9a-n-(n'-carbarnoyl)- or 9a-n-(n'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin and method for their production and pharmaceutical composition based on them

 

(57) Abstract:

9a-N-(N'-Carbarnoyl)- or 9a-N-(N'-thiocarbamoyl)-derivatives 9 deoxo-9a-Aza-9a-homoerythromycin And formula 1

< / BR>
where R is C1-C3-alkyl, C6-C10-aryl or C6-C10-arils1-C3-alkyl, 5 - or 6-membered aromatic ring having 1 or 2 heteroatoms selected from nitrogen or oxygen;

X is O or S,

are new semi-synthetic macrolide antibiotic azalides series that have antibacterial properties. 3 S. and 14 C.p. f-crystals, 1 table.

This invention relates to 9a-N-(N'-carbarnoyl - and 9a-N-(N'-thiocarbamoyl) derivative 9 deoxo-9a-Aza-9a-homoerythromycin A new semi-synthetic macrolide antibiotics azalides series, which have antibacterial activity and having the General formula (I)

< / BR>
in which R represents a C1-3alkyl, aryl or aracelio group, and X is O or S, to their pharmaceutically acceptable additive salts with inorganic or organic acids, as well as the way they are received, to a method for producing pharmaceutical compositions, and also to pharmaceutical compositions for the treatment of bacterial infections.

Erythrom the new ring, having a carbonyl group in position C-9 (Antibiot. Chemother., 1952, 2 : 281) and is reliable and efficient antimicrobial agent in the treatment of diseases caused by gram-negative and some gram-positive microorganisms. However, in the acidic environment, it is easily converted into anhydroerythromycin A, inactive C-6/C-12 metabolite spirochaetales patterns (Kurath, P., and others, Experientia, 1971, 27 : 362). It is known that spiritlessly aliceooa ring of erythromycin A was successfully inhibited by chemical transformation of ketones C-9 or hydroxy groups at position C-6 and/or C-12. Aksamitowana ketones C-9 (Djokic S. and others , Tetrahedron Lett 1967, 1945) and later modified received 9 (E)-oxime, 9-[0-(2-methoxyethoxy)-methyloxime] erythromycin A (ROKSITROMICIN) (Ambrieres, G. S., FR 2 473 525/1981) or 9 (S)-erythromycylamine (R. Egan S, etc., J. Org. Chem 1974, 39; 2492) or more complex oxazinone derivative, 9-deoxo-11 decode-9,11{imino[2-(2-methoxyacetanilide] -oxy} -9(S)- erythromycin A (DIRITROMICIN) (R. Lugar and others, J. Crist. Mol. Struct./, 1979; 9 : 329) synthesized new semi-synthetic macrolides, the main characteristic which, in addition to greater stability in the acidic environment is higher pharmacokinetic indicator and measure of the time half-life compared to ishodniki 9 (E)-oxime and restoring the received aminoether (Kobrehel G. and others, U.S. Pat. USA 4 328 334, 56/1982) 11-Aza-10-deoxo-10-dihydroartemisinin A (9 deoxo-9a-Aza-9a - homoerythromycin A) when turning 14-membered katolickiego ring 15-membered azlactone ring. Reductive N-methylation 9a-amino group using the method of Eschweiler-Clark (Kobrehel G. and others, U.S. Pat. BE 892 357, 7/1982) or by pre-protection of the amino group by conversion into the corresponding oxides and then alkylation and recovery (Bright G. M., U.S. Pat. USA 4 474 768, 10/ 1984 synthesized N-methyl-11-Aza-10-deoxo-10-dihydroartemisinin A (9 deoxo-9a-methyl-9a-Aza-9a-homoerythromycin A, AZITROMICIN), which is the closest to salignum antibiotics, which, in addition to widely antimicrobial spectrum of activity, including gram-negative bacteria and intracellular microorganisms, characterized by its specific transfer mechanism used on the site, the duration of the biological half-life and short treatment period. Known (EUR. Pat. application N 0 316 128) new 9a-allyl and 9a-propargyl derivative 9 deoxo-9a-Aza-9a - homoerythromycin A, and (U.S. Pat. USA N 4 492 688) synthesis and antibacterial activity of the corresponding cyclic ethers. In the patent application Croatian 381-03/93-05/041 (559-93-1), in addition, raskryvayutsya-methyl derivatives.

