JPH0430399B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel 14-substituted carbamoyl-14-
The present invention relates to a de(hydroxymethyl)-mycaminosyltylonolide derivative and a method for producing the same. More specifically, the present invention provides the formula (In the formula, R is a hydrogen atom or a hydroxyl group, R ₁ is a lower alkyl group or a phenyl-lower alkyl group,
R ₂ represents a hydrogen atom or a lower alkyl group. ) or a salt thereof. The present invention also provides the formula (In the formula, R ₃ is a hydrogen atom or -OR ₄ group, R ₄ is a hydroxyl protecting group, R ₅ and R ₆ each represent a lower alkyl group, or together represent a lower alkylene group) formula the compound (In the formula, R ₁ and R ₂ have the same meanings as above)
Also included is a method for producing a compound represented by formula [1] or a salt thereof, which is characterized by amidation with an amine represented by formula [1], followed by removal of a protecting group for a hydroxyl group and deacetalization. The above salts are pharmaceutically acceptable salts.
Such suitable salts include salts with inorganic acids such as hydrochloric, sulfuric, and phosphoric acids, and salts with organic acids such as acetic, propionic, tartaric, citric, succinic, malic, aspartic, and glutamic acids. is included. Other non-toxic salts are also included. The above novel compound [1] has stronger antibacterial activity against Gram-positive bacteria than the known tylosin, and is an antibacterial agent that is expected to have excellent clinical therapeutic effects not only as an oral agent but also as an injectable agent. It is very useful as a drug. It is also useful as a therapeutic agent for animal infections, and as a feed additive for preventing infection or promoting growth. When naming compounds according to the present invention, the formula In the case where R is a hydroxyl group, O-mycaminosyltylonolide (O-
mycaminosyltylonolide [Tetrahedron Letters,
4737-4740 (1970)], when R is a hydrogen atom, 4'-deoxy-O-mycaminosyltylonolide [J. Antibiotics, 34 (10), 1374-1376
(1981)]. The starting material [6] used in the present invention has the formula (wherein R ₃ , R ₄ , R ₅ and R ₆ have the same meanings as above) -CHO of the compound represented by -
Obtained by oxidation to COOH. The intermediate [5] is a compound obtained by protecting the hydroxyl group at the 2' and 4' positions or the hydroxyl group at the 2' position with an appropriate protecting group, and protecting the aldehyde group by acetalization. (wherein R ₃ , R ₄ , R ₅ and R ₆ have the same meanings as above) -CH ₂ OH of the compound represented by -
Obtained by oxidation to CHO. In the above method, the aldehyde group may be first protected by acetalization, and then the hydroxyl protecting group may be protected. Examples of the above-mentioned protecting group for the hydroxyl group include lower alkanoyl groups such as acetyl, propionyl, and butyryl, and halogenated acetyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl, with the acetyl group being particularly preferred. Introduction of the acetyl group is carried out by reacting the compound [2] with acetic anhydride in an inert organic solvent, such as dichloromethane, chloroform, or acetone.
