JPS6316394B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel mycaminosyl tylonolide derivatives, more specifically, the general formula [In the formula, R is a hydroxyl group, a halogen atom, or a formula

[Formula] (wherein R ₁ and R ₂ are the same or different and represent a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, or _a cycloalkyl group having 5 _to 10 carbon atoms. may be bonded to each other to form an alkylene group having 3 to 20 carbon atoms. ] The present invention relates to a 19-decarbonyl-4'-deoxymycaminosyl tylonolide derivative represented by the following. The lower alkyl group mentioned above means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, a butyl group, a hexyl group, and the like. Examples of halogen atoms include chlorine, iodine, and bromine; examples of aryl groups include phenyl and naphthyl; and examples of aralkyl include benzyl, phenethyl, and phenylpropyl. etc. The compound of the present invention exhibits excellent antibacterial activity, particularly strong antibacterial activity against Gram-negative bacteria, and is a useful compound as an antibacterial agent. As a result of intensive research on macrolide compounds, the present inventors have developed a compound in which the 4'-position of mycaminosyl tylonolide is deoxylated and the 19-position is decarbonylated, and a compound in which a halogen atom or an amino substituent is added to the 22-position. The present invention was completed based on the discovery that the compound has excellent antibacterial activity. The compound of the present invention can be produced by the following method. 1st Production Method A compound in which R is a hydroxyl group in the general formula [] has the structural formula It can be produced by reacting 4'-deoxy mycaminosyl tylonolide represented by chlorotris(triphenylphosphine)rhodium [C ₆ H ₅ ) ₃ P] ₃ RhCl. This reaction is preferably carried out in an organic solvent such as benzene, toluene, or xylene at room temperature or with heating, preferably under a nitrogen stream. Second Production Method A compound in which R is a halogen atom in the general formula [] has the structural formula obtained by the first production method. It can be produced by halogenating 19-decarbonyl-4'-deoxymycaminosyl tylonolide represented by: This halogenation is preferably carried out at room temperature or under cooling, preferably under ice cooling, using a halogenating agent such as chlorine, bromine, iodine, carbon tetrachloride, carbon tetrabromide, carbon tetraiodide, or the like. Addition of triphenylphosphine and, if necessary, a base such as pyridine is preferred for promoting the reaction. Some of these additives can also serve as a solvent, and if necessary, solvents such as pyridine, acetonitrile, tetrahydrofuran, and dioxane may be used alone or in an appropriate mixture. Third manufacturing method In the general formula [], R is the formula

