WO1998018807A1 - Erythromycin a derivatives - Google Patents

Abstract

Erythromycin A derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof having a potent antibacterial activity wherein R represents optionally hydroxylated C3-5 alkyl.

Description

 Description Eris mouth mycin A derivative Technical field

 The present invention relates to novel derivatives of the antibiotic erythromycin A.

 Background art

 Erythromycin A is an antibiotic widely used as a treatment for infectious diseases caused by gram-positive bacteria, mycoplasma, and the like. However, erythromycin A has the disadvantage that it is degraded by acid in the stomach because it is unstable to acid, and its pharmacokinetics is not constant. Many erythromycin A derivatives have been produced to date to improve such biological or pharmacodynamic properties. For example, a 6-0-methylerythromycin A derivative (US Pat. No. 4,331,803) is reported to have improved acid stability and better in vivo antibacterial activity when administered orally than erythromycin A. Have been.

 An object of the present invention is to provide an erythromycin A derivative or a salt thereof, which is a new macrolide antibiotic having a strong antibacterial activity, and a composition containing the same as an active ingredient.

 Another object of the present invention is to provide a use of the erythromycin A derivative or a salt thereof for the treatment of bacterial infection, which comprises applying an effective amount of the erythromycin A derivative or a salt thereof to a patient. To provide.

 Disclosure of the invention

 The present inventors have conducted various studies on the antibacterial activity of the erythromycin A derivative, and as a result, have found that a compound having a specific group introduced at the 6-position has strong antibacterial activity, and completed the present invention.

The present invention provides a compound of the formula (I)

[In the formula, R represents an alkyl group having 3 to 5 carbon atoms or an alkyl group having 3 to 5 carbon atoms substituted with a hydroxyl group. ] The erythromycin A derivative represented by these, or its pharmacologically acceptable salt.

 In the present invention, the alkyl group having 3 to 5 carbon atoms is linear or branched, and examples thereof include a propyl group, an isopropyl group, a butyl group, a pentyl group, and an isopentyl group. The alkyl group having 3 to 5 carbon atoms substituted by a hydroxyl group is linear or branched and includes a 2,3-dihydroxypropyl group, a 2,3-dihydroxy-3-methylbutyl group, and the like. be able to. Also, pharmaceutically acceptable salts refer to salts used in chemotherapy and prevention 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, ethyl succinic acid, lactobionic acid, dalconic acid, dalcoheptonic acid, benzoic acid, methanesulphonic acid, ethane Sulfonic acid, 2-hydroquinethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, lauryl sulfate, malic acid, aspartic acid, glutamate, adipic acid, cysteine, N-acetylcystine, hydrochloric acid, bromide Examples include salts with acids such as hydrogenic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, pendenic acid, acrylic acid polymers, and carboxylic acid vinyl polymers. be able to.

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

However, the method for producing the compound of the present invention is not limited to the method shown below.

(i)

£ S9 £ 0 / L6d £ / lDd 0881/86 OAV Step (1): Inactivating 2 ', 4 "10-bis (trimethylsilinole) erythromycin A9- (0-C1- (1-methylethoxyquin) cyclohexyl] oxime} described in US Pat. No. 4,990,602 After reacting with acryl bromide or prenyl bromide in a solvent in the presence of a base at -15 ° C to room temperature, deprotection and regeneration of the 9-position ketone using sodium bisulfite in a lower alcohol in the presence of an acid At the same time to obtain a compound represented by the formula (a) (wherein R ¹ represents a hydrogen atom or a methyl group), wherein N, N-dimethylformamide or dimethylsulfoxide is used as the inert solvent. Alternatively, a mixed solvent of them and tetrahydrofuran is used, and as the base, lithium hydroxide, sodium hydroxide, lithium hydride or sodium hydride is used. As the alcohol, methanol, ethanol or isopropanol is used.

Step (2): The compound (a) is hydrogenated by a conventional method to obtain a compound of the present invention represented by the formula (b) (wherein R ¹ is the same as described above). . Step (3): The compound represented by the formula (c) (where R 'is the same as described above) is obtained by subjecting the compound (a) to a normal diolation reaction using osmium tetroxide. The compounds of the invention can be obtained.

