Crystalline modifications of n-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonyl piperazide and/or salts thereof

FIELD: chemistry.

SUBSTANCE: invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide and/or its salts. Such crystalline modifications have high stability particularly at low hygroscopicity compared to known amorphous forms of the compound.

EFFECT: invention relates to a method of obtaining such new crystalline modifications, to pharmaceutical compositions containing these new crystalline modifications and their use as an anti-tumour agent.

26 cl, 7 tbl, 13 ex, 20 dwg

 

The technical field to which the invention relates.

The present invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and/or its salts, which can be used as pharmaceuticals, as well as containing these new crystalline modification of pharmaceutical compositions and pharmaceutical applications.

New according to the present invention, the crystalline modification, formed from the compounds known under the chemical name N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl, are effective inhibitors semipretioase urokinase and is therefore particularly suitable for treatment-associated urokinase diseases, such as malignant tumors and metastasis, in particular, by oral administration. Free basic form is denoted as WX-671.

The level of technology

Plasminogen activator urokinase type (uPA) plays a key role in cancer invasion and metastasis (Schmitt et al., J. Obst. Gyn. 21 (1995), 151-165). uPA is expressed in cancer cells of different types (Kwaan, Cancer Metastasis Rev. 11 (1992), 291-311) and joins associated with cancer uPA-receptor (uPAR), where the activation of plasminogen to plasmin. PL is the change in able to break down the various components of the extracellular matrix (ECM), for example, fibronectin, laminin and collagen IV type. It also activates some other destructive ECM enzymes, in particular matrix metalloproteinases. High content associated with cancer uPA correlate with increased risk of metastasis for cancer patients (Harbeck et al., Cancer Research 62 (2002), 4617-4622). Therefore, the inhibition of the proteolytic activity of uPA is a good starting point for antimetastatic therapy.

Some active and selective inhibitors of the urokinase already described. For example, uPA inhibitors benzamidine type represented in the EP 1098651, uPA inhibitors ariguanabo type in WO 01/96286 and in WO 02/14349. A common feature of these synthetic inhibitors is a key residue, consisting of amidino or/and guanidinium.

International application WO 03/072559 is WX-671 as an intermediate product in the synthesis of an inhibitor of urokinase-N-α-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenylalanine-4-ethoxycarbonylphenyl. WO 03/072559 is also a method for the production of compounds of WX-671 in the form of free base in the form of its salts with acids. Specific salts, in particular acid sulfate and sulfate forms, are not mentioned. Also does not describe methods of crystallization. Set out the way get free base WX-671 in the form of an amorphous product, which which is prone to instability and hygroscopic, and also exhibits poor properties in terms of filtration and drying. For this reason, production on a large scale it is not suitable and must be protected from heat and moisture.

WO 2004/011449 is also a method of obtaining derivatives of phenylalanine, which may be in the form of salts, for example salts of mineral acids or salts of organic acids. Among the obtained compounds called WX-671. But there is no indication that these compounds can be obtained in a stable crystalline form.

PCT/EP 2004/005682 says hydroxyamine and hydroxyguanidine compounds as inhibitors of urokinase. The claimed medicinal products include as the active substance other WX-671, as well as active substances in the form of salts, such as hydrochloride or acidic sulfate or salts of organic acids. To declare here medicines confirmed the best bioavailability for oral use. But this publication does not disclose any sulfate salt of the compound inhibitor of urokinase.

The aim of the present invention was to obtain crystalline modifications of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and/or its salts, which have advantages over the known prior art is soedinenijam.

Disclosure of inventions

The present invention relates to crystalline modifications of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and/or its salts.

In accordance with the present invention revealed a new crystalline modification of the above-mentioned inhibitor of urokinase, which in relation to the amorphous form compounds exhibit important advantages. Corresponding to the invention crystalline modifications have significant advantages with respect to handling, storage and combination with other compounds.

It was unexpectedly found that the compound N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl and/or its salts can be converted to the crystalline state, which until now was impossible, and therefore it is in their properties than the known from the prior art amorphous compounds. For example, corresponding to the invention crystalline modifications have very low hygroscopicity. They also very resistant to decay and therefore suitable for longer storage. In addition, corresponding to the invention, the crystalline modification exhibit improved properties in relation to filtration and drying. Moreover, the crystalline modificati the N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and its salts are ideal for inclusion in drugs.

Used here, the reduction of WX-671 means free base N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine. WX-671.1 means the acid sulfate of the above compounds, and WX-671.2 means sulphate named connection.

As mentioned above, corresponding to the modification of the invention WX-671 and its salts are mostly crystalline. Previously it was impossible to produce such hydroxyamine compounds in crystalline form. And already known in the prior art compounds do not have the ability to crystallization.

Under the relevant invention crystalline modifications of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and its salts here understand first of all acidic sulfate salt (WX-671.1) and sulfate salt (WX-671.2), as well as free base (WX-671).

