Macrolides and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to 3’-Destinationin-9 oxyimino macrolides of formula (I):

in which R represents hydrogen or methyl; R1and R2both represent hydrogen or together form a chemical bond; R3represents hydrogen or linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated and contains from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups, X and Y, identical or different, represent O or NR4where R4is hydrogen, linear or branched C1-C5alkyl group, benzyloxycarbonyl group; r is an integer from 1 to 6; m is an integer from 1 to 8; n is an integer from 0 to 2; and their pharmaceutically acceptable salts; except for compounds of the oxime of 3’-destinationin-3’,4’-dihydroanthracene and 9-O-methyloxime 3’-destinationin-3’4’-dihydroanthracene A. the Invention also relative to the eat, and the use of oxime 3’-destinationin-3’,4’-dihydroanthracene And as anti-inflammatory agents. The technical result - receiving anti-inflammatory drugs. 3 BC and 3 C.p. f-crystals, 2 PL.

The present invention relates to macrolide possessing anti-inflammatory activity and more specifically it relates des-dimethylaminopropionic macrolides with anti-inflammatory activity, their pharmaceutically acceptable salts, and pharmaceutical compositions containing these compounds as active ingredients.

It is known that many antibiotics, in particular antibiotics of the class of macrolides with 14 atoms representing a derivative of erythromycin, in addition to antibacterial activity and have anti-inflammatory properties [Clin. Immunother., (1996), 6, 454-464].

Erythromycin is a natural macrolide (The Merck Index, XII edition, n°3720, page 625), with a very wide spectrum of clinical applications in the treatment of infections caused by gram-positive bacteria, some gram-negative bacteria or Mycoplasma.

Recently, the interest of the scientific community focused on anti-inflammatory and immunomodulating camponesa confirmed by the materials of clinical trials in vivo and in vitro.

For example, the proven efficacy of macrolides in the treatment of inflammatory processes, such as panbronchiolitis [Thorax, (1997), 52, 915-918], bronchial asthma [Chest, (1991), 99, 670-673] and cystic fibrosis [The Lancet, (1998), 351, 420]; or when modeling in animals of inflammatory processes, such as peritonitis mice caused simhasanam [Journal of Antimicrobial Chemotherapy, (1992), 30, 339-348] and neutrophil recruitment trachea of rats induced by endotoxin [Antimicrobial Agents and Chemotherapy, trachea of rats, caused by endotoxin [Antimicrobial Agents and Chemotherapy, (1994), 38, 1641-1643]; or in the in vitro study of such immune cells like neutrophils [The journal of Immunology, (1997), 159, 3395-4005] and T-lymphocytes [Life Sciences, (1992), 51, PL 231-236]; or when the modulation of cytokines, such as interleukin 8 (IL-8) [Am. J. Respir. Crit. Care Med., (1997). 156, 266-271] or interleukin 5 (IL-5) (EP 0775489 and EP 0771564, Taisho Pharmaceutical Co., Ltd.

Specific therapeutic efficacy of macrolides in cases in which conventional anti-inflammatory drugs (such as corticosteroids) has proved ineffective [Thorax, (1997), 52, 915-918, cited above], explains the high interest addressed this potential new class of anti-inflammatory drugs.

However, high antibacter the inflammatory processes, not caused by pathogens due to the rapid emergence of resistant strains.

It would therefore be desirable to have new substances with macrolide structure, which have anti-inflammatory activity and at the same time deprived of the properties of antibiotics. For clarity we give the formula for erythromycin, which shows the numbering adopted in the description of this application.

Some classes erythromycin derivatives having anti-inflammatory activity described in the literature.

For example, in the already cited applications EP claimed the right to Taisho (isho)-derivatives of erythromycin for 3-, 9-, 11And 12-positions as strong inhibitors of the synthesis of interleukin 5.

In the application EP 0283055 (Sour Pliva) N-alkyl derivatives of azithromycin without cladinose and desosamine formula

in which

R1represents hydrogen, lower alkyl or lower alkanoyl;

R2, R3and R4identical or different, represent hydrogen or lower alkanoyl described as anti-inflammatory agents.

In the application WO 92/16226 on behalf of Smith-Kline Beecham Corporation declared using erythromycinonline interleukin 1.

Among macrolide derivatives described in the literature, there are several 3-destinationin-9 oxyimino derivatives. Limited interest in this class of compounds is confirmed by the fact that already known significant role dimethylamino group in the activity of ribosomal binding typical of macrolides [Tetrahedron Letters, (1994), 35, 3837-3840].

In the application of the U.S. 3928387 (Hoffmann-La Roche Inc.) describes the reaction of 3’-destinationin-3’, 4’-dihydroanthracene And as an intermediate connection, suitable for receiving antibiotic 1745 And/X.

In the application EP 0254534 (Robinson, William S.) claimed in a very wide class of macrolides with antiviral activity. Among them are described compound of the formula

the correct chemical name is 9-O-methyloxime 3’-destinationin-3’, 4’-dihydroanthracene And contrary to the text of the application EP 0254534 mistakenly listed as 9-O-methyloxime of destinationunreachable (S. 10, line 46).

Currently, it has been found that the removal of the dimethylamino group of the 3’-position of desosamine 9-oxyimino macrolides formed compounds possessing anti-inflammatory activity and largely devoid of properties of antibiotics.

Sledovateljam a hydrogen or methyl;

R1and R2both represent hydrogen or together they form a chemical bond;

R3represents hydrogen, linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated, containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups;

X and Y, identical or different, represent O or NR4where R4is hydrogen, linear or branched C1-C5alkyl group, benzyloxycarbonyl group;

r is an integer from 1 to 6;

m is an integer from 1 to 8;

n is an integer from 0 to 2;

and their pharmaceutically acceptable salts;

this excludes compounds of the oxime 3'-destinationin-3',4'-dihydroanthracene and 9-O-methyloxime 3'-destinationin-3'4'-dihydroanthracene A.

