JPS6242919B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to Tylosin derivatives. Tylosin is a 16-membered ring macrolide antibiotic consisting of a 16-membered lactone moiety and three constituent sugars [mycarose, mycinose, and mycaminose]. Through research on its acid hydrolysis,
The presence of lactone moieties and mycaminose was found to be important for the expression of antibacterial activity, and mycaminosil
Tyronolide or a compound iodinated at the 23rd position is known (Special Publication No. 18633/1983, 100th Annual Meeting of the Pharmaceutical Society of Japan). In particular, it has been reported that the latter compound has significantly increased antibacterial activity compared to tylosin. The present inventors have completed the present invention by discovering that a derivative of mycaminosyl tylonolide with an amino substituent introduced at the 23-position has further enhanced antibacterial activity compared to known similar compounds such as tylosin and mycaminosyl tylonolide. The tylosin derivative of the present invention has the general formula [In the formula, R ₁ is an amino group, a mono- or di-lower alkylamino group, or a

R ₂ represents a hydrogen atom or a hydroxyl group, and R ₃ represents an aldehyde group which may have a protecting group. ] This is a new compound represented by Examples of the mono-lower alkylamino group include a methylamino group, ethylamino group, isopropylamino group, isobutylamino group, and hexylamino group, and examples of the di-lower alkylamino group include a dimethylamino group, a diethylamino group, and a dimethylamino group. Propylamino group, dibutylamino group, diisobutylamino group, dihexylamino group, N-
Methyl-N-ethylamino group, N-methyl-N-
Isopropylamino group, N-methyl-N-hexylamino group, N-ethyl-N-butylamino group,
N-ethyl-N-hexylamino group, N-propyl-N-pentylamino group, N-pentyl-N-
Examples include hexylamino group. Table 1 shows the antibacterial activity of the target compound of the present invention.

【table】

[Table] In the present invention, the target compound [] has the general formula [In the formula, R ₃ ' represents a protected aldehyde group, X represents a halogen atom, and R ₂ represents the same meaning as above. ) is reacted with a compound represented by the general formula R ₁ -H [] (wherein R ₁ has the same meaning as above), and then, if desired, the protecting group of the aldehyde group is removed. Therefore, it can be manufactured. The aldehyde group with a protecting group is one protected in the form of an acetal or thioacetal, and specifically, dimethyl acetal, diethyl acetal, diethyl thioacetal, ethylene acetal, ethylene thioacetal, propylene acetal, or any of these. Examples include those having a substituent such as a methyl group. The reaction between compound [] and [] is preferably carried out in an organic solvent such as tetrahydrofuran, acetonitrile, dioxane, dimethylformamide, dimethyl sulfoxide, etc. at room temperature or under heating. The protective group for the aldehyde group can be removed by treatment with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as trifluoroacetic acid or trichloroacetic acid, usually in the presence of water. In addition, compounds in which R ₁ is a mono- or di-lower alkylamino group in the target compound [ ],
Produced by reacting a target compound [] in which R ₁ is an amino group and R ₃ is an aldehyde group attached with a protecting group with a halogenated lower alkyl, and then optionally removing the protecting group of the aldehyde group. You can also do it. As halogenated lower alkyl,
Methyl iodide, ethyl iodide, butyl bromide, bromide
Tert-butyl etc. are used. This reaction can be carried out under heating in an organic solvent such as acetonitrile, acetone, dimethylformamide, etc. When 1 mol of lower alkyl halide is used, the target compound in which R ₁ is a mono-lower alkylamino group [] However, when 2 moles are used, the target compound [] in which R ₁ is a di-lower alkylamino group can be obtained. Removal of the protecting group for the aldehyde group can be carried out in the same manner as in the above production method. The target compound [] can be prepared into tablets, powders, granules, capsules, injections, etc. using common pharmaceutical carriers, and can be administered orally or parenterally. Dosage: 10-1000mg once a day
~4 doses are appropriate. Next, the present invention will be explained in more detail with reference to Examples. Example 1 (a) 23-deoxy-23-iodo mycaminosyl tylonolide diethylacetal 110mg
was dissolved in 2.2 ml of anhydrous acetonitrile, 63.5 mg of ethylamine was added thereto, the mixture was reacted at 80°C for 5 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 5.5 ml of chloroform, washed once each with 2 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a 11 g silica gel column using a solvent system of chloroform-methanol-ammonia water (15:1:0.1) to obtain 23-deoxy-23-ethylamino mycaminosyl tylonolide diethyl acetal. Yield 71.4mg (yield 72.5%)

[Table] Example 2 23-deoxy-23-ethylamino mycaminosyl tylonolide diethylacetal 30.5
Dissolve mg in 0.6ml acetonitrile and add 1.3ml
A 0.1N aqueous hydrochloric acid solution was added and the mixture was reacted for 60 minutes to remove diethyl acetalization. After the reaction was completed, 15 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 3 ml of chloroform.
The chloroform layers were combined, washed twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a 4 g silica gel (Kieselgel 60, 230-400 mesh) column with the solvent system chloroform-methanol-concentrated aqueous ammonia (12:1:0.1).
23-deoxy-23-ethylamino mycaminosyl tylonolide was obtained. Yield 24.0mg (yield 89%)

[Table] Example 3 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 150mg 3
ml of anhydrous acetonitrile, 70 mg of n-butylamine was added thereto, the mixture was reacted at 80°C for 12 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 7.5 ml of chloroform, washed once each with 2.5 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 120 mg of the residue was dissolved in 2.4 ml of acetonitrile, 4.9 ml of 0.1N aqueous hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to perform de-diethylacetalization. After the reaction was completed, 64.5 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 2.4 ml of chloroform. The chloroform layers were combined, washed twice with 2.4 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a 12 g silica gel (Kieselgel 60, 230-400 mesh) column with a solvent system of chloroform-methanol-concentrated aqueous ammonia (12:1:0.1).
23-deoxy-23-butylamino mycaminosyl tylonolide was obtained. Yield 92.6mg (yield 86%)

【table】

[Table] Example 4 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 85.5mg
The mixture was dissolved in 1.7 ml of anhydrous acetonitrile, 40.2 mg of isobutylamine was added thereto, the mixture was reacted at 80°C for 24 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 4.3 ml of chloroform, washed once each with 2 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in 1.7 ml of acetonitrile, 3.3 ml of 0.1N aqueous hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to perform de-diethylacetalization. After the reaction was completed, 28 mg of sodium hydrogen carbonate was added to the reaction solution.
Extracted three times with 1.5 ml of chloroform. The chloroform layers were combined, washed twice with 1.5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a 11 g silica gel (Kieselgel 60, 230-400 mesh) column with a solvent system of chloroform-methanol-concentrated aqueous ammonia (12:1:0.1) to obtain 23-deoxy-23-isobutylamino mycaminosil.
Got Tyronolide. Yield 58.8mg (yield 82%)

[Table] Example 5 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 170.9mg
It was dissolved in 3.4 ml of anhydrous acetonitrile, 0.440 ml of 4.98M dimethylamine acetonitrile solution was added, and the mixture was reacted at 80° C. for 30 minutes. Then again 4.98M
0.440ml of dimethylamine acetonitrile solution
was added, and the reaction was continued for an additional 30 minutes. The reaction solution was concentrated under reduced pressure to remove acetonitrile, chloroform was added, and the mixture was concentrated again. The residue was dissolved in 8 ml of chloroform, washed once with 2 ml of saturated aqueous sodium bicarbonate solution and twice with 2 ml of saturated aqueous sodium sulfate solution, and then concentrated under reduced pressure. After adding benzene to the residue, it was concentrated, and benzene-n-hexane was added and allowed to stand to obtain crystals of 23-deoxy-23-dimethylamino mycaminosyl tylonolide diethyl acetal. Yield: 149.7 mg (yield: 98%) 41.9 mg of the obtained crystals were recrystallized from dichloromethane-n-hexane. Yield 36.1mg (recrystallization rate 86%)

[Table] Example 6 23-deoxy-23-dimethylamino mycaminosyl tylonolide diethyl acetal
Dissolve 88.4 mg in 1.8 ml acetonitrile, 0.1N
4.80 ml of hydrochloric acid aqueous solution was added and reacted for 75 minutes. 44 mg of sodium hydrogen carbonate was added to the reaction solution, then 1 ml of saturated sodium hydrogen carbonate aqueous solution was added to neutralize it, and 2 ml of sodium hydrogen carbonate was added.
The mixture was extracted three times with chloroform. Combine the chloroform layers and dilute with 2 ml of saturated aqueous sodium sulfate solution.
The mixture was washed twice, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with 9 g of silica gel (Kieselgel 60,
230-400 mesh) was charged to a column packed with chloroform-methanol-concentrated aqueous ammonia (30:1:0.1) with the same solvent, and the solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:0.1) was charged.
23-deoxy-23-
Dimethylamino mycaminosyl tylonolide was obtained. Yield 67.9mg (yield 86%)

