Improved crystalline material

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline forms of 3-[[3,5-dribromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid, characterised by X-ray powder diffraction pattern with principal peaks either at 2θ = 16.1 ± 0.2, 20.1 ± 0.2, 20.7 ± 0.2, and 24.2 ± 0.2, or at 2θ = 9.0 ± 0.2, 14.7 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2 and 24.3 ± 0.2. The invention also relates to methods of obtaining the disclosed crystalline forms, a pharmaceutical composition having thyroid beta-receptor agonist properties, a method for selective agonist action on thyroid beta-receptor, use of said forms to produce a medicinal agent and a method of treating mammals suffering from thyroid dysfunction associated conditions.

EFFECT: obtaining novel crystalline forms of 3-[[3,5-dribromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid, having thyroid beta-receptor agonist properties.

19 cl, 3 tbl, 7 ex

 

This invention relates to improved crystalline material and its use for the treatment of conditions associated with dysfunction of the thyroid gland.

WO 01/60784 discloses novel compounds which are agonists thyroid beta-receptor. Example 1 describes the synthesis of 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]-amino]-3-oxopropanoic acid. This connection later in this document referred to as Compound I and has the formula

Synthesis of Compound I is quite complicated, in US 2003/0157671 described an improved method of synthesis. This method and the method according to Example 1 of WO 01/60784 provides the specific crystalline form, designated herein as crystalline form N-1. Unfortunately, it is proved that the crystalline form N-1 is unstable.

Now found that the Compound I can be synthesized in two new crystalline forms, which have improved properties compared with the same connection in other forms.

Accordingly, the first aspect of the present invention is 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]phenyl]amino]-3-oxopropanoic acid (Compound I) in crystalline form characterized by a powder rentgendifraktsionnogo (XRD)having a main peaks at 2θ= 16,1 ± 0,2, 20,1 ± 0,, 20,7 ± 0,2 and 24.2 ± 0,2. This is the first of the new crystalline materials according to this invention will be further referred to in this description as a Form N-6. Other significant, but less pronounced peaks in XRD can be detected at 2θ= 8,9 ± 0,2, 23,0 ± 0,2, 25,9 ± 0,2, 29,1 ± 0,2, 29,4 ± 0,2 and 30.3 ± 0,2. A typical set of peaks in x-ray diffraction pattern shown in Fig. 1. Table 1 shows peaks with intensity of more than 10% (normalized to the most intense peak).

Table 1
XRD Form N-6
2-ThetaI%
8,9441,7
10,01the 10.1
11,0011,8
16,12100,0
16,8211,7
18,5416,2
20,1275,4
20,6673,9
22,59of 21.2
23,0044,6
24,2169,1

25,9328,2
29,1444,5
29,3723,0
30,3325,0

An additional way the characteristics of the new crystalline material Form N-6 in this invention is a thermogram obtained by differential scanning calorimetry (DSC). Typically, the material has a DSC-thermogram, which shows only ectothermy, with a maximum at 174 ± 6°C (and extrapolated beginning at 170 ± 6°C). Complete melting is observed at 182 ± 6°C and the heat of fusion is about 88 j/g Typical DSC thermogram shown in Fig. 2.

In addition, the new crystalline material Form N-6 according to this invention can be characterized by infrared spectrum with the Fourier transform. A typical FTIR spectrum is shown in Fig. 3.

Of course, the specific details of any types XRD, DSC or FTIR depend on many factors, such as the used device and purity of the material. In particular, the DSC may depend on the device. Numerical data presented in the present description, Tsatsa to that obtained using MDSC-2920, TA instruments).

Preferably, Form N-6, obtained according to this invention has a purity level which at least 90%, particularly at least 95%, most preferably almost entirely Compound I represented by Form N-6.