The aim of the present invention is the extension of the range of semi-synthetic macrolide antibiotics azalides series, which can be used in the form of farmakonisi in the treatment of bacterial infections.

This goal is achieved by the new 9a-N - (N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a - homoerythromycin A new semi-synthetic macrolide antibiotic azalides series and their pharmaceutically acceptable additive salts with inorganic or organic acids, which is produced by interaction of 9-deoxo-9a-Aza-9a-homoerythromycin a with isocyanates or isothioscyanates and, optionally, the reaction is obtained 9a-N - (N'-carbamoyl) and 9a-N(N-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin A with inorganic and organic acids.

New 9a-N - (N'-carbamoyl) and 9a-N - (N'-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin A formula (I)

< / BR>
in which R represents a C1-3alkyl, aryl or aracelio group, and X is O or S, and pharmaceutically acceptable additive salts with inorganic or organic acids produced by interaction of 9-deoxo-9a-Aza-9a-gomanee higher values in toluene, xylene or any other aprotic solvent at a temperature of from 20 to 110oC, and isocyanates of General formula (II) in which R represents a phenyl group, 1-naftalina group or unsubstituted or substituted aromatic 5-membered and 6-membered rings having one or two heteroatoms, obtained in situ by rearrangement of kurzius the corresponding acid azide at elevated temperature.

Pharmaceutically acceptable acid additive salts, which are also the object of the present invention, obtained by the interaction of 9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin A with at least equimolar amounts of the corresponding inorganic or organic acid, such as hydrochloric acid, itestosterone acid, sulfuric acid, phosphoric acid, acetic acid, triperoxonane acid, propionic acid, benzoic acid, benzolsulfonat acid, methanesulfonate, laurylsulfate, stearic acid, palmitic acid, succinic acid, Atlanterra acid, lactobionic acid, oxalic acid, salicylic acid and similar acid, in a solvent, filtrowanie after spontaneous deposition or precipitation by addition of non-polar co-solvent.

9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin A formula (I) and their pharmaceutically acceptable additive salts with inorganic or organic acids have antibacterial activity in vitro. The minimum inhibiting concentration (MIC, μg/ml) determined by the method of dilution on microcash in accordance with the recombinations of the National Committee for clinical laboratory standards (NCCLS, M7-A2). From the table it is obvious that the standard strains and tested clinical isolates are sensitive to newly synthesized compounds. Thus, they can be used for disinfection of rooms, surgical instruments and people, and as therapeutic agents for the treatment of infectious diseases in animals, especially mammals and humans, caused by gram-positive bacteria broad spectrum mycoplasmas and common pathogens that are sensitive to the compounds of formula (I). With this purpose, the above compounds and their pharmaceutically acceptable acid additive salts are given orally in conventional doses of 0.2 mg/kg body weight daily until problem injection.

The way to obtain 9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin of the present invention is illustrated by the following Examples, which should not be construed as limiting the scope of invention.

Example 1

9 deoxo-9a-N-(N'-isopropyl-carbarnoyl)-9a-Aza-9a-homoerythromycin A

A mixture of 9-deoxo-9a-Aza-9a-homoerythromycin A (7,27 g; 0.01 mol), isopropylmalate (0,94 g, to 0.011 mol) and toluene (40 ml) is stirred for one hour at a temperature of 30oC. Reactional the mixture is evaporated under reduced pressure (40oC) until dry, forming a crude 9-deoxo-9a-N-(N'-isopropyl-carbarnoyl)-9a-Aza-9a-homoerythromycin A (7.0 g, 86.2 per cent), so pl. 128 - 136oC. Recrystallization of the resulting product from methanol-water mixture get chromatographically homogeneous substance having the following physical-chemical constants:

So pl. 135 ~ 144oC.

