus on the first day, the points E 36(2), T14, T 20, GI 4(2), TR 2 (2), C 9(2) are covered. On the second day, the exposure involves VB 10(2), T 13, GI 11(2), MC 3(2). On the third day, there are exposed C 7(2), MC 6(2), RP 6(2), MC 4(2). On the fourth day, GI 10(2), RP 4(2), MC 6(2) are exposed. On the fifth day, MC 5(2), C 7(2), RP 6(2), C 8(2) are exposed, for the next days said exposure is performed once again. One hour after the session, oxygen cocktail is introduced.

EFFECT: method improves clinical effectiveness, increases remission length due to combined application of extremely high frequencies puncture and oxygen doses; it is simple, and has no by-effects.

3 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to anesthesiology and can be used in carrying out regional anesthesia with application of clonidine. For this purpose in pre-operation period Kerdo's vegetative index is determined. In case Kerdo's vegetative index is higher than zero, hemodynamics correction is not necessary, if index is lower than -30, such correction is necessary.

EFFECT: method allows to ensure considerable reduction of anesthesia risk due to prediction of possible complications on the part of hemodynamics and therefore taking necessary measures aimed at their prevention.

3 tbl, 3 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns normalisation of antiplasmin alpha-2 level in arterial hypertension (AH) with impaired glucose tolerance. That is ensured by complex treatment involving graduated physical activities, and introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril in a dose 10 mg once a day in the morning within 1.5 months.

EFFECT: such complex of specific pharmacological preparations combined with drug-free modalities, as well as fitted duration of treatment provide reduced risk of thrombotic complications that is ensured by normalisation and correction of antiplasmin alpha-2 level, thereby fibrinolytic systems in the given group of patients.

3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to haematology, cardiology and endocrinology, and covers normalising the level of inhibitor of plasminogen activator in arterial hypertension (AH) with impaired glucose tolerance. It is ensured by complex treatment that involves graduated physical activities, as well as introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril 10 mg once a day in the morning.

EFFECT: invention provides normalising the level of inhibitor of plasminogen activator that resulted from 1,5-month therapeutic course; than in turn allows reducing risk of thrombotic complications in the given group of patients.

1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to application of compounds of general formula I where R1=H, CH3CO, C2H5CO, CH2=CHCO, CH2=C(CH3)CO, C6H5CO, m-FC6H4CO, m-ClC6H4CO, BrC11H22CO. R2=CH3, C2H5, n-C3H7, i-C3H7, C4H9, C4H8F, C2H4F, C2H4OH, CH2=CH-CH2-, CH2-CH-CH2 X=Cl, Br, I, dialkylphosphate, methane sulfonate, as hypotensive medication. In duration of hypertensive action proposed substances exceed mesatone and other medications, applied in medical practice for hypotensive condition treatment. Also described is pharmacological composition, based on formula I compounds.

EFFECT: obtaining of medication, which in duration of action exceeds mesatone and other medications, applied in medical practice for hypotensive condition treatment.

3 cl, 4 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to gastroenterology and cardiology and concerns method of objectifying indications for choosing treatment of patients with ulcer disease (UD) in combination with artery hypertension (AH). For this purpose in accordance with WHO/ISAH classification of 1999, degree of AH and risk of development of cardio-vascular complications (RDCVC) is determined for patients. Patients with UD in combination with AH of I degree and RDCVC of 1-4 degree, as well as patients with UD with AH of II degree and RDCVC of 2 degree undergo traditional anti-ulcer and conventional hypertension therapy. Patients with UD and AH of II degree and RDCVC of 3-4 degree and patients with UD and AH of III degree and RDCVC of 4 degree are examined for presence of immune disorders, intestine disbacteriosis, depressive disorders, sympaticotonia, metabolic syndrome. If said disorders are found immunomodulators, antidepressants, vegetotropic medications are administered and metabolic syndrome therapy is performed, as hypotensive medications ACE inhibitors are introduced. Patients with UD with AH of III degree and RDCVC of 4 degree are administered combined therapy with ACE inhibitors and pulse slowing calcium antagonists, excluding preparations with make QT interval longer.

EFFECT: method ensures individualised treatment of said category of patients taking into account unfavourable development of ulcerous process depending on expression of systemic microcirculation disorders, determined by AH and RDCVC degree, which allows to influence different links of pathologic process fully and prevent development of complications.

8 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to anaesthesiology, and can be used at the patients operated in the conditions of epidural anaesthesia. For this purpose Gelatinolum preparation is administered to the patient with rate of 80-90 drops a minute by means of infusional system before an epidural space catheterisation. Simultaneously by means of additional infusional system Reamberine preparation is administered with rate of 80-90 drops in a minute. Reamberine and Gelatinolum parity makes 1:1. During operation intake of Reamberine and Gelatinolum in the same parity is performed with rate of 50-60 drops in a minute.

EFFECT: method allows improving and stabilising a hemodynamic and bioelectric activity of heart at patients during operation due to combined application of these preparations allowing strengthening energy processes in a cell against maintenance of a hemodynamic.

2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new compound - acid mesylate of 4-(4-trans-hydroxycyclohexyl) amino-2-phenyl-7H-pyrrolo [2,3d]pyrimidine and its polymorphous α and β forms. The compound has agonistic activity towards adenosine-1 receptor and can be used for making medicinal preparations for treating hypertensive diseases, congestive heart failure and renal failure.

EFFECT: obtaining a compound with better bioavailability due to high solubility and which is more stable in ambient conditions.

17 cl, 6 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: novel derivatives of 4-phenyltetrahydroisoquinolines have total formula I: , in which R1, R2, R3 and R4 independently on each other represent H, F, CI, Br, I, alkyl with 1, 2, 3 or 4 C-atoms; R5 represents H, alkyl with 1, 2, 3 or 4 C-atoms; R6 represents H, alkyl with 1, 2, 3 or 4 C-atoms; R7, R8 and R9 independently on each other represent H, COOR60, -L-G; R60 represents H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; L represents -NR30CO-, -CONR30-, -NR30CONR31-, -NR30COO-; and R30 and R31 independently on each other represent H; G represents groups Ca(OR32)xH2a+1-x, and one or more CH2-groups can be substituted with O; Cb(OR32)yH2b-1-y,and one or more CH2-groups can be substituted with O; CcH2c+1 and two or more CH2- groups can be substituted with O; -(CH2)z-COOR34, where atom of H group -(CH2)z - can be substituted with group OR32; -CR38R39-COOR40, -(CH2)Z-SO3R34; -(CH2)z-N+R35R36R37; -CR38R39NR41R42; a is equal 2, 3, 4, 5 or 6; x is equal 2, 3, 4, or 5 R32 represents H; b is equal 6; y is equal 4; c is equal 5; z is equal 1 or 2; R34, R35, R36 and R37 independently on each other represent H or alkyl with 1, 2, 3, 4, 5 or 6 C-atoms; R38 represents -(CH2)n-Y; n is equal 1 or 3; Y represents H, -COOR44, -CONR45R46, -NHC(NH)NH2, imidazole -4-yl; R44, R45 and R46 independently on each other represent H; R39 represents H; R40 represents H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; R41 and R42 independently on each other represent H; and, at least, one of residues of R7, R8 or R9 must represent group -L-G, as well as their pharmaceutically acceptable salts and salts of trifluoroacetic acid. Invention also relates to medication and its application for treatment and prevention of number of diseases.

EFFECT: novel derivatives of 4-phenyltetrahydroisoquinalines, which have inhibiting effect on NHE3.

14 cl, 2 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

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