The connection I itself can be synthesized as described in WO 01/60784 or US 2003/0157671. The obtained Compound I, having excellent Form N-6 physical structure, may then be converted into a Form N-6 method, which includes the preparation of a solution of Compound I in a suitable solvent and seed crystals of Form N-5 (see below), or Form N-6, in such circumstances as are Form N-6. Alternatively, a solution of Compound I can be prepared in situ, and this solution is used directly to obtain crystals of Form N-6. Compound I is characterized by the fact that thermodynamic equilibrium between Forms N-5 and N-6 well balanced. Thus, when the temperature is lower than about 50°With crystals or Form N-5 or Form N-6 can be used to seed [crystallization] a solution of Compound I for the preparation of crystals of N-6. Suitable solvents in this context include, for example, water, alcohols, for example methanol, ethanol, isopropanol or hexanol, ketones, for example acetone, dimethylsulfoxide (DMSO), esters such as ethyl shall zett, acid, for example acetic acid, NITRILES, such as acetonitrile, amides, such as dimethylformamide (DMF), nitromethane or nitroethane, or hydrocarbons, such as toluene or hexane; or mixtures thereof. Form N-5 may be prepared as described below.

When the crystals of Form N-6 is obtained, one of the preferred ways of further preparation of Form N-6 includes the preparation of a solution of Compound I in alcohol or mixture of alcohols, for example a mixture of ethanol/isopropanol; adding water, if necessary, filtering the resulting solution; and a seed crystal obtained solution with crystals of Form N-6 for new crystals of Form N-6.

Although the Form N-5 is generally very stable, under certain conditions, it can be converted into a Form N-6. Accordingly, the method further preparation of Form N-6 includes the suspension of Form N-5 in a mixture of alcohol/water for a sufficient period of time to allow the conversion from Form N-6. This usually requires a long period of time from 6 to 10 days.

It was found that the Form N-6 has a lot of preferred properties. In particular, it is highly stable, being stable at least up to 170°C, and nephroscopy to a relative humidity of 95%.

The second aspect of the present invention is 3-[[3,5-dibromo-4-[4-is hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid (Compound I) in crystalline form, which is characterized by a powder rentgendifraktsionnogo (XRD)having a main peaks at 2θ= 9,0 ± 0,2, 14,7 ± 0,2, 19,6 ± 0,2, 21,6 ± 0.2 and 24.3 ± 0,2. This second new crystalline material according to this invention will be referred to in this document as Form N-5. Other significant, but less pronounced peaks can be detected at 2θ= 14,1 ± 0,2, 16,1 ± 0,2, 18,6 ± 0,2, 23,1 ± 0,2, 23,5 ± 0,2, 24,7 ± 0,2 and 29.4 ± 0,2. A typical set of peaks on rentgendifraktsionnye shown in Figure 4. Table 2 shows peaks having an intensity greater than 8% (normalized to the peak of greatest intensity).

Table 2
XRD Form N-5
2-ThetaI%
8,658,0
9,00100,0
14,1113,6
14,7231,3
16,1214,9
17,568,0
18,5915,0
KZT 19.0910,9
19,56 23,1
21,6154,1
23,1414,5
23,5118,6
23,8625,1
24,2931,7
to 24.6617,9
27,118,9
29,4018,5
30,2912,3

An additional way the characteristics of the new crystalline material Form N-5 for this invention is a thermogram obtained by differential scanning calorimetry (DSC). Typically, the material has a DSC-thermogram, which demonstrates the endotherm with a maximum at 173 ± 6°C (and extrapolated beginning at 176°C). The heat of fusion is about 81 j/g Typical DSC thermogram shown in Fig. 5.

Of course, the specific details of any type XRD or DSC depend on many factors, such as the used device and purity of the material.

Preferably Form N-5 under this invention presents with a purity level of at which at least 90%, of obanno, at least 95%, and most preferably almost entirely Compound I represented by the Form N-5.