The next subject of the present invention is the use of oxime 3'-destinationin-3',4'-desparetely funds.

These compounds of formula I are macrolides anti-inflammatory action, devoid of antibiotic activity, and therefore, they are suitable for the treatment of inflammatory processes.

The term linear or branched C1-C5alkyl group means a group selected from methyl, ethyl, n-sawn, ISO-propyl, n-butilkoi, isobutylene, secondary butilkoi, tert-butilkoi, n-Panteley and isopentyl groups.

The term 5 - or 6-membered heterocycle, saturated or unsaturated with 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, understand such heterocycles as pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazol, isoxazol, oxazole, pyridine, pyrazin, pyrimidine, pyridazine, triazole, thiadiazole or partially or fully saturated form.

Preferred compounds of formula I are those compounds in which R, R1and R2represents hydrogen.

In the class of these compounds are preferred, in particular, such compounds in which R3represents a chain of formula

in which

X, Y, A, r, m and n have the above-mentioned values.<

in which

r is equal to 2, m is 2 or 6, n is 1, Y represents NR4X represents O or NR4, R4represents hydrogen and a represents a phenyl or thiazolyl.

Examples of pharmaceutically acceptable salts of formula (I) are salts of organic or inorganic acids such as hydrochloric, Hydrobromic, itestosterone, nitric, sulfuric, phosphoric, acetic, tartaric, citric, benzoic, succinic, and glutaric acid.

The compounds of formula I, which is the subject of the present invention, receive, using the scheme of synthesis, which includes: (a) the removal of the dimethylamino group from 3’-position, and (6) optional introduction of functional groups specified oxime.

The specified removal of the dimethylamino group is carried out by oxidation, pyrolysis, and optional recovery, which carry well-known methods. People skilled in this field, it is obvious that in order to avoid interference from the functional groups that are not necessarily present when the substituent R3, preferably, the removal of the dimethylamino group was made on the basis of the intermediate compounds with yet a hydrogen, or linear or branched C1-C5alkyl group.

Their oxidation obtain the corresponding N-oximes with the formula

in which

R and R3’ have the previously indicated meanings;

And their pyrolysis, with optional subsequent recovery, get connection with formulas

which is the subject of the present invention (I-R3=hydrogen or C1-C5alkyl).

The compounds of formula I in which R3different from hydrogen, can be obtained according to the conventional technique, based on the compounds of formulas I-A and I-B in which R3’ represents hydrogen, by introducing a functional group specified oxime.

Usually specified the introduction of functional groups carried out by the interaction with the compound of the formula

R3”-W (IV)

in which R3" has all values of R2except for hydrogen, and W is a leaving group (preferably, a chlorine atom or bromine, or mesyl group). Another way of synthesis, especially suitable for producing compounds of the formula I, in which R3represents a chain of formula

where

X, Y, A, r, m and n are they dstanley a hydrogen, with an intermediate compound of the formula

where W, X, Y, m and n have the meanings indicated previously, a Z is a protective group; obtaining the intermediate compounds of formula

in which R, R1, R2X, Y, Z, r and m have the meanings given above;

after removal of the specified protective group Z this compound interacts with the derived formulas

where A, W and n have the meanings given above; with obtaining the compounds of formula I.

These compounds of formula I in which Y represents NR4you can follow the above scheme of synthesis, as well as when using the aldehyde of the formula

A-CHO (VIII)

in which a has the value given above,

instead of the compounds of formula VII to produce the deletion of the specified protective group Z from the intermediate compounds of formula VI.

In addition, the compounds of formula I in which R1=R2=H, can be obtained by reduction of corresponding compounds of the formula I, in which R1and R2form a chemical bond.

These compounds of formula I, which is the subject of the present invention have protivoanemi formula I were evaluated in tests in vitro and in vivo, comparing it with the activity of known macrolides, such as erythromycin, clarithromycin and roxithromycin that possess both anti-inflammatory activity and antibiotic activity.

Specified anti-inflammatory activity in vitro was assessed by suppression of the release of interleukin 8 and release anion peroxide (example 11), a in vivo suppression of neutrophilia caused by repeated injections of LPS (example 12).

In all these experiments the compounds that are the subject of the present invention showed a very high activity as anti-inflammatory agents, and anti-inflammatory activity equivalent to the activity of one of these compounds or above it.

For therapeutic use of the compound of the formula I can be used as a pharmaceutical form suitable for oral or parenteral administration.

Thus, the object of the present invention are pharmaceutical compounds containing a therapeutically active amount of the compound of formula I or its salt in a mixture with a pharmaceutically acceptable carrier.

For better illustration of the present invention are sledowatelxno acid

To a solution of benzyl ether (6-hydroxyhexyl)-carbamino acid (25 g; 99,47 mmol), obtained as described in the application WO 96/18633, CH2Cl2(350 ml) and cooled with ice to a temperature of about 10°With the first added a solution of KBR (1.18 g; 9,94 mmol) in water (20 ml) and TEMPO (0,155 g; 0,994 mmol). Then, dropwise, maintaining the temperature at 10-12°C for about 15-20 min was added to the solution obtained from Panso3(7.5 g; 89,28 mmol) and NaClO (4,5% aqueous solution; 197 ml, 125 mmol).

After 15 min. after completion of addition, the resulting phases were separated and the aqueous phase is once was extracted with CH2Cl2(100 ml). The collected organic extracts washed twice with brine (20% NaCl) and dried on sodium sulfate.

To the resulting solution (about 800 ml) was added 3-a molecular sieves (30 g), and then with the rapid prikatyvanie and cooled water and ice a solution of 2-aminoethanol (35,9 ml; 0,597 mol) in ethanol (600 ml).

Upon completion of the addition the mixture was kept with stirring at room temperature for 2 h, and then filtered.

To the resulting solution was added dropwise NaBH4(4,54 g; 120 mmol), cooled viderjivali with stirring at room temperature for 2 h, then the solvent is boiled away.

