JP2002241391A - Erythromycin A derivative - Google Patents

Abstract

(57) Abstract: A novel erythromycin A derivative having excellent antibacterial activity is provided. SOLUTION: Formula (1) (Wherein R ¹ is unsubstituted or “nitro group, bromo group,
A phenyl, pyridyl, thienyl or furyl group substituted with 1-3 groups selected from a chloro group, an alkyl group having 1-4 carbon atoms and an alkoxy group having 1-4 carbon atoms, and R ² represents a hydroxyl group , A cladinosyloxy group, an acetoxy group or a pyridylacetyloxy group, R ³ represents a hydrogen atom, or R ² and R ³ together represent an oxo group. Or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel erythromycin A derivative. More specifically, the present invention relates to a novel erythromycin A derivative having antibacterial activity in which the 6-position and the 9-position of 9-deoxo-9-hydroxyerythromycin are linked by an acetal structure.

[0002]

2. Description of the Related Art Erythromycin is a macrolide antibiotic widely used as a therapeutic drug for infectious diseases caused by gram-positive bacteria, mycoplasma and the like. However, erythromycin has the drawback that it is easily decomposed by acid in the stomach because it is unstable to acid, and its pharmacokinetics is unstable. Many derivatives have been investigated for the purpose of improving the instability to this acid. For example, a 6-O-methylerythromycin A derivative (U.S. Pat.
It has been reported that the acid stability is increased and the in vivo antibacterial activity upon oral administration is superior to that of erythromycin. Also, various novel erythromycin derivatives having enhanced antibacterial activity have been synthesized.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel erythromycin A derivative having antibacterial activity and effective for treating infectious diseases.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have developed a novel compound having an antibacterial activity by an erythromycin A derivative obtained by linking the 6-position and 9-position of 9-deoxo-9-hydroxyerythromycin with an acetal structure. And completed the present invention.

That is, the present invention provides the following formula (1)

[0006]

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(Wherein R ¹ is unsubstituted or a group 1- selected from “nitro group, bromo group, chloro group, alkyl group having 1-4 carbon atoms and alkoxy group having 1-4 carbon atoms”). Represents a phenyl, pyridyl, thienyl or furyl group substituted by three, R ² represents a hydroxyl group, a cladinosyloxy group, an acetoxy group and a pyridylacetyloxy group, R ³ represents a hydrogen atom, or R ² R ³ together represent an oxo group.) Or a pharmaceutically acceptable salt thereof.

[0008]

DETAILED DESCRIPTION OF THE INVENTION In the present invention, the number of carbon atoms is 1-4.
The alkyl group is a straight or branched chain, such as a methyl group, an ethyl group, a propyl group or a butyl group, and an alkoxy group having 1 to 4 carbon atoms is a straight or branched chain, A methoxy group, an ethoxy group, a propoxy group or a butoxy group.

[0009] Pharmaceutically acceptable salts refer to salts used in chemotherapy and prophylaxis of bacterial infections. They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, lauryl sulfate, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid And salts with acids such as sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymer and carboxyvinyl polymer.

The compounds of the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules,
Powders, troches, ointments, suspensions, suppositories, injections and the like, which can be produced by conventional formulation techniques. The dosage is 10 times daily for treating adults.
0-1000 mg, which can be administered 2-3 times a day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.

The compound of the present invention can be produced, for example, as follows.

[0012]

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Step 1: 9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate is dissolved in an inert solvent such as toluene in a solvent of the formula

[0014]

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(Wherein R ¹ is a phenyl group, a nitro group, a bromo group, a chloro group, an alkyl group having 1-4 carbon atoms or an alkoxy group having 1-4 carbon atoms)
Represents a phenyl group, a pyridyl group, a thienyl group, or a furyl group, and R ⁴ represents an alkyl group having 1 to ⁴ carbon atoms. Is reacted at 0 ° C. to 120 ° C. in the presence of 0.2 equivalents of an acid catalyst such as pyridinium p-toluenesulfonate, so that in the formula (1), R ² is a cladinosyloxy group, R ³ Is a compound of the present invention represented by a hydrogen atom.