The connection I itself can be synthesized as described in WO 01/60784 or US 2003/0157671. The obtained Compound I, having excellent Form N-5 physical structure, may then be converted into a Form N-5 method, which includes the preparation of a solution of Compound I in a suitable solvent and recrystallization under conditions in which the formation of crystals of Form N-5. Alternatively, a solution of Compound I can be prepared in situ, and this solution is used directly to obtain crystals of Form N-5. Suitable solvents in this context include, for example, water, alcohols, for example methanol, ethanol, isopropanol or hexanol, ketones, such as acetone, DMSO, esters such as ethyl acetate, acids, for example acetic acid, NITRILES, such as acetonitrile, amides, such as DMF, nitromethane or nitroethane, or hydrocarbons, such as toluene or hexane; or mixtures thereof. In one embodiment, the implementation of the solution of Compound I in alcohol is prepared, preferably at room temperature, and recrystallization was achieved by the addition of water. Alternatively, a solution of Compound I in nitroethane can be produced at elevated temperature and recrystallization of the achievements is correspondingly cooled.

In one variation of the above process for the preparation of Form N-5 may be used in the process of suspension. For example, can be prepared solution of Compound I in a suitable solvent, such as alcohol or mixture of alcohols and water can be added to obtain a suspension. The resulting slurry can be stirred for a period of time sufficient to obtain the Form N-5.

Under certain conditions, Form N-5 can be transformed to the Form N-6, and, therefore, it is necessary to take measures to minimize such conversion in the manufacture of Form N-5. For example, prolonged contact (i.e. contact in a few days) with certain solvents, especially alcohol solvents should be excluded.

Found that the Form N-5 has a lot of preferred properties. In particular, it is highly stable, being thermally stable up to at least 170°C, and non-hygroscopic up to a relative humidity of 95%. In General, it is not converted to other forms, or converted only very slowly; for example, if it is suspended in the presence of alcohol, it is stable for many days, but after a very long period of time, possibly converting it to a Form N-6.

As will be apparent hereinafter, the similar process can be applied to DL the receipt of Form N-6 and Form N-5. The nature of the product is determined by the exact reaction conditions, which can be easily identified by experts in the field of technology with the help of the Examples in this document.

In contrast to Forms N-6 and N-5, the crystal form obtained by the method according to US 2003/1057671 referred to in this document as the Form N-1 has a major peaks of x-ray diffraction pattern 2θ= 7,2 ± 0,2, 9,1 ± 0,2, 11,5 ± 0,2, 18,1 ± 0,2, 19,7 ± 0,2, 24,8 ± 0,2, 27,3 ± 0,2 and of 29.3 ± 10,2 additional significant, but with lower intensity peaks 2θ= 18,5 ± 0,2, 22,3 ± 0,2, 26,8 ± 0,2 and 30.4 ± 0,2. Typical full rentgenodiffraction Form N-1 shown in Fig. 6, together with the for comparison, XRD Form N-5 and Form N-6. The first peak for the Form N-1 of Fig. 6 due to contamination and should not be taken into account. Table 3 represents those peaks whose intensity is above 10%.

Table 3
XRD of the Form N-1
7,1791,9
9,1343,5
11,5140,8
br15.1517,8
18,0760,8
18,4636,4
19,6746,0
20,7313,7
21,2416,4
22,3231,6
23,0220,0
24,0320,3
24,82100,0
25,4320,7
26,8236,3
27,32to 43.1
27,9218,7
29,3049,4
30,4135,7

Usually the Form N-1 has the DSC-thermogram, which shows only ectothermy with a maximum at 116 ± 6°C (and extrapolated beginning at 111 ± 6°C). The heat of fusion is about 58 j/g Typical DSC thermogram for Form N-1 shown in Fig. 7.

Form N-1 less stable than the N-6 and Form N-5, being stable only up to about 125°C and becoming hygroscopic at a relative humidity of 50%. Form N-1 is converted to the Form N-5 and/or the Form N-6 (depending on specific conditions) being dissolved or suspended in many common solvents, for example alcohols, such as methanol, ethanol or isopropanol, nitromethane or nitroethane, and mixtures of alcohols, such as methanol, ethanol or isopropanol with water.