The residue was collected, added water and ethyl acetate and the resulting phases were separated, and then double-spent extraction of the aqueous phase with ethyl acetate.

The collected organic extracts were washed with brine (20% NaCl, dried on sodium sulfate and agglomerated to obtain an oily residue, which is then brought to thickening.

The residue was ground into powder in hexane, filtered, and washed with a mixture of hexane and ethyl ether, receiving in the form of a white solid substance benzyl ether [6-(2-hydroxyethylamino)-hexyl]-carbamino acid (26,22 g; yield 89%).

1H-NMR (200 MHz, CDCl3) (ppm): 7.33-7.25 (m, 5H, Ar); 5.05 (s. 2H, SOON2); 4.96 (extended-t, 1H, NH); 3.63-3.58 (m, 2H. *CH2-OH); 3.19-3.09 (m, 2H, CH2NCO); 2.72-2.67 (m, N-*CH2-CH2O); 2.59-2.52 (m, 4H, HE and CH3); 1.53-1.23 (m, 8H, 4CH2).

Example 2

Getting benzyl ester 6-(benzyloxycarbonylamino)-(2-hydroxyethyl)-carbamino acid

A solution of benzyl ester benzylchloride (50% in toluene; 42,5 ml; 0,128 mol) in ethyl acetate (85.5 ml) and 1N NaOH (128 ml; 0,128 mol) was added dropwise to a solution of benzyl ether [6-(2-hydroxyethylamino)-hexyl]-carbami the Tata (180 ml). Cooled at 0-5°C, controlling the temperature and pH (approximately equal to 8).

Upon completion of addition the reaction mixture was stirred at 0-5°C With stirring for 30 min, then the cooling was stopped and added 1N NaOH (15 ml) again to return to the previous value of pH 8. Then the reaction mixture was left overnight under stirring at room temperature.

The resulting phases were separated and the aqueous phase was again extracted with ethyl acetate. The collected organic extracts were washed with brine, dried on sodium sulfate and agglomerated under vacuum to obtain an oily residue.

Chromatographic purification (eluant ethyl acetate:petrolatum at a ratio of from 60:40 to 70:30) was obtained in the form of oil-benzyl ester 6-(benzyloxycarbonylamino)-(2-hydroxyethyl)-carbamino acid (42.5 g; yield 92%).

1H-NMR (200 MHz, Dl3) (ppm): 7.39-7.25 (m, 10H, Ar); 5.07 5.10 and (2s, 4H, 2COOCH2); 3.71 (broadened signal, 2H, *CH2-HE); 3.43-3.01 (m, 4H, 2CH2NCO); 1.57-1.19 (m, 8H, SN2).

Acting similarly obtained the following compounds:

Benzyl ether (2-benzyloxycarbonylamino)-(2-hydroxy-ethyl)-carbamino acid

Benzyl ether [2-(benzyl-benzyloxycarbonylamino)-ethyl]-(2-hydroxyethyl)-carbamino acid

on the basis of 2-[2-(benzylamino)-ethylamino]-ethanol, obtained as described in the application WO 96/18633.

(yield 50%)

1H-NMR (200 MHz, Dl3) (ppm): (strongly broadened signals) 7.42-7.13 (m, 15H, Ah); 5.12 5.09 (2s, 4H, SOON2*); 4.55 (s, 2H, N-*CH2-Ph);

Benzyl ether [2-(2-hydroxyethoxy)-ethyl]-carbamino acid

based on 2-(2-aminoethoxy)-ethanol

(yield 85%)

1H-NMR (200 MHz, Dl3) (ppm): 7.36-7.28 (m, 5H, Ar); 5.18 (broadened signal, 1H, NH); 5.08 (s, 2H, Ph-*CHO); 3.74-3.34 (m, 8H, *CH2-*CH2-O-*CH2-*CH2-HE); 2.13 (extended-t, 1H, HE).

Example 3

Obtaining___ethyl___ether___2-[benzyloxycarbonyl-(6-benzyloxycarbonylamino)-amino]-methanesulfonic acid

The triethylamine (8,95 ml; 64,31 mmol) was added to a solution of benzyl ester 6-(benzyloxycarbonylamino)-(2-hydroxy-ethyl)-carbamino acid (13,78 g; 32,15 mmol), obtained as described in example 2, CH2CL2(140 ml). The resulting mixture was cooled at 0-5°C, and then dropwise on the AI this process, the mixture was stirred at room temperature with stirring for 60 min, washed first with 5% aqueous citric acid, then with brine (20% NaCl), 5% aqueous NaHCO3and finally again with brine. After drying on sodium sulfate and evaporation in vacuum in the form of a brown oil was obtained ethyl ester 2-[benzyloxycarbonyl-(6-benzyloxycarbonylamino)-amino]-methanesulfonic acid (16,37 g; yield 100%).

1H-NMR (200 MHz, CDCl3) (ppm): 7.35-7.27 (m, 10H, Ar); 5.07 5.11 and (2s, 4H, SOON2); 4.36-4.19 (m, 2H, CH2OSO2); 3.57-3.51 (m, 2H, SO-CH2-*CH2N); 3.32-3.07 (m, 4H, 2CH2N); 2.91 and 2.85 (2s-conformational variants of patterns, 3H, CH3); 1.50-1.20 (m, 8H, SN2).

Acting similarly obtained the following compounds:

Ethyl____ether 2[2-(benzyloxycarbonylamino)-ethoxy]-methanesulfonic acid, based on the benzyl ester [2-(2-hydroxy-ethoxy)]-carbamino acid, obtained as described in example 2.