Under the relevant invention crystalline modifications can understand the mixture of free base and salts and mixtures of salts. Preferably under an appropriate modification of the invention should be understood in crystalline form or free base or the sulphate salt or acid sulphate salt. Especially preferably under the relevant invention crystalline modification to understand monoc Italy corresponding crystalline modification.

Appropriate modification of the invention were studied using x-ray diffractometry and are mainly presented in table 3.1 (for sulphate salt WX-671.2), table 7.1 (for acid sulfate salt WX-671.1) and table 11.1 (free base) peaks. Corresponding to the invention crystalline modifications are mainly depicted in figure 5 (sulfate salt WX-671.2), Fig (for acid sulfate salt WX-671.1) and Fig (for free base) peaks.

As shown in the following examples, in addition to the analyses of x-ray diffractometry were also carried out by thermo analytical study (differential scanning calorimetry, DSC, and Tg, TGA). It was found that crystalline compound acid sulfate salt WX-671.1 decomposes at a temperature of about 175°C-195°C, more precisely about 185°C (heating rate 2 K·min-1).

Corresponding to the invention, the crystalline modification WX-671.2 detects predominantly N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl and sulfate anions in a molar ratio of 2:1, and this ratio can vary in the range from 1.5 to 2.5:1. Preferably a ratio of about 1.25 to 2.25:1, particularly preferably from 1.1 to 2.1:1 and most preferably about 2:1.

Crystal is ical modification WX-671.2 usually detects structural units, consisting of 2 molecules of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and one sulfate anion, and each of these units of 2 molecules of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine can be in the same conformation or, mostly, and in different conformations.

Additionally crystalline modification WX-671.2 is present mainly in the form of a hydrate, in particular the three-hydrate, i.e. for every 1 mol of salt approximately 3 mol of water. And this ratio is, of course, may be subject to minor fluctuations, i.e. for every 1 mol of salt may on average be from 2.5 to 3.5 moles of water, preferably from 2.25 to 3.25, particularly preferably from 2.2 to 3.2, most preferably from 2.1 to 3.1.

The sulfate salt of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine proved, regardless of the crystallinity, thermodynamically stable connection. Therefore, the present invention also claims a new connection sulfate salt of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine. And non-crystalline sulfate salt WX-671.2 suitable in the same manner as set forth below regarding crystallize is such modifications, for the production of medicines.

In the crystalline modification WX-671.1 N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl and acid sulfate anions are mainly in a molar ratio from 0.5 to 1.5:1, particularly preferably from 0.8 to 1.2:1, more preferably from 0.9 to 1.1:1 and even more preferably about 1:1.

Crystalline modification WX-671.1 may also be in the form of a hydrate.

Crystalline modification WX-671.1 (free base) is not primarily in the form of a hydrate. Hydrated form, however, possible.

Corresponding to the invention crystalline modifications, if necessary, can be applied together with a suitable pharmaceutical auxiliary substances and carriers for the production of medicines. When it is possible to use them in combination with other active substances, such as other inhibitors of urokinase, in particular antibodies and/or peptides, as well as chemotherapeutically and cytostatics and/or other cytostatic and cytotoxic active substances.

Corresponding to the invention crystalline modifications can be therefore presented in the form of appropriate pharmaceutical form, for example in the form of tablets, pills, capsules, lozenges, powder, si is the ASO, suspension, solution and the like, especially preferred dosage form for oral administration.

Corresponding to the invention, the crystalline modification suitable for treatment of diseases associated with pathological overexpression of uPA and/or receptor plasminogen activator urokinase type uPAR. For example, they are able to inhibit with high efficiency the growth of malignant tumors, and metastasis of tumors. Examples of this are such cancers, such as breast cancer, lung cancer, bladder cancer, stomach cancer, cervical cancer, ovarian cancer, kidney cancer, prostate cancer and sarcoma of soft tissues, particularly associated with a high degree of metastasis of cancer.

Appropriate modification of the invention can be used alone or in combination with other physiologically active substances, for example with radiotherapeutical or with cytotoxic and/or cytostatic agents, as, for example, cis-Platin, doxorubicin, 5-fluorouracil, Taxol derivatives, and/or other chemotherapeutic agents, such as representatives from the group of alkylating agents, antimetabolites, antibiotics, epidemiological and Barvinkove alkaloids. May also be combined with radiation therapy or/and girorgioarmanicosmetics.com.

In addition, corresponding to the invention, the crystalline modification effective in relation to associated with uPA diseases. Examples of such diseases can be pulmonary hypertension and/or heart disease (e.g., WO 02/00248), gastrointestinal diseases, such as inflammatory intestinal diseases, precancerous adenoma of the colon, inflammatory diseases, including osteoporosis, cholesteatoma, skin and eye diseases, such as age-related macular degeneration (AMD), as well as viral and bacterial infections, and emphasizes mentioned in EP-A-0691350, EP-A-1182207 and US 5712291 disease.