The reaction proceeds satisfactorily at room temperature. Since the progress of the reaction can be monitored by thin layer chromatography (TLC) using silica gel or the like, high performance liquid chromatography (HPLC), etc., the reaction can be appropriately terminated after waiting for the disappearance of the compound [2]. Formula obtained from reaction solution To collect the compound represented by (wherein R ₃ and R ₄ have the same meanings as above), water is added to the reaction solution, and a non-hydrophilic organic solvent such as chloroform is used under alkalinity of pH 8 to 9.5. This is done by extraction with dichloroethane, methyl isobutyl ketone, ethyl acetate, butyl acetate, etc. If further purification is required, column chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin and elution with an appropriate solvent such as a benzene-acetone solvent or a chloroform-methanol solvent is performed. Can be purified. Examples of the production of the above compound [3] include JP-A-57-5000, JP-A-58-140096,
It is described in Japanese Patent Application No. 57-78895, Japanese Patent Application No. 57-78898, etc. The above acetalization is performed on compound [3] by a known acetalization method. For example, it is carried out by reacting a lower alcohol such as methanol or ethanol, or a lower glycol such as ethylene glycol or propylene glycol in the presence of an acid such as trifluoroacetic acid, trichloroacetic acid, or p-toluenesulfonic acid. The obtained acetal [4] can be separated and purified from the reaction solution in the same manner as the method for separating and purifying the compound [3] described above. An example of the production of the acetal [4] is described in Japanese Patent Application Laid-Open No. 57-28100, Japanese Patent Application No. 57-78897, etc. The oxidation reaction of -CH ₂ OH of acetal [4] to -CHO is performed by converting the reaction product of (CH ₃ ) ₂ S and N-chlorosuccinimide into acetal [4] in an inert organic solvent such as dichloromethane, benzene, or toluene. ] or react the reaction product of (CH ₃ ) ₂ SO with p-toluenesulfonyl chloride, p-toluenesulfonic anhydride or methanesulfonic anhydride in an organic solvent such as hexamethylphosphoramide to form an acetal [ 4], or acetal [4] and (CH ₃ ) ₂ SO are reacted with N,N'-dicyclohexylcarbodiimide (DCC) in the presence of trifluoroacetic acid, and the resulting sulfoxonium salt is reacted with triethylamine. , by treatment with a base such as ammonia. The obtained intermediate substance [5] can be separated and purified from the reaction solution in the same manner as the method for separating and purifying the compound [3] described above. To oxidize -CHO of intermediate [5] to -COOH to obtain starting material [6], an alkali chlorite, e.g.
Performed by NaClO2 oxidation. The above reaction was performed by TLC,
Since it can be tracked by HPLC, etc., the reaction can be appropriately terminated after waiting for the disappearance of the intermediate substance [5]. To obtain the starting material [6] from the above reaction solution, the reaction solution is PH-PHENED with an alkaline aqueous solution, such as aqueous ammonia.
5 to 7, extraction is performed with a non-hydrophilic organic solvent such as chloroform, and the solvent is distilled off. Next, the carboxyl group of the starting material [6] is amidated using a known amidation method. A particularly preferred amidation method includes a mixed acid anhydride method. For example, starting material [6]
is reacted with a chloroformate such as ethyl chloroformate in an inert organic solvent in the presence of a tertiary organic amine, and then the formula (In the formula, R ₁ and R ₂ have the same meanings as above)
What is necessary is to react an amine represented by Examples of the amine [7] include known primary organic amines. Examples include alkylamines and aralkylamines. Also included are secondary amines having an N-lower alkyl group in the above-mentioned primary amine. The above amidation reaction proceeds sufficiently at room temperature,
Since it can be traced by TLC, HPLC, etc., the reaction product, i.e. the formula (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ have the same meanings as above) The reaction may be terminated as appropriate by waiting until the maximum amount of the compound is produced. . Compound [8] can be separated and purified from the reaction solution in the same manner as the method for separating and purifying compound [3] described above. Next, the hydroxyl protecting group, particularly the acetyl group, of compound [8] is removed by heat treatment in a lower alcohol which may contain water. Methanol is a lower alcohol,
Examples include ethanol, but methanol is particularly preferred. Since the above reaction can be monitored by TLC, HPLC, etc., the reaction can be appropriately terminated after waiting for the disappearance of compound [8]. Deacetalization is carried out by hydrolysis with acidic water. This deacetalization may be performed before the step of removing the hydroxyl protecting group. To collect the target product [1] from the reaction solution, the pH is adjusted to 9 to 10 with an alkaline aqueous solution, such as aqueous ammonia, extraction is performed with a non-hydrophilic organic solvent, such as chloroform, and the solvent is distilled off. If further purification is required, it can be carried out by known means for separating and purifying macrolide antibiotics, such as chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin. Next, the results of measuring the minimum inhibitory concentration (MIC) of the target compound [1] of the present invention are as follows.
