Erythromycin A derivatives

An erythromycin A derivative represented by the formula: ##STR1## wherein n is an integer of from 1 to 8, R.sup.1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R.sup.2 is a pyridylmethyl group, a quinolylmethyl group, a pyridylsulfonyl group or quinolylsulfonyl group, R.sup.3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cinnamyl group, R.sup.4 is a cladinosyloxy group or a group represented by the formula: ##STR2## wherein m is 0 or 1, R.sub.5 is a pyridyl group, a quinolyl group, a phenyl group, a phenyl group substituted with one, two or three members selected from alkyl groups having 1 to 6 carbon atoms, a nitro group, alkoxy groups having 1 to 3 carbon atoms and halogen atoms, or a pyridyl or quinolyl group substituted with one or two members selected from alkyl groups having 1 to 6 carbon atoms, a nitro group, alkoxy groups having 1 to 3 carbon atoms and halogen atoms; or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD 
 The present invention relates to novel derivatives of antibiotic 
 erythromycin A. 
 BACKGROUND ART 
 Erythromycin A is an antibiotic widely used as an agent for the treatment 
 of infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc.
 However, erythromycin A is decomposed by gastric acid due to its 
 instability to acids, and thus has a drawback of no constancy of movement 
 in the body. Hitherto many erythromycin derivatives have been prepared for
 the purpose of the improvement of such biological or pharmaceutically 
 effective properties. For example, it is reported that 
 6-O-methylerythromycin A derivatives have an improved stability to acids 
 and have a superior in vivo antibacterial activity in comparison with 
 erythromycin A when administered orally (U.S. Pat. No. 4,331,803). There 
 are also recent reports relating to 11,12-cyclic carbamate derivatives 
 obtained from 6-O-methylerythromycin A as a starting material with the aim
 of expansion of antibacterial spectrum as well as a stability to acids 
 (EP. Patent No. 487411, U.S. Pat. No. 4,742,049). In addition, the present
 inventors have reported the antibacterial activity of the ester 
 derivatives esterified at the 3-position (EP. Patent No. 619320). 
 An object of the present invention is to provide post-generational 
 macrolide antibiotics having a strong antibacterial activity not only 
 against previous erythromycin-sensitive bacteria but also against 
 erythromycin-resistant bacteria which recently show a tendency to 
 increase. 
 DISCLOSURE OF THE INVENTION 
 The present inventors have found that the compounds wherein a certain 
 substituted aminoalkyl group or a certain alkyl group having an 
 arylsulfonamide group has been introduced into the hydroxyl group formed 
 by the reduction of the carbonyl group at the 9-position of erythromycin A
 have a strong antibacterial activity not only against sensitive bacteria 
 but also resistant bacteria, thereby the present invention has been 
 accomplished. 
 The present invention relates to an erythromycin A derivative represented 
 by the formula: 
 ##STR3## 
 wherein n is an integer of from 1 to 8, R.sup.1 is a hydrogen atom or an 
 alkyl group having 1 to 6 carbon atoms, R.sup.2 is a pyridylmethyl group, 
 a quinolylmethyl group, a pyridylsulfonyl group or a quinolylsulfonyl 
 group, R.sup.3 is a hydrogen atom, an alkyl group having 1 to 6 carbon 
 atoms or a cinnamyl group, R.sup.4 is a cladinosyloxy group or a group 
 represented by the formula: 
 ##STR4## 
 wherein m is 0 or 1, R.sup.5 is a pyridyl group, a quinolyl group, a phenyl
 group, a phenyl group substituted with one, two or three members selected 
 from alkyl groups having 1 to 6 carbon atoms, a nitro group, alkoxy groups
 having 1 to 3 carbon atoms and halogen atoms, or a pyridyl or quinolyl 
 group substituted with one or two members selected from alkyl groups 
 having 1 to 6 carbon atoms, a nitro group, alkoxy groups having 1 to 3 
 carbon atoms and halogen atoms; or a pharmaceutically acceptable salt 
 thereof. 
 In the present invention, examples of the alkyl group having 1 to 6 carbon 
 atoms are a methyl group, an ethyl group, a propyl group, a butyl group, a
 pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a 
 t-butyl group, an isopentyl group and a cyclohexyl group; examples of the 
 alkoxy group having 1 to 3 carbon atoms are a methoxy group, an ethoxy 
 group, a propoxy group and an isopropoxy group; and the halogen atom 
 refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine 
 atom. 