The next object of the present invention is a medicinal product, which contains the relevant invention crystalline modification. Such medicinal products may optionally further comprise pharmaceutically compatible carriers and/or excipients. These medicinal products for human or animal can be applied topically, orally, rectally or parenterally, for example intravenously, subcutaneously, intramuscularly, vnutriuretrale, or sublingual, nasal and/or Inhalative. Suitable for use dosage forms in the form of, for example, tablets, pills, capsules, hearts, granules, powder, with whom positories, solutions, syrups, emulsions, suspensions, liposomes, inhalation of sprays or transdermal systems, such as patches. A particularly preferred drug is suitable for oral administration, including a slow acting form (Slow-Release-Retard).

In addition, the invention concerns the use of the corresponding crystalline modifications for the production of pharmaceutical agents for treating diseases that are associated with pathological overexpression of urokinase and/or urokinase receptor. This drug with the relevant invention the active substance is particularly suitable for the treatment and/or prevention of cancer and for the treatment or prevention of metastasis, for the treatment of primary and secondary cancers.

Thanks to the present invention there is a possibility of inhibiting urokinase in living beings, in particular in humans, through the use of effective dose corresponding to the modification of the invention. The magnitude of the required dose depends on the type and severity treat disease. For example, the daily dose is in the range of 0.01-100 mg/kg of active substance per 1 kg of body weight, more preferably 0.1 to 50 mg/kg, even more preferably 0.5 to 40 mg/kg, far preferably 1-30 mg/kg, most preferred -25 mg/kg

Another object of the present invention is a method of obtaining a mainly crystalline modification of one of the salts of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine that includes the following steps:

(a) obtaining the compound N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl or one of its salts;

(b) dissolving or suspending the this compound or its salt obtained in step (a) is suitable for the formation of a crystalline modification of the solvent;

(c) separating the crystalline modification.

Unexpectedly it was discovered that crystalline modification of WX-671, WX-671.1 and WX-671.2 can easily be converted to crystalline form. Preferably as a source of material to apply salt of N-α- (2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine, particularly preferably an acidic sulfate salt.

Can be, however, used as starting compounds for the formation of crystalline modifications and other salt compounds, for example basilinna salt, cleaners containing hydrochloride salt, mutilata salt, Teatralna salt and other.

As the solvent for step (b) can be mostly used various organic solvents. Prigodin is, in particular, water and various alcohols, for example methanol, ethanol, propanol, butanol and their isoforms, as for example, isopropanol, Isobutanol and the like, Other suitable solvents are tetrahydrofuran (THF) and acetonitrile. Particularly preferred as solvents, particularly acetone and acetonitrile.

You can, however, as solvent use and water. In particular, for recrystallization (see step (d)) is mainly used water.

If the production of crystalline modification of any desired salt of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine as the source material is free basis, to get on the stage (b) is added to the corresponding salts or acids of the N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine.

Corresponding to the invention the method may also include the additional step (d) recrystallization of the crystalline compound from step (C). This particularly relates to the production of WX-671.2 from WX-671.1. This is usually obtained at the step (C) of crystalline modification again precrystallization in suitable solvent or mixture of solvents. The above-mentioned solvents can also be used in this case. Especially prepact the sory is water or recrystallization with the formation of the desired crystalline modification is usually carried out in the presence of sufficient water. Water is particularly preferred if, as in the case of WX-671.2 formed hydrate (in the case of WX-671.2 trihydrate).

Read more the invention is explained using the following drawings and examples.

Description of the drawings

Figure 1 shows the Ortep diagram (50%) with the scheme of symbols for molecules And (WX-671.2).

Figure 2 shows the Ortep diagram (50%) with the scheme of symbols for molecules In (WX-671.2).

Figure 3 shows the independent molecules within the unit cell structural units of the two molecules WX-671.2 and sulfate anion.

Figure 4 shows simulation rentgenodiffraction crystallization WX-671.2.

Figure 5 shows the experimental rentgenodiffraction crystallization WX-671.2.

Figa shows the overlay simulation and experimental rentgenodiffraction respectively 4 and 5 for WX-671.2.

Fig.6b shows the DSC and TGA-thermogram WX-671.2 after mixing in the water.

7 contains data on the crystallization and development patterns WX-671.2.

Fig contains data on the length of the bonds [Å] and angles [º] for WX-671.2.

Fig.9 shows the data for torsion angles [°] for WX-671.2.

Figure 10 shows the DSC and TGA-thermogram WX-671.1 (option A).

11 shows the DSC and TGA-thermogram of the sample (mesophase) WX-671.1.

Fig shows the DSC and TGA-thermogram mesophases With the WX-671.1.

Fig shows rentgenodiffraction option is the ratification And WX-671.1.

Fig shows rentgenodiffraction mesophases In the WX-671.1.

Fig shows rentgenodiffraction mesophases With the WX-671.1.

Fig shows the DSC and TGA-thermogram of amorphous initial substance free base WX-671.