TCS, EtAc - (h-C6H6) - NHEt2(100 : 100 : 20), Rf 0,351

CHC3-CH3OH - conc. NH4OH (6 : 1 : 0,1) Rf 0,553

X (KBr) cm-11730, 1625, 1515, 1455, 1380, 1270, 1165, 1050, 950.

1H-NMR (300 MHz, CDCl3) 5,00 (1H, H-13), IS 4.85 (1H, H-1'), 4,47 (1H, H-1'), WAS 4.02 (1H, H-3), 3,91 (1H- (CH3)2), 3,50 (1H, H-5), of 3.43 (1H, H-9a), or 3.28 (3H, 3"-OCH3), 2,49 3H, 8-CH3)

13C NMR (75 MHz, CDCl3) 175,5 (C-1), 158,2 (9a-NCONH), to 103.8 (C-1'), 96,0 (C-1'), 87,9 (C-5), of 78.8 (C-3), and 48.8 (3"-OCH3), AND 45.5 (C-2), 42,2 [-CH(CH3)2] , 39,9 [3'-N(CH3)2], A 27.4 (C-8), 22,9 [-CH(CH3)2], 20,5 (8-CH3), AND 12.2 (10-CH3)

Example 2

9 deoxo-9a-N-{ N'[(4-methyl-5-oxazol)-carbarnoyl)} -9a-Aza-9a - homoerythromycin A

A mixture of 9-deoxo-9a-Aza-9a-homoerythromycin A (4.8 g, 0,0065 mol), azide 4 - methyl-5-oxazol-carboxylic acid (1.0 g, 0,0066 mol) and dry toluene (30 ml) is heated for 15 minutes at boiling temperature and then distilled under reduced pressure (40oC) is evaporated until dry. The obtained residue suspension in acetone (20 ml), stirred at room temperature and then the resulting crystals are filtered, giving 9 deoxo-9a-N-{ N'[(4-methyl-5-oxazol)carbarnoyl)} -9a-Aza-9a - homoerythromycin A (5,4 g, 93,3%): So pl. 174-177oC. Recrystallization from hot acetone receive chromatographically homogeneous product having the following physical-chemical constants: So pl. 181 ~ 183oC.

TLC-analysis - EtAc - (h-C6H6) - NEH2(100 : 100 : 2), Rf 0,149

CHCl3-CH3OH-conc. NH4OH (6 : 1 : 0,1) Rf 0,491

X (KBr) cm-11730, 1680, 1655, 1490, 1460, 1380, 1170, 1050, 755, 660.

1H-NMR (30UB>3), 2,50 (1H, 1H-9b), 2,32 [(6H, 3' - N(CH3)2] , was 2.34 (1H, 1H-8), 2,35 (1H, H-7a), by 1.68 (3H, 10-CH3), of 1.97 (1H, H-7b), of 1.09 (3H, 8-CH3).

13C NMR (75 MHz, Pyd5, 50oC) 177,2 (C-1), 157,2 (9a-NCONH), 104,2 (C-1'), to 96.8 (C-1'), 86,6 (C-5), 80,5 (C-3), 50,1 (3"-OCH3), A 46.5 (C-2), 42,2 (C-4), 41,0 [3-N(CH3)2] , 29,1 (C-8), 21,2 (8-CH3), 14,1 (10-CH3), 149,9, 142,2, 128,2 and 12.2 (4-methyl-5-oxazol).