This invention is also a pharmaceutical composition comprising Form N-6 and/or Form N-5 together with a pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated for administration to a human or other mammal using any suitable method. A preferred form for oral administration in solid or liquid form or for local use, for parenterally injection, or for rectal administration. Suitable forms of the pharmaceutical compositions and methods of administration include those described in WO 01/60784.

The pharmaceutical compositions according to this invention may also contain one or more other therapeutic agents. Suitable compounds for use in combination therapy are listed in WO 01/60784.

The crystalline materials of this invention can be used to treat or prevent conditions associated with thyroid receptor, due to the agonistic effects, particularly on the thyroid beta-receptor. Such conditions include obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism or subclinical GUI is thyroidism, non-toxic goiter papillary or follicular thyroid cancer, glaucoma, cardiovascular disease, congestive heart failure, as well as pathological skin conditions such as psoriasis, skin atrophy, wound healing, keloids, scars, cellulite, coarsening of the skin, radiation damage of the skin, planus, ichthyosis, acne, psoriasis, the disease Dernie, eczema, atopic dermatitis, chlorine acne, pytilias and skin scars. Further details can be found in WO 01/60784. Accordingly, this invention is also crystalline materials according to this invention or a pharmaceutical composition according to this invention for use in therapy; the use of such crystalline materials or compositions for obtaining a medicinal product for the treatment of conditions associated with the thyroid gland; and a method of selective agonistic effects on thyroid beta-receptor in a mammal, which includes the introduction of a therapeutically effective amount of a crystalline material or a pharmaceutical composition according to this invention to a mammal.

The dose level required in each case depends on various factors, including route of administration and the severity of the treated condition. In General terms the level to which irowiki is the introduction of from about 0.001 to 500, more preferably from about 0.01 to about 100, most preferably from about 0.01 to 25 mg, such as 0.01 - 1 mg of Compound I per day per patient. If desired, the effective daily dose may be divided for purposes of administration for multiple doses, for example two to four a day.

The invention is illustrated by the following figures in which:

Fig. 1 represents the XRD Form N-6.

Fig. 2 is a curve of differential scanning calorimetry Form N-6.

Fig. 3 is a FTIR Form N-6.

Fig. 4 shows XRD Form N-5

Fig. 5 represents a curve of differential scanning calorimetry Form N-5.

Fig. 6 represents the XRD of the Form N-1 together with XRD Form N-5 and Form N-6.

Fig. 7 is a curve of differential scanning calorimetry of the Form N-1.

The following examples illustrate this invention. Powder rentgenodiffraction were obtained using Rigaku Ru300 (Rigaku Corporation 4-14-4, Sendagaya, Shibuya-Ku,Tokyo 151-0051, Japan). The radiation source was a rotating anode x-ray tube) at 50 kV and 100 mA emitting CuKa radiation (l=1,54179 Å). The data recorded on the photographic plate MAR345 (firm Marresearch GmbH, Norderstedt (Hamburg, Germany). In the data analysis used the software Fit2D (v. 12.081 A P Hammersley, ESRF, BP 220, 38043 Grenoble, France) in order to reduce the diffraction rings and to optimize the alignment of the tube and is of locates.

DSC thermograms were obtained using the instrument 2920 MDSC V2.5F by testing approximately 5-10 mg of sample in an aluminum crucible for DSC in the temperature gradient of 10°C/min

The following Examples illustrate the invention.

Example 1: Obtain Form N-6

Example 1A: the Way A

3-[[3,5-Dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]-phenyl]amino]-3-oxopropanoic acid (8,15 g, Form N-1, prepared in accordance with US 2003/0157671), was dissolved in 60 ml of solvent (40 ml ethanol + 20 ml water) by heating the solution to 30°C and kept at this temperature for 10 minutes Then the solution was cooled to 25°C at 1°C/min without the formation of crystallization centers. Seed (for which, with the help of DSC, IR and XRD confirmed that it is a pure N-5) was added a suspension (0.1 g suspended in 20 ml of water), very slowly - 200 ál/min, the temperature of the solution during the addition was maintained constant. After 1 hour, the solution became turbid. Additional water (about 30 ml) was added at the same speed. Add water then stopped when the solution became opaque and viscous. After 17 hours at 25°C. the solution was cooled to 8°C at the rate of 0.33°C/min and was filtered. Received Form N-6, whose identity was confirmed using XRD.