The compound that is a group represented by [Formula] has the structural formula obtained by the second production method. (In the formula, X represents a halogen atom.) 19-decarbonyl-22,4'-dideoxy-22-halogenomycaminosyl tylonolide and the general formula It can be produced by reacting with the amine shown below. This reaction is preferably carried out in an organic solvent such as tetrahydrofuran, acetonitrile, dioxane, dimethylformamide, dimethyl sulfoxide, etc. at room temperature or under heating. Next, the present invention will be explained in more detail by reference examples (preparation of starting materials) and examples. Reference example 1 (a) Mycaminocil tylonolide 825mg 8.3
ml of anhydrous ethanol, and while stirring under ice cooling, 356 mg of anhydrous p-toluenesulfonic acid was added, and after returning to room temperature, the mixture was reacted for 20 minutes. The reaction solution was ice-cooled again, 0.3 ml of triethylamine was added, and then concentrated under reduced pressure. The residue was dissolved in 41 ml of chloroform and washed once each with 10 ml of a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous sodium chloride solution, and water, and the chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. residue
Chromatography was performed on a 40 g silica gel column using a solvent system of chloroform-methanol (7:1) to obtain mycaminosyl tylonolide diethyl acetal. Yield: 852 mg (yield: 92%) (b) Dissolve 510 mg of the product from (a) above in 2.6 ml of acetonitrile, and add 0.16 mg of acetic anhydride with stirring at room temperature.
ml was added and allowed to react for 30 minutes. The reaction solution was concentrated and well azeotroped with toluene to remove excess acetic anhydride and acetic acid, then dissolved in 50 ml of chloroform, washed once each with 25 ml of saturated aqueous sodium bicarbonate solution and water, and dissolved with anhydrous sodium sulfate. After drying, it was concentrated under reduced pressure to obtain 2',4'-di-O-acetyl mycaminosyl tylonolide diethyl acetal (quantitative). (c) 574 mg of the product from (b) above was dissolved in anhydrous methylene chloride.
The mixture was dissolved in 11.5 ml, and while stirring under ice cooling, 590 mg of diisopropylethylamine was added, and then 367 mg of chloromethyl methyl ether was added, the temperature was returned to room temperature, and the reaction was allowed to proceed for 1 day. The reaction solution was poured into 29 ml of a saturated aqueous sodium hydrogen carbonate solution, and while washing the reaction vessel with 10 ml of chloroform, the mixture was added thereto and extracted. Add another 10 ml of chloroform.
Repeat the extraction twice, combine the chloroform layers,
Wash once each with 15 ml of saturated aqueous sodium chloride solution and water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 3,23-di-O-methoxymethyl-2',4'-di-O-acetyl mycaminocil. Tyronolide diethyl acetal was obtained (quantitative). (d) When 641 mg of the product from (c) above was dissolved in 30 ml of methanol and reacted overnight at 50°C, the acetyl groups at the 2' and 4' positions were eliminated and the 3,23-di-O-methoxy Methyl mycaminosyl tylonolide diethyl acetal was obtained. Yield 509mg
(Yield 88%). (e) After dissolving 489 mg of the product in (d) above in 9.8 ml of anhydrous pyridine, 185 mg of benzylsulfonyl chloride was slowly added while stirring at -40°C (approx.
minutes) and reacted for 2 hours. Next, 0.02 ml of water was added at -40°C, and the mixture was allowed to react at room temperature for 30 minutes to decompose excess benzylsulfonyl chloride.
After concentration under reduced pressure, pyridine was azeotroped well with toluene. Dissolve the reaction solution in 25 ml of chloroform and dilute for 10
Wash once each with 1 ml of saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, and water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure.
3,23-di-O-methoxymethyl-4'-O-benzylsulfonyl mycaminosyl tylonolide diethylacetal was obtained. Since this substance was unstable, the next reaction was carried out as it was. Yield approximately 80% (f) Dissolve 588 mg of the product from (e) above in 12 ml of anhydrous methyl ethyl ketone and add 145 mg of sodium iodide.
was added, the tube was sealed tightly, and the mixture was allowed to react at 80°C for 20 minutes. After the reaction was completed, the precipitated solid was filtered through a glass filter, washed several times with acetone, and then concentrated under reduced pressure. When 20 ml of chloroform was added to the residue, a precipitate formed again, so this too was filtered through a glass filter. After washing the solid several times with chloroform, the chloroform layer was mixed with 8 ml of saturated aqueous sodium bicarbonate solution, 0.1 M aqueous sodium thiosulfate solution and The mixture was washed once with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was chromatographed on a 25 g silica gel column using a solvent system of cyclohexane-acetone (7:3).
3,23-di-O-methoxymethyl-4'-deoxy-4'-iodo mycaminosyl tylonolide diethylacetanol was obtained. Yield 452
mg (g) 452 mg of the product from (f) above was dissolved in 9 ml of anhydrous benzene, 445 mg of tri-n-butyltin hydride,
Next, 8.2 mg of α,α'-azobisisobutyronitrile as a reaction initiator was added, the mixture was tightly stoppered under a nitrogen stream, and the mixture was allowed to react at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, developed on a 40 g silica gel column with a solvent system of cyclohexane-acetone (4:1), and the tri-n-butyltin compound was eluted (flowing 250 ml).
After that, the system was diluted with chloroform-methanol (9:
Convert to 1), perform chromatography, and obtain 3,23-
Di-O-methoxymethyl-4'-deoxy mycaminosyl tylonolide diethyl acetal was obtained. Yield: 311 mg (yield: 82%) (h) Dissolve 45.5 mg of the product from (g) above in 0.23 ml of dioxane, and add 2.3 ml of 10% trifluoroacetic acid aqueous solution.
was added, and the reaction was carried out at room temperature for 2 days. Next, 301 mg of sodium hydrogen carbonate was slowly added to neutralize the mixture, and the mixture was extracted three times with 1 ml of chloroform. The chloroform layers were combined, washed once each with 1 ml of saturated aqueous sodium chloride solution and once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After putting the residue in the same system on a column packed with 4 g of silica gel in a solvent system of chloroform-methanol-concentrated aqueous ammonia (30:1:0.1), the system was packed with chloroform-methanol-concentrated aqueous ammonia (8:1).
1:0.1), chromatography, and 4'-
Deoxy mycaminosyl tylonolide was obtained. Yield 26.0mg (yield 73%) Physical and chemical properties