Example 3

9 deoxo-9a-N-[N'[(2-furyl)-carbarnoyl)]-9a-Aza-9a - homoerythromycin A

Similar to the way, opened in Example 2, from 9 deoxo-9a-Aza-9a-homoerythromycin A (2,18 g of 0.003 mol) azide 2-frankenboob acid (0.5 g, 0,0036 mol) and toluene (15 ml) receive resinous residue (2.1 g), from which chromatographytandem on silikagelevye column using the solvent CHCl3- CH3OH (7:3) receive 9 deoxo-9a-N-[N'-(2-furyl)carbarnoyl]-9a-Aza-9a-homoerythromycin A (1.7 g; 77,0%) having the following physical-chemical constants:

So pl. 155 ~ 159oC

TLC-analysis - EtAc - (h-C6H6) - NHt2(100 : 100 : 20), Rf 0,262,

CHCl3-CH3OH-conc, NH4OH (6 : 1 : 0,1) Rf 0,574

X (CHCl3) cm-11730, 1665, 1520, 1460, 1380, 1270, 1165, 1050, 1000, 955, 900, 830, 730.

1H-NMR (300 MHz, DMSO) 8,51 (9a-N-CONH), 7,24 (-O-CH=), 6,34 (-O-CH= CH-), 6,00 (=CH=C-NH), 5,04 (1H, H-13), of 4.77 (1H, H-1"), 4,47 (1H, H-1'), to 4.01 (1H, H-3), 3,42 (1H, H-5), 3,47 (1H, 3H, 8-CH3).

13C NMR (75 MHz, DMSO) 175,5 (C-1), 155,4 (9a-NCONH), 101,9 (C-1'), to 95.3 (C-1'), 84,4 (C-5), of 78.6 (C-3), and 48.8 (3"-OCH3) AND 44.6 (C-2), 40,0 (C-4), 40,1 [3'-N(CH3)2] , TO 27.7 (C-8), 19,7 (8-CH3), 13,2 (10-CH3), 147,7, 136,5, 118,9, 98,0 (5-turmoil).

Example 4

9 deoxo-9a-N-[N'[(4-pyridyl)-carbarnoyl)]-9a-Aza-9a - homoerythromycin A

Similar to the method described in Example 2 from 9-deoxo-9a-Aza-9a-homoerythromycin A (2,18 g of 0.003 mol), azide isonicotinic acid (0,53 g, 0,0036 mol) and toluene (15 ml) receive resinous residue (of 2.26 g), from which by recrystallization from methanol-water get 9 deoxo-9a-N-[N'[(4-pyridyl)-carbarnoyl)]-9a-Aza-9a - homoerythromycin A (1.9 g; 74,8%), having the following physical-chemical constants:

So pl. 149 ~ 153oC

TLC-analysis - EtAc - (h-C6H6) - NHEt2(100 : 100 : 2), Rf 0,089.

CHCl3-CH3OH-conc. NH4OH (6 : 1 : 0,1) Rf 0,441

X (CHCl3) cm-11730, 1650, 1590, 1510, 1460, 1380, 1330, 1280, 1165, 1050, 1000, 955, 900, 830, 730.

1H-NMR (300 MHz) Pyd5, DMSO) 8,66 (9a-N-CONH), 8,25, 7,35 (4-pyridyl), 5,16 (1H, H-13), 4,89 (1H, H-1"), to 4.52 (1H, H-1), is 4.15 (1H, H-3), 3,53 (1H, H-5), 3,51 (1H, H-9a), to 3.33 (3H, 3"-OCH3), or 3.28 (1H, 1H-9b), 2,34 [6H, 3 - (CH3)2] , 2,28 (1H, H-8), of 1.62 (1H, 1H-7a), 1,23 (1H, H-7b), of 1.36 (3H, 10-CH3), WAS 1.04 (3H, 8-CH3).