Example 1B: Method B

3-[[3,5-Dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]-phenyl]amino-3-oxopropanoic acid (0,63 kg, Form N-1, prepared in accordance with US 2003/0157671) was dissolved in ethanol, denatured with isopropanol (2,77 l) at 30°C. was Added deionized water (1,39 l), maintaining the temperature at 30°C. the Solution was filtered through a filter with replaceable filter element (0.3 mm), and the filter was washed with a mixture of ethanol, denatured with isopropanol (0,38 l) and deionized water (0,19 l). The resulting solution was cooled to 25°C. the Suspension Form N-6 (13 g) in deionized water (1,26 l) was added over about 1.5 hours the addition funnel was washed with deionized water (0,32 l), which was added over about 45 minutes Deionized water (1,58 l) was added over about 4 hours, and the resulting suspension was stirred for about 15 hours Deionized water (0,79 l) was added over about 4 h and the suspension was cooled to 8°C for 3 h and was stirred for about 15 hours the Product was filtered and the precipitate was washed with deionized water (0,95 l). The wet precipitate was dried at a temperature in the jacket 25°C for about 24 hours Received 0,61 kg Form N-6 (yield 94%).

Example 1C: Method C

Solid Connection I, consisting mainly of Form N-5, obtained as in Example 2, below, suspended in a mixture of ethanol:water (volumes 1:5) at 20°C for 8 days. Received Form N-6.

Example 2: obtain the Form N-5

Example 2A: the Way A

-[[3,5-Dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]-phenyl]amino]-3-oxopropanoic acid (100 mg, Form N-1, made in accordance with US 2003/0157671) was dissolved in ethanol (300 μl) at room temperature. Deionized water (400 ml) was added under stirring, the solution after adding water remained clear. Was added water (100 μl), and the solution became turbid. Added additional deionized water (100 μl)and the mixture was stirred for 2 h at room temperature on a magnetic stirrer. The solution was filtered and the solid was dried by a stream of air to obtain 66 mg of Form N-5, identified by XRD.

Example 2B: Method B

3-[[3,5-Dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]-phenyl]amino]-3-oxopropanoic acid (100 mg of Form N-1, obtained in accordance with US 2003/0157671) was dissolved in 2-propanol (500 μl) at room temperature. Was added under stirring deionized water (1500 ml)and the mixture was further stirred for 2 h at room temperature on a magnetic stirrer. The solution was filtered, and the resulting solid was dried by a stream of air to obtain 58 mg of Form N-5, identified by XRD.

Example 2C: Method C

A solution of Compound I that corresponds to the saturated concentration at 70°C was prepared by dissolving Form N-1 in 20 ml nitroethane and heating the solution up to 78°C. Then the solution was cooled to 65°C. When the temperature of the mold is reached the desired temperature, the temperature was maintained constant within 24 hours. Nucleation of crystals was not observed. Then the temperature was lowered to 64°C and then for 24 hours - up to 63°C. the Nucleation of crystals started 4 days. This experiment was repeated three times, and in all cases formed Form N-5.

Example 2D: Stability of Form N-5

The stability of suspensions of N-5 in mixtures of ethanol:water (1:1/1:1.3 and 1:2) at 5, 25 and 30°C was determined after 1 h, 48 h and 5 days. Pure N-5 was transformed in any other form in any of these experiments. This is confirmed by DSC and FTIR.

1. 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid in crystalline form characterized by a powder rentgendifraktsionnogo having main peaks at 2θ=16,1±0,2, 20,1±0,2, 20,7±0,2 and 24.2±0,2.

