9-n-ethenylene derivative 9(s)-erythromycylamine and method of production thereof

 

(57) Abstract:

The invention relates to a new 9-N-ethenylene derivative 9 (S)-erythromycylamine General formula I, where R1and R2the same or different and represent a nitrile group, a carboxyl group of the formula COOR3where R3represents a C1-C4is an alkyl group, or ketogroup formula COR4where R4represents a C1-C4is an alkyl group, or of pharmaceutically acceptable salts of the accession of inorganic or organic acids, as well as the way they are received. The invention may be useful for the preparation of pharmaceutical drugs to combat bacterial infections. 2 C. and 16 h.p. f-crystals, 1 PL.

The invention relates to 9-N-ethenylene derivative 9(S)-erythromycylamine, new semi-synthetic antibiotic of the class of macrolides, have antibacterial properties, the General formula (I):

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where R1and R2the same or different and represent a nitrile group, a carboxyl group of the formula COOR3where R3represents a C1-C4is an alkyl group, or ketogroup formula COR4where R4is with organic acids, the way they are received, to a method for producing pharmaceutical compositions, and using the obtained pharmaceutical compositions in the fight against bacterial infections.

Art

Erythromycin is A macrolide antibiotic whose structure is characterized by a 14-membered macrolactone ring having a carbonyl group at C-9 position. He was discovered McGuire in 1952 (Antibiot. Chemother. , 1952; 2:281), and for 40 years was considered to be a reliable and effective antimicrobial agent for the treatment of diseases caused by gram-positive and some gram-negative microorganisms. However, in the acidic environment, it is easily converted into anhydroerythromycin, inactive metabolite C-6/C-12 spirochaetales patterns (P. Kurath et al., Experientia 1971; 27: 362). It is well known that spiritlessly aliceooa ring of erythromycin A was successfully inhibited by chemical rearrangement of the C-9 ketone or hydroxyl groups at C-6 and/or C-12 position. By oxymorphine C-9 ketone (S. Djokic et al., Tetrahedron Lett., 1967; 1945) and subsequent modification received 9 (E)-oxime, 9-[O-(2-methoxyethoxy)-methyloxime] erythromycin A (ROXITHROMYCIN) (Ambrieres, G. S., FR 2473525 /1981) or 9(S)-erythromycylamine (Egan R. S. et al., J.Org. Chem., 1974; 39:2492) or more complex the product is, . Crist. Mol. Struct., 1979; 9:329) were synthesized new semi-synthetic macrolides, the main characteristic which, in addition to greater stability in the acidic environment, is the best pharmacokinetics and longer biological half-life than erythromycin A as the original antibiotic.

The first successful synthesis of erythromycylamine by catalytic reduction erythromycin-oxime in glacial acetic acid with platinum oxide was carried out by Massey et al. (Tetrahedron Lett, 1970; 157), and, along with the 9(S)-isomer, was obtained also less active 9(R)-isomer (Massey E. H. et al., J. Med. Chem. 1974, 17, 105).

Kobrehel et al. (J. Med. Chem. 1978, 13, 83) synthesized a series of N-substituted benzazolilformazanatov. By processing erythromycylamine ethylene carbonate resulting after preliminary protection 9(S)-amino (Boyarska-Dahlig H. Et al., Pol. J. Chem., 1979, 53, 2551; Sciavolino F. C., U.S. patent N 4283527/ 1982) were obtained 11,12-cyclic carbonate. Through the synthesis of erythromycylamine (LeMahieu, R. A et al., J. Antib., 1982, 35, 10631) were obtained derivatives erythromycylamine without any whatsoever antibiotic activity. Most studies of erythromycylamine included the reaction of erythromycylamine with aldehydes and ketones in chega 4048306 /1977). By restoring the condensation product with NaBH4were established 9-N-alkyl-or 9-N-benzyl derivatives (E. Wildsmith et al., J. Med. Chem., 1973; 16; 1059), and 9-N, 11-O-oxazin-derivatives that are beyond repair, were the exception.

In 1989, were obtained photosensitive derivative of erythromycylamine by joining erythromycylamine photoreactive groups (Arevalo M. A. et al., J. Med. Chem. 1989, 32, 2200). In addition, also received a number of Schiff bases derived erythromycylamine (Aries R., patent application FR 2311029-1976; Ewans D., the United Kingdom patent 1345524/1974; Werner R. G. et al., Biochem. Biophys. Res. Commun. 1978, 83, 1147).