As shown in the table. The symbols in the table have the following meanings. A: 14-butylcarbamoyl-14-de(hydroxymethyl)-O-mycaminosyltylonolide (target compound [1] where R ₁ = butyl, R ₂ = H, R = OH) B: 14-benzyl Carbamoyl-14-te(hydroxymethyl-O-mycaminosyltylonolide (target compound [1] where R ₁ = benzyl, R ₂ = H, R=OH) C; 14-(N-methyl-benzylcarbamoyl )−
14-de(hydroxymethyl)-O-mycaminosyltylonolide (target compound [1] where R ₁ = benzyl, R ₂ = methyl, R = OH) *; Macrolide-resistant group A bacteria (erythromycin, olefin) andmycin, 16-membered ring maschloride antibiotic-resistant patient isolates)

[Table] Next, production examples of the present invention will be specifically explained with reference to reference examples and examples. Note that the R values in Reference Examples and Examples were measured by TLC using the following carrier and developing solvent unless otherwise specified. Carrier: DC-Fertigplatten manufactured by Merck & Co.
kieselgel 60F ₂₅₄ , Art5715 Developing solvent; a; Benzene-acetone (3:1) b; Benzene-acetone (5:1) c; Chloroform-methanol-concentrated aqueous ammonia (100:10:1) d; Chloroform-methanol ( 3:1) Reference example 1 2',4'-di-O-acetyl-O-mycaminosyl tylonolide dimethyl acetal 2',4'-di-O-acetyl-O-mycaminosyl tylonolide 4.23g was dissolved in 27 ml of methanol, 3 ml of trifluoroacetic acid was added thereto under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 7% aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water, passed through Watzmann 1PS paper, and dried under reduced pressure to obtain 3.96 g of 2',4'-di-O-acetyl-O-mycaminosyltylonolide dimethyl acetal as a foamy solid. . TLC; Rfa=0.35, Rfb=0.15 Reference example 2 2',4'-di-O-acetyl-23-didihydro-
O-Mycaminosyl tylonolide dimethyl acetal 1.37 g of N-chlorosuccinimide was dissolved in 40 ml of dry dichloromethane, and 1.03 ml of dimethyl sulfide was quickly added to this under ice cooling, resulting in a white precipitate. The reaction mixture was cooled to -25°C under a stream of argon gas and mixed with 2',4'-di-O-acetyl-O-mycaminosyltylonolide, dimethyl acetal.
A solution of 5.0 g in dry dichloromethane (10 ml) was added over 10 minutes and stirred at -25°C for 2 hours without moisture. To this reaction solution was added 2 ml of a methylene chloride solution containing 0.24 ml of triethylamine, and the mixture was stirred for 5 minutes.
The resulting reaction solution was returned to room temperature, 50 ml of water was added, and the mixture was separated. Watmann dichloromethane layer
After passing through 1PS paper, it was concentrated under reduced pressure. The residue was charged to a 100 g column of silica gel (Merck & Co., Art 7734), and column chromatography was performed by eluting with benzene-acetone (12:1).
Fractions around Ra=0.53 were collected and concentrated under reduced pressure to obtain 2.6 g of the title compound. PMR (CDCl ₃ , 100MHz) δ ^TMS _ppn ; 1.86 (s, 3H,
12−CH ₃ ), 2.06 (s., 6H, OCOCH ₃ ×2), 2.35
(s., 6H, -N(CH ₃ ) ₂ ), 3.22 (s., 3H, OCH ₃ ),
3.29 (s., 3H, OCH ₃ ), 4.39 (d., 1H, H-1′),
4.50 (dd, 1H, H-20), 4.77 (t., 1H, H-4′)
,
4.91 (dd, 1H, H-2'), 5.25 (dt, 1H, H-
15), 5.82 (d., 1H, H-13), 6.37 (d., 1H, H-
10), 7.29 (d., 1H, H-11), 9.69 (d., 1H,
CHO, J=2.7) Mass (CI, isobutane); 726 (MH ⁺ , very small), 694 (MH ⁺ −32), 676, 664, 662 (694 −
32), 258, 216, 156, 129 Reference example 3 2',4'-di-O-acetyl-14-carboxy-
14-de(hydroxymethyl)-O-mycaminosyltyloride dimethyl acetal 2',4'-di-O-acetyl-23-didihydro-
Dissolve 2.6 g of O-mycaminosyltylonolide dimethyl acetal in 36 ml of acetone and add to this.
Add 17.9 ml of 0.3M sulfamic acid aqueous solution and 19.3 ml of 0.2M sodium chlorite aqueous solution, and stir at room temperature for 30 minutes.
Stir for a minute. Adjust the reaction solution to pH5~ with dilute ammonia water.
6 and extracted twice with 100 ml of chloroform. The extract was dried over anhydrous magnesium sulfate and then dried under reduced pressure to obtain 2.5 g of the title compound. TLC; Rfa=0, Rfd=0.66 PMR (CDCl ₃ , 100MHz) δ ^TMS _ppn ; 1.81 (s, 3H),
2.06, 2.07 (each s., 3H, OCOCH ₃ ), 2.38 (s., 6H,
-N( _CH3 ) ₂ ), 3.22(s., 3H, _OCH3 ), 3.29(s.,
3H, OCH ₃ ), 4.40 (d., 1H, H-1′), 4.51 (br.t.,
1H, H-20), 4.79 (t., 1H, H-4'), 4.93 (dd
，
1H, H-2'), 5.2 (m., 1H, H-15), 5.95 (d.,
1H, H-13), 6.31 (d., 1H, H-10), 7.27 (d.,
1H, H−11) Mass (CI, isobutane); 666 (MH ⁺ −CO ₂ −
32), 634 (666-32), 258, 216, 156, 29 Example 1 14-Butylcarbamoyl-14-de(hydroxymethyl)-O-mycaminosyltylonolide 2',4'-di-O -acetyl-14-carboxy-
Dissolve 200 mg of 14-de(hydroxymethyl)-O-mycaminosyltylonolide dimethyl acetal in 2 ml of dry dichloromethane, add 95μ of triethylamine, cool to 0°C, add 49μ of ethyl chloroformate, and cool to 0°C. The mixture was stirred for 30 minutes. Next, 0.27 ml of butylamine was added to this reaction solution, and the mixture was stirred at room temperature for 1 hour. 20 ml of chloroform was added to the reaction solution, and the mixture was washed with dilute hydrochloric acid, water, and dilute aqueous ammonia in this order. Watmann the chloroform layer
After passing through 1PS paper, it was concentrated under reduced pressure. The residue was charged to 5 g of silica gel (Merck & Co., Art 9385), and the fraction eluted with benzene-acetone (6:1 to 4:1) was collected and concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol and deacetylated by heating at 55° C. overnight. Methanol is distilled off under reduced pressure,
The residue was dissolved in 5 ml of acetonitrile-water-trifluoroacetic acid (3:2:0.1 v/v) and deacetalized by stirring for 1 hour at room temperature. Add the reaction solution to 10ml of water.
The pH was adjusted to 9 with dilute ammonia water, and the mixture was extracted twice with 20 ml of chloroform. After drying the chloroform layer with anhydrous magnesium sulfate, it was dried under reduced pressure to obtain the target product 76.
I got mg. Mass (CI, isobutane); 667 (MH ⁺ ), 649,
192, 174, 133 PMR (CDCl ₃ , 100MHz) δ ^TMS _ppn ; 0.98 (t., 3H, −
NH( _CH2 ) _3CH3 ), 1.83(s. , 3H, 12− _CH3 ),
2.50 (s., 6H, -N( _CH3 ) ₂ ), 4.25 (d., 1H, H-
1'), 5.29 (d., 1H, H-15), 5.71 (t., 1H,
NH), 5.95 (d., 1H, H-13), 6.32 (d., 1H, H
-10), 7.30 (d., 1H, H-11), 9.69 (s., 1H,
CHO) Example 2 14-benzylcarbamoyl-14-de(hydroxymethyl-O-mycaminosyltylonolide) In Example 1, the title target product was obtained by using 0.3 ml of benzylamine instead of 0.27 ml of butylamine. .Yield 85.6 mg Mass (CI, isobutane); 701 (MH ⁺ ), 683,
493, 475, 192, 174, 133 PMR (CDCl ₃ , 100MHz) δ ^TMS _ppn ; 1.80 (s., 3H,
12- _CH3 ), 2.51 (s., 6H, -N( _CH3 ) ₂ ), 4.24 (d.