[0016]

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Step 2: 9-deoxo-9-hydroxyerythromycin A protected at the 2'-position with an acetyl group or the like
In an inert solvent such as toluene, 11,12-cyclic carbonate is represented by the formula

[0018]

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(Wherein R ¹ and R ⁴ are as defined above)
In the presence of 1 equivalent or more of an acid catalyst such as pyridinium p-toluenesulfonate at 0 ° C. to 120 ° C., wherein R ² is a hydroxyl group, R ^2
The compound A of the present invention in which ³ is represented by a hydrogen atom is obtained.

Step 3: Compound A is converted to the compound of International Patent WO9823628.
Acylation at the 3-position using the method described in (1), followed by deprotection in methanol from room temperature to heating under reflux, wherein in the formula (1), R ² is an acetoxy group or a pyridylacetyloxy group. To obtain a compound of the present invention wherein R ³ is represented by a hydrogen atom.

Step 4: After the compound A is treated with an acid anhydride such as acetic anhydride in an inert solvent to selectively protect the 2′-position, the hydroxyl group at the 3-position is oxidized by a known method, and further added with methanol at room temperature. ~ Deprotection under heating reflux,
R ² and R ³ together can provide a compound of the present invention that represents an oxo group.

[0022]

The compounds of the present invention have antibacterial activity and are useful as antibacterial agents for treating bacterial infections in humans and animals (including farm animals).

[0023]

EXAMPLES Example 1 (9S) -9-Deoxo-9-hydroxy-6-O, 9-O-
Synthesis of benzylidene erythromycin A 1.3 g of (9S) -9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate (1.75 mmol)
l) was dissolved in 20 ml of toluene, and 0.27 g (1.8 mmol) of benzaldehyde dimethyl acetal and 88 mg (0.35 mmol) of pyridinium p-toluenesulfonate were added, followed by heating under reflux for 12 hours. After cooling the reaction mixture to room temperature, ethyl acetate 100 ml
And washed successively with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 50 ml of a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.83 g of a residue. This was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 15: 1: 0.
Purification from 1) afforded 0.295 g of the title compound. IonSprayMS m / z = 850.8 [M + H] + 1 H-NMR (500MHz, CDCl 3), δ (ppm): 0.81 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.29 (6H, s, 3'-N (CH ₃ ) ₂ ), 3.31 (3H, s,
_{3 "-OCH 3), 4.49 (} 1H, d, J = 7.3Hz, H-1 '), 4.76 (1H, d, J
= 4.3Hz, H-1 "), 4.99 (1H, dd, J = 11.0, 1.8Hz, H-13),
5.35 (1H, s, H-11), 6.06 (1H, s, -CHAr), 7.26-7.34 a
nd 7.51-7.52 (5H, m, -Ar)

Example 2 (9S) -9-Deoxo-9-hydroxy-6-O, 9-O-
Synthesis of (p-dimethylamino) benzylideneerythromycin A 5.03 g (6.6 mmol) of (9S) -9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate
Using 5.15 g (26.4 mmol) of p-dimethylaminobenzaldehyde dimethyl acetal as a starting material, the same operation as in Example 1 was performed to obtain 3.24 g of the title compound. IonSprayMS m / z = 893.6 [M + H] + 1 H-NMR (500MHz, CDCl 3), δ (ppm): 0.82 (3H, t, J = 7.3
Hz, 14-CH ₃ ), 2.30 (6H, s, 3'-N (CH ₃ ) ₂ ), 2.93 (6H, s,-
ArN (CH ₃ ) ₂ ), 3.31 (3H, s, 3 "-OCH ₃ ), 4.51 (1H, d, J = 7.3
Hz, H-1 '), 4.82 (1H, d, J = 4.9Hz, H-1 "), 5.04 (1H, d
d, J = 11.0, 1.8Hz, H-13), 5.39 (1H, s, H-11), 5.99 (1
H, s, -CHAr), 6.69 and 7.34 (each 2H, each d, J = 9.2H
z, -Ar)