Fig shows the DSC and TGA-thermogram crystallized in the freezer from acetonitrile samples free base WX-671.

Fig shows a microscopic picture free base WX-671 after crystallization in the freezer from acetonitrile.

Fig shows rentgenodiffraction free base WX-671 after crystallization in the freezer from acetonitrile.

Fig shows the sorption isotherm of water vapor in the free base WX-671 at 22°C.

The implementation of the invention

EXAMPLES

Example

Obtaining various salts of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine

Salt is obtained by dissolving 6.0 g of WX-671 in 50 ml of acetone. Used acid without dilution add at 25%excess and stirred for 2 hours at room temperature.

Conditions of crystallization

Table 1.1
AcidEquivalentsCondition the conditions of crystallization Drying
HCl1.25 mol EQ.The clarified solutionDeep vacuum
H2SO1.25 mol EQ.Crystallization from a solution of acetoneDeep vacuum
MsOH1.25 mol EQ.Crystallization from a solution of acetoneDeep vacuum
BsOH1.25 mol EQ.The clarified solutionDeep vacuum
Tartaric acid1,2 5 mol equiv.The clarified solutionDeep vacuum
MsOH: methansulfonate acid; BsOH: benzolsulfonat acid

In the second phase of salt within 7 days suspension in the appropriate solution, filtered and dried at room temperature.

The study of crystallinity

Method: roentgendifractometric (XRD)

Table 1.2
ConnectionXRDMicroscopy
Free baseMostly crystalSmall particles
BesultMainly amorphousAgglomerates
HydrochlorideFully amorphousSmall particles
MasulatLCDAgglomerates
GidrogensulfatLCDAgglomerates
TartrateFully amorphousGlass

The study of hygroscopicity

Method: storage for 1 week at a relative humidity of 85%; thermogravimetric analysis (TGA)

Table 1.3
ConnectionTGA
Free base1,5% (hemihydrate)
Besult(adsorbed)
Hydrochloride(adsorbed)
Masulat(adsorbed)
Gidrogensulfat(adsorbed)
Tartrate(adsorbed)

Example 2

Monocrystalline x-ray analysis WX-671.2 (sulfate salt)

A new form of sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine obtained by suspending the acid sulfate salt (WX-671.1) connection WX-671 in water and separating the resulting crystalline substance.

Crystal WX-671.2 receive two different ways.

(a) About 50 mg WX-671.1 suspended in about 0.5 ml of water. The slurry is at room temperature. After 6 days, the suspension is filtered and the residue dried at room temperature in air.

b) About 0.2 g WX-671.1 suspended in about 2 ml of water. The suspension is shaken at 25°C. After 3 days the residue is filtered and the crystals WX-671.2 dried at room temperature in air.

Therefore produced crystalline material (WX-671.2), subject to rent instructorname analysis. You get the crystals.

Structure determination crystals are using diffractometer Bruker-Nonius, equipped with a planar detector Proteum-CCD, a FR591 rotating anode with Cuα-radiation, Montel mirror as monochromator and a low-temperature device Cryoflex" (T=K). Pornosfree displaying information omega and phi scans. Used: data Collection Proteum V.I.37 (Bruker-Nonius 2002), "data reduction" Saint+Version 6.22 (Bruker-Nonius 2001), "Correcting for the absorption SADABS V.2.03 (2002). Structure determination crystals were carried out using direct methods in accordance with the SHELXTL Version 6.10 (Sheldrick, göttingen University) and displayed using the XP program.

By differential Fourier synthesis missing atoms were located and added to the list of atoms. "Optimization of least-squares on F2 for all measured intensities were carried out using the program SHELXTL Version 6.10 (Sheldrick, göttingen University, 2000). All non-hydrogen atoms were optimized using the coefficient anisotropic displacement".

tr>
Table 2.1
The definition of chirality*The true structureInverted structure
Flack-coefficient (standard deviation)0,0298 (0,0282)0,9694 (0.0307)
Twin Basf (standard deviation)0,03 (3)0,97 (3)
wR2-value (with Flack-ratio)0,20160,2219
ChiralityS(C9)R(C9)
*
.D.Flack, Ada Cryst, 1983, A39, 876-881.
H.D.Flack, G.Bernardineili, Acta Cryst, 1999, A55, 908-915.
.D.Flack, G.Bernardinelli, J. Appl. Cryst, 2000, 33, 1143-1148.

The results of x-ray analysis are presented in figures 1-3 and 7-9.

Example 3

Roentgendifractometric WX-671.2 (sulfate salt)

Rentgenodiffraction obtained using a Debye-Scherrer - diffractometer STOE STADI-P, equipped with a position-sensitive detector (PSD, 5°), Germanium [1 1 1] - primär - monochromator and CuKα 1.6 kW - ceramic x-ray tube (1,5406 Å). Used program: Stoe WinXpow, Version 2.03 (2003).