 The pharmaceutically acceptable salt refers to a salt used in chemotherapy 
 or prophylaxis of bacterially infectious diseases. It includes, for 
 example, a salt with an acid such as acetic acid, propionic acid, butyric 
 acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, 
 citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic 
 acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic 
 acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic 
 acid, p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic 
 acid, glutaminic acid, adipic acid, cysteine, N-acetylcysteine, 
 hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, 
 hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic 
 acid, undecanoic acid, polyacrylate or carboxyvinyl polymer. 
 The compounds of the present invention can be prepared according to the 
 bellow-mentioned examples. 
 The erythromycin A derivatives of the present invention can be administered
 orally or parenterally. They can be administered in a dosage form such as 
 tablets, capsules, powders, troches, ointments, suspensions, suppositories
 or injectional preparations, all of which can be prepared by ordinary 
 preparation techniques. The dose is from 100 to 1,000 mg per day for the 
 treatment of adults, and it can be administered once or in several divided
 portions. This dose can be properly increased or decreased depending on 
 the age, body weight and conditions of the patient. 
 BEST MODE FOR CARRYING OUT THE INVENTION 
 The present invention is illustrated in more detail by the following 
 examples and experiment.

EXAMPLE 1 
 9-Deoxo-9-hydroxy-9-O-[2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl]erythromy
 cin A 
 (1) In 100 ml of tetrahydrofuran was dissolved 2.2 g (3.0 mmol) of 
 2'-O-acetyl-9-deoxo-9-hydroxyerythromycin A synthesized by the method 
 described in the literature (J. Org. Chem., 47, 5019 (1982)), and then 1.8
 g (8.8 mmol) of 2-bromoethylamine hydrochloride and 1.6 g (28.5 mmol) of 
 potassium hydroxide were added, followed by stirring overnight. The 
 reaction solution was diluted with ethyl acetate, washed with water and a 
 saturated aqueous sodium chloride solution successively, and dried over 
 anhydrous magnesium sulfate. The solvent was evaporated under reduced 
 pressure, and the resulting residue was purified by silica gel column 
 chromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) to give 0.8 
 g (yield: 34%) of 
 2'-O-acetyl-9-deoxo-9-hydroxy-9-O-(2-aminoethyl)erythromycin A. 
 (2) In 10 ml of methylene chloride was dissolved 1.3 g (1.6 mmol) of the 
 compound obtained in the above (1), and then 0.18 g (1.7 mmol) of 
 nicotinaldehyde and 0.64 g (3.0 mmol) of sodium triacetoxyborohydride were
 added, followed by stirring for an hour. Then, 0.25 ml (3.0 mmol) of 37% 
 aqueous formaldehyde solution and 0.32 g (1.5 mmol) of sodium 
 triacetoxyborohydride were added, followed by stirring for an hour. The 
 reaction solution was diluted with chloroform, washed with an aqueous 
 sodium hydroxide solution and a saturated aqueous sodium chloride solution
 successively, and the organic layer was dried over anhydrous magnesium 
 sulfate. The solvent was evaporated under reduced pressure, and the 
 resulting residue was purified by silica gel column chromatography 
 (acetone:hexane:triethylamine=10:10:0.2) to give 0.70 g (yield: 48%) of 
 2'-O-acetyl-9-deoxo-9-hydroxy-9-O-[2-[N-methyl-N-(3-pyridylmethyl)amino]et
 hyl]erythromycin A. 
 (3) In 10 ml of methanol was dissolved 0.68 g (0.74 mmol) of the compound 
 obtained in the above (2), followed by reflux under heating for 5 hours. 
 The solvent was evaporated under reduced pressure to give 0.64 g (yield: 
 99%) of the title compound. 