In accordance with known and established data prior art in this field, still no description 9-N-ethynyl-derivatives of 9-(S)-erythromycylamine and their pharmaceutically acceptable salts accession inorganic or organic acids, method of production thereof, and methods of preparation and use as pharmaceuticals.

Installed, and it is an object of the present invention, which is 9-N-ethynyl-derivatives of 9-(S)-erythromycylamine and their pharmaceutically acceptable salts accession inorganic or is advised of ethoxymethylene and if this is acceptable, through the interaction of the obtained derivatives of 9-N - Attila with inorganic or organic acids.

Detailed description of the invention

Found that 9-N-ethenylene derivatives of 9-(S)-erythromycylamine General formula (I):

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where R1and R2are the same or different and represent nitrile, carboxyl group of the formula COOR3where R3represents a C1-C4is an alkyl group or ketogroup formula COR4where R4represents a C1-C4is an alkyl group, and their pharmaceutically acceptable salts accession inorganic or organic acids can be obtained by reacting 9-(S)-erythromycylamine formula (II);

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derivative of amoxicilina General formula (III)

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where R1and R2the same or different and represent nitrile, carboxyl group of the formula COOR3where R3represents a C1-C4is an alkyl group, or ketogroup formula COR4where R4represents a C1-C4is an alkyl group. The reaction is carried out in toluene, xylene or some other aromatic solvents at a temperature of the om present invention, get through interaction of 9-N-atenilol derivative 9-(S)-erythromycylamine with equimolar amount of a suitable inorganic or organic acid, such as hydrochloric acid, itestosterone acid, sulfuric acid, phosphoric acid, acetic acid, triperoxonane acid, propionic acid, benzoic acid, benzosulfimide, methansulfonate, laurylsulfate, stearic acid, palmitic acid, succinic acid, ethyl-succinic acid, lactobionic acid, oxalic acid, salicylic acid and the like acid, in a solvent inert to the reaction.

Compounds of General formula (I), where R1, R2, R3and R4having values as defined here above, demonstrate in vitro antibacterial action, and the range of their action is similar to that of erythromycin. Thus, they can be used for the same purpose and by the same procedure as erythromycin A.

Their action is determined by the dilution on microplastics in accordance with the Protocol of the National Committee for Clinical laboratory standards (NCCLS, M7 - A2). The results, expressed as MIC (MIC) the minimum ingibirujut the example rooms and medical instruments, and industrial microbial agents, for example, to protect the walls and wood coatings.

The way to obtain 9-N-ethenylene derivatives of 9-(S)-erythromycylamine is illustrated by the following examples, which in no way limit the scope of the present invention.

Example 1

9 (S)-N-(,-dicarbocyanine)erythromycylamine

A mixture of 9(S)-erythromycylamine (1.0 g; of 1.36 mmol) and diethylethoxymethylenemalonate (3.2 ml; 16.0 mmol) was heated under reflux for 90 minutes. In the reaction mixture is cooled to a temperature of 0 to 5oC, was added a simple diethyl ether (14 ml) and the resulting suspension was stirred for 15 minutes at the same temperature and for 15 minutes at room temperature. Was obtained to 0.480 g of 9(S)-N-(,-dicarbocyanine) erythromycylamine.

A sample for analysis and biological research was purified by chromatography on a column of silica gel in the solvent system CHCl3:MeOH = 9: 1, with a yield of 0.27 g of 9 (S)-N-(,-dicarbocyanine)erythromycylamine with the following physical-chemical constants:

IR (CHCl3) cm-1: 3500, 2950, 1725, 1670, 1600, 1450, 1380, 1250, 1225, 1170, 1080;

1H NMR (300 MHz, CDCl3)CH3)2], 2.26 (1H, H-10), 1.96 (1H, H-8), 1.32 and 1.28 , 1.16 (3H, 8-CH3), 1.06 (3H, 10-CH3);

13C NMR (75 MHz, CDCl3) : 177.7 (C-1), 168.7 , 166.7 , 160.2 , 132.2 (9-NH-CH=C), 102.2 (C-1'), 95.7 (C-1'), 81.5 (C-5), 79.4 (C-3), 59.2 , 59.1 , 77.3 (C-4"), 70.5 (C-2'), 74.7 (C-9), 48.9 (3"-OCH3), 40.0 [3'-N(CH3)2], 32.3 (C-10), 32.3 (C-8), 18.3 (8-CH3), 14.1 , 13.9 , 13.0 (10-CH3);