Table 3.1
The list of peaks of roentgendifractometric for WX-671.2
WX-671.2
Reflexes 2 Theta Reflexes 2 Theta
3,726,8
4,227,2
7,127,5
7,427,8
10,328,1
10,829,1
11,129,7
the 11.630,2
12,130,6
12,631,1
13,3of 31.4
13,831,9
14,232,1
14,833,2
15,1to 33.8
15,734,2
16,436,3
16,837,3
the 17.3
17,8
18,0
18,6
19,2
19,8
20,1
20,4
20,8
21,0
of 21.2
21,8
22,2
22,9
23,4
23,9
24,6
25,0
25,5
26,2
26,3
26,5

Example 4

Recrystallization WX-671.1 (acid sulfate salt)

WX-671.1 was dissolved in the solvents (isopropanol, ethanol, methanol) of different polarity. The solutions were filtered, diluted four times and with different speeds solvent was removed.

WX-671.1 exists in its crystalline form (option a) and two metaphases and In C. It decomposes at temperatures above about 185°C (option a and mesophase) or 156°C (mesophase). To determine the crystallinity modification And carried out x-ray analysis. Modification And at room temperature is thermodynamically stable form.

Example 5

Differential scanning calorimetry (DSC) and thermogravimetry (TGA) WX-671.1 (acid sulfate salt)

In this example, the obtained thermograms using differential scanning calorimetry (DSC) and thermogravimetry (TGA). Figure 10 shows the DSC and TGA-thermogram subjected at 25°C for one week, mixing in isopropanol WX-671.1 (WX-671.1 (option A)). It decomposes at temperatures above about 185°C (ectothermy peak in DSC - thermogram, the mass loss in the TGA-thermogram in the relevant temperature range). Temperature decay is strongly dependent on the heating rate and identified them in the DSC calorimeter at a heating rate of 2 K·min-1. Displayed visual DSC results were recorded at a heating rate of 2 K·min-1. Decomposition of the respectively registered at higher temperatures.

At 150°C is not registered any significant weight loss. A weak endothermic effect before the peak decomposition could be caused by partial melting or fractional transformation.

11 shows DSC - thermogram one used for this screening sample WX-671.1 (mesophase). Modification and mesophase In thermo analytical identical. The mesophase was obtained from isopropanol (room temperature/freezer) and ethanol (room temperature).

Fig shows the AET DSC and TGA-thermogram of the active substance, obtained experience by crystallization from ethanol at room temperature (mesophase). It decomposes at temperatures above approximately 156°C (heating rate 2 K·min-1). When heated to 175°C was noted a weight loss of 4.5%. The DSC-thermogram endothermic effect before the peak decomposition is missing. This form has a less ordered state as compared with the modification and the mesophase Century It was obtained in experiments on crystallization from methanol (room temperature, refrigerated camera) and ethanol (cooling chamber). These samples celebrated the mass loss from 4.5 to 4.8 wt.%. Stochiometric indicator for weight loss 2 water molecules per one molecule of the active substance is 4.7%. In the case of this form it is, however, not the hydrate.

Example 6

Thermomicroscopy WX-67L1 (acid sulfate salt)

One of the samples WX-67L1 produced thermomicroscopes images (not shown). Observed the presence of agglomerates, which had no specific habitus. The active substance is decomposed with the formation of bubbles at temperatures above about 197°C. Differences in relation to observed in DSC calorimeter temperature is due to the different heating rates. In the solvent is formed WX-671.1 nonspecific forms. Active ingredient detects partially double refraction that nature is Erno for crystalline and mesomorphic substances.

Example 7

Roentgendifractometric WX-671.1 (acid sulfate salt)

In rentgendifraktsionnye modification And (Fig) shows characteristic crystalline phases the distribution of numerous sharp peaks for larger 2-Theta-angles. To confirm the existence of the crystalline phase of the additional studies, such as x-ray diffraction analysis.

In rentgenodiffraction mesophases In (Fig) found a sharp peak at 2-Theta-angle of about 5° and other reflexes of lower intensity in the range of between about 8° and about 25°. The location and number of peaks similar to those of A. modification Manifested at low 2-Theta-angle peak indicates the presence of long-range order of the molecules, the peaks with lower intensity demonstrated the presence of short-range order. From this we can conclude that the mesophase In the presented either in crystalline or amorphous forms, as likely as mesophases.

Radiograph of mesophases With (Fig) also shows a characteristic of the mesomorphic compounds distribution: intense peak at low 2-Theta-angle. The radiograph shows that the mesophase With not a crystalline phase and due to the existing long-range order of the molecules cannot be attributed to the amorphous phase. Comparison with rentgendifraktsionnogo mesophases In shows that the mesophase With, probably, not only is em a phase with a lower degree of order. Evidence of this is expressed stronger and more intense reflexes between 2-Theta-angles of about 8° and about 25°.

In the one-week mixing in isopropanol at room temperature mesophase In turns into a modification of A. the result of mixing in water : ethanol (1:1) do not modify it. Under the influence of mechanical stress (pounding, pressing under a pressure of 9 kbar) turning it also does not occur.