(yield 98%)

1H-NMR (200 MHz, CDCl3) (ppm): 7.36-7.28 (m, 5H, Ar); 5.16 (broadened signal, 1H, NH); 5.08 (s, 2H, SOON2); 4.34-4.30 (m, 2H, SO3CH2); 3.72-3.67 (m, 2H, SO3-CH2-*CH2);

3.60-3.34 (m, 4H, N-*CH2-*CH2); 2.98 (s, 3H, SO3CH3);

ethyl___ether___2-[2-benzyl-benzyloxy-(benzyl-benzyloxycarbonylamino)-ethyl]-(2-hydroxyethyl)-carbamino acid, obtained as described in example 2.

(yield 72%)

1H-NMR (200 MHz, Dl3) (ppm): 7.40-7.00 (m, 15 NM. AG); 5.13-5.01 (broadened signal, 4H, SOON2); 4.51-3.30 (extended-m, 10H, 4CH2N and CH2SO3); 2.92-2.76 (broadened signal, 3H, CH3);

ethyl_________the ether_________2-[benzyloxycarbonyl-(2-benzyloxycarbonylamino)-amino]-methanesulfonic acid

on the basis of the benzyl ether (2-benzyloxycarbonylamino)-(2-hydroxyethyl)-carbamino acid, obtained as described in example 2.

(yield 100%)

1H-NMR (200 MHz, DCl3) (ppm): 7.35-7.27 (m, 10H. AG); 5.04 5.10 and (2s, 4H, SOON2); 4.41-4.15 (m, 2H. *CH2-MeSO2); 3.63-3.23 (m, 6H, N-*CH2-*CH2-N*CH2); 2.90 (broadened s, 3H, MeSO2).

Example 4

Obtaining N-oxide of the oxime of erythromycin And

A solution of N2O2(72,00 g; title 34% weight/volume; to 0.72 mol) in water (780 ml) dropwise over 1 h was added to a solution of oxime erythromycin A (35,00 g; 0,0467 mol) in methanol (1400 ml) under mechanical stirring, maintaining the temperature at 20-25°C. At the end of this process of adding the reaction mixture was kept under stirring for 24 h at room those whom Ivanyi within 6 hours

The methanol was boiled away in vacuum at a temperature of about 40°C, while maintaining a constant volume of water (approximately 700 ml).

After filtration, washing with water and drying there was obtained N-oxide of the oxime of erythromycin in the form of a white crystalline solid (36,3 g; yield 99%).

1H-NMR (200 MHz, DMSO-d6) (ppm): 10.71-10.19 (broadened signal, 2H, shift H); 5.14-5.08 (m, 1H, H-13); 4.72 (d, 1H, JNN=4.4 Hz, H-1"); 4.45 (d, 1H, JNN=7,0 Hz, H-1').

Example 5

Getting oxime 3'-de(dimethylamino)-3',4'-dihydroanthracene A (compound 1)

A solution of N-oxide oxime erythromycin A (30,00 g; to 38.3 mmol), obtained as described in example 4 in dimethylformamide (235 ml) was heated at 150°C in a pre-heated oil bath (175-180°C), and then left at this temperature and under mechanical stirring for 15-20 minutes After cooling and evaporation of dimethylformamide oil residue is gathered with demineralized water, heated and cooled. The filtered solid was ground to a powder under vacuum at 40 to 45°C, receiving the crude product (25,5 g).

This crude product is recrystallized first from acetonitrile (110 ml), Hotfile recrystallization from a mixture of methanol/water=65/35 (400 ml), was filtered and dried under vacuum at 40-50°C. the Thus obtained compound 1 in the form of a crystalline product (10.3 g; output 38,2%).

From the crystallization solution then extracted additional amount of product (3.7 g), giving a total output amounting to 51.8%.

1H-NMR (200 MHz, CDCl3) (ppm): 5.67-5.55 (m. 2H, *SN=*SN); 4.44 (d, 1H, JHH=7,0 Hz, H-1’); 4.33-4.22 (m, 1H, H-5’); 4.13-4.04 (m, 1H, H-2’); 3.84-3.73 (m, 1H, H-8); 3.69 (s, lH, H-11).

13C-NMR (200 MHz, CDCl3) (ppm): 171.11 (s, C-9); 132.2 and 126.1 (2s, C-3’ and C-4’).

Example 6

Getting oxime of 3’-de(dimethylamino)-erythromycin A (compound 2)

The platinum oxide (of 0.615 g) was added at room temperature to a solution of compound 1 (20,00 g, 28.4 mmol), obtained as described in example 5, in ethanol (850 ml) (complete dissolution was obtained after weak heat).

The resulting mixture was first made in the apparatus Parra (1,36 ATM), and was absorbed without intermediate stages.

After the catalyst was filtered and vacuum removed the solvent, the obtained white crystalline residue was ground into powder with petroleum butter. Then it was filtered and dried under vacuum at 50°With obtaining the compound (d, 1H, JNN=7,4 Hz, H-1’); 3.44-3.30 (m, 1H, H-2’); 2.07-1.21 (m, 2H, H-3’); 1.65-1.45 (m, 2H, H-4’).

13C-NMR (200 MHz, CDCl3) (ppm): 171.2 (s, C-9); 104.7 (s, C-1'); 31.8(s, C-3’); 29.5 (s, C-4’).

Example 7

Receive E-9-[O-[2-[benzyloxycarbonyl-(6-benzyloxycarbonylamino)-amino]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 3).

Compound 2 (12,51 g; 17,73 mmol), obtained as described in example 6, was added to 95% solution of tert-butyl calcium (2,45 g; 19,48 mmol) in anhydrous tetrahydrofuran (120 ml) under stirring in a nitrogen atmosphere while maintaining the temperature at about 25°C. the reaction mixture was kept under stirring for 30 min at room temperature. Then added 18-crown-6 ether (4,69 g; 17,73 mmol) and a solution of ethyl ester of 2-[benzyloxycarbonyl-(6-benzyloxycarbonylamino)-amino]-methanesulfonic acid (8,98 g; 17,73 mmol), obtained as described in example 3, in anhydrous tetrahydrofuran (60 ml) and stirring continued at room temperature overnight.