 IonSprayMS: m/z=884.7 (M+H).sup.+ 
 .sup.1 H-NMR (500 MHz, CDCl.sub.3) .delta.(ppm): 0.91 (t, 3H, J=7.5 Hz, 
 H-15), 2.17 (s, 3H, NCH.sub.3), 2.29 (s, 6H, 3'-N(CH.sub.3).sub.2), 4.57 
 (d, 1H, J=7.3 Hz, H-1'), 4.99 (d, 1H, J=3.5 Hz, H-1"), 5.11 (dd, 1H, 
 J=9.5, 3.4 Hz, H-13) 
 .sup.13 C-NMR (125 MHz, CDCl.sub.3) .delta.(ppm): 91.8 (C-9), 95.2 (C-1"), 
 102.2 (C-1'), 176.8 (C-1) 
 EXAMPLE 2 
 9-Deoxo-5-O-desosaminyl-9-hydroxy-9-O-[2-[N-methyl-N-(3-pyridylmethyl)amino
 ]ethyl]-3-O-(2-pyridyl)acetylerythronolide A 
 (1) In 1 N hydrochloric acid was dissolved 0.50 g (0.57 mmol) of the 
 compound obtained in Example 1(3), followed by stirring for 2 hours. The 
 reaction solution was neutralized with an aqueous sodium hydroxide 
 solution and separated by addition of ethyl acetate. The organic layer was
 washed with a saturated aqueous sodium chloride solution and dried over 
 anhydrous magnesium sulfate. The solvent was evaporated under reduced 
 pressure, and purification of the residue by silica gel column 
 chromatography gave 0.41 g of the decladinosyl compound quantitatively. 
 (2) In 5 ml of acetone was dissolved 0.40 g (0.61 mmol) of the compound 
 obtained in the above (1), and then 0.1 ml (1.1 mmol) of acetic anhydride 
 was added, followed by stirring overnight. After evaporation of the 
 solvent under reduced pressure, the residue was dissolved in ethyl acetate
 and washed with a saturated aqueous sodium bicarbonate solution and a 
 saturated aqueous sodium chloride solution successively, and the organic 
 layer was dried over anhydrous magnesium sulfate. The solvent was 
 evaporated under reduced pressure to give 0.41 g (yield: 91%) of the 
 2'-O-acetyl compound. 
 (3) In 3 ml of methylene chloride was dissolved 0.20 g (0.27 mmol) of the 
 compound obtained in the above (2), and then 0.31 g (1.6 mmol) of 
 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.28 g (1.6 
 mmol) of 2-pyridylacetic acid hydrochloride and 0.066 g (0.54 mmol) of 
 4-dimethylaminopyridine were added, followed by stirring overnight. The 
 reaction solution was diluted with chloroform and separated by addition of
 an aqueous sodium hydroxide solution. The organic layer was washed with a 
 saturated aqueous sodium chloride solution and dried over anhydrous sodium
 sulfate. The solvent was evaporated under reduced pressure, and the 
 resulting residue was dissolved in 30 ml of methanol and refluxed under 
 heating for 3 hours. After evaporation of the solvent under reduced 
 pressure, the resulting residue was purified by silica gel column 
 chromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) to give 0.11
 g (yield: 48%) of the title compound. 
 FABMS (3-NBA): m/z=845 (M+H).sup.+ 
 .sup.1 H-NMR (500 MHz, CDCl.sub.3) .delta.(ppm): 0.85 (t, 3H, J=7.5 Hz, 
 H-15), 2.20 (s, 3H, NCH.sub.3), 2.29 (s, 6H, 3'-N(CH.sub.3).sub.2), 4.15 
 (d, 1H, J=7.0 Hz, H-1'), 5.29-5.32 (m, 2H, H-3 and H-13) 
 .sup.13 C-NMR (125 MHz, CDCl.sub.3) .delta.(ppm): 92.1 (C-9), 103.5 (C-1'),
 170.2 (3-OCOR), 173.8 (C-1) 
 EXAMPLE 3 
 9-Deoxo-9-hydroxy-9-O-[2-[N-(4-quinolylmethyl)amino]ethyl]erythromycin A 
 (1) In 100 ml of methanol was dissolved 5.1 g (6.2 mmol) of the compound 
 obtained in Example 1(1), followed by reflux under heating for 5 hours. 
 The solvent was evaporated under reduced pressure to give 4.8 g (yield: 
 48%) of 9-deoxo-9-hydroxy-9-O-(2-aminoethyl)erythromycin A. 