Table 7.1
The list of peaks of roentgendifractometric for modification WX-671.1 (acid sulfate salt)
WX-671.1
Reflexes
2-Theta
4,3
8,6
the 10.1
10,3
10,6
11,0
11,2
11,3
the 11.6
to 12.0
12,3
13,8
14,8
15,9
of 17.5
17,7
19,3
19,7
20,2
21,0
21,4
21,7
of 21.9
22,6
23,3
24,0
25,8
26,9
27,4
28,0
29,7
30,8
31,3
32,2
33,3
35,5
37,1

Example 8

Recrystallization WX-671 (free base)

Active substance WX-671 is investigated on polymorphia thermo analytical (DSC, TGA), using roentgendifractometric, as well as by crystallization from organic solvents. WX-671 crystallizes in one of the modifications (modification). Active ingredient detects a very low tendency to crystallization.

Modification And is at room temperature, thermodynamically stable form. The final assessment of polymorphia and pseudopolymorphic WX-671 is it possible the ü after conducting research on polymorphia.

WX-671 was dissolved in the solvent (tetrahydrofuran, acetonitrile, methanol) of different polarity. The solutions were filtered, diluted four times and at different speeds has led the active substance. After drying at room temperature were recorded thermograms (DSC, TGA) and rentgenodiffraction.

Used for screening of polymorphia starting material managed to get in a predominantly crystalline form. Crystallization has been acetonitrile in a freezer at about -18°C.

Example 9

Differential scanning calorimetry (DSC) and thermogravimetry (TGA) WX-671 (free base)

Fig shows the DSC and TGA-thermogram of amorphous educt. As DSC /TGA thermograms of most of the other samples studied, it shows a thermal effect in the interval between 45°C and 85°C. under screening of polymorphia this thermal effect is not manifested. It could go about turning glass. On this basis, we can talk about crystalline form with a melting point of about 190°C. This substance is decomposed, depending on the heating rate at temperatures above about 155°C. For this reason, the melting point of the crystalline sample (GBA 190903-8C) cannot be determined. Thermograms of amorphous and crystalline substances therefore largely identical(Fig and 17).

Example 10

Microscopy WX-671 (free base)

From acetonitrile WX-671 crystallizes in the freezer in the form of prisms (Fig). Other solvents, the active substance is not crystallized or only to a minor extent, from the melt, it is not crystallized.

Example 11

Roentgendifractometric WX-671 (free base)

Fig shows rentgenodiffraction active substance after crystallization from acetonitrile in the freezer (option A).

Table 11.1
The list of peaks of roentgendifractometric for WX-671 (free base)
A sample was crystallized from acetonitrile in the freezer.
WX-671
Reflexes
2 Theta
3,2
5,5
6,4
8,5
the 9.7
10,2
10,7
11,2
11,5
11,7
12,1
the 13.4
13,8
14,1
14,6
14,8
15,5
16,5
18,1
19,1
19,7
20,5
20,7
21,3
22,4
22,7
23,6
26,5

Example 12

Hygroscopicity WX-671 (free base)

Fig shows the sorption isotherm of water vapor WX-671 at 22°C. relative humidity continuously absorbing the water of the amorphous active substance increases from 0% to 95%. When drying the absorbed water is removed. In most points of the isotherm equilibrium state during the relevant time had not been reached. The weight of the sample was reduced or increased. This experience showed no evidence of hydrate formation.

Example 13

The stability of WX-671 (free base)

In the one-week stirring in diisopropyl ether and ethanol/water (1:1) at room temperature, the active substance is not crystallized in the modification or crystallizes in the very low degree. It is not converted into any other polymorphic form. Under the influence of mechanical stress (pounding, pressing under a pressure of 9 kbar) it is also not converted, only even more reduced crystallinity.

1. Crystalline modification of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and/or its salt, which comprises crystalline modification sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and x-ray diffraction analysis reveals mainly the following peaks:
3.7V
10,3
12,1
13,8
16,4
19,2
22,2 or
crystalline modification of acid sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and x-ray diffraction analysis reveals mainly the following peaks:
4,3
the 10.1
20,2
21,4
24,0 or
crystal modification of a N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine in the form of a free base and x-ray diffraction analysis reveals mainly the following peaks:
3,2
6,4
10,2
19,7.

2. The crystalline modification according to claim 1, which includes sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-f is kilalanin-4-ethoxycarbonylpyrimidine in the form of a single crystal.

3. Crystalline modification sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine according to any one of claims 1 and 2, which upon x-ray diffraction analysis reveals mainly shown on figure 5 of spades.

4. The crystalline modification according to claim 1, which includes acidic sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine in the form of a single crystal.

5. Crystalline modification of acid sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine according to claim 1 or 4, which upon x-ray diffraction analysis reveals mainly displayed on Fig peaks.