 The erythromycin A derivative of the present invention is administered orally or parenterally, and is 50 to 2000 mg when treating an adult, and is administered in 2 to 3 times a day. This dosage may be adjusted appropriately according to the age, weight and condition of the patient. The compound of the present invention can be used in various pharmaceutical forms for the purpose of application due to its pharmacological action. The pharmaceutical compositions of the present invention can be prepared by uniformly mixing an effective amount of the compound of the present invention in the form of the free or acid addition salt as an active ingredient with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. As the formulation of the present invention, for oral administration, excipients, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, coloring agents, flavoring agents, etc. are mixed. Preparations include powders, granules, capsules, tablets and the like, and for parenteral administration, preparations such as injections and infusions. When formulating, a usual formulation method can be used.

BEST MODE FOR CARRYING OUT THE INVENTION Next, the present invention will be described in more detail with reference to examples.

 Example 1-one. —Production of professional reerythromycin A

 Step (1) 2 *, 4 "— 0-bis (trimethylsilyl) erythromycin A 9-1 {0- [1- (1-methylethoxy) cyclohexyl] oxime 1 (30.0 g, 0.027 mol) is added to dimethyl sulfoxide After dissolving in tetrahydrofuran (1: 1; 300 ml), arypromide (9.85 g) and potassium hydroxide (3.17 g) were added under ice cooling, and the mixture was stirred for 1.5 hours under ice cooling. An aqueous solution (5 ml) was added, the mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with hexane.The hexane layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in ethanol (150 ml), 90% formic acid (3.47 ml) and water (150 ml) were added at room temperature, and the mixture was heated under reflux for 1 hour. Then, sodium hydrogen sulfite (19.8 g) was added to add 2%. The reaction solution was concentrated under ice cooling and 2N sodium hydroxide. The solution was adjusted to pH 11, water was added, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off. Purification by column chromatography (elution solvent; chloroform: methanol: aqueous ammonia = 94: 6: 0.6 to 9: 1: 0.1), followed by crystallization from chromatoform-isopropyl ether to give 6-0-a Rilerythromycin A (3.56 g) was obtained.

MS (FAB) m / z; 774 [M + H] ⁺

'Η-NR (CDC1 ₃ ) δ (ppm); 2.30 (6H, s, N (CH ₃ ) ₂ ), 3.33 (3H, s, 0CH ₃ ), 3.86, 4.01 (1H each, dd, J = 7.4 , 11.2Hz, 0CH ₂ CHCH ₂ ), 5.16 (2H, dd, J = 1.5, 17.3Hz, OC ^ CHC ^), 5.90 (1H, dddd, J = 1.5, 7.4, 11.2, 17.3Hz, 0CH ₂ CHCH ₂ )

¹ CN R (CDCh) δ (ppm); 40.22 (Q, N (CH ₃ ) ₂ ), 65.97 (T, 0CH ₂ CHCH _Z ), 116.74 (T, 0CH ₂ CHCH ₂ ), 135.91 (D, 0CH ₂ CHCH ₂ ).

Step (2) Ethanol (3 ml) was added to the compound obtained in step (1) (0.30 g, 0.39 referred to) and 10% palladium carbon (50% wet, 0.12 g), and the mixture was added at room temperature under a stream of hydrogen at room temperature. Stirred for days. The reaction mixture was filtered through celite, the solvent was distilled off, and the residue was purified with silica gel gel chromatography (elution solvent; chloroform: methanol: aqueous ammonia = 9: 1: 0.1). Further crystallization gave the title compound (0.21 g).

_{'H-NMR (CDC1 3)} 5 (ppm); 1.80 (3H, t, J = 7.5Hz, OCzW ^), 1.2-1.5

(4H, m, OCsHiCHa), 2.40 (6H, s, N (CH 3) 2), 3.31 (3H, s, 0CH 3).

 Example 2 Production of 6-0-isopentylerythromycin A

 Step (1) 2,, 4 "— 0-bis (trimethylsilyl) erythromycin A 9— {0— [1- (1-methylethoxy) cyclohexyl] oxime} (37.8 g, 0.037 mol) and prenyl bromide The reaction was carried out in the same manner as in the step (1) of Example 1 using amide (16.36 g) and potassium hydroxide (4.28 g) to obtain 6-0-prenylerythromycin A (10.16 g).