 (2) In 15 ml of methylene chloride was dissolved 2.0 g (2.6 mmol) of the 
 compound obtained in the above (1), and then 0.44 g (2.8 mmol) of 
 4-quinolinecarboxyaldehyde and 1.1 g (5.2 mmol) of sodium 
 triacetoxyborohydride were added, followed by stirring overnight. The 
 reaction solution was diluted with chloroform, washed with water and a 
 saturated aqueous sodium chloride solution successively, and dried over 
 anhydrous magnesium sulfate. After evaporation of the solvent under 
 reduced pressure, the resulting residue was purified by silica gel column 
 chromatography (chloroform:methanol:aqueous ammonia=15:1:0.1) to give 1.9 
 g (yield: 80%) of the title compound. 
 IonSprayMS m/z=920.5 (M+H).sup.+ 
 .sup.1 H-NMR (500 MHz, CDCl.sub.3) .delta.(ppm): 0.90 (t, 3H, J=7.5 Hz, 
 H-15), 2.29 (s, 6H, 3'-N (CH.sub.3).sub.2), 4.53 (d, 1H, J=7.3 Hz, H-1'), 
 4.93 (d, 1H, J=4.6 Hz, H-1"), 5.03 (dd, 1H, J=9.5, 3.0 Hz, H-13) 
 .sup.13 C-NMR (125 MHz, CDCl.sub.3) .delta.(ppm): 91.3 (C-9), 95.3 (C-1"), 
 102.3 (C-1'), 176.8 (C-1) 
 EXAMPLE 4 
 9-Deoxo-9-hydroxy-9-O-[2-[N-methyl-N-(4-quinolylmethyl)amino]ethyl]erythrom
 ycin A 
 In 5 ml of methylene chloride was dissolved 0.50 g (0.54 mmol) of the 
 compound obtained in Example 3(2), and then 0.1 ml (1.2 mmol) of 37% 
 aqueous formaldehyde solution and 0.23 g (1.1 mmol) of sodium 
 triacetoxyborohydride were added, followed by stirring 3 hours. The 
 reaction solution was diluted with chloroform and washed with an aqueous 
 sodium hydroxide solution and a saturated aqueous sodium chloride solution
 successively, and the organic layer was dried over anhydrous magnesium 
 sulfate. The solvent was evaporated under reduced pressure, and the 
 resulting residue was purified by silica gel column chromatography 
 (chloroform:methanol:aqueous ammonia=15:1:0.1) to give 0.45 g (yield: 89%)
 of the title compound. 
 SIMS m/z=934 (M+H).sup.+ 
 .sup.1 H-NMR (300 MHz, CDCl.sub.3) .delta.(ppm): 0.93 (t, 3H, J=7.4 Hz, 
 H-15), 2.29 (s, 6H, 3'-N(CH.sub.3).sub.2), 2.30 (s, 3H, NCH.sub.3), 4.57 
 (d, 1H, J=7.3 Hz, H-1'), 4.92 (d, 1H, J=4.3 Hz, H-1"), 5.07 (dd, 1H, 
 J=9.0, 3.7 Hz, H-13), 7.54-7.61 (m, 2H, quinolyl), 7.70 (m, 1H, quinolyl),
 8.11 (m, 1H, quinolyl), 8.17 (m, 1H, quinolyl), 8.93 (d, 1H, J=4.4 Hz, 
 quinolyl) 
 EXAMPLE 5 
 9-Deoxo-5-O-desosaminyl-9-hydroxy-9-O-[2-[N-methyl-N-(3-quinolylmethyl)amin
 o]ethyl]-3-O-(2-pyridyl)acetylerythronolide A 
 Repeating the same procedures as in Example 2(1), (2) and (3) with 0.45 g 
 (0.48 mmol) of the compound obtained in Example 4 gave 0.19 g (yield: 45%)
 of the title compound. 