【table】

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) 2960 -CH ₃ 2930 -CH ₂ - 1730 -COO- 1680 >C=O 1590 -C=C-C=C- (iii) Colorless Amorphous solid (purified from acetone-n-hexane) (iv) Elemental analysis values (as C ₃₁ N ₅₁ NO ₉ ) C (%) H (%) N (%) Theoretical value 64.00 8.84 2.41 Experimental value 63.72 8.81 2.21 ( v) [α] ²⁵ _D −12 (c1.2, CHCl) ₃ (vi) Ultraviolet absorption spectrum λ ^MeOH _nax 282.5 (ε=
21000) (vii) Rf0.39 Wakogel B-5 (trade name) Chloroform-methanol (6:1) Example 1 Dissolve 344 mg of 4'-deoxy mycaminosyl tylonolide in 8.6 ml of anhydrous benzene and add chlorotris (triphenylphosphine) in a nitrogen stream.
The rhodium was suspended and heated at 80° C. with stirring for 12 hours. The reaction solution was filtered and extracted three times with 9 ml of 1N hydrochloric acid, and the aqueous layer was made basic with 10% aqueous sodium hydroxide solution and extracted with 10 ml of chloroform three times.
Extracted twice. The chloroform layers were combined, washed three times with 10 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified on a silica gel column using a solvent system of chloroform-methanol (10:1) to obtain 19-decarbonyl-4'-deoxy mycaminosyl tylonolide. Yield 166.1 mg (yield 51%) Recrystallized from acetone-n-hexane Physical and chemical properties

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ − 1700 −COO− 1675 >C=O 1590 −C=C−C=C− (iii ) Colorless prismatic crystal (recrystallized from acetone-n-hexane) (iv) Melting point 181-183℃ (v) Elemental analysis value (as C ₃₀ H ₅₁ NO ₈・H ₂ O) C (%) H (%) N (%) Calculated value 63.02 9.34 2.45 Experimental value 62.95 9.14 2.34 (vi) [α] ²⁵ _D +35° (c1.0, CHCl ₃ ) (vii) Ultraviolet absorption spectrum λ ^MeOH _nax 282 nm (ε=
23000) Example 2 88.7 mg of 19-decarbonyl-4'-deoxy mycaminosyl tylonolide obtained in Example 1
was dissolved in 4.4 ml of anhydrous pyridine, 92.2 mg of triphenylphosphine was added, and 91.3 mg of carbon tetraiodide was added while stirring under ice cooling, followed by stirring for 90 minutes under ice cooling. After terminating the reaction by adding 0.06 ml of methanol to the reaction solution, the solvent was distilled off. (Pyridine was removed by azeotropic distillation several times with toluene.) The residue was dissolved in chloroform, and after removing insoluble matter, the chloroform layer was dissolved in a saturated aqueous sodium bicarbonate solution, a 0.1M aqueous sodium thiosulfate solution, and a saturated aqueous sodium sulfate solution. After washing once each and drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified on a silica gel column using the solvent system chloroform-methanol to obtain 19-decarbonyl-22,4'-deoxy-
22-Iodomycaminosyl tylonolide was obtained. Yield 94.4 mg (yield 89%) Recrystallized from acetone-n-hexane Physical and chemical properties