After evaporation in vacuo of the solvent the residue was combined with a mixture of ethyl acetate and brine (20% NaCl) and the resulting phases were separated. The aqueous phase is again this crude product (23,4 g).

When chromatographic purification (eluent CH2CL2:CH3HE=97:3) was obtained slightly contaminated compound 3 (15,42 g) which was used without further purification.

1H-NMR (200 MHz, DCl3) (ppm): 7.35-7.28 (m, 10H, Ar); 5.14-5.06 (m, 1H, H-13); 5.07 5.11 and (2s, 4H, SOON2); 4.84 (d, 1H, JHH=4.4 Hz, H-1’); 4.28 (d, 1H, JHH=7.4 Hz, H-l’).

Acting in a similar way, received the following connections:

(E)-9-[O-[2-[2-benzyloxycarbonylamino)-ethoxy]-ethyl]-oxime____3'-de(dimethylamino)-erythromycin A (compound 4), based on the ethyl ester of 2-[2-(benzyloxycarbonylamino)-ethoxy]-methanesulfonic acid.

(yield 62%)

1H-NMR (200 MHz, CDCl3) (ppm): 7.34-7.21 (m, 5H, Ar); 6.09 (broadened signal, 1H, NH); 5.13-5.05 (m, 1H, H-13); 5.06 (s, 2H, SOON2); 4.79 (d, 1H, JHH=4.4 Hz, H-1’); 4.26 (d, 1H, JHH=7,4 Hz, H-1’);

(E)-9-[O-[2-methoxyethoxy-methyl]-oxime_____3’-de(dimethylamino)-erythromycin A (compound 5), based on methoxyethoxymethyl

(exit 32.5 per cent)

1H-NMR (200 MHz, Dl3) (ppm): 5.21-5.12 (m, 2H, O-CH2-Oh); 5.12-5.05 (m, 1H, H-13); 4.85 (d, 1H, JHH=5.4 Hz, H-1’); 4.39 (d. 1H, JHH=7.5 Hz, H-1’); 3.40 (s. 3H, CH2-O-*CH3); 3.27 (s, 3H, H-3”).

13C-NMR (200 MHz, C is the IMT-amino)-ethyl]-benzyloxycarbonylamino]-ethyl]-oxime of 3’-de(dimethylamino-erythromycin A (compound 12), on the basis of the ethyl ester of 2-[[2-(benzyl-benzyloxycarbonylamino)-ethyl]-benzyloxycarbonylamino]-methanesulfonic acid

1H-NMR (200 MHz, CDCl3) (ppm): 7.40-7.16 (extended-m, 15 NM, 3Ph); 5.17-5.00 (m. 5H, 2*CH2-Ph and H-13).

(E)-9-[O-[2-[[2-(benzyloxycarbonylamino)-ethyl-benzyloxycarbonyl-amino]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 13), based on the ethyl ester of 2-[benzyloxycarbonyl-(2-benzyloxycarbonylamino)-amino]-methanesulfonic acid

(yield 42%)

1H-NMR (200 MHz, CDCl3) (ppm): 7.38-7.25 (m, 10H, 2Ph); 5.11 and 5.05 (2s, 4H, SOON2); 5.14-5.00 (m, 1H, H-13); 4.89-4.79 (extended m, 1H, H1’); 2.26 (d, 1H, JHH=7,4 Hz, H1’).

Example 8

Precept (E)-9-[O-[2-[(6-aminohexyl)-amino]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 6)

10% Pd/C (1.6 g) was added to a solution of compound 3 (15.42 g; of 13.8 mmol), obtained as described in example 7, in ethanol (160 ml).

The resulting mixture was first made in the apparatus Parra (of 1.02 ATM). After 2 h, the catalyst was filtered, and the solvent is boiled away.

The residue was purified by thin-layer chromatography (eluent CH2CL2:CH3HE:NH3=85:15:1,5; then 80:20:2), resulting in compound 5 (8 1H, H-13); 4.79 (d, 1H, JHH=4.4 Hz, H-1’); 4.21 (d, 1H. JHH=7,4 Hz, H-1’).

13C-NMR (200 MHz, CDCl3) (ppm): 171.8 (s, C-9); 71.6 (s,=N-O-C); 49.43 and 49.0 (2s,=N-O-C-*C-N*C); 41.1 (s,-NH2)

Acting in a similar way, received the following connections:

(E)-9-[O-[2-(2-aminoethoxy)-ethyl]-oxime______3’-de(dimethylamino)-erythromycin A (compound 7), on the basis of connections 4

(yield 85%)

1H-NMR (200 MHz, Dl3) (ppm): 5.12-5.05 (m, 1H, H-13); 4.83 (d, 1H, JHH=4.4 Hz, H-l’); 4.26 (d, 1H,JHH=7.5 Hz, H-1’).

(E)-9-[O-[2-[(2-benzylamino)-amino]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 14), based on the connection 12

(yield 48%)

1H-NMR (200 MHz, l3) (ppm): 7.32-7.17 (m, 5H, Ph); 5.08-5.00 (m, 1H. H-13); 4.74 (d, 1H, JHH=4,6 Hz, H-1’); 4.22 (d, 1H, JHH=7,4 Hz, H-1’); AB system: Va=3.80, Vb=3.76, Jab=13,7 Hz, *CH2Ph.

13C-NMR (200 MHz, CDCl3) (ppm): 171.3 (s, C-9); 105.0 (s, C-1’); 32.2 (s, C-3’); 29.8 (s, C-4’).

(E)-9-[O-[2-[(2-amino-ethyl)-amino]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 15), based on the connection 13

(yield 70%)

1H-NMR (200 MHz, CDCl3) (ppm): 5.08-5.00 (m, 1H, H-13); 4.76 (d, 1H, JHH=4,6 Hz, H-1’); 4.23 (d, 1H, JHH=7,4 Hz, H-1’).

Example 9

Getting >P CLASS="ptx2">A suspension of compound 6 (3 g; of 3.53 mmol), obtained as described in example 8, and 97% 2-thiazolecarboxamide (0,412 g; of 3.53 mmol) and molecular sieves (3 , 6.75 g) in ethanol (60 ml) was kept under stirring for 3 hours

After the molecular sieve was filtered on celite, added 10% Pd/C (0.3 g) and the resulting mixture was first made in hydrogenator Parra (of 1.02 ATM). After 20 h the catalyst was filtered, and the solvent is boiled away.

Chromatographic purification of the residue (eluent SNS3:petrolatum:triethylamine=90:10:10) in the form of an amorphous solid were obtained compound 8 (1.66 g; output 49,8%).

1H-NMR (200 MHz, CDCl3) (ppm): 7.66 (d, 1H, JHH=the 3.2 Hz, CHN); 7.22 (d, 1H, CHS); 5.08-5.02 (m, 1H, H-13); 4.78 (d, 1H, JHH=4.4 Hz, H-1’); 4.21 (d, 1H, JHH=7.4 Hz, H-1’); 4.07 (s, 2H, *CH2-thiaz).

13C-NMR (200 MHz, CDCl3) (ppm): 172.0 (s, S-C=N); 171.7 (s, C-8); 142.4 (s, CHN); 118.7 (s, CHS); 104.9 (s, C-1’); 96.3 (s, C-1’); 71.7 (s, N-O-C).

Acting in a similar way, there were obtained the following compounds:

(E)-9-[O-[2-[6-(benzylamino)-hexylamino]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 9), starting from compound 6 and benzaldehyde.

1H-NMR (200 MHz, CDCl3) (ppm): 7.27-7.17 (m, 5H, Ar); 5.07-5.01 (m, 1SUB>) (ppm): 171.8 (s, C-9); 104.9 (s, C-1’); 96.3 (s, C-1”); 71.8 (s,=N-O-C); 53.8 (s, N-*C-Ph); 49.7, and 49.2 49.1 (3s, 3N-C).

(E)-9-[O-[2-[2-[(thiazol-2-yl-methyl)-amino]-ethoxy]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 10), starting from compound 7 and 2-thiazolecarboxamide.

1H-NMR (200 MHz, CDCl3) (ppm): 7.64 (d, 1H, J=3.2 Hz, CHN); 7.19 (d. 1H, CHS); 5.10-5.02 (m, 1H, H-13); 4.78 (d, 1H, J=4.4 Hz, H-1’); 4.21 (d, 1H. JHH=7,4 Hz, H-1’); 4.13 (s, 2H,*CH2-thiaz).

13C-NMR (200 MHz, Dl3) (ppm): 172.7 (s, SC=N); 171.5 (s, C-9); 142.4 (s. CHN’); 118.6 (s, CHS); 104.7 (s, C-1’); 96.4 (s, C-1’); 50.7 (s, N-*C-thiaz).

(E)-9-[O-[2-[2-(benzylamino)-ethoxy]-ethyl]-oxime of 3'-de(dimethylamino)-erythromycin A (compound 11), starting from compound 7 and benzaldehyde.

1H-NMR (200 MHz, CDCl3) (ppm): 7.33-7.10 (m, 5H, AT); 5.12-5.04 (m, 1H, H-13); 4.78 (d, 1H, JNN=4.4 Hz, H-N; 4.72 (d, 1H, JHH=7,4 Hz, H-1'); 3.80 (s, 2H, NCH2).

13C-NMR (200 MHz, CDCl3) (ppm): 171.5 (s, C-9); 104.8 (s, -1'); 96.5 (s, C-1'); 69.4, and 70.8 72.4 (3s, ON2); 53.6 (s, *C-Ph); 48.2 (s, O-C-*C-N).

(E)-9-[O-[2-[2-[(thiazol-2-yl-methyl)-amino]-ethylamino]-ethyl]-oxime of 3'-de(dimethylamino)-erythromycin A (compound 16), based on the connection 15 and 2-thiazolecarboxamide.

1H-NMR (200 MHz, CDCl3) (ppm): 7.62 (d, 1H, JHH=3.0 Hz, N-*CH=CH); 7.18 (d, 1H, S-*CH=CH); 4.18 (d, 1H, JHH=7,4 G is"); 32.17 (s, C-3'); 29.8 (s, C-4').

(E)-9-[O-[2-[6-[(2-phenyl-1H-imidazol-4-yl-methyl)-amino]-hexylamino]-ethyl]-oxime of 3'-de(dimethylamino)-erythromycin A (compound 17), on the basis of compounds 6 and 2-phenyl-1H-imidazole-4-carbaldehyde.

1H-NMR (200 MHz, CDCl3) (ppm): 7.86-7.21 (m, 5H, Ar); 6.91 (s, 1H, CH Imid.); 5.11-5.02 (m, 1H, H13); 4.76 (d, 1H, JNN=4,2 Hz, H1"); 4.21 (d, 1H, JHH=7,4 Hz, H1'); 3.76 (s, 2H, *CH2-Imid); 3.23 (s, 3H, OMe).

13C-NMR (200 MHz, CDCl3) (ppm): 171.7 (s, C-9); 104.8 (s, -1'); 96.3 (s, C-1'); 32.1 (s, C-3'); 29.9 (s, C-4').

(E)-9-[O-[2-[6-[(1-methyl-2-phenyl-1H-imidazol-4-yl-methyl)-amino]-hexylamino]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 18), on the basis of the connections 6 and 1-methyl-2-phenyl-1H-imidazole-4-carbaldehyde.

1H-NMR (200 MHz, l3) (ppm): 7.57-7.31 (m, 5H, Ar); 6.87 (s, 1H, CH-Imid); 5.09-5.00 (m, 1H, H13); 4.76 (d, 1H, JHH=4,2 Hz, H1”); 4.20 (d, 1H, JHH=7,4 Hz, H1’); 3.71 (s, 2H,*CH2-Imid); 3.62 (s, 3H, NMe); 3.21 (s, 3H, OMe).