Example 3 (9S) -9-Deoxo-9-hydroxy-6-O, 9-O-
Synthesis of (2,4-dimethoxy) benzylideneerythromycin A (9S) -9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate 3.80 g (5.0 mmol)
Using 4.2 g (19.8 mmol) of 2,4-dimethoxybenzaldehyde dimethyl acetal as a starting material and the same operation as in Example 1, a crude product was obtained. This was recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 0.99 g of the title compound. IonSprayMS m / z = 910.7 [M + H] + 1 H-NMR (500MHz, CDCl 3), δ (ppm): 0.88 (3H, t, J =
_{7.3Hz, 14-CH 3),} 2.30 (6H, s, 3'-N (CH 3) 2), 3.30 (3H,
s, 3 "-OCH ₃ ), 3.76 and 3.80 (each 3H, each s, Ar (OM
e) ₂ ), 4.49 (1H, d, J = 7.3Hz, H-1 '), 4.75 (1H, d, J = 4.
3Hz, H-1 "), 5.17 (1H, dd, J = 11.0, 1.8Hz, H-13), 5.4
5 (1H, s, H-11), 6.33 (1H, s, -CHAr), 6.35 (1H, d, J =
2.4Hz, -Ar), 6.56 (1H, dd, J = 8.5,2.4Hz, -Ar), 7.61
(1H, d, J = 8.5Hz, -Ar)

Example 4 (9S) -9-Deoxo-9-hydroxy-6-O, 9
-O- (3-thienyl) methylideneerythromycin A
Synthesis of 11,12-cyclic carbonate (9S) -9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate 8.0 g (10.5 mm
ol) and 3-thiophenaldehyde dimethyl acetal 7.3
The same operation as in Example 1 was carried out using g (46.1 mmol) to obtain 2.1 g of the title compound. IonSprayMS m / z = 854.6 [MH ] - 1 H-NMR (500MHz, CDCl 3), δ (ppm): 0.81 (3H, t, J = 7.3
Hz, 14-CH ₃ ), 2.29 (6H, s, 3'-N (CH ₃ ) ₂ ), 3.32 (3H, s,
3 "-OCH ₃ ), 4.48 (1H, d, J = 7.3Hz, H-1 '), 4.81 (1H, d,
J = 4.9Hz, H-1 "), 4.97 (1H, dd, J = 11.0, 1.8Hz, H-13),
5.30 (1H, s, H-11), 6.10 (1H, s, -CHAr), 7.13 (1H, d
d, J = 4.9, 1.2Hz, Ar-H), 7.22 (1H, dd, J = 4.9, 3.1Hz,
Ar-H), 7.41 (1H, d, J = 3.1Hz, Ar-H)