S (FAB) m / z; 802 [M + H] ⁺

_{'H - NMR (CDC1 3)} 6 (pm); 1.64, 1.72 ( each 3H, each _{s, 0CH 2 CHC (CH 3} ) 2), 2.30

(6H, s, N (CH ₃ ) ₂ ), 3.31 (3H, s, 0CH ₃ ), 3.9-4.0 (2H, m, OC ^ CHC CH ₂ ), 5.21 (1H, dd, J = 7.5, 7.5Hz , 0CH ₂ CHC (CH ₃ ) ₂ )

_{^{13 C-NMR (CDC1 3)}} δ (ppm); 17.95, 25.64 ( each _{Q, 0CH 2 CHC (H 3} ) 2), 40.30

(Q, N (CH 3) ₂ ), 60.87 (T, OCH 2 CHC (CH 3) 2), 122.77 (D, OCH 2 CHC (CH 3) 2) o

 Step (2) Using the compound (0.30 0.37 咖 01) obtained in the above step (1) and 10% palladium carbon (50! ¾ wet, 0.06 g), react in the same manner as in step (2) of Example 1. The title compound (0.157 g, crystallized from methanol) was obtained.

MS (FAB) m / z; 804 [M + H] ⁺

'H- NMR CDC) S (ppm ); 0.90, 0.91 ( each 3H, each _{d, J = 7.5Hz, 0CH 2} CH 2 CH (CH 3) 2), 1.4-1.6 (4H, m, OC ^ C ^ _{CHCCHJ 2), 2.29 (6H,} s, N (CH 3) 2), 3.06 (1H, m, 0CH 2 CH 2 CH (CH 3) 2), 3.32 (3H, s, 0CH 3).

Example 3 6-O— (2,3-dihydroxypropyl) erythromycin A The compound (l.Og, 1.29 dl) obtained in Step (1) of Example 1 was dissolved in tetrahydrofuran (5 ml). At room temperature, N-methylmorpholine N-oxide (0.908 g) and osmium tetroxide solution (3.64 ml) were added, and the mixture was stirred at room temperature under a nitrogen stream for 15 hours. A saturated aqueous sodium sulfite solution (10 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry over anhydrous magnesium sulfate. The residue obtained by distilling off the residue was purified by silica gel column chromatography (elution solvent: acetone: hexane: triethylamine = 6: 10: 0.2 to 10: 10: 0.2), and the title was obtained. Compound (0.23 g) was obtained.

MS (FAB) m / z; 808 [M + H] ^< +>.

 Example 4 Preparation of 6-0- (2,3-dihydroxy-3-methylbutyl) erythromycin A

 Using the compound (2.0 g, 2.49 mol) obtained in step (1) of Example 2 and an osmium tetroxide solution (6.34 ml), the title compound ( l. Olg).

MS (FAB) m / z; 836 [M + H] ^< +>.

 Test example (in vitro antibacterial activity)

 As an example of the compound of the present invention, the in vitro antibacterial activity of the compound obtained in Example 1 against various test bacteria was measured using a medium for susceptible discs (manufactured by Eiken Chemical Co., Ltd.) according to the MIC assay method of the Japan Society of Chemotherapy did.

 The results were expressed as MIC values (minimum inhibitory concentration of microbial growth / g / m 1) and are shown in Table 1. The compound obtained in Example 1 showed strong antibacterial activity.

 table 1

産業上の利用可能性

Industrial applicability

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

Claims

The scope of the claims 1. Formula (I)

[In the formula, R represents an alkyl group having 3 to 5 carbon atoms or an alkyl group having 3 to 5 carbon atoms substituted with a hydroxyl group. ] The erythromycin A derivative represented by these, or its pharmacologically acceptable salt.  2. A pharmaceutical composition comprising an effective amount of the erythromycin A derivative according to claim 1 or a pharmaceutically acceptable salt thereof.  3. An antibacterial agent comprising the erythromycin A derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.  4. A method for treating a bacterial infection, which comprises applying an effective amount of the erythromycin A derivative or a pharmaceutically acceptable salt thereof according to claim 1 to a patient.  5. Use of an erythromycin A derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment of a bacterial infection.