 IonSprayMS m/z=895.5 (M+H).sup.+ 
 .sup.1 H-NMR (500 MHz, CDCl.sub.3) .delta.(ppm): 0.85 (t, 3H, J=7.5 Hz, 
 H-15), 2.29 (s, 6H, 3'-N(CH.sub.3).sub.2), 2.31 (s, 3H, NCH.sub.3), 4.17 
 (d, 1H, J=7.3 Hz, H-1'), 5.26 (dd, 1H, J=11.0, 2.5 Hz, H-13), 5.36 (d, 1H,
 J=11.6 Hz, H-3) 
 .sup.13 C-NMR (125 MHz, CDCl.sub.3) .delta.(ppm): 92.6 (C-9), 103.6 (C-1'),
 170.3 (3-OCOR), 174.1 (C-1) 
 EXAMPLE 6 
 9-Deoxo-9-hydroxy-9-O-[2-(quinoline-8-sulfonylamino)ethyl]erythromycin A 
 In 5 ml of methylene chloride and 5 ml of pyridine was dissolved 0.52 g 
 (0.67 mmol) of the compound obtained in Example 3(2), and then 0.69 g (3.0
 mmol) of quinoline-8-sulfonylchloride was added, followed by stirring 
 overnight. The reaction solution was diluted with chloroform and separated
 with an aqueous sodium hydroxide solution, and the organic layer was dried
 over anhydrous magnesium sulfate. The solvent was evaporated under reduced
 pressure, and the resulting residue was purified by silica gel column 
 chromatography (chloroform:methanol:aqueous ammonia=10:1:0.1) to give 0.57
 g (yield: 92%) of the title compound. 
 IonSprayMS m/z=970.5 (M+H).sup.+ 
 .sup.1 H-NMR (500 MHz, CDCl.sub.3) .delta.(ppm) : 0.93 (t, 3H, J=7.5 Hz, 
 H-15), 2.29 (s, 6H, 3'-N(CH.sub.3).sub.2, 4.62 (d, 1H, J=7.3 Hz, H-1'), 
 4.89 (dd, 1H, J=11.0, 2.5 Hz, H-13), 5.04 (d, 1H, J=4.2 Hz, H-1"), 6.82 
 (t, 1H, J=4.3 Hz, NH) 
 .sup.13 C-NMR (125 MHz, CDCl.sub.3) .delta.(ppm) : 93.1 (C-9), 94.9 (C-1"),
 101.9 (C-1'), 177.0 (C-1) 
 EXAMPLE 7 
 9-Deoxo-9-hydroxy-5-O-desosaminyl-3-O-(2-pyridyl)acetyl-9-O-[2-(quinoline-8
 -sulfonylamino)-ethyl]erythronolide A 
 Repeating the same procedures as in Example 2(1), (2) and (3) with 0.51 g 
 (0.53 mmol) of the compound obtained in Example 6 gave 0.34 g (yield: 69%)
 of the title compound. 
 IonSprayMS m/z=931.5 (M+H).sup.+ 
 .sup.1 H-NMR (500 MHz, CDCl.sub.3) .delta.(ppm): 0.87 (t, 3H, J=7.3 Hz, 
 H-15), 2.29 (s, 6H, 3'-N(CH.sub.3).sub.2), 4.22 (d, 1H, J=7.3 Hz, H-1'), 
 5.07 (dd, 1H, J=10.4, 2.4 Hz, H-13), 5.35 (d, 1H, J=9.8 Hz, H-3), 6.91 
 (br, 1H, N-H) 
 .sup.13 C-NMR (125 MHz, CDCl.sub.3) .delta.(ppm): 93.3 (C-9), 103.7 (C-1'),
 170.6 (3-OCOR), 174.5 (C-1) 
 EXPERIMENT 1 
 The in vitro antibacterial activity of the compound obtained in Example 5, 
 representative of the compounds according to the present invention, 
 against various experimental bacteria was measured using sensitive disc 
 media (produced by Eiken Chemical Co.) according to the MIC measuring 
 method specified by the Japan Society of Chemotherapy. The results are 
 expressed as MIC value (Minimum Inhibitory Concentration against 
 microorganism, .mu.g/ml), and shown in Table 1. 
 TABLE 1 
 In Vitro Antibacterial Activity (.mu.g/ml) 
 Compound 
 Microorganism Example 5 
 S. aureus 209-JC 3.13 
 S. aureus Smith 6.25 
 S. epidermidis IID866 3.13 
 E. faecalis CSJ1212 1.56 
 S. pneumoniae BM225 50 
 S. pneumoniae BM205 100 
 INDUSTRIAL APPLICABILITY 
 The compounds of the present invention have an antibacterial activity not 
 only against erythromycin-sensitive bacteria but also against 
 erythromycin-resistant bacteria. Accordingly, the compounds of the present
 invention are useful as antibacterial agents for the treatment of 
 bacterially infectious diseases in human beings and animals (including 
 farm animals).