13C NMR (75 MHz, DMSO) 176,1 (C-1), 155,5 (9a-N-CONH), 10B>3), 149,8, 148,0, 113,9 (4-pyridyl)

Example 5

9 deoxo-9a-N-(N'-phenyl-carbarnoyl)]-9a-Aza-9a - homoerythromycin A

Similar to the method described in Example 2 from 9-deoxo-9a-Aza-9a-homoerythromycin A (2.0 g, 0,0027 mol), benzoic acid azide (0.5 g, 0,0034 mol) and toluene (15 ml) receive resinous residue (2,43 g), from which chromatographytandem on silikagelevye acid using solvents CH2Cl2- CH3OH (85 : 15) get 9 deoxo-9a-N-(N'-phenyl-carbarnoyl)]-9a-Aza-9a - homoerythromycin A (1.4 g; 61,4%) having the following physical-chemical constants:

So pl. 126 ~ 130oC

TLC-analysis - EtAc - (h-C6H6) - NHE2(100 : 100 : 2), Rf 0,345 CHCl3-CH3OH-conc. NH4OH (6 : 1 : 0,1) Rf 0,637.

X (KBr) cm-11730, 1645, 1600, 1539, 1510, 1455, 1380, 1315, 1240, 1165, 1045, 950, 895, 755, 690.

1H-NMR (300 MHz, DMSO) 8,11 (9a-N-CONH), 7,30, 7,35 (phenyl), of 5.05 (1H, H-13), 4,79 (1H, H-1"), to 4.46 (1H, 1'), Android 4.04 (1H, H-3), of 3.46 (1H, H-5), or 3.28 (1H, H-9a), 3,23 (3H, 3"-OCH3), and 3.16 (1H, H-9b), 2,34 [(6H, 3' - N(CH3)2], of 2.16 (1H, H-8), was 1.58 (1H, H-7a) and 1.15 (1H, H-7b), 1,25 (3H, 10-CH3), OF 0.90 (3H, 8-CH3).

13C NMR (75 MHz, DMSO) covers 175.6 (C-1), 156,1 (9a-N-CONH), 102,0 (C-1'), 95,4 (C-1'), 84,4 (C-5), was 78.5 (C-3), 48,9 (3"-OCH3) AND 44.6 (C-2), TO 39.4 (C-4), 40,1 [3'-N(CH3)2] AND 27.3 (C-8), 20,0 (8-CH3), 14,0 (10-CH3), 140,6, 127,9 and to 114.4 (phenyl).

The example 1 from 9 deoxo-9a-Aza-9a-homoerythromycin A (7,27 g, 0.01 mol), benzenesulfonate (1,33 g, 0.01 mol) and toluene (15 ml) receive resinous residue (8,4 g), from which chromatographytandem on silikagelevye column using the solvent CHCl3- CH3OH (7:3) receive 9 deoxo-9a-N-(N'-benzyl-carbarnoyl)-9a-Aza-9a - homoerythromycin A (6.5 g, 75,6%) having the following physical-chemical constants:

So pl. 142 ~144oC

TLC-analysis - EtAc - (h-C6H6) - NHEt2(100 : 100 : 20), Rf 0,355 CHCl3- CH3OH - conc. NH4OH (6 : 1 : 0,1), Rf 0,621

X (KBR) cm-11730, 1630, 1525, 1410, 1380, 1270, 1165, 1045, 950, 895, 755, 700.

1H-NMR (300 MHz, CDCl3) 7,30, 5,00, AND 4.40 (-CH2-C6H5), 5,04 (1H, H-13), a 4.83 (1H, H-1"), 4,48 (1H, H-1'), 4,00 (1H, H-3), 3,52 (1H, H-5), of 3.48 (1H, H-9a), or 3.28 (3H, 3"-OCH3), of 2.51 (1H, H-9b), 2,56 [6H, 3' - N(CH3)2], was 2.34 (1H, H-8), of 1.66 (1H, H-7a), 1,10 (1H, H-7b), 0,99 (3H, 10-CH3), OF 1.36 (3H, 8-CH3).