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ − 1710 −COO− 1680 >C=O 1590 −C=C−C=C− (iii ) Colorless needle crystals (recrystallized from acetone-n-hexane) (iv) Melting point 209-210℃ (v) Elemental analysis values (as C ₃₀ H ₅₀ NO ₇ I) C(%) H(%) N(% ) I(%) Calculated value 54.30 7.59 2.11 19.12 Experimental value 54.58 7.51 2.31 19.25 (vi) [α] ²⁵ _D +97° (c1.0, CHCl ₃ ) (vii) Ultraviolet absorption spectrum λ ^MeOH _nax 282 nm (ε=
24000) Example 3 19-decarbonyl-22 obtained in Example 2,
4'-dideoxy-22-iodo mycaminosyl
63.6 mg of tylonolide was dissolved in 1.3 ml of anhydrous acetonitrile, and 0.24 ml of about 4M dimethylamine-acetonitrile solution was added. Seal tightly and heat at 80℃.
After heating for 30 minutes, 0.24 ml of the above solution was further added and heated for 30 minutes. After evaporating the solvent, the residue was dissolved in chloroform, and the chloroform layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was dissolved in the solvent system chloroform methanol-28% ammonia aqueous solution (25:1:
Purify with a silica gel column using 19-
Decarbonyl-22,4'-dideoxy-22-dimethylamino mycaminosyl tylonolide was obtained. Yield 47.8mg (yield 86%) Physical and chemical properties

【table】

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) Attribution 2980 −CH ₃ 2950 −CH ₂ − 1730 −COO− 1680 >C=O 1595 −C=C−C=C− (iii ) Colorless amorphous solid (recrystallized from acetone-n-hexane) (iv) Elemental analysis value (as C ₃₂ H ₅₆ N ₂ O ₇ ) C (%) H (%) N (%) Calculated value 66.18 9.72 4.82 Experiment Value 65.94 9.43 4.60 (v) [α] ²⁵ _D +74° (c1.0, CHCl ₃ ) (vi) Ultraviolet absorption spectrum λ ^MeOH _nax 283 nm (ε=
22000) Example 4 19-decarbonyl-22,4'-dideoxy-22-
Iodo Mycaminocil Tyronolide 78.5mg
was dissolved in 1.6 ml of anhydrous acetonitrile, 76 mg of diisobutylamine was added, and the mixture was heated at 80°C for 2 days. After evaporating the solvent, the residue was dissolved in 4 ml of chloroform, and the chloroform layer was washed with 2 ml of saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified with a silica gel column using a solvent system of chloroform-methanol-28% ammonia aqueous solution (25:1:0.1) to obtain 19-decarbonyl-22,4'-dideoxy-22-diisobutylamino mycaminosyl tylonolide. . Yield 59.5 mg (yield
76%) Physical and chemical properties

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) Attribution 2980 −CH ₃ 2950 −CH ₂ − 1730 −COO− 1680 >C=O 1595 −C=C−C=C− (iii ) Elemental analysis value (as C ₃₆ H ₆₈ N ₂ O ₇ ) C (%) H (%) N (%) Calculated value 68.64 10.31 4.21 Experimental value 68.52 10.21 4.33 (iv) [α] ²³ _D +55° (c1. 0, CHCl ₃ ) (v) Ultraviolet absorption spectrum λ ^MeOH _nax 285 nm (ε=
23000) Example 5 19-decarbonyl-22,4'-dideoxy-22-
Iodo Mycaminocil Tyronolide 82.5mg
was dissolved in 1.7 ml of anhydrous acetonitrile, 52.3 mg of piperidine was added, and the mixture was heated at 80°C for 60 minutes. After evaporating the solvent, the residue was dissolved in 4 ml of chloroform, washed with 2 ml of saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was dissolved in a solvent system of chloroform-methanol-28% ammonia aqueous solution (25:1:0.1).
19-decarbonyl-22,4'-dideoxy-22-piperidino
I got mycaminocil tylonolide. yield
70.7mg (yield 92%) Physical and chemical properties