2. The compound according to claim 1, characterized by rentgendifraktsionnogo, optionally having major peaks at 2θ=8,9±0,2, 23,0±0,2, 25,9±0,2, 29,1±0,2, 29,4±0,2 and 30.3±0,2.

3. The compound according to claim 2, characterized by rentgendifraktsionnogo containing mainly the following main peaks:

2-ThetaI%
8,9441,7
10,01the 10.1
11,0011,8
16,12100,0
16,8211,7
18,5416,2
20,1275,4
20,6673,9
22,59of 21.2
23,0044,6
24,2169,1
25,9328,2
29,1444,5
29,3723,0
30,3325,0

4. The compound according to any one of claims 1 to 3, characterized by thermogram obtained by differential scanning calorimetry, which shows only ectothermy with a maximum at 174±6°C.

5. 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid in crystalline form characterized by a powder rentgendifraktsionnogo having main peaks at 2θ=9,0±0,2, 14,7±0,2, 19,6±0,2, 21,6±0,2 and 24.3±0,2.

6. The compound according to claim 5, characterized by the type entendimento the Amma, additionally having major peaks at 2θ=16,1±0,2, 18,6±0,2, 23,1+0,2, 23,5±0,2, 24,7±0,2 and 29.4±0,2.

7. The connection according to claim 6, characterized by rentgendifraktsionnogo, having the following main peaks:

2-ThetaI%
8,658,0
9,00100,0
14,1113,6
14,7231,3
16,1214,9
17,568,0
18,5915,0
KZT 19.0910,9
19,5623,1
21,6154,1
23,1414,5
23,5118,6
23,8625,1
24,2931,7
to 24.6617,9
27,118,9
28,287,5
29,4018,5
30,2912,3

8. The compound according to any one of pp.5-7, which has a thermogram obtained by differential scanning calorimetry, which shows only ectothermy with a maximum at 173±6°C.

9. A method of obtaining a compound according to any one of claims 1 to 4, comprising preparing a solution of 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid in a suitable solvent which is a mixture of ethanol and water, and seed crystals of the compound according to any one of claims 1 to 4 or 5-8 at a temperature of less than approximately 50°C to obtain the desired crystalline form.

10. A method of obtaining a compound according to any one of pp.5-8, comprising preparing a solution of 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid in a suitable solvent, which represents ethanol or 2-propanol, and recrystallization by adding water to obtain the desired crystalline form.

11. A method of obtaining a compound according to any one of pp.5-8, comprising preparing a solution of 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid in a suitable p is storytale, representing nitroethane, at elevated temperature and the recrystallization by cooling to obtain the desired crystalline form.

12. Pharmaceutical composition having the properties of agonist thyroid beta receptor, comprising a compound according to any one of claims 1 to 4 or 5-8, and a pharmaceutically acceptable carrier.

13. The compound according to claim 1 or 5, or the composition according to item 12, intended for the treatment of conditions associated with thyroid dysfunction.

14. The compound or the composition according to item 13, intended for the treatment of obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism or subclinical hypothyroidism, non-toxic goiter papillary or follicular thyroid cancer, glaucoma, cardiovascular disease, congestive heart failure and skin diseases.

15. The use of compounds according to any one of claims 1 to 4 or 5-8 to obtain drugs for the treatment of conditions associated with thyroid dysfunction.

16. The application indicated in paragraph 15, in which the state represents obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism or subclinical hypothyroidism, non-toxic goiter papillary or follicular thyroid cancer, glaucoma, cardiovascular disease, congestive heart not echnosti or skin disorders.

17. The method of selective agonistic effects on thyroid beta-receptor in a mammal, which includes the introduction of a therapeutically effective amount of a compound according to any one of claims 1 to 4 or 5-8 or the composition of item 12 to the mammal.

18. A method of treating a mammal suffering from a condition associated with thyroid dysfunction, which includes an introduction to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 4 or 5-8 or composition according to item 12.

19. The method according to p, in which States represent obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism or subclinical hypothyroidism, non-toxic goiter papillary or follicular thyroid cancer, glaucoma, cardiovascular disease, congestive heart failure, or skin disorders.