13C NMR (75 MHz, CDCl3) 175,7 (C-1), 159,3 (9a-NCONH), to 103.8 (C-1'), 96,5 (C-1'), and 88.8 (C-5), of 78.8 (C-3), 48,9 (3"-OCH3), TO 45.9 (C-2), 40,4 (C-4), 40,2 [3'-N(CH3)2] AND 27.3 (C-8), 20,5 (8-CH3), TO 12.3 (10-CH3), 139,1, 128,3, 127,2 and 126.8, 45,9 - (-CH2- C5H5).

Example 7

9 deoxo-9a-N-(N'-benzyl-thiocarbamoyl)-9a-Aza-9a - homoerythromycin A

Similar to the method described in Example eshiwani the reaction mixture for 8 hours at a temperature of 30oC emit a resinous residue (8.6 g), from which chromatographytandem on a column of silica gel using solvent CHCl3- CH3OH (7:3) receive 9 deoxo-9a-N-(N'-benzyl-thiocarbamoyl)-9a-Aza-9a - homoerythromycin A (7.2 g, 82.1 per cent) having the following physical-chemical constants:

So pl. 119 ~ 122oC

TLC analysis, EtAc - (h-C6H6) - NHEt2(100 : 100 : 20), Rf 0,370 CHCl3- CH3OH - conc. NH4OH (6 : 1 : 0,1), Rf 0,689

X (KBr) cm-11730, 1630, 1525, 1410, 1380, 1270, 1165, 1045, 950, 895, 755, 700.

1H-NMR (300 MHz, CDCl3) OF 7.36, 4,85, 4,72 (-CH2-C6H5), AND 4.75 (1H, H-13), TO 4.87 (1H, H-1"), TO 4.41 (1H, H-1'), 4,10 (1H, H-3), 3,81 (1H, H-11), 3,49 (1H, H-5), 3,30 (3H, 3"-OCH3), 3,03 (1H, H-4"), 2,34 [6H, 3 - N(CH3)2], 2,31 (1H, H-8), of 1.52 (1H, H-7a), of 1.26 (1H, H-7b), is 1.31 (3H, 10-CH3), IS 0.96 (3H, 8-CH3).

Example 8

9 deoxo-9a-N-[N'-(1-naphthyl)-carbarnoyl]-9a-Aza-9a - homoerythromycin A

Similar to the method described in Example 1 from 9-deoxo-9a-Aza-9a-homoerythromycin A (7,27 g, 0.01 mol), 1-naphthylisocyanate (1.7 g, 0.01 mol) and toluene (40 ml) stirring the reaction mixture for 1 hour at a temperature of 20oC emit a resinous residue (9.0 g), from which chromatographytandem on silikagelevye column using the solvent CHCl3
So pl. 134 ~ 137oC

TLC analysis, EtAc - (h-C6H6) - NHE2(100 : 100 : 20), Rf 0,335

CHCl3- CH3OH - conc. NH4OH (6 : 1 : 0,1), Rf 0,658

X (CHCl3) cm-11740, 1635, 1530, 1500, 1455, 1380, 1340, 1265, 1160, 1050, 1010, 960, 890, 795, 775, 735, 700.

Example 9.

Obtain compositions in the form of tablets.

Active ingredient (compound of example 1) 500 mg

The hypromellose 250 mg

Lactose 250 mg

Corn starch - 35 mg

Magnesium stearate 15 mg

The ingredients are thoroughly mixed and pressed into tablets containing 500 mg of active ingredient per tablet.

Tablets obtained by the method commonly used in pharmaceutical technology, can be entered as an antibacterial agent for treatment of various infections in accordance with the present invention.

1. 9a-N-(N'-Carbarnoyl-)- or 9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin And formulas I

< / BR>
in which R represents a C1- C3-alkyl, C6- C10-aryl or C6- C10-aryl C1- C3is an alkyl group, 5 - or 6-membered aromatic ring, imeushego R represents a C1- C3is an alkyl group, and X is O.

3. Connection on p. 2, where C1- C3is an alkyl group is an isopropyl group.

4. Connection on p. 1, in which R represents a C6- C10-aryl group, and X is O.

5. Connection on p. 4, in which C6- C10-aryl group is a phenyl group.

6. Connection on p. 4, in which C6- C10the aryl group is a 1-naftalina group.

7. Connection on p. 1, in which R is 5 - or 6-membered aromatic ring with one or two heteroatoms, selected from nitrogen and oxygen, and X is O.

8. Connection on p. 7, in which 5 - or 6-membered aromatic ring with one or two heteroatoms, selected from nitrogen and oxygen, is a 4-methyl-5-oxazoline group.

9. Connection on p. 7, in which 5 - or 6-membered aromatic ring with one or two heteroatoms selected from oxygen and nitrogen, is follow group.

10. Connection on p. 7, in which 5 - or 6-membered aromatic ring with one or two heteroatoms, selected from nitrogen and oxygen, is a3is an alkyl group, and X is O.

12. Connection on p. 11, in which C6- C10-aryl C1- C3is an alkyl group is a benzyl group.

13. Connection on p. 1, in which R is C6- C10-aryl C1- C3is an alkyl group, and X is sulfur.

14. Connection on p. 13, in which C6- C10-aryl C1- C3is an alkyl group is a benzyl group.

15. 9a-N-(N'-carbarnoyl-)- or 9a-N-(N'-thiocarbamoyl) derived 9 deoxo-9a-Aza-9a-homoerythromycin And PP.1 - 14, which have antibacterial activity.

16. The way to obtain 9a-N-(N'-carbarnoyl-)- or 9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin And formulas I

< / BR>
in which R represents a C1- C3-alkyl, C6- C10-aryl or C6- C10-aryl C1- C3is an alkyl group, 5 - or 6-membered aromatic ring with one or two heteroatoms, selected from nitrogen and oxygen;

X is O or S

and their pharmaceutically acceptable additive salts with inorganic or organic acids, characterized in that 9 deoxo-9a-Aza-9a-homoerythromycin And interacts with socionatural at a temperature of from 20 to 100oWith a compound of General formula II in which R represents a C6- C10-aryl group or 5 - and 6-membered aromatic ring having one or two heteroatoms, selected from nitrogen and oxygen, and X is O or S, receive in situ by rearrangement of kurzius the corresponding acid azide at elevated temperature and optionally subjected to interaction with an inorganic or organic acid to obtain the corresponding additive salts.

17. Pharmaceutical composition having antibacterial activity comprising the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains an antimicrobial-effective amount of the derivative 9 deoxo-9a-Aza-9a-homoerythromycin And p. 1.

 

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The invention relates to new N-substituted [2R, 3R (2'R, 3'R), 6R, 7S, 8S, 9R, 10R]-3-(2',3'-dihydroxyphenyl-2'-yl)-7-[(2,6-dideoxy-3-C-methyl-3-O--L-RIBO-hexopyranosyl)-oxy] -9-[(3,4,6-trideoxy-3-amino-B-D-Xylo-hexopyranosyl)-oxy] -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8,2,1] -tridec-12-EN-5-he-connections with metalinguistically properties, to their salts, the acid products of accession, as well as to pharmaceutical remedies containing these compounds and methods and intermediate products for their production
The invention relates to the pharmaceutical industry, relates to a method of production of inulin from tubers of Jerusalem artichoke (Helianthus tuberosus L.) is a crop
The invention relates to medicine, namely to Oncology, and for the treatment of Kaposi's sarcoma

The invention relates to medicine

The invention relates to the production of drugs used in atherosclerosis

- cyclodextrin with antiherpes activity" target="_blank">

The invention relates to new biologically active compounds, namely the connection include 9-(2-acetoxymethyl)guanine with-cyclodextrin with the content of 9-(2-acetoxymethyl)guanine 10 to 30 wt
The invention relates to medicine, namely to dentistry

The invention relates to carbamate rapamycin, which is a macrocyclic trinovum antibiotic produced by the microorganism Strephemyces hygroscopicus

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

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