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) Attribution 2980 −CH ₃ 2950 −CH ₂ − 1730 −COO− 1680 >C=O 1600 −C=C−C=C− (iii ) Colorless solid (iv) Elemental analysis value (as C ₃₅ H ₆₀ N ₂ O ₇ ) C (%) H (%) N (%) Calculated value 67.71 9.74 4.51 Experimental value 67.65 9.62 4.66 (v) [α] ²² _D +42゜(c1.0, CHCl ₃ ) (vi) Ultraviolet absorption spectrum λ ^MeOH _nax 284nm (ε=
25000) Example 6 19-decarbonyl-22,4'-dideoxy-22-
Iodine Mycaminocil Tyronolide 84mg
The mixture was dissolved in 1.7 ml of anhydrous acetonitrile, 72 mg of N-methylcyclohexylamine was added, and the mixture was heated at 80°C for 4 hours. After evaporating the solvent, the residue was dissolved in 5 ml of chloroform, washed with 2 ml of saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified with a silica gel column using a solvent system of chloroform-methanol-28% ammonia aqueous solution (25:1:0.1) to obtain 19-decarbonyl-22,4'-dideoxy-22-(N-methylcyclohexylamino). I got mycaminocil tylonolide. Yield 77.7mg (yield 92%) Physical and chemical properties

【table】

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) Attribution 2980 −CH ₃ 2950 −CH ₂ − 1730 −COO− 1680 >C=O 1600 −C=C−C=C− (iii ) Colorless solid (iv) Elemental analysis value (as C ₃₇ H ₆₅ N ₂ O ₇ ) C (%) H (%) N (%) Calculated value 68.49 9.94 4.32 Experimental value 68.27 9.83 4.51 (v) [α] ²² _D +77゜(c1.0, CHCl ₃ ) (vi) Ultraviolet absorption spectrum λ ^MeOH _nax 284nm (ε=
25000) Example 7 19-decarbonyl-22,4'-dideoxy-22-
Iodo Mycaminocil Tyronolide 94.3mg
was dissolved in 2 ml of anhydrous acetonitrile, 86 mg of N-methylbenzylamine was added, and the mixture was heated at 80°C for 3 hours. After evaporating the solvent, the residue was dissolved in 5 ml of chloroform, washed with 2 ml of saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified on a silica gel column using a solvent system of chloroform-methanol-28% ammonia aqueous solution (25:1:0.1) to give 19-decarbonyl-22,4'-dideoxy-22
-(N-methylbenzylamino)mycaminosyltylonolide was obtained. Yield 81mg (yield 87%) Physical and chemical properties

[Table] (ii) Infrared absorption spectrum (KBr) WN (cm ^-1 ) Attribution 2980 −CH ₃ 2950 −CH ₂ − 1730 −COO− 1680 >C=O 1595 −C=C−C=C− (iii ) Colorless solid (iv) Elemental analysis value (as C ₃₈ H ₆₀ N ₂ O ₇ ) C (%) H (%) N (%) Calculated value 69.48 9.21 4.26 Experimental value 69.20 9.11 4.32 (v) [α] ²³ _D +32゜(c1.0, CHCl ₃ ) (vi) Ultraviolet absorption spectrum λ ^MeOH _nax 284nm (ε=
26000)

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydroxyl group, a halogen atom, or [Formula] (wherein, R ₁ and R ₂ are the same or different and are a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, or a cyclocarbon group having 5 to 10 carbon atoms. represents an alkyl group. R ₁ and R ₂ may be bonded to each other to form an alkylene group having 3 to 20 carbon atoms. ] A 19-decarbonyl-4'-deoxy mycaminosyl tylonolide derivative represented by: