JPS634551B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 3″-O-acyl-9-dehydro-16-membered ring macrolide antibiotic derivatives.More specifically, the present invention relates to novel 3″-O-acyl-9-dehydro-16-membered ring macrolide antibiotic derivatives. (In the formula, R ₁ is a hydrogen atom or an alkanoyl group having 2 to 3 carbon atoms, R ₂ is an alkanoyl group having 2 to 6 carbon atoms, and R ₃ is an alkanoyl group having 2 to 5 carbon atoms.) It is a compound or a salt thereof. 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] is a known 16-membered ring macrolide antibiotic, such as the leucomycin group,
Diyosamycin, antibiotic SF-837 group, antibiotic
It has stronger antibacterial activity against susceptible bacteria and some resistant bacteria than YL-704 group, espinomycin group, etc. In addition, the 4″ position of 16-membered ring macrolide antibiotics is less susceptible to deacylation, which is one of the causes of inactivation, resulting in increased persistence of blood concentration.Furthermore, the general properties of macrolide antibiotics is strong,
It reduces the persistent bitter taste, making it useful as a syrup for children who cannot take tablets or capsules, and is an antibacterial substance that is expected to have an extremely excellent clinical effect in treating infections. The object compound [1] of the present invention has the formula It can be obtained by dehydrogenating the hydroxyl group at the 9-position of a compound represented by the formula (wherein R ₁ , R ₂ and R ₃ mean the same groups as above) with CrO ₃ . The above starting material [2] is a compound known from JP-A-54-148793, and can be produced by the method described in the same publication. Dehydrogenation of the hydroxyl group at the 9-position is carried out by reacting an aqueous solution of chromic acid in pyridine. The reaction usually proceeds sufficiently under ice cooling. To collect the target compound [1] from the reaction solution, adjust the reaction solution to pH 8 to 10 in water with an alkali, and add a suitable non-hydrophilic organic solvent such as chloroform, methylene chloride, ethyl acetate, methyl isobutyl ketone, If further purification is required after extraction with benzene, etc., use an appropriate solvent such as benzene-acetone solvent, chloroform-methanol solvent, benzene-acetic acid solvent using an adsorbent such as silica gel, activated alumina, or adsorption resin. It can be separated and purified by column chromatography using ethyl-methanol solvent. The above target compound [1] can also be obtained by the following alternative method, that is, the formula It can be produced by a method using an antibiotic represented by the formula (wherein R ₁ and R ₂ mean the same groups as above). Among the above antibiotics [3], nidamycin [R ₁ = H, R ₂ = COCH ₂ CH (CH ₃ ) ₂ ], carbomycin B [R ₁ = COCH ₃ , R ₂ = COCH ₂ CH (CH _{3 )} ) ₂ ],
SF―837A ₃ (R ₁ = COCH ₂ CH ₃ , R ₂ =
COCH ₂ CH ₃ ), SF-837A ₄ (R ₁ = COCH ₂ CH ₃ , R ₂
= COCH ₂ CH ₂ CH ₃ ), YL-704W ₁ [R ₁ =
COCH ₂ CH ₃ , R ₂ = COCH ₂ CH (CH ₃ ) ₂ ], etc. are known. A method of synthesizing carbomycin B by reacting leucomycin A ₃ (diyosamycin) with manganese dioxide is also known, but this method had a low yield. A newly developed method for oxidizing the hydroxyl group at the 9-position of a 16-membered ring macrolide antibiotic to a carbonyl group using the above-mentioned aqueous solution of chromic acid in pyridine can be used to oxidize a known 16-membered ring macrolide antibiotic, that is, a leuco The above antibiotic [3] can be produced in good yield by dehydrogenating the 9-position hydroxyl group of mycin group, diyosamycin, antibiotic SF-837 group, antibiotic YL-704 group, espinomycin group, etc. . The above alternative method is to obtain the desired target compound [1].
The difference in whether R ₁ is a hydrogen atom or a lower alkanoyl group affects whether or not the hydroxyl group is protected.
The methods are different as described below. When obtaining compound [1] in which R ₁ is a hydrogen atom, first protect the 2'-hydroxyl group of antibiotic [3] with a lower alkanoyl group, and then (In the formula, R ₄ is a lower alkanoyl group and R ₂ is an alkanoyl group having 2 to 6 carbon atoms.) The hydroxyl group was silylated, and the resulting silylated product was 3″-acylated with an aliphatic carboxylic acid halide having 2 to 5 carbon atoms under heating in an inert organic solvent in the presence of a tertiary organic amine to obtain 3 This is carried out by treating the acylated product in aqueous lower alkanol in the presence of a base to desilylate it, and then heating it in methanol to eliminate the 2'-position acyl group. As the protecting group for the 2'-position hydroxyl group, a lower alkanoyl group, particularly an acetyl group, is preferred. The 2'-acylation in this case is carried out according to the method described in Japanese Patent Publication No. 7434/1983. Examples of the silylating agent that silylates the hydroxyl group at the 3-position of the compound [4] include tri-substituted halogenosilanes and hexa-substituted disilazane. Examples of tri-substituted halogenosilanes include tri-lower alkylhalogenosilanes, and for example, trimethylchlorosilane is preferred. Examples of the hexa-substituted disilazane include hexa-lower alkyldisilazane, and for example, hexamethyldisilazane is preferred.