Example 5 5-O-desosaminyl- (9S) -9-deoxo-3-
Deoxy-9-hydroxy-6-O, 9-O- (4-nitro) benzylidene-3-oxoerythronolide A 1
Synthesis of 1,12-cyclic carbonate (1) 2'-O-acetyl- (9S) -9-deoxo-9
-Hydroxyerythromycin A 11,12-cyclic carbonate 6.6 g (8.2 mmol) and 4-nitrobenzaldehyde dimethyl acetal 6.5 g (33.0 mmol) were added to toluene 70
dissolved in 1 mL of pyridinium p-toluenesulfonate
2.5 g (9.9 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with an aqueous sodium hydroxide solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol:
28% aqueous ammonia = 20: 1: 0.1) to purify 2'-O-
4.0 g of acetyl-5-O-desosaminyl- (9S) -9-deoxo-9-hydroxy-6,9-O- (4-nitro) benzylideneerythronolide A 11,12-cyclic carbonate was obtained. (2) 2.38 g (3.06 mmol) of the compound obtained in Example 5 (1) was dissolved in 50 mL of dichloromethane, and 3.3 ml of dimethyl sulfoxide was dissolved.
L (46.5 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 1.76 g (9.18 mmol), pyridinium trifluoroacetate 1.77 g (9.16 mmol)
Were sequentially added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with chloroform and washed sequentially with an aqueous sodium hydroxide solution and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (acetone: hexane: triethylamine = 10: 2
0: 0.3) and 2′-O-acetyl-5-O-desosaminyl- (9S) -9-deoxo-3-deoxy-9
-Hydroxy-6,9-O- (4-nitro) benzylidene-3-oxoerythronolide A 11,12-cyclic carbonate was obtained. This was dissolved in 30 mL of methanol and stirred at room temperature overnight. Then, the solvent was distilled off under reduced pressure and dried to obtain 1.29 g of a target compound (a mixture of diastereomers of about 4: 1).
I got IonSprayMS m / z = 735.4 [M + H] ⁺ <major diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.86 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.28 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.35 (1H, d,
J = 7.3Hz, H-1 '), 5.22 (1H, s, H-11), 6.05 (1H, s, -CHA
r), 7.48 (2H, d, J = 8.8Hz, Ar-H), 8.18 (2H, d, J = 8.8H
<sub-diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.83 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.28 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.20 (1H, d,
J = 7.3Hz, H-1 '), 5.26 (1H, s, H-11), 6.23 (1H, s, -CHA
r), 7.60 (2H, d, J = 8.8Hz, Ar-H), 8.25 (2H, d, J = 8.8H
z, Ar-H).

Example 6 6-O, 9-O- (3-bromo) benzylidene-5-O
-Desosaminyl- (9S) -9-deoxo-3-dideoxy-9-hydroxy-3-oxoerythronolide A
Synthesis of 11,12-cyclic carbonate (1) 2'-O-acetyl- (9S) -9-deoxo-9
-Hydroxyerythromycin A 11,12-cyclic carbonate 5.8 g (7.2 mmol) and 3-bromobenzaldehyde dimethyl acetal 6.7 g (29.0 mmol) were used to carry out 2'-O-acetyl by the same operation as in Example 5 (1). − 6−
O, 9-O- (3-bromo) benzylidene-5-O-desosaminyl- (9S) -9-deoxo-9-hydroxyerythronolide A 11,12-cyclic carbonate
4.2 g were obtained. (2) The same operation as in Example 5 (2) was performed on 2.49 g (3.06 mmol) of the compound obtained in Example 6 (1) to obtain 1.84 g of the target compound.
(About a 3: 1 mixture of diastereomers) was obtained. IonSprayMS m / z = 766.4 [MH] ^- <major diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.88 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.27 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.45 (1H, d,
J = 7.3Hz, H-1 '), 5.25 (1H, s, H-11), 5.95 (1H, s, -CHA
r), 7.18-7.46 (4H, m, Ar-H). <Sub-diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.85 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.27 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.18 (1H, d,
J = 7.3Hz, H-1 '), 5.29 (1H, s, H-11), 6.13 (1H, s, -CHA
r), 7.18-7.46 (4H, m, Ar-H)