6. Crystalline modification of acid sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine according to claim 1, which decomposes at temperatures above 175-195°C (DSC, heating rate 2 K·min-1).

7. The crystalline modification according to claim 1, which is a crystalline modification of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine in the form of free base in the form of a single crystal.

8. Crystalline modification of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-ethoxycarbonylpyrimidine as free base according to claim 1 or 7, which x-ray diffraction analysis reveals mainly displayed on Fig peaks.

9. The crystalline modification according to claim 1, which contains N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl and sulfate anions in a molar ratio of 1.5-2.5:1.

10. The crystalline modification according to claim 9, which contains N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl and sulfate anions in a molar ratio of 2:1.

11. The crystalline modification according to claim 1, which contains N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl and acid sulfate anions in a molar ratio from 0.5 to 1.5:1.

12. The crystalline modification according to claim 11, which contains N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl and acid sulfate anions in a molar ratio of 1:1.

13. The crystalline modification according to claim 1, which includes the structural units, consisting of about two molecules of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and one sulfate anion.

14. The crystalline modification according to item 13, in which the two molecules of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-FeNi is alanine-4-ethoxycarbonylpyrimidine in the structural unit represented in different conformations.

15. The crystalline modification according to claim 1, in which each mol of salt has about three moles of water.

16. Method of manufacturing crystalline modification of molecules of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and/or its salt according to claim 1, comprising steps
(a) preparation of the compound N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylphenyl or one of its salts,
(b) dissolution and/or suspension of these compounds or salts from step a) is suitable for the formation of a crystalline modification of the solvent,
(c) separating the crystalline modification.

17. The method according to clause 16, including the additional step:
(d) recrystallization of the crystalline modification of step (C) is suitable for this purpose solvent or solvent mixture.

18. The method according to item 16 or 17, in which step (a) is made acidic sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine.

19. Drug, possess inhibitory activity against the urokinase and/or urokinase receptor, containing as active substance crystalline modification according to any one of claims 1 to 15, optionally, with pharmaceutically compatible carrier or/and support the substance.

20. Drug in claim 19, characterized in that it is oral, nasal, ingalatore, rectal or parenteral applied by the tool.

21. The use of crystalline modification of acid sulfate N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine and/or its salt according to claim 1 for the production of pharmaceutical agents for diseases associated with pathological overexpression of urokinase and/or urokinase receptor.

22. Use item 21 for the treatment and/or prevention of cancer.

23. Use item 21 for the treatment or prevention of metastasis.

24. Use item 21 for the treatment of primary cancers.

25. Use PP-24 for the production of orally applied tools.

26. Use A.25 for the production of tools in the form of tablets, pills, capsules, granules, powders, suppositories, solutions, syrups, emulsions, liposomes and/or suspensions.



 

Same patents:

FIELD: chemistry, pharmaceutical.

SUBSTANCE: invention pertains to compounds with formula I , where: n is an integer equal 1 or 2; p is an integer from 1 to 7; A is chosen from one or more radicals X and/or Y; X represents methylene group, substituted when necessary by one or two C1-6-alkyl groups; Y represents C2-alkenyl, C2-alkenyl; G represents a single bonds, oxygen or C=O. The compound can be used as ferment FAAH inhibitor for pain killing, inflammation or nerve-degenerative diseases. Description is given of the method of obtaining compounds, pharmaceutical compositions based on them and their use.

EFFECT: design of a method of obtaining alkylhomopiperazinecarboxylates and their use for pain killing, treating inflammation or nervous degenerative diseases.

11 cl, 2 tbl, 7 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology, and concerns normalising functional reactivity of cardiovascular system (CVS) at arterial hypertension and abdominal obesity. To that end, the state of CVS functional reactivity at psychoemotional stress is assessed by recording systolic, diastolic and average dynamic blood pressure (BP av.dyn) and heart rate (HR). These data serve as the basis for determining functional reactivity index (FRI) prior to and after the stress, according to the following formula: FRI = (BP av.dyn. × heat rate)/100 (conv. un.). If FRI value after stress rises by more than 20 conventional units, complex therapy is implemented including individual hypocaloric diet calculated by a formula considering sex and age, sensibly graded static and dynamic physical exercise as well as administration of irbesartan in a dose of 50 mg once a day, in the morning, over at least 4 months.

EFFECT: complex of drug and non-drug treatment combined with empirically chosen course duration ensures normalisation of CVS functional reactivity among the specified group of patients due to potentiation of certain components of the therapeutic complex.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology, and concerns normalising functional reactivity of cardiovascular system (CVS) at arterial hypertension and abdominal obesity. To that end, the state of CVS functional reactivity at psychoemotional stress is assessed by recording systolic, diastolic and average dynamic blood pressure (BP av.dyn) and heart rate (HR). These data serve as the basis for determining functional reactivity index (FRI) prior to and after the stress, according to the following formula: FRI = (BP av.dyn. × heat rate)/100 (conv. un.). If FRI value after stress rises by more than 20 conventional units, complex therapy is implemented including individual hypocaloric diet calculated by a formula considering sex and age, sensibly graded static and dynamic physical exercise as well as administration of losartane in a dose of 50 mg once a day, in the morning, over at least 4 months.