In addition to the above, any silylating agent may be used as long as it can introduce a silyl group that is not eliminated by water. The above silylation is usually carried out in an inert organic solvent such as methylene chloride, chloroform, methyl isobutyl ketone, dichloroethane at room temperature or below. The silylating agent may be used in a molar ratio of about 1 to 2 times that of the starting material [4]. In the above silylation, when a trisubstituted halogenosilane is used as the silylating agent, it is preferable to use a suitable tertiary organic amine as the dehalogenating agent. For example, pyridine, picoline,
Examples include collidine, quinoline, isoquinoline, N-methylpiperidine, N-methylmorpholine, dimethylaniline, and tribenzylamine. The silylated product obtained by silylation can be obtained by pouring the reaction solution into water, adjusting the pH to 8 to 10, and extracting with a suitable non-hydrophilic organic solvent. This extract is washed with a dilute aqueous acid solution and a dilute aqueous alkali solution as necessary, concentrated, and used for the next reaction. Next, the silylated product obtained above is 3″-acylated with an aliphatic carboxylic acid halide having 2 to 5 carbon atoms under heating in an inert organic solvent. Examples of the inert organic solvent include tetrahydrofuran, dioxane, Examples include methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, benzene, toluene, chloroform, dichloroethane, etc., with dioxane, methyl ethyl ketone, methyl isobutyl ketone, and dichloroethane being preferred.As the aliphatic carboxylic acid halide, acetyl chloride, propionyl chloride , butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, etc. The above 3″-acylation reaction is preferably carried out in the presence of a known tertiary organic amine.
Examples of such tertiary organic amines include dimethylaniline, tribenzylamine, pyridine,
Picoline, collidine, N-methylpiperidine, N
-Methylmorpholine, quinoline, isoquinoline, etc., but tribenzylamine is particularly preferred. The heating temperature for the above reaction is usually in the range of 50 to 120°C. The reaction time mainly depends on the type of acylating agent and the reaction temperature, but since the progress of the reaction can be tracked using thin layer chromatography such as silica gel, the end point of the reaction can be determined by waiting for the silylated product to disappear. . The 3″-acylated product obtained by the above 3″-acylation can be obtained by pouring the reaction solution into water, adjusting the pH of the aqueous layer to 8 to 10, and extracting with a suitable non-hydrophilic organic solvent. . This extract is washed with a dilute aqueous acid solution and a dilute aqueous alkali solution as necessary, concentrated, and used for the next reaction. Next, the 3″-acylated product obtained above is desilylated by treating it in an aqueous lower alkanol in the presence of a base. The lower alkanol in the above is preferably methanol or ethanol. The base is an alkali carbonate or triethylamine. , basic resins, etc. The above desilylation usually proceeds sufficiently at room temperature,
Since the reaction can be tracked by thin layer chromatography using silica gel or the like, the end point of the reaction can be appropriately determined. The resulting reaction solution can be neutralized with a suitable acid, such as acetic acid, and used for the next reaction without isolating the product. Next, the 2'-position acyl group of the desilylated product is eliminated to obtain the desired compound [1], and this reaction is carried out by heat treatment in methanol. Therefore, when methanol is used in the desilylation reaction, the heat treatment may be performed without distilling off the solvent.
Heating is usually carried out under refluxing methanol. Since the reaction 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 the product. Methanol was distilled off from the reaction solution, a suitable non-hydrophilic organic solvent was added thereto, the mixture was washed with an alkaline aqueous solution with a pH of 8 to 10, and the target compound [1] was obtained by distilling off the solvent from the resulting extract. Obtainable. If further purification is required, column chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin may be used. Next, when obtaining a compound [1] in which R ₁ is a lower alkanoyl group, the above 2'-acyl compound [4] is heated in an inert organic solvent in the presence of a tertiary organic amine, and the number of carbon atoms is This is carried out by 3''-acylating with 2 to 5 aliphatic carboxylic acid halides and heating the resulting 3''-acylated product in methanol to eliminate the acyl group at the 2' position. The above 3″-acylation and elimination of the acyl group at the 2′ position can be carried out in the same manner as in the case of obtaining the compound [1] in which R ₁ is a hydrogen atom. The obtained target compound [1] ] is collected from the reaction solution and separated and purified in the same manner as above.Next, the results of measuring the antibacterial spectrum of the target compound [1] of the present invention are listed in Table 1.

