JPS634836B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel mycinamicin derivatives. More specifically, the present invention provides the formula (wherein R represents a hydrogen atom or a hydroxyl group) or a salt thereof. Mycinamicin is a general name for the components of a basic 16-membered ring macrolide antibiotic produced by Micromonospora griseorubida A-11725, namely mycinamicin, and, The chemical structure of each component is J.Chem.Soc.Chem.Comm., 1980,
119-121, J. Antibiotics, 33 (4), 364-376 (1980)
and were originally listed as antibiotics A11725, respectively.
, , , a and a (Japanese Unexamined Patent Publication No. 148701/1989, Patent Application No. 24788/1989, Japanese Patent Application No. 1983)
−31316). The object compound [1] of the present invention includes two types of epimers and mixtures thereof depending on the coordination of the hydroxyl group at the 9-position. The above salts include pharmaceutically acceptable salts, such as salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, succinic acid, malic acid, aspartic acid, glutamic acid, It is a salt with various organic acids such as sulfonic acids. Other non-toxic salts are also included. The above target compound [1] and its salts have antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and mycoplasma, and are not only antibacterial substances that are expected to have excellent clinical effects in treating infections, but also in animals. It is useful as a preventive and therapeutic agent for diseases, and is also useful as a feed additive. The object compound [1] of the present invention can be obtained by reducing mycinamicin with sodium borohydride in an inert organic solvent. As the inert organic solvent, lower alkanols such as methanol and ethanol are preferred. The reaction usually proceeds at room temperature. Since the reaction time can be monitored by thin layer chromatography using silica gel or the like, the reaction can be appropriately terminated after waiting for the disappearance of mycinamicin or the like. To collect the obtained compound [1] from the reaction solution, the reaction solution was poured into water, extracted with a non-hydrophilic organic solvent, and the obtained extract was washed with water and dried under reduced pressure. It is obtained by purification by column chromatography using an adsorbent such as alumina or adsorption resin. Next, Table 1 shows the results of measuring the antibacterial spectrum of the object compound [1] of the present invention.

【table】

[Table] Next, production examples of the compound [1] of the present invention will be specifically explained with reference to Examples. The Rf values in the examples were measured by thin layer chromatography (TLC) using the following carrier and developing solvent, unless otherwise specified. Carrier: Merck silica gel 60 plate F2
54Art5715 Developing solvent: Chloroform-methanol-28% aqueous ammonia (150:10:1) Example 1 9-dihydromycinamicin 1.02 g of mycinamicin (Rf0.72) was mixed with a mixed solvent of ethanol-methanol (4:1 V/V). 40ml
Dissolve in this and add 103mg of sodium borohydride.
and stir at room temperature for 20 hours. Add 40ml of water to the reaction solution.
was added, the solvent was distilled off under reduced pressure, and 30% of ethyl acetate was added.
Extract 3 times with ml. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain a residue.
Get 959mg. This was subjected to column chromatography using silica gel (50 g, manufactured by Merck & Co., Ltd.) using chloroform-methanol-28% aqueous ammonia (400:
By elution at a ratio of 10:1), a classification of Rf0.34 was obtained. This fraction was dried under reduced pressure to obtain 614 mg of 9-dihydromycinamicin. Amorphous white powder MS; 713 (M ⁺ ) Elemental analysis [as C ₃₇ H ₆₃ NO ₁₂ ] C% H% N% Measured value 61.69 9.03 1.66 Calculated value 62.25 8.89 1.96 [α] ²⁷ _D −31.7° (C = 1.0 , methanol) UV; λ ^MeOH _nax 215nm (ξ=12800) IR; ^KBr _nax 3460 (OH), 1710, 1650 (αβ unsaturated lactone), 1165, 1110, 1070, 980 ^-1 _cn NMR; δ ^CDC13 _ppn 0.81~ 1.31 (6×CH ₃ ) 2.28 [S., N
(CH ₃ ) ₂ ], 3.56 (S., OCH ₃ ) 3.62 (S., OCH ₃ ),
4.28 (d., 1′ H), 4.56 (d., 1st H), 5.30 (m.
,
15th position H), 5.40-6.95 (2×HC=CH) Example 2 9-dihydromycinamicin 1.03 g of mycinamicin (Rf0.56) was added to 40 ml of a mixed solvent of ethanol-methanol (4:1 V/V).
Dissolve in this and add 104 mg of sodium borohydride.
and stir at room temperature for 20 hours. Add 40ml of water to the reaction solution.
was added, the solvent was distilled off under reduced pressure, and 30% of ethyl acetate was added.
Extract 3 times with ml. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain a residue.
Get 959mg. This was subjected to column chromatography using silica gel (50 g, manufactured by Merck & Co., Ltd.) using chloroform-methanol-28% aqueous ammonia (400:
10:1) to separate the Rf0.28 fraction. This fraction was dried under reduced pressure to obtain 686 mg of 9-dihydromycinamicin. Amorphous white powder MS; 729 (M ⁺ ) Elemental analysis [as C ₃₇ H ₆₃ NO ₁₃ ] C% H% N% Measured value 59.32 8.82 1.61 Calculated value 60.89 8.70 1.92 [α] ²⁷ _D −14.4 (C = 1.0, methanol) UV; λ ^MeOH _nax 215nm (ξ=13300) IR; ν ^KBr _nax 3440 (OH), 1710, 1640, (α, β unsaturated lactone), 1160, 1110, 1070, ^{975 -1} _cn NMR; δ ^CDC13 _ppn 0.80-1.24 (6×CH ₃ ), 2.28 (S., N
(CH ₃ ) ₂ ], 3.76 (S., 2×OCH ₃ ), 4.36 (d.,
1′ position H), 4.58 (d., 1″ position H), 5.40 (dd, 15th position H), 5.82 to 6.93 (2 x CH = CH)

Claims (1)

[Claims] 1 formula (wherein R represents a hydrogen atom or a hydroxyl group) or a salt thereof.