，
1H, H−1′), 4.44 (d., 2H, −CH ₂ NH−), 5.29
(d., 1H, H-15), 5.95 (d., 1H, H-13), 6.00
(br., t., H, NH), 6.30 (d., 1H, H-10), 7.1
~7.4 (6H, H-11, phenyl proton), 9.68
(s., 1H, CHO) Example 3 14-(N-methyl-benzylcarbamoyl)-14
-de(hydroxymethyl)-O-mycaminosyltylonolide In Example 1, 0.35 ml of N-methyl-benzylamine was used instead of 0.27 ml of butylamine to obtain the title product. Yield 60.5 mg Mass (CI, isobutane); 715 (MH ⁺ ), 697,
507, 192, 190, 174 PMR (CDCl ₃ , 100MHz) δ ^TMS _ppn ; 1.69, 1.87 (each
br.s., 3H, 12− _CH3 ), 2.50(s., 6H, −N
( _CH3 ) ₂ ), 2.85, 3.01 (each s., 3H,

[Formula]), 4.25 (br., d., 1H, H-1'), 4.47, 4.59 (each br.s., 2H,

[Formula]), 5.5 (m., 1H, H-15), 5.92 (br., d., 1H, H-
13), 6.29, 6.35 (each br.d., 1H, H-10), 7.0-7.4
(6H, H-11, phenyl proton), 9.70 (s.,
1H, CHO) Example 4 14-diethylcarbamoyl-14-de(hydroxymethyl)-O-mycaminosyltylonolide In Example 1, the title object was prepared using 0.28 ml of diethylamine instead of 0.27 ml of butylamine. Obtained. Yield 53mg Mass (CI, isobutane); 667 (MH ⁺ ), 649,
476, 192, 190, 174, 156, 132 IR (KBr); 1640 cm ^-1 (−CON−) PMR (CDCl ₃ , 100 MHz) δ ^TMS _ppn ; 1.17 (t., 6H,

[Formula]), 1.87 (4., 3H, 12-CH ₃ ), 2.50 (s., 6H, -N(CH ₃ ) ₂ ), 4.25 (d., 1H, H-
1'), 5.47 (dt, 1H, H-15), 5.91 (d., 1H, H
-13), 6.35 (d., 1H, H-10), 7.33 (d., 1H, H
-11), 9.70 (s., 1H, CHO) Example 5 14-dimethylcarbamoyl-14-de(hydroxymethyl)-O-mycaminosyltylonolide In Example 1, dimethylamine was used instead of 0.27 ml of butylamine. The title target product was obtained using a solution of 223 mg of hydrochloride and 0.38 ml of triethylamine dissolved in 4 ml of dichloromethane. Yield 49 mg Mass (CI, isobutane); 639 (MH ⁺ ), 621,
192, 190, 174, 132 PMR (CDCl ₃ , 100MHz) δ ^TMS _ppn ; 1.89 (s., 3H,
12−CH ₃ ), 2.51 (s., 6H, −N(CH ₃ ) ₂ ), 2.97 (s.
,
6H,

[Formula]), 4.25 (d., 1H, H-1'), 5.46 (dt, 1H, H-15), 5.94 (d., 1H, H-
13), 6.35 (d., 1H, H-10), 7.32 (d., 1H, H-
11), 9.70 (s., 1H, CHO)

Claims (1)

[Claims] 1 formula (In the formula, R represents a hydrogen atom or a hydroxyl group, R ₁ represents a lower alkyl group or a phenyl-lower alkyl group, and R ₂ represents a hydrogen atom or a lower alkyl group)
A compound represented by or a salt thereof. 2 formulas (In the formula, R ₃ is a hydrogen atom or -OR ₄ group, R ₄ is a hydroxyl protecting group, R ₅ and R ₆ each represent a lower alkyl group, or together represent a lower alkylene group) Formula (In the formula, R ₁ is a lower alkyl group or phenyl-
a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group), followed by elimination of the protecting group of the hydroxyl group and deacetalization. (In the formula, R represents a hydrogen atom or a hydroxyl group, and R ₁
and _R2 has the same meaning as above) or a method for producing a salt thereof. 3. Claim 2 in which the protecting group for the hydroxyl group is a lower alkanoyl group or a halogenated acetyl group
Manufacturing method described in section. 4. The production method according to claim 3, wherein the lower alkanoyl group is an acetyl group. 5. The production method according to claim 2, wherein the amidation is carried out by a mixed acid anhydride method. 6. The manufacturing method according to claim 2, in which the hydroxyl group and the protective group are removed by heat treatment in a lower alcohol which may contain water. 7. The production method according to claim 2, wherein the deacetalization is carried out by hydrolysis with acidic water.