 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to geranyl compounds represented by the following formulas (I-1) , (I-2) or (I-3) wherein R1 means compounds of the following formulas: or R2 means a group remaining after removing all carboxyl groups presenting in carboxylic acid chosen from group consisting of malic acid, citric acid, succinic acid, fumaric acid and others; m = 1, 2 or 3; n = 0, 1 or 2, and m + n represent a number of carboxylic groups presenting in indicated carboxylic acid; R3 means p-hydroxyphenyl or mercapto-group. Also, invention relates to derivatives of mevalonic acid represented by the following formula (I-4): wherein R means -CH2OH or CH3. Also, invention to an antitumor agent comprising as an active component geranyl compound of formulas (I-1), (I-2) or (I-3) or derivative of mevalonic acid of the formula (I-4), and optionally a pharmaceutically acceptable carrier or solvent. Also, invention relates to a method for treatment of liver cancer based on using geranyl compound of formulas (I-1), (I-2) or (I-3), or derivative of mevalonic acid of the formula (I-4) and using proposed compounds in manufacturing an antitumor agent. Invention provides using geranyl compounds or derivatives of mevalonic acid as antitumor agents.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 3 tbl, 17 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to preparing new ligands of thyroid receptors of the general formula: wherein X means oxygen (-O-); Y means -(CH2)n-; n means a whole number from 1 to 3; or -C=C- that represents cis- or trans-isomer. R1 means alkyl comprising 3-6 carbon atoms; R2 and R3 are similar or distinct and mean hydrogen, halogen atom, alkyl comprising 1-4 carbon atoms wherein at least one of R2 and R3 doesn't mean hydrogen atom; R4 means hydrogen atom or lower alkyl; R5 means hydrogen atom; R6 means carboxylic acid or its ester; R7 means hydrogen atom and including its all stereoisomers or its pharmaceutically acceptable salt. New compounds can be useful for prophylaxis, suppression or treatment of disease caused by the metabolism dysfunction or the expression of T3-regulated gene, for example, such diseases as obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmia, depression, osteoporosis, hypothyroidism, goiter, thyroid gland cancer, glaucoma, congestive cardiac insufficiency and skin injures.

EFFECT: valuable medicinal properties of ligands.

19 cl, 1 tbl, 19 ex

The invention relates to the neurotropic agent, representing the (RS)-N-pantoyl-aminobutyric acid or its pharmaceutically acceptable salt: sodium, potassium, calcium, magnesium or zinc, as well as two means of obtaining it, which is or condensing RS-pantolactone salt-aminobutyric acid in alcohol followed by treatment of the salts with organic or mineral acid or a cation exchange resin in the H+form; or in condensing RS-pantolactone salt-aminobutyric acid in alcohol followed by treatment received calcium or magnesium salt of an inorganic salt or cation exchange resin in the corresponding salt form

The invention relates to a new method of obtaining the ethyl ester of 4-carboxyphenylazo of malonic acid by the interaction of malonic ester and a derivative of aminobenzoic when heated in the presence of an organic solvent

The invention relates to organic chemistry and relates to a new derived-aminobutyric acid ketopantolactone calcium (calcium salt of N-(4-hydroxy-3,3-dimethyl-2-CCA-1 - butyryl)-aminobutyric acid) of the formula I, showing a sedative effect, and can be used in medicine

FIELD: chemistry.

SUBSTANCE: novel phenyloxyaniline derivative labelled with radioactive halogen has formula (I), where R1 denotes an unsubstituted alkyl group having 1-10 carbon atoms, X4 denotes a hydrogen atom, and X1, X2 and X3 are identical or different and each denotes a hydrogen atom, an alkoxy group, having 1-5 carbon atoms, a halogen atom, or a radioactive halogen atom selected from a group comprising 121I, 123I, 124I, 125I, 131I, provided that X2 or X3 denote a radioactive halogen atom selected from a group comprising 121I, 123I, 124I, 125I, 131I, which is a compound which is suitable during early detection, prevention and treating diseases such as dementia of the Alzheimer's type.