13C-NMR (200 MHz, l3) (ppm): 171.8 (s, C-9); 104.9 ('s. C-1’); 96.3 (s, C-1”); 32.1 (s, C-31); 29.7 (s, C-4’).

Example 10

Obtaining (E)-9-[O-[2-[2-[(thiazol-2-yl-methyl)-(magellano)-ethoxy]-ethyl]-oxime of 3’-de(dimethylamino)-erythromycin A (compound 19)

Compound 10 (0,23 g; 0,258 mmol), formaldehyde (37% weight/volume; 42 m is when Parra of 1.02 ATM. After 2 h and 3 h was added an additional amount of formaldehyde (42 μl + 21 μl). Upon completion of the reaction (which took a total of 6 hours), the catalyst was filtered, and the solvent is boiled away. The resulting residue was purified by thin-layer chromatography (eluent CH2CL2:CH3HE=95:5), receiving a connection 19 in the form of an amorphous solid.

1H-NMR (200 MHz, l3) (ppm): 7.64 (d, 1H, JHH=3,6 Hz, N-*CH=CH); 7.21 (d, 1H, S-*CH=CH); 5.10-5.00 (m, 1H, H13); 4.80 (d, 1H, JHH=4,6, H1”); 4.23 (d, 1H, JHH=7,4 Hz, H1’); 3.94 (s, 2H,*CH2-Thiaz.).

13C-NMR (200 MHz, CDCl3) (ppm): 172.0 (s, SC=N); 171.8 (s, C-9); 142.2 (s, CHN); 119.3 (s, CHS); 104.9 (s, C-1’); 96.4 (s, C-1’); 32.2 (s, C-3’); 29.9 (s, C-4’).

Example 11

Pharmacological activity in vitro

A) the Release of interleukin 8

Immortalitya endothelial cell line person (ECV304) were obtained from the American collection of tissue culture (Rockville, Md). It was grown in medium (Medium 199, mod. Earie's salts) (GIBCO, Life Technologies, Grand Island, N. Y.) with the addition of 20% fetal calf serum (GIBCO), penicillin 100 units/ml and streptomycin (SIGMA, St. Louis, MO) in an amount of 100 g/ml; the process was performed in a humid atmosphere containing 5% CO2when Nene, that ought to produce, dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10-2M and diluted in culture medium.

These connections before carrying out provocative samples were pre-incubated for 1 h with the indicated cells.

The release of interleukin 8 caused by adding 0.66 g/ml of lipopolysaccharide (E. coli 055:B5, Difco, Detroit, Mi) to a final volume of 200 L.

After the night of the resulting supernatant was collected for the test in relation to interleukin 8.

Specific immunoreactivity specified culture supernatant against interleukin 8 was measured using a kit ELISA kit (Amersham, UK).

The measurement results are expressed by the values achieved the highest inhibition (efficiency), and, where possible, as the concentration at which up to 50% of this effect (IC50).

B) the Release of anions peroxide

Neutrophils were isolated by centrifugation (centrifuge Ficoll-Hypaque) venous blood of healthy volunteers during subsequent deposition of 6% dextran and osmotic lysis of erythrocytes. Then the neutrophils were washed and re-suspended in the medium, sostavlennoj acid (adtc). The cells were kept for 24 h at 4°C, and before conducting the test, the suspension was centrifuged and re-suspended in balanced salt solution Hanks. The viability and purity of the drug received neutrophils was tested by staining Trifanova blue and alizarin blue.

Superoxide anions were determined chemiluminescence way, enhanced through the use of Lucigenin (nitrate bis-N-methylacridinium).

Neutrophils (2×106cells/ml) pre for 30 min were incubated at 37°With 900 l of balanced salt solution Hanks in the presence of the test compound and in the absence (reading system).

The production of peroxide anions were determined using a biological counter Lumac/ZM; process conducted after the introduction of the reading system 100 l balanced nitrate bis-N-methylacridinium salt Hanks solution (2 mmol/l) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine as a stimulating agent at a concentration of 1×10-5M

N-formyl-L-methionyl-L-leucyl-L-phenylalanine was dissolved in DMSO (1×10-2M), and then diluted in balanced salt solution Hanks. The connection is obtained from this solution and tested. The amount of DMSO present in the given reading was below 1%.

The peak brightness of light received for each of the studied concentrations of the compounds were converted into values of percentage inhibition in comparison with the reference compounds.

Concentration able to inhibit the production of peroxide anions by 50% (IC50), was calculated using the obtained curve “dose-response”.

In table.1 shows the results obtained for some compounds of formula I, which are representatives of the whole class; and these results are compared with data for erythromycin, clarithromycin and roxithromycin.

Example 12

Pharmacological activity in vivo

- Animals

Used male rats Sprague-Dawley, who weighed 200 300,

Rats used in the experiments had no obvious signs of infection. These animals before killing was kept for 7 days under standard conditions.

- Introduction endotoksina

LPS (E. coli liposaccharide) (endotoxin; type serum 055:B5; Sigma Chemical Co., St. Louis, MO) was dissolved in sterile salt solution and introduced the tion by injection was introduced salt solution and/or the vehicle (saline +0.5% tween-20).

Introduction compounds (preventive treatment)

Each of the compounds were injected method intraperitoneally injections twice a day for 6 days and on day 7 for 1 h before LPS injection and 5 h after its introduction. These compounds suspended in salt solution with 0.5% tween-20.

- Bronchoalveolar lavage irrigation

After 24 h after injection of LPS in rats usersfile by an overdose of Nembutal (100 mg/kg, intraperitoneally injection). Spent catheterization trachea and tongue washed installation at 37°With two 5 ml aliquot of phosphate-saline buffer and the liquid immediately removed. The liquid is again introduced by injection and for each aliquot entire procedure was repeated three times.