Example 7 5-O-desosaminyl- (9S) -9-deoxo-3-
Deoxy-9-hydroxy-3-oxo-6-O, 9-
O- (3-pyridyl) methylideneerythronolide A 1
Synthesis of 1,12-cyclic carbonate (1) 6.0 g of (9S) -9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate (7.
9 mmol) and 3-pyridinealdehyde dimethyl acetal
Using 4.8 g (31.3 mmol) of 5-O-desosaminyl- (9S) -9-deoxo-9 in the same manner as in Example 5 (1).
3.6 g of -hydroxy-6-O, 9-O- (3-pyridyl) methylideneerythronolide A 11,12-cyclic carbonate were obtained. (2) 1.5 g (2.16 mmol) of the compound obtained in Example 7 (1) was dissolved in 30 mL of acetone, 0.23 mL (2.44 mmol) of acetic anhydride was added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with an aqueous sodium hydroxide solution.
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to the same operation as in Example 5 (2) to obtain 1.3 g of a target compound (about 3: 1 mixture of diastereomers). IonSprayMS m / z = 691.4 [M + H] ⁺ <major diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.87 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.27 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.35 (1H, d,
J = 7.3Hz, H-1 '), 5.26 (1H, s, H-11), 6.06 (1H, s, -CHA
r), 7.28 (1H, dd, J = 7.3, 4.3Hz, Ar-H), 7.72 (1H, m,
Ar-H), 8.45 (1H, d, J = 1.8Hz, Ar-H), 8.51 (1H, dd, J =
4.9, 1.5 Hz, Ar-H) <Sub-diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.82 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.27 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.16 (1H, d,
J = 7.3Hz, H-1 '), 5.26 (1H, s, H-11), 6.26 (1H, s, -CHA
r), 7.36 (1H, dd, J = 7.9, 4.9Hz, Ar-H), 7.90 (1H, m,
Ar-H), 8.56-8.58 (2H, m, Ar-H)

Example 8 5-O-desosaminyl- (9S) -9-deoxo-3-
Deoxy-9-hydroxy-3-oxo-6-O, 9-
O- (3-thienyl) methylideneerythronolide A 1
Synthesis of 1,12-cyclic carbonate (1) 2'-O-acetyl- (9S) -9-deoxo-9
-Hydroxyerythromycin A 11,12-cyclic carbonate (8.7 g, 10.8 mmol) and 3-thiophenaldehyde dimethyl acetal (6.9 g, 43.6 mmol) were used to carry out 2'-O-acetyl by the same operation as in Example 5 (1). −5-
O-desosaminyl- (9S) -9-deoxo-9-hydroxy-6-O, 9-O- (3-thienyl) methylideneerythronolide A 11,12-cyclic carbonate
7.2 g were obtained. (2) The same operation as in Example 5 (2) was performed on 3.3 g (4.46 mmol) of the compound obtained in Example 8 (1) to obtain 1.8 g of the target compound.
(About a 2: 1 mixture of diastereomers) was obtained. IonSprayMS m / z = 696.3 [M + H] ⁺ <major diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.88 (3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.27 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.35 (1H, d,
J = 7.3Hz, H-1 '), 5.27 (1H, s, H-11), 6.08 (1H, s, -CHA
r), 7.00 (1H, m, Ar-H), 7.20-7.22 (2H, m, Ar-H) <sub diastereomer> ¹ H-NMR (500 MHz, CDCl ₃ ), δ (ppm): 0.85 ( 3H, t, J = 7.
3Hz, 14-CH ₃ ), 2.27 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.15 (1H, d,
J = 7.3Hz, H-1 '), 5.32 (1H, s, H-11), 6.25 (1H, s, -CHA
r), 7.00 (1H, m, Ar-H), 7.31 (1H, dd, J = 4.9, 3.1Hz,
Ar-H), 7.40 (1H, d, J = 2.4Hz, Ar-H)

Continued on the front page (72) Inventor Tetsuya Tanigawa 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Tomohiro Sugimoto 3-24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. In-house (72) Inventor Yoichiro Suga 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.F-term (reference) 4C057 BB02 DD01 KK13 4C086 AA02 AA03 EA13 MA01 MA52 NA03 NA10 ZB35

Claims (1)

[Claims] (1) Formula (1) (Wherein R ¹ is unsubstituted or “nitro group, bromo group,
A phenyl, pyridyl, thienyl or furyl group substituted with 1-3 groups selected from a chloro group, an alkyl group having 1-4 carbon atoms and an alkoxy group having 1-4 carbon atoms, and R ² represents a hydroxyl group , A cladinosyloxy group, an acetoxy group or a pyridylacetyloxy group, R ³ represents a hydrogen atom, or R ² and R ³ together represent an oxo group. Or a pharmaceutically acceptable salt thereof.