FAB-MS m/z 906 (M+H)+< / BR>
Example 2

9(S)-N-(a-cyano--carbetocin)erythromycylamine

A mixture of 9(S)-erythromycylamine (0.5 g; of 0.68 mmol) and atlatonementaustin (0.2 g; 1.18 mmol) in toluene (20 ml) was heated under reflux for 60 minutes. The reaction mixture is then quickly cooled and evaporated to dryness. The obtained yellow crystals of the crude product (0.5 g) was purified by chromatography on a column of silica gel in the solvent system EtOAc: Me2CO = 1: 1, with a yield of 0.14 g of 9(S)-N-(a-cyano--carbetocin) erythromycylamine with the following physical-chemical constants:

IR (CHCl3) cm-1: 3500, 2950, 2200, 1730, 1675, 1625, 1450, 1380, 1250, 1225, 1170, 1080;

1H NMR (300 MHz, CDCl3) : 9.46 , 7.05 , 5.07 (1H, H-1"), 4.61 (1H, H-1'), 4.22 (1H, H-3), 4.19 , 3.76 (1H, H-5), 3.34 (3H, 3"-OCH3), 3.25 (1H, H-2'), 2.29 [6H, 3'-N (CH3)2], 2.20 (1H, H-10), 1.96 (1H, H-8), 1.31 , 1.14 (3H, 8-CH3), 1.05 (3H, 10-CH3);

13C NMR (75 MHz, CDCl3) : 177.5 (C-1), 167.6 , 159.1 (9-NH-CH= C), 119.4 32.1 (C-10), 32.7 (C-8), 18.4 (8-CH3), 14.2 , 13.2 (10-CH3);

FAB-MS m/z 858 (M+H)+.

Example 3

9(S)-N-(,-diacetylactis)erythromycylamine

In accordance with the procedure described in example 2, by reaction of 9(S)-erythromycylamine (0.5 g; of 0.68 mmol) and ethoxymethylenemalonic (1.0 ml; to 6.88 mmol) in toluene (20 ml) by heating for 90 minutes at 50oC was obtained 0.54 g of the crude product. By chromatography on a column of silica gel in the solvent system EtOAc:Me2CO = 1:1, was obtained 0.21 g of 9(S)-N-(,-diacetylactis) erythromycylamine with the following physical-chemical constants:

IR (CHCl3) cm-1: 3500, 2950, 1725, 1610, 1550, 1450, 1375, 1320, 1170, 1080;

1H NMR (300 MHz, CDCl3) : AT 10.89 , 5.14 (1H, H-1"), 4.71 (1H, H-1'), 3.84 (1H, H-3), 3.70 (1H, H-5), 3.35 (3H, 3"-OCH3), 3.30 (1H, H-2'), 2.31 [6H, 3'-N (CH3)2] , 2.21 (1H, H-10), 1.99 (1H, H-8), 1.96 , 1.87 (3H,-COCH3), 1.20 , 1.06 (3H, 10-CH3);

13C NMR (75 MHz, CDCl3) : 193.4 , 176.8 (C-1), 163.1 , 101.9 (C-1'), 95.2 (C-1'), 79.1 (C-5), 78.2 (C-3), 77.6 (C-4"), 70.7 (C-2'), 65.5 (C-9), 48.9 (3"-OCH3), 40.0 [3'-N(CH3)2], 32.9 (C-10), 33.4 (C-8), 28.2 , 19.1 , 18.3 (8-CH3), 12.5 (10-CH3).

Example 4

9(S)-N-(,-dicyanobutane)erythromycylamine

A mixture of 9(S)-erythromycylamine (0.5 g; of 0.68 mmol) and ethoxymethylenemalononitrile (0.18 g; 1,47 mmol) in t and the obtained yellow crystals (0.65 g) was purified by chromatography on a column of silica gel in the solvent system CHCl3:MeOH = 9:1, with a yield of 0.26 g of 9(S)-N-(,-dicyanobutane)erythromycylamine with the following physical-chemical constants:

IR (CHCl3) cm-1: 3500, 2950, 2200, 1725, 1625, 1550, 1450, 1375, 1320, 1175, 1050, 750;

1H NMR (300 MHz, CDCl3) : 8.22 , 7.13 , 5.04 (1H, H-1"), 4.59 (1H, H-1'), 3.82 (1H, H-3), 3.68 (1H, H-5), 3.29 (3H, 3"-OCH3), 3.23 (1H, H-2'), 2.31 [6H, 3'-N (CH3)2], 2.22 (1H, H-10), 1.94 (1H, H-8), 1.13 (3H, 8-CH3), 1.05 (3H, 10-CH3);

13C NMR (75 MHz, CDCl3) : 177.1 (C-1), 160.4 , 132.2 , 116.1 (-CN), 114.6 (-CN), 101.6 (C-1'), 95.4 (C - 1'), 80.8 (C-5), 78.9 (C-3), 77.3 (C-4"), 70.5 (C-2'), 74.4 (C-9), 49.0 (3"-OCH3), 40.0 [3'-N(CH3)2], 31.8 (C-10), 32.5 (C-8), 18.9 (8-CH3), 13.6 (10-CH3).