- Counting the cells and their differentiation

200 μl of fluid bronchoalveolar lavage (BALF) was diluted with 1 ml of cold water and 19 ml of Isoton. The total number of cells was counted twice when using a Contraves autolyser 800. If the total number was less than 2000, bronchoalveolar fluid irrigation was centrifuged for 10 min at a rotation speed of 800 rpm to separate cells from supernatant. The resulting supernatant decanted, and the cells re-suspended the second solution and the recent re-suspension of cells was centrifuged at Shandon Cytospin centrifuge for 1 min at a speed of 1300 rpm Slides were fixed in acetone and dried with DiffQuick. Differential counting of cells was performed on each slide by counting randomly selected 200 cells; according to standard morphological criteria cells were classified as neutrophils, eosinophils and mononuclear cells.

In table.2 presents the results for some compounds of formula I, which are representatives of the entire class as a whole.

1. The compound of the formula

in which R represents hydrogen or methyl;

R1and R2both represent hydrogen or together they form a chemical bond;

R3represents hydrogen, linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated, containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups;

X and Y, same or different, predstavlyayuschaya group;

r is an integer from 1 to 6;

m is an integer from 1 to 8;

n is an integer from 0 to 2;

and their pharmaceutically acceptable salts; this excludes compounds: reaction of 3’-destinationin-3’,4’-dihydroanthracene and 9-O-methyloxime 3’-destinationin-3’4’-dihydroanthracene A.

2. Connection on p. 1, characterized in that R, R1and R2represent hydrogen.

3. Connection on p. 2, wherein R3represents a chain of formula

in which X, Y, A, r, m and n have the meanings specified in paragraph 1.

4. Connection on p. 2, wherein R3represents a chain of formula

in which r is 2;

m is 2 or 6;

n = 1;

Y represents NR4;

X represents O or NR4;

R4represents hydrogen;

Rather it represents a phenyl or thiazolyl.

5. The use of oxime 3’-destinationin-3’,4’-dihydroanthracene And as anti-inflammatory agents.

6. Pharmaceutical composition having anti-inflammatory effect, containing pharmaceutically aktywnosci acceptable carrier.



 

Same patents:

The invention relates to organic chemistry, in particular to methods of producing the compounds of formula (I):

in which m denotes 0, 1 or 2; n is 0, 1, 2 or 3 and a represents a double bond, represents a double or a simple link, With denotes a double bond, D represents a simple bond, E and F represent a double bond; r1denotes N or C1-C8alkyl; r2denotes H, C1-C8alkyl or HE; R3and R4each independently of one another denote H or C1-C8alkyl; R5denotes N or C1-C8alkyl; R6denotes H; R7IT denotes; R8and R9independently of one another denote H or C1-C10alkyl; in free form or in salt form, which consists in the fact that the compound of formula (II):

enter in contact with the biocatalyst, which is able to selectively oxidize the alcohol in position 4", obtaining the compounds of formula (III):

in which R1-R7, m, n, a, b, C, D, E and F have the same meaning as Kazakistan an amine of the formula HN(R8R9in which R8and R9have the same meaning as indicated for formula (I), with subsequent isolation of the target product in free form or in salt form

The invention relates to medicine, in particular to Oncology, and for the treatment of cancer in a mammal

The invention relates to a process for the preparation of clarithromycin in the form of crystals of form II, as well as to new intermediate compounds used in the specified way

The invention relates to a process for the preparation of clarithromycin of formula (I), including the interaction of the N-oxide erythromycin And formula (II) with meteorous agent with obtaining N-oxide 6-O-methyl-erythromycin a of formula (III) and processing of N-oxide-6-O-methylerythromycin And reducing agent

The invention relates to 12,13-dihydroxypropane tylosin General formula I, where R, R1CHO, CH=NOH, CH(OCH3)2; R2- H, mikrosil; R3- N(CH3)2NO(CH3)2;- double or a simple link, a new semisynthetic compounds of the macrolide class and method of production thereof

The invention relates to a derivative of (2R, 3S, 4S, 5R, 6R, 10R,11R)-2,4,6,8,10-pentamethyl-11-acetyl-12,13-dioxabicyclo[8.2.1] tridec-8-EN-1-it General formula (I), where R1denotes hydrogen or methyl and R2denotes hydrogen or (NISS
The invention relates to the field of medicine

The invention relates to compounds represented by the General formula (I)

< / BR>
where A represents NH group, and thus C=O-group or A - C=O-group and thus NH-group, R1HE band, L-clavesilla group of the formula (II)

< / BR>
or together with R2is a ketone; R2is hydrogen or together with R1represents a ketone; R3is hydrogen or C1-C4-alcoolica group, and pharmaceutically acceptable salts of the accession of organic and inorganic acids

The invention relates to a derivative of 9-O-benzodithiophene erythromycin And formula (III), where Y1and Y2represent hydrogen atoms or trimethylsilyl group, or its crystalline MES, which are used as intermediate compounds for the synthesis of clarithromycin

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

The invention relates to new compounds which are inhibitors of interleukin-1-converting enzyme (IAP), is characterized by a specific structural formula; to pharmaceutical compositions having the ability to inhibit interleukin-1-converting enzymes, method of treatment and prophylaxis of diseases selected from the group consisting of IL-1-mediated autoimmune inflammatory, neurodegenerative diseases, as well as the selection method of the IAP inhibitor

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to organic chemistry and can find application in medicine

The invention relates to medicine, in particular the production of medicinal substances from the funds of vegetable origin

The invention relates to the pharmaceutical industry, in particular the production of medicines used for colds, relieving headaches and neuralgia

The invention relates to medicine, in particular for orthopedics and neurosurgery, vertebrology, and can be used in the intervertebral disc

The invention relates to pharmaceutical

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to enriched troxerutin containing at least 92 wt.% 7,3',4'-trihydroxyethylrutoside, from 2 to 4 wt.% 5,7,3',4'-tetrahydrochloride and from 1 to 3 wt.% 7,4'-dihydroxytoluene and method thereof
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