EFFECT: complex of drug and non-drug treatment combined with empirically chosen course duration ensures normalisation of CVS functional reactivity among the specified group of patients due to potentiation of certain components of the therapeutic complex.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology, and concerns normalisation of cardiovascular system (CVS) functional reactivity among patients suffering from arterial hypertension at the stage of recovery form cerebral circulation disorder without pareses or paralyses. To that end, the state of CVS functional reactivity at psychoemotional stress is assessed by recording systolic, diastolic and average dynamic blood pressure. These data serve as the basis for determining functional reactivity index (FRI) prior to and after the stress, according to the following formula: FRI = (BP av.dyn. × heat rate)100 (conv. un.). If FRI value after stress rises by more than 20 conventional units, telmisartan and labetalole are administered in doses of 40 mg per day and 200 mg twice a day respectively.

EFFECT: method normalises functional reactivity of cardiovascular system and increases tolerance to psychoemotional stresses at the specified group of patients during a 2 month course of therapy.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of perindopril of formula I: . Also proposed are methods for synthesis of amorphous and crystalline perindopril using starting substance in form of stereospecific amino acid, N-[(S)-carbethoxy-1-butyl]-(S)-alanine, which is protected by a trimethylsilyl group and converted to reactive acid chloride using thionyl chloride or its complex with 1-H-benzotriazole (1:1), which reacts with (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid, having a protected carboxy group. The invention also relates to a pharmaceutical composition based on the said crystalline form of perindopril.

EFFECT: novel form of perindopril is obtained, which can be used in medicine for treating cardiovascular diseases.

8 cl, 4 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: therapeutic course involves examination that implies photography of eye-ground vessels and measurement of diametre of retinal vessels on an empty stomach of the patient prior to and after administration of a medicine. Observed increase in diametre of supero-temporal branch of central retinal artery at a distance of one vertical diametre of disk of optic nerve from an edge of disk of optic nerve by 10% and more from the initial one ensures to diagnose efficiency of the administered medicine. The absence of increase in diametre of supero-temporal branch of central retinal artery by 10% and more in administration of the same dosage of the medicine enables to diagnose development of tolerance.

EFFECT: method extends range of means to determine antihypertensive drug tolerance.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

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21 cl, 20 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns normalisation of thromboplastin formation in patients suffering from arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated static and dynamic physical exercises, and also introduction of pioglitazone in a dose 30 mg once in the morning and a lisinopril in a dose 10 mg once a day in the morning during 1.5 months.

EFFECT: complex of specific medical agents and physical activity combined with empirically specified duration of treatment provides normalisation of thromboplastin formation that in turn reduces risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and can be used for treatment of pulmonary cancer. Essence of invention lies in the fact that before initiation of treatment an extracorporeal ray treatment of 300 ml of patient's blood in red diapason range with λ=0.67 mcm in continuous-wave mode during 3 minutes at maximum radiant power 17 mlW, radiation level w=3.06 J/cm2 is conducted. Then irradiated blood is incubated with cytostatic in therapeutic dose during 40 minutes at T=37°C, whereafter the irradiated blood with cytostatic is inserted to patient intravenously by drop infusion. During course of treatment three or four such procedures are conducted at three days interval, in total one or two courses of treatment at three weeks interval are conducted.

EFFECT: use of this invention enables to transfer patients with tumors of stage three or four into resectable condition by means of stimulating involution and regress of neoplastic deposits from lymphonodus at neoadjuvant therapy delivery of photo- modified autoblood.

2 ex

FIELD: medicine.

SUBSTANCE: group of invention concerns medicine, namely to oncology and can be used in prostate cancer treatment. The methods of the invention imply administration of a composition containing therapeutically effective quantities of supercritical extracts of rosemary, curcuma, marjoram and ginger, as well as therapeutically effective quantities of water-alcoholic extracts of holy basil, ginger, curcuma, Scutellaria baicalensis, rosemary, green tea, Polygonum cuspidatum, Coptis chinensis Franchet and barberries.

EFFECT: inhibition of prostate cancer cell growth due to the effect of COX-2 composition without any significant side-effects.

36 cl, 1 tbl, 5 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for regiospecific synthesis of rapamycin 42-ester derivatives of formula , where R is ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, linear or branched C1-C10 alkyl, which possibly contains a halogen, C2-C8 alkenyl, or phenyl, where the said method involves acylation of 42-hydroxyrapamycin with an acyl donor in the presence of lipase. The invention also relates to regiospecific preparation of rapamycin 42-ester from ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in the presence of lipase.

EFFECT: increased output of the product under mild conditions.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.

EFFECT: increased effectiveness of using the compounds.

7 cl, 3 dwg, 1 tbl, 3 ex

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