[Table] From the results in Table 1, it can be seen that the target compound of the present invention [1] has stronger antibacterial activity against susceptible bacteria than the known control antibiotics, namely leucomycin A ₃ (dijosamycin) and leucomycin A ₅ . I understand. Next, a production example of the target compound [1] of the present invention will be specifically explained with reference to Examples. Unless otherwise specified, Rf values in the examples were measured by thin layer chromatography (TLC) using the following carrier and developing solvent. Support: Merck silica gel 60 plate Art5721 Developing solvent: A: Hexane-benzene-acetone-ethyl acetate-methanol (90:80:25:60:30) B: Chloroform-methanol-acetic acid-water (80:
7:7:1) Example 1 9-dehydro-3″-O-propionylleucomycin A 50% chromic acid aqueous solution (20 g) was gradually added to ₄₀ ml of pyridine under ice-cooling to a solution prepared with stirring under ice-cooling. 3″-O-propionylleucomycin A ₅ 10.7
A solution prepared by dissolving 1.5 g in 5 ml of pyridine was slowly added. After addition, it was stirred at room temperature for 20 minutes. 200 ml of ice water was poured into the reaction solution, the pH was adjusted to 9 with a 10% aqueous sodium hydroxide solution, and the mixture was extracted with 100 ml of chloroform. The extract was sequentially washed with dilute hydrochloric acid, water, and dilute ammonia water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8 g of a crude product. This was subjected to silica gel column chromatography eluting with chloroform methanol (100:1), and ₂₈ g of 9-dehydro-3''-O-propionylleucomycin A was added.
I got it. TLC; Rf _A = 0.59, Rf _B = 0.73 (TLC of 3″-O-propionylleucomycin A ₅ ; Rf _A =
0.50, Rf _B = 0.44) UV; λ ^EtoH _nax 280nm Mass (m/e); 825 (M ⁺ ), 752 (M ⁺ -73), 738
(M ⁺ −87), 555, 444, 365, 271, 197, 190,
174,173 3″-O-propionylleucomycin mentioned above
_A5 was obtained by the method described in JP-A-54-143793. Example 2 3″-O-acetyl-9- _dehydro -leucomycin A ₅ In Example 1, 3″-O-acetylleucomycin A ₅ (specifically 2.42 g of 3''-O-acetyl-9-dehydro-leucomycin A 5 was obtained using 10.5 g of 3''-O-acetyl-9-dehydro-leucomycin A ₅ (obtained by the method described in JP-A-54-143793). TLC; Rf _A = 0.58, Rf _B = 0.72 (TLC of 3″-O-acetylleucomycin A ₅ ; Rf _A = 0.49,
Rf _B = 0.43) UV: λ ^EtOH _nax 279 nm (ε = 2.2 × 10 ⁴ ) Mass (m/e); 811 (M ⁺ ), 752 (M ⁺ -59), 724
(M ⁺ −87), 555, 539, 430, 365, 347, 257,
197, 190, 174, 173 Example 3 3″-O-acetyl-9-dehydro-leucomycin A ₃ In Example 1, 3″-O- instead of 10.7 g of 3″-O-propionylleucomycin A ₅ Using 11.3 g of acetyl leucomycin A ₃ (obtained by the method described in JP-A-54-143793), 9.95 g of a crude product of 3″-O-acetyl-9-dehydro-leucomycin A ₃ was obtained. Ta. This was subjected to silica gel column chromatography eluting with chloroform-methanol (150:1) to obtain 2.14 g of purified product. TLC; Rf _A = 0.70, Rf _B = 0.82 (TLC of 3″-O-acetylleucomycin A ₃ ; Rf _A = 0.63,
Rf _B = 0.61) UV; λ ^EtOH _nax 279 nm (ε = 2.1 × 10 ⁴ ) Mass (m/e) 867 (M ⁺ ), 808 (M ⁺ -59), 766
(M ⁺ −101), 706, 597, 581, 444, 407, 347,
271, 211, 190, 174, 173 Example 4 9-dehydro-3″-O-propionylleucomycin A ₅ 20 g of 50% chromic acid aqueous solution was gradually added to 40 ml of pyridine under ice cooling to a solution prepared. While stirring, a solution of ₅ 10 g of leucomycin A dissolved in 5 ml of pyridine was slowly added.