FAB-MS m/z 811.5 (M+H)+.

Example 5

9(S)-N-acetyl--carbetocin)erythromycylamine

In accordance with the procedure described in example 4, via reaction 9(S)-erythromycylamine (0.5 g; of 0.68 mmol) and ethyl -(ethoxymethylene)acetoacetate (1.0 ml; 5,77 mmol) in toluene (20 ml) was received of 0.54 g of sediment in the form of a resin. By chromatography on a column of silica gel in the solvent system CHCl3: MeOH = 9:1, got to 0.29 g of 9(S)-N-acetyl--carbetocin)erythromycylamine with the following physical-chemical constants:

IR (CHCl3) cm-1: 3500, 2950, 1725, 1680, 1640, 1570, 1450, 1380, 1250, 1170, 1080;

1H NMR (300 MHz, CDCl3) : 12], 2.22 (1H, H-10), 1.94 (1H, H-8), 1.27 , 1.15 (3H, 8-CH3), 1.04 (3H, 10-CH3);

13C NMR (75 MHz, CDCl3) : 198.5 , 177.1 (C-1), 167.7 , 159.8 , 132.2 , 101.7 (C-1'), 95.3 (C-1'), 80.9 (C-5), 78.8 (C-3), 58.9 , 77.4 (C-4"), 70.5 (C-2'), 75.1 (C-9), 48.8 (3"-OCH3), 39.9 [3'-N (CH3)2], 32.1 (C-10), 33.2 (C-8), 30.4 (-COCH3), 18.1 (8-CH3), 14.0 , 12.9 (10-CH3);

FAB-MS m/z 875.2 (M+H)+.

1. 9-N-Ethenylene derivative 9(S)-erythromycylamine General formula I

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where R1and R2the same or different and represent a nitrile group, a carboxyl group of the formula R3where R3represents a C1- C4alkyl group, or ketogroup formula R4where R4represents a C1- C4alkyl group,

or their pharmaceutically acceptable salts accession inorganic or organic acids.

2. Connection on p. 1, wherein R1and R2the same or different and are a carboxyl group of the formula R3.

3. Connection on p. 2, wherein R3represents a C1- C4alkyl group.

4. Connection on p. 3, characterized in that WITH1- C4an alkyl group is an ethyl group, the other is a carboxyl group of the formula R3.

6. Connection on p. 5, wherein R3represents a C1- C4alkyl group.

7. Connection on p. 6, characterized in that WITH1- C4an alkyl group is an ethyl group.

8. Connection on p. 1, wherein R1and R2are the same and represent ketogroup formula R4.

9. Connection on p. 8, wherein R4represents a C1- C4alkyl group.

10. Connection on p. 9, characterized in that WITH1- C4the alkyl group is a methyl group.

11. Connection on p. 1, wherein R1and R2the same and represent nitrile.

12. Connection on p. 1, wherein one of R1and R2represents a carboxyl group of the formula R3and the other is ketogroup formula R4.

13. Connection on p. 12, wherein R3represents a C1- C4alkyl group.

14. Connection on p. 13, characterized in that WITH1- CF>4represents a C1- C4alkyl group.

16. Connection on p. 15, characterized in that WITH1- C4the alkyl group is a methyl group.

17. The way to obtain 9-N-ethenylene derivatives 9(S)-erythromycylamine General formula I

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where R1and R2the same or different and represent a nitrile group, a carboxyl group of the formula R3where R3represents a C1- C4alkyl group, or ketogroup formula R4where R4represents a C1- C4alkyl group,

their pharmaceutically acceptable salts accession inorganic or organic acids, characterized in that the 9(S)-erythromycylamine General formula II

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subjected to interaction with derivatives amoxicilina General formula III

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where R1and R2the same or different and represent nitrile, carboxyl group of the formula R3where R3represents a C1- C4alkyl group, or ketogroup formula R4where R4represents a C1- C4alkyl group,

in toluene, xylene or other aromatic solvent is a mini acids.

18. The compound according to any one of paragraphs.1 - 16, useful for the preparation of pharmaceutical drugs to combat bacterial infections.

 

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