EFFECT: more effective use of the compounds.

3 cl, 6 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to new cycloalkylidene compounds with formula (I), to their pharmaceutical salts, esters and amide, capable of selective bonding ERα- and ERβ-estrogen receptors, as well as to pharmaceutical compositions based on them, their use in making medicinal preparations and the method of selective bonding ERα- and ERβ-estrogen receptors. . Denotations of R1-R7, X, p, q, as well as specific representatives of new cycloalkylidene compounds are given in the formula of invention.

EFFECT: obtaining new cylcoalkylidene compounds.

31 cl, 6 dwg, 108 ex

FIELD: organic chemistry, pharmacy, pharmacy.

SUBSTANCE: invention relates to novel compounds designated for delivery of active substances to tissues of the following formula: wherein values of radicals R1-R7 are determined in claim 1 of the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to compositions designated for delivery of active substances to tissues and containing: (A) active substance and (B) at least one compound designated for delivery of active substance to animal tissues of the formula: wherein values of radicals R1-R7 are determined in claims 3-5 of the invention claim. Also, proposed invention relates to a standard medicinal formulation designated for delivery of active substances to body tissues and to a method for preparing indicated compositions and administration of substances for their delivery to body tissues.

EFFECT: valuable properties of compounds.

23 cl, 11 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

The invention relates to new compounds for delivery of biologically active agents to the scene, having a high permeability with respect to biological membranes

The invention relates to new compounds of the formula (I), where a represents the group CH2or atom That denotes H or halogen, D is CH2, OCH2, NHCH2CH2CH2, R denotes phenyl, benzothiazolyl, indolyl, indazoles, purinol, pyridyl, pyrimidyl, thiophenyl, each of these groups may be substituted or unsubstituted
The invention relates to the technology of production of organic intermediates and dyes, namely, the color-forming component for color films

FIELD: medicine.

SUBSTANCE: invention refers to experimental medicine and can be used for developing molecular methods of treating coronary insufficiency. For this purpose, the simulated myocardial ischemia requires experimental myocardial injections of an endotheliocyte growth factor gene in the form of the phVEGF165 vector at 50-100 mcg/cm2 of an ischemic region at an area pitch of 5 mm. 2-dimethylaminoethanol is added to the vector preparation to provide more effective myocardiocyte transfection.

EFFECT: unlike peptide growth factors requiring the regular administration, the use of a gene construct with the endotheliocyte growth factor gene introduced in a single dose according to the developed method provides the intensified myocardial construct delivery and the activation of a greater number of cells involved in angiogenesis that promotes repaired perfusion in the ischemic myocardium region.

2 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, pharmacology and biology and concerns application of Trecresan as an agent to decrease cholesterol esterase activity.

EFFECT: invention allows extending the range of agents used to decrease cholesterol esterase activity.

4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: compounds activate glucokinase and can be used to prepare medicine for treating of metabolic disorders, for lowering blood glucose level, for treating hyperglycemia, for treating IGT, for treating Syndrome X, for treating impaired fasting glucose (IFG), for treating type 2 diabetes, for treating type 1 diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for treating dyslipidemia, for treating hyperlipidemia, for treating hypertension, for lowering food intake, for appetite regulation, for for treating obesity, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins. In compounds of formula , A denotes , R3 is selected from a group consisting of phenoxy and benzyloxy, each possibly substituted with one or more substitutes independently selected from R12; R12 is F, CI, Br, -CF3, -CN methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH3 or -S(O)2-CH3; R30 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy or cyclopropyl-methoxy, each possibly substituted with one or more substitutes independently selected from R12; R8 is methylthio, isopropylthio, ethylthio or 2-methylpropylthio, each substituted with one or more substitutes independently selected from R34; R34 is carboxy.

EFFECT: improved properties of the compound.

13 cl, 1 tbl, 242 ex

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