Stir for a minute. Pour the reaction solution into 200ml of ice water and dilute to 10%
After adjusting the pH to 9 with an aqueous sodium hydroxide solution, the mixture was extracted with 100 ml of chloroform. Dilute the extract with diluted hydrochloric acid,
The mixture was washed with water and diluted ammonia water in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.5 g of a crude reaction product. This was purified by silica gel column chromatography eluting with benzene-ethyl acetate-methanol (32:4:1) to obtain 6.1 g of 9-dehydro-leucomycin _A5 . TLC; Rf _A = 0.42, Rf _B = 0.48 (leucomycin
TLC of _A5 ; Rf _A = 0.38, Rf _B = 0.33) UV; λ ^EtOH _nax 278.2 nm (ε = 2.2 × 10 ⁴ ) Mass (m/e); 769 (M ⁺ ), 682 (M ⁺ -87) ,
584, 555, 365, 215, 190, 174, 173 Dissolve ₅ g of 9-dehydro-leucomycin A in 25 ml of dry dichloroethane, and add 2.1 g of acetic anhydride to this.
ml and stirred at room temperature for 1.5 hours. Pour the reaction solution into water.
After pouring into 100 ml of water and adjusting the pH of the aqueous layer to 10 with aqueous ammonia, 25 ml of dichloroethane was added for extraction. The dichloroethane layer was washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure to give 2'-O-acetyl-
A crude product of 9-dehydro-leucomycin A ₅ was obtained. Dissolve this in 25ml of dry dichloroethane,
After adding 5 g of tribenzylamine to this, 3.3 ml of trimethylchlorosilane was added under ice cooling, and the mixture was stirred for 15 hours. The reaction solution was poured into 100 ml of water, and the pH of the aqueous layer was adjusted to 9.5-10 with aqueous ammonia, followed by extraction with 25 ml of dichloroethane. Wash the dichloroethane layer with water,
After drying with anhydrous sodium sulfate, drying under reduced pressure gives 2′-
A crude product of O-acetyl-9-dehydro-3-O-trimethylsilyl-leucomycin _A5 was obtained.
This was dissolved in 25 ml of dry dichloroethane, 16 g of tribenzylamine was added thereto, 5.62 ml of propionyl chloride was added, and the mixture was reacted at 75° C. for 20 hours. Add 50 ml of dichloroethane to the reaction solution, wash with dilute ammonia water and then with water, dry over anhydrous sodium sulfate, and dry under reduced pressure to obtain 2'-O-acetyl-
9-Dehydro-3″-O-propionyl-3-O-
Trimethylsilyl-leucomycin A ₅ and 2′-
A mixed crude product of O-acetyl-9-dehydro-17,18-enol-18,3″-di-O-propionyl-3-O-trimethylsilyl-leucomycin A ₅ was obtained. This was dissolved in 250 ml of methanol. To this, 30 ml of 8% potassium carbonate aqueous solution was added, and the mixture was stirred at room temperature for 1 hour.After neutralizing the reaction solution by adding 1.2 ml of acetic acid, it was heated under reflux at 70°C for 20 hours.Methanol was distilled off under reduced pressure. Dilute the residue with 250ml of dichloroethane
It was dissolved in This solution was washed successively with diluted ammonia water and water, dried over anhydrous sodium sulfate, and then dried under reduced pressure. The residue was treated with 50 ml of methanol and the precipitate was separated. Dry the liquid under reduced pressure to obtain 9-dehydro-
4.95 g of crude powder of 3″-O-propionyl-leucomycin A ₅ was obtained. This was purified by silica gel column chromatography eluting with benzene-ethyl acetate-methanol (36:4:1).
The corresponding fraction was dried under reduced pressure to obtain 3.2 g of purified product. TLC; Rf _A = 0.59, Rf _B = 0.73

Claims (1)

[Claims] 1 formula (In the formula, R ₁ is a hydrogen atom or an alkanoyl group having 2 to 3 carbon atoms, R ₂ is an alkanoyl group having 2 to 6 carbon atoms, and R ₃ is an alkanoyl group having 2 to 5 carbon atoms.) compound or its salt. 2. The compound or salt thereof according to claim 1, wherein R ₁ is a hydrogen atom. 3. The compound or salt thereof according to claim ₂ , wherein R 2 is a propionyl, butyryl or isovaleryl group, and R ₃ is an acetyl or propionyl group. 4. The compound according to claim 3, which is 3″-O-acetyl-9-dehydro-leucomycin A ₅ or 3″-O-propionyl-9-dehydro-leucomycin A ₅ or a salt thereof. 5. The compound or salt thereof according to claim 1, wherein _R1 is an alkanoyl group having 2 to 3 carbon atoms. 6. The compound or salt thereof according to claim 5, wherein R ₂ is a propionyl, butyryl or isovaleryl group, and R ₃ is an acetyl or propionyl group. 7. The compound according to claim 6, which is 3″-O-acetyl-9-dehydro-leucomycin A ₃ or 3″-O-propionyl-9-dehydro-leucomycin A ₃ or a salt thereof.