[Table] Example 7 23-deoxy-23-iodo mycaminosyl
152.1 mg of tylonolide diethyl acetal was dissolved in 3 ml of anhydrous acetonitrile, 0.2 ml of diethylamine was added, and the mixture was reacted at 80°C for 6 hours. The reaction solution was concentrated under reduced pressure to remove acetonitrile, chloroform was added, and the mixture was concentrated again. The residue was dissolved in 10 ml of chloroform, washed twice with 2 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with 15 g of silica gel (Kieselgel60, 230-400
A column packed with chloroform-methanol-concentrated ammonia water (30:1:0.1) was charged with the same solvent, and chromatography was performed using the solvent system chloroform-methanol-concentrated ammonia water (15:1:0.1). 23-deoxy-23-diethylamino mycaminosyl tylonolide diethylacetal was obtained. Yield 129.7mg (yield 92%)

[Table] Example 8 23-deoxy-23-dimethylamino mycaminosyl tylonolide diethyl acetal
Dissolve 36.1mg in 0.722ml acetonitrile,
A 0.1N aqueous hydrochloric acid solution was added and the mixture was allowed to react for 90 minutes. The reaction solution was neutralized by adding 17.8 mg of sodium hydrogen carbonate and 0.5 ml of a saturated aqueous sodium hydrogen carbonate solution, and extracted three times with 2 ml of chloroform. The chloroform layers were combined, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was mixed with 5.5 g of silica gel (Kieselgel 60, 230-400 mesh) in chloroform-methanol-concentrated aqueous ammonia (30:1:
Charge a column packed with 0.1) with the same solvent,
Chromatography was performed using the solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:0.1), and 23-
Deoxy-23-diethylamino mycaminosyl tylonolide was obtained. Yield 31.7mg (yield 98%)

[Table] Example 9 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 200mg 4
ml of anhydrous acetonitrile, 0.175 ml of di-n-propylamine was added, and the mixture was reacted at 80°C overnight. The reaction solution was concentrated under reduced pressure to remove acetonitrile, chloroform was added, and the mixture was concentrated under reduced pressure again. Dissolve the residue in 10ml of chloroform and add 2ml
The mixture was washed once with saturated aqueous sodium bicarbonate solution and twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then azeotroped three times with toluene, charged to a column filled with 20 g of silica gel (Kieselgel 60, 230-400 mesh) with chloroform-methanol (50:1), and the solvent system chloroform-methanol (6:1) was charged with the same solvent. Chromatography was performed using 1) to obtain a crude product. Yield: 160.5 mg (yield: 80%) 110 mg of this crude product was chromatographed on an 11 g silica gel (Kieselgel 60, 230-400 mesh) column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (15:1:0.1). conduct, 23-
Deoxy-23-dipropylamino mycaminosyl tylonolide diethylacetal was obtained. Yield 76.7mg (yield approx. 82%)

[Table] Example 10 23-deoxy-23-dipropylamino mycaminosyl tylonolide diethylacetal
Dissolve 51.0mg in 1.0ml acetonitrile, 0.1N
2.03 ml of hydrochloric acid aqueous solution was added and reacted for 60 minutes. The reaction solution was neutralized by adding 22.7 mg of sodium hydrogen carbonate and 1 ml of saturated aqueous sodium hydrogen carbonate solution, and extracted three times with chloroform. Combine the chloroform layers,
The mixture was washed twice with a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel (Kieselgel 60, 230-400 mesh) column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (15:1:0.1) to obtain 23-deoxy-23-dipropylamino mycaminosyl tylonolide. Obtained. Yield 32.9mg (yield 72%)

[Table] Example 11 23-deoxy-23-iodo mycaminosyl
120.7 mg of tylonolide diethyl acetal was dissolved in 2.4 ml of anhydrous acetonitrile, 0.132 ml of di-n-butylamine was added, and the mixture was reacted at 80°C for 20 hours. The reaction solution was concentrated under reduced pressure to remove acetonitrile, chloroform was added, and the mixture was concentrated under reduced pressure again.
The residue was dissolved in 10 ml of chloroform, washed once with 2 ml of saturated aqueous sodium bicarbonate solution and twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 2.4 residue
It was dissolved in 1 ml of acetonitrile, 6.1 ml of 0.1N hydrochloric acid aqueous solution was added, and the mixture was reacted for 90 minutes. The reaction solution was neutralized by adding 64.9 mg of sodium hydrogen carbonate and 0.3 ml of a saturated aqueous sodium hydrogen carbonate solution, and extracted three times with 2 ml of chloroform. Combine the chloroform layers, 2
The mixture was washed twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with 12 g of silica gel (Kieselgel 60, 230-400
A column packed with chloroform-methanol-concentrated ammonia water (30:1:0.1) was charged with the same solvent, and chromatography was performed using the solvent system chloroform-methanol-concentrated ammonia water (15:1:0.1). , 23-deoxy-23-dibutylamino mycaminosyl tyloride was obtained. Yield 74.7mg (yield 68.0%)

[Table] Example 12 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 94.6mg
The mixture was dissolved in 2.4 ml of anhydrous acetonitrile, added with 0.105 ml of diisobutylamine, reacted at 80°C for 48 hours, and then concentrated under reduced pressure. The residue was dissolved in 10 ml of chloroform, washed once with 2 ml of saturated aqueous sodium bicarbonate solution and twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue (ca. 88 mg) was dissolved in 1.75 ml of acetonitrile, 3.36 ml of 0.1N aqueous hydrochloric acid solution was added, and the mixture was reacted for 60 minutes. The reaction solution was neutralized by adding 39.5 mg of sodium hydrogen carbonate and 0.5 ml of saturated aqueous sodium hydrogen carbonate solution, and
Extracted three times with ml of chloroform. The chloroform layers were combined, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was mixed with 9 g of silica gel (Kieselgel 60, 230-400 mesh) in chloroform-methanol-concentrated aqueous ammonia (30:1:
Charge a column packed with 0.1) with the same solvent,
Chromatography was performed using the solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:0.1).
23-deoxy-23-diisobutylamino mycaminosyl tylonolide was obtained. Yield 63.2mg (yield 73.6%)

[Table] Example 13 (a) 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal
49.0 mg was dissolved in 0.98 ml of anhydrous acetonitrile, 0.1 ml of about 5 M dimethylamine-acetonitrile solution was added, and the mixture was reacted for 30 minutes at 80° C. under a sealed stopper. Next, an additional 0.1 ml of the dimethylamine-acetonitrile solution was added to the reaction solution, reacted for 30 minutes, and then concentrated. Chloroform the residue
After dissolving in 2.5 ml, the solution was washed once each with 1 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (b) Dissolve the residue in 0.98 ml of acetonitrile,
1.9 ml of 0.1N hydrochloric acid aqueous solution was added, and the mixture was reacted at 20°C for 60 minutes. 22 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 1 ml of chloroform. The chloroform layers were combined, washed once with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a 5 g silica gel (Kieselgel 60, 230-400 mesh) column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (18:1:0.1) to obtain 23,4'-dideoxy-23-dimethyl. Amino mycaminosyl tylonolide was obtained. Yield 31.0mg (yield 80%)

【table】

[Table] Example 14 (a) 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal
Dissolve 51.0mg in 1.0ml of anhydrous acetonitrile, add 24.3mg of diethylamine, and store at 80℃ under a tightly stopper.
The mixture was allowed to react for 3 hours. Next, an additional 24.3 mg of diethylamine was added to the reaction solution, and the mixture was reacted for 3 hours and then concentrated. The residue was dissolved in 2.5 ml of chloroform, washed once each with 1 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (b) Dissolve the residue in 1.0 ml of acetonitrile,
20 ml of 0.1N hydrochloric acid aqueous solution was added and reacted at 20°C for 60 minutes. Add 22.4 ml of sodium hydrogen carbonate to the reaction solution.
mg and extracted three times with 1 ml of chloroform. The chloroform layers were combined, washed once with 1 ml of saturated aqueous sodium sulfate solution, and concentrated under reduced pressure.
The residue was washed with 5 g of silica gel (Kieselgel 60, 230
-400 mesh) on the column, solvent system chloroform-methanol-concentrated ammonia water (20:1:
0.1) to obtain 23,4'-dideoxy-23-diethylamino mycaminosyl tylonolide. Yield 25.7mg (yield 61%)

[Table] Example 15 23,4'-dideoxy-23-iodo mycaminosyl tylonolide diethylacetal98.0
Dissolve mg in 2.0 ml of anhydrous acetonitrile and dilute
82.6 mg of n-butylamine was added, and the mixture was reacted at 80°C for 20 hours, and then concentrated under reduced pressure. The residue was dissolved in 5 ml of chloroform, and then dissolved in 2 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution.
The mixture was washed twice, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Dissolve the residue in 2 ml of acetonitrile and
2.8 ml of 0.1N hydrochloric acid water was added and reacted for 60 minutes.
After the reaction was completed, 44 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 2 ml of chloroform. The chloroform layers were combined, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Next, 10g of silica gel (Kieselgel60, 230-
400 mesh) on the column, solvent system chloroform-
Chromatography was performed with methanol-concentrated aqueous ammonia (20:1:0.1), and 23,4′-dideoxy-23
- Dibutylamino mycaminosyl tylonolide was obtained. Yield 74.4mg (yield 84%)

[Table] Example 16 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal 118
mg was dissolved in 2.4 ml of anhydrous acetonitrile, 99.1 mg of diisobutylamine was added, and the mixture was reacted at 80°C for 48 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 6 ml of chloroform, washed once each with 2 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in 2.4 ml of acetonitrile, 3.4 ml of 0.1N aqueous hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to perform de-diethylacetalization. After the reaction was completed, 53 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 2.4 ml of chloroform. The chloroform layers were combined, washed twice with 2.4 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a 120 g silica gel (Kieselgel 60, 230-400 mesh) column with a solvent system of chloroform-methanol-concentrated aqueous ammonia (20:1:0.1) to obtain 23,4'-dideoxy-23-diisobutylamino. I got mycaminocil tylonolide. Yield 75.0mg (yield 71%)

[Table] ^D
Example 17 23-deoxy-23-iodo mycaminosyl
Dissolve 199.9 mg of tylonolide diethyl acetal in 4 ml of anhydrous acetonitrile, and dissolve piperidine in 4 ml of anhydrous acetonitrile.
0.13 ml was added and reacted at 80°C for 90 minutes. The reaction solution was concentrated under reduced pressure to remove acetonitrile, a small amount of chloroform was added, and the mixture was concentrated again under reduced pressure. Dissolve the residue in 10ml of chloroform and add 2ml
The mixture was washed once with saturated aqueous sodium bicarbonate solution and twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To remove piperidine, the mixture was azeotroped several times with toluene and concentrated to dryness under reduced pressure. The residue was charged to a 20 g silica gel (Kieselgel 60, 230-400 mesh) column packed with chloroform-methanol-concentrated aqueous ammonia (30:1:0.1) with the same solvent, and the solvent system chloroform-
Chromatography was performed using methanol-concentrated aqueous ammonia (15:1:0.1) to obtain 23-deoxy-23-piperidino mycaminosyl tylonolide diethyl acetal. Yield: 179.5 mg (yield: 95%) 65.1 mg of the obtained target product was recrystallized from ethyl acetate-n-hexane. Yield 53.8mg (recrystallization rate 82.6%)

[Table] Example 18 23-deoxy-23-piperidino mycaminocil tylonolide diethylacetal 91.9mg
Dissolve in 1.84ml of acetonitrile and add 3.5ml of
A 0.1N aqueous hydrochloric acid solution was added and the mixture was allowed to react for 60 minutes. The reaction solution was neutralized by adding 41.8 mg of sodium hydrogen carbonate and 1 ml of a saturated aqueous sodium hydrogen carbonate solution, and extracted three times with 2 ml of chloroform. The chloroform layers were combined, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel (Kieselgel 60, 230-400 mesh) filled with chloroform-methanol-concentrated ammonia water (30:1:0.1)
Charge the column with the same solvent and change the solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:
0.1) to obtain 23-deoxy-23-piperidino mycaminosyl tylonolide. Yield 76.1mg (yield 92%)

【table】

[Table] ^D
Example 19 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 60.0mg
The mixture was dissolved in 1.2 ml of anhydrous acetonitrile, 48.4 mg of nonamethyleneimine was added thereto, the mixture was reacted at 80°C for 5 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 3 ml of chloroform, washed once each with 1 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in 1.2 ml of acetonitrile, 1.9 ml of 0.1N aqueous hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to perform de-diethylacetalization. After the reaction was completed, 32 mg of sodium hydrogen carbonate was added, and the mixture was extracted three times with 1.2 ml of chloroform. Combine the chloroform layers and dilute with 1.2 ml of saturated sodium sulfate solution.
The mixture was washed twice, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was chromatographed on a 6 g silica gel (Kieselgel 60, 230-400 mesh) column with a solvent system of chloroform-methanol-concentrated aqueous ammonia (15:1:0.1) to obtain 23-deoxy-23-nonamethyleneimino mycaminosyl tylonolide. I got it. Yield 50.3mg (yield 91%)

[Table] ^D
Example 20 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 90.0mg
The mixture was dissolved in 1.8 ml of anhydrous acetonitrile, 97.2 mg of undecamethyleneimine was added thereto, the mixture was reacted at 80°C for 10 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 4.5 ml of chloroform, washed once each with 1.5 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Dissolve the residue in 1.8 ml acetonitrile and add 8.1
ml of 0.1N aqueous hydrochloric acid solution was added and reacted for 60 minutes to remove diethyl acetalization. After the reaction is completed, 77mg
of sodium hydrogen carbonate was added, and the mixture was extracted three times with 3.6 ml of chloroform. Combine the chloroform layer,
The mixture was washed twice with 3.6 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was washed with 12 g of silica gel (Kieselgel 60,
230 to 400 mesh) on the column, solvent system chloroform-methanol-concentrated ammonia water (18:1:
0.1) and 23-deoxy-
23-Undecamethylene imino mycaminocil
Got Tyronolide. Yield 71.5mg (yield 83%)

[Table] ^D
Example 21 (a) 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal
93.0 mg was dissolved in 1.9 ml of anhydrous acetonitrile, 43.3 mg of pyrrolidine was added, the mixture was reacted at 60°C for 80 minutes, and then concentrated under reduced pressure. The residue was dissolved in 5 ml of chloroform, washed once with 2 ml of saturated aqueous sodium bicarbonate solution and twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. It was azeotroped several times with toluene to remove pyrrolidine. (b) Dissolve the residue in 1.9 ml of acetonitrile,
3.4 ml of hydrochloric acid aqueous solution was added and reacted for 60 minutes. Add 41 mg of sodium hydrogen carbonate to the reaction solution, then 2 ml of saturated aqueous sodium hydrogen carbonate solution, and add 2 ml of sodium hydrogen carbonate.
The mixture was extracted three times with chloroform. The chloroform layers were combined, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Transfer the residue onto a 10 g silica gel (Kieselgel 60, 230-400 mesh) column.
Chromatography was performed using a solvent system of chloroform-methanol-concentrated aqueous ammonia (18:1:0.1) to obtain 23,4'-dideoxy-23-pyrrolidino mycaminosyl tylonolide. Yield 69.6mg (yield 90%)

【table】

[Table] ^D
Example 22 (a) 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal
92.3 mg was dissolved in 1.9 ml of anhydrous acetonitrile, 51.4 mg of piperidine was added, the mixture was reacted at 80°C for 60 minutes, and then concentrated under reduced pressure. The residue was dissolved in 6 ml of chloroform, washed once with 2 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium sulfate solution, and then concentrated under reduced pressure. It was azeotroped several times with toluene to remove piperidine. (b) Dissolve the residue in 1.9 ml of acetonitrile,
3.6 ml of hydrochloric acid aqueous solution was added and reacted for 60 minutes. To the reaction solution was added 40.7 mg of sodium hydrogen carbonate, then 2 ml of saturated aqueous sodium hydrogen carbonate solution.
Extracted three times with ml of chloroform. The chloroform layers were combined, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. On a silica gel (Kieselgel 60, 230-400 mesh) column with 10 g of residue,
Chromatography was performed using a solvent system of chloroform-methanol-concentrated aqueous ammonia (18:1:0.1) to obtain 23,4'-dideoxy-23-piperidino mycaminosyl tylonolide. Yield 73.0mg (yield 93%)

[Table] ^D
Example 23 (a) 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal
62.5 mg was dissolved in 1.3 ml of anhydrous acetonitrile, 40.5 mg of hexamethyleneimine was added, and the mixture was reacted at 80°C for 60 minutes under a tightly stopper, and then concentrated under reduced pressure. After dissolving the residue in 3.2 ml of chloroform, 1 ml
The mixture was washed once with saturated sodium bicarbonate and twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (b) Dissolve the residue in 1.3 ml of acetonitrile,
2.5 ml of 0.1N hydrochloric acid aqueous solution was added and reacted for 60 minutes. 28 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 1.5 ml of chloroform. The chloroform layers were combined, washed once with 1.5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a 6 g silica gel (Kieselgel 60, 230-400 mesh) column with a solvent system of chloroform-methanol-concentrated aqueous ammonia (20:1:0.1), and chromatographed with 23,4'-dideoxy-23-hexamethylene. Imino mycaminocil tylonolide was obtained. Yield 52.4 mg (yield 97%) (recrystallized from acetone-n-hexane, recrystallization yield 80%)

[Table] ^D
Example 24 (a) 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal
Dissolve 70.0mg in 1.4ml of anhydrous acetonitrile, add 51.8mg of heptamethyleneimino, and heat at 80℃.
After reacting for 2.5 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in 3.5 ml of chloroform, washed once with 1 ml of saturated aqueous sodium bicarbonate solution and twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (b) Dissolve the residue in 1.4 ml of acetonitrile,
2.8 ml of 0.1N hydrochloric acid aqueous solution was added and reacted for 60 minutes. 30 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 1.5 ml of chloroform. The chloroform layers were combined, washed once with 1.5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a 7 g silica gel (Kieselgel 60, 230-400 mesh) column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (20:1:0.1) to obtain 23,4'-dideoxy-23-pepyl. Tamethylene imino mycaminosyl tylonolide was obtained. Yield 58.5mg (yield 95%)

【table】 '''

[Table] ^D
Example 25 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethylacetal64.0
mg was dissolved in 1.3 ml of anhydrous acetonitrile, 76.8 mg of dodecamethyleneimine was added, and the mixture was reacted at 80°C for 24 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure. The residue was dissolved in 3.2 ml of chloroform, washed once each with 1 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. residue
It was dissolved in 1.3 ml of acetonitrile, 2.5 ml of 0.1N hydrochloric acid aqueous solution was added, and the reaction was carried out for 60 minutes to remove diethylacetalization. After the reaction was completed, 28 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 1.5 ml of chloroform. Combine the chloroform layers, 1.5
The mixture was washed twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. Pour the residue into 7 g of silica gel (Kieselgel60, 230-
400 mesh) on the column, solvent system chloroform-
Chromatography was performed with methanol-concentrated ammonia water (20:1:0.1), and 23,4'-dideoxy-23-
Dodecamethyleneimino mycaminosyl tylonolide was obtained. Yield 50.2mg (yield 80%)

[Table] ^D
Example 26 Dissolve 970 mg of 23,4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal in 19 ml of anhydrous acetonitrile,
mg of isopropylamine was added and heated at 78°C overnight. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 9 ml of acetonitrile, 38 ml of 0.1N hydrochloric acid was added, and the mixture was allowed to stand at room temperature for 60 minutes. 373 mg of sodium hydrogen carbonate was added to the reaction solution, extracted three times with chloroform, and the chloroform layers were combined and washed with a saturated aqueous sodium sulfate solution. The residue obtained by distilling off the solvent was developed using chloroform-methanol-28% aqueous ammonia (15:
23,4'-dideoxy-23-
280 mg (yield 35%) of mycaminosyl tylonolide (isopropylamino) was obtained.

[Table] Example 27 Dissolve 2g of 23,4'-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal in 40ml of anhydrous acetonitrile to obtain 953mg.
of t-butylamine was added, and the mixture was heated at 80°C for 1 day. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 9.3 ml of acetonitrile, 39 ml of 0.2N hydrochloric acid was added, and the mixture was allowed to stand at room temperature for 60 minutes. 330 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with chloroform. The chloroform layers were combined, washed with a saturated aqueous sodium sulfate solution, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was separated and purified using a silica gel column with a developing system of chloroform-methanol-28% aqueous ammonia (15:1:0.1) to obtain 23,4'-dideoxy-23-(t- 1.12 g (yield: 67%) of mycaminosyl (butylamino) tylonolide was obtained.

[Table] Example 28 Dissolve 1.28 g of 23,4'-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal in 26 ml of anhydrous acetonitrile,
mg of neopentylamine was added, and the mixture was heated at 80°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 6 ml of acetonitrile, 50 ml of 0.1N hydrochloric acid was added, and the mixture was allowed to stand for 60 minutes.
460 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with chloroform. The chloroform layers were combined, washed with a saturated aqueous sodium sulfate solution, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was developed with chloroform-methanol-28
% aqueous ammonia (15:1:0.1) on a silica gel column to obtain 23,4′-dideoxy-23-
480 mg (yield 44%) of neopentylamino mycaminosyl tylonolide was obtained.

【table】

[Table] Example 29 23-deoxy-23-iodo mycaminosyl
Tyronolide diethylacetal 190mg 3.8
ml of anhydrous acetonitrile, 120 mg of hexamethyleneimine was added, and the mixture was heated under reflux for 60 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 1.9 ml of acetonitrile, 6.4 ml of 0.1N hydrochloric acid was added, and after standing for 60 minutes, 55 mg of sodium hydrogen carbonate was added and extracted three times with chloroform. The chloroform layers were combined, washed once with a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in 19 g of silica gel (Kieselgel, 230-
400 mesh) on the column, solvent system chloroform-
Methanol-28% ammonia water (15:1:0.1)
128 mg of 23-deoxy-23-hexamethyleneimino mycaminosyl tylonolide
(yield 78%).

[Table] ^D
Example 30 23-deoxy-23-iodo mycaminosyl
Tylonolide diethylacetal (930 mg) was dissolved in acetonitrile (19 ml), heptamethyleneimine (672 mg) was added, and the mixture was heated under reflux for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in 4.6 ml of acetonitrile, 14 ml of 0.2N hydrochloric acid was added, and the mixture was left at room temperature for 1 hour. The reaction solution was made weakly basic by adding sodium bicarbonate, extracted with chloroform, washed with water, dried over saturated sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in the solvent system chloroform-methanol-28% aqueous ammonia (15:
1:0.1) to obtain 370 mg (yield: 45%) of 23-deoxy-23-heptamethyleneimino mycaminosyl tylonolide as a colorless solid.

[Table] Example 31 23-amino-23,4'-dideoxy mycaminocil tylonolide diethylacetal 65mg
was dissolved in 1.5 ml of anhydrous acetonitrile, 63 mg of methyl iodide was added, and the mixture was reacted at 80°C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with 3 ml of chloroform.
The mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Dissolve the residue in 1.5 ml of acetonitrile,
After adding 4 ml of 0.1N hydrochloric acid and allowing the mixture to stand at room temperature for 1 hour, 3 ml of saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with 3 ml of chloroform. The extract was washed with 3 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluent: chloroform]
Methanol-28% ammonia water (18:1:01)]
10 mg of 23,4'-dideoxy-23-dimethylamino mycaminosyl tylonolide was obtained. The physicochemical properties of this compound were consistent with the physicochemical properties of the target product in Example 13. Example 32 23-amino-23,4'-dideoxy mycaminocil tylonolide diethylacetal 66mg
Dissolve tert bromide in 6.6 ml of anhydrous acetonitrile.
-14 mg of butyl was added and stirred at 80°C for 1 hour.
The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 3 ml of chloroform.
After extraction, the extract was washed twice with 2 ml of a saturated aqueous sodium bicarbonate solution, then washed with 2 ml of a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluent: chloroform-methanol-
28% aqueous ammonia (30:1:01)], the obtained product was dissolved in 0.5 ml of acetonitrile,
1.4 ml of 0.1N hydrochloric acid was added and left at room temperature for 1 hour.
1 ml of a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with 1.5 ml of chloroform. The extract was washed with 1 ml of a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluent: chloroform-methanol-28% aqueous ammonia (15:
1:0.1)], 23,4'-dideoxy-23-
21 mg of tert-butylamino mycaminosyl tylonolide was obtained. The physicochemical properties of this compound were consistent with the objective physicochemical properties of Example 27.

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is an amino group, a mono- or di-lower alkylamino group, or a group represented by the formula [Formula] (wherein n represents an integer from 2 to 20), and R ₂ is a hydrogen atom or R 3 represents a hydroxyl group, and R ₃ represents an aldehyde group which may have a protecting group. ] Tylosin derivative represented by.