WO2001010879A1

WO2001010879A1 - Erythromycin a derivatives

Info

Publication number: WO2001010879A1
Application number: PCT/JP2000/005145
Authority: WO
Inventors: Toshifumi Asaka; Masato Kashimura; Akira Manaka; Tetsuya Tanikawa; Tomohiro Sugimoto
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1999-08-06
Filing date: 2000-07-31
Publication date: 2001-02-15
Also published as: AU6316400A

Abstract

Novel erythromycin derivatives of general formula (1), characterized by an acyl group introduced at the 3-position, a cyclic carbamate structure fused at the 11- and 12-positions, and an aryl-substituted five-membered heterocycle, one of the carbon or nitrogen atoms of which is bonded to the carbamate nitrogen atom through a C2-C6 alkyl group, and having potent antimicrobial effects on erythromycin-resistant bacteria and Haemophilus influenzae.

Description

Specification

Eris mouth mycin A derivative

The present invention relates to novel erythromycin A derivatives of antibiotics. More specifically, the present invention relates to an erythromycin A derivative having antibacterial activity not only against conventional erythromycin-sensitive bacteria but also against erythromycin-resistant bacteria (eg, resistant pneumococci and streptococci). Background art

Erythromycin is a macrolide antibiotic that is widely used as a treatment 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 not constant. Many derivatives have been investigated for the purpose of improving the instability to this acid. For example, it has been reported that a 6-〇_methylerythromycin A derivative (US Pat. No. 4,331,803) has improved stability against acids and has an excellent antibacterial activity in vivo upon oral administration as compared to erythromycin. I have. Furthermore, there is a report on a 3-position acyl derivative of erythromycin with the aim of expanding the antibacterial spectrum in addition to acid stability (US Pat. No. 5,631,354 W09823628). Disclosure of the invention

The present inventors have conducted various studies on the antibacterial activity of the erythromycin derivative, and as a result, introduced a certain acyl group at the 3-position of erythromycin, where the 11- and 12-positions were cyclic carbamates, and A novel erythromycin derivative in which a nitrogen atom or one of the carbon atoms of a substituted 5-membered heterocyclic ring is bonded to a nitrogen atom of a cyclic carbamate group via an alkyl group having 2 to 6 carbon atoms, and is resistant to erythromycin The present inventors have found that they have an extremely strong antibacterial activity against bacteria and Influenza bacteria, and have completed the present invention.

The present invention relates to the formula (1)

(1) oo ²

(In the formula, A represents an alkyl group having 2 to 6 carbon atoms, an alkenyl group, or an alkynyl group, R ¹ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ² represents a pyridyl group, virazyl. X represents a thiazolyl group, and X is a group represented by the formula (2)

Represents a carbon atom, and X ² , X ³ , and X ³ represent a sulfur atom, a nitrogen atom, an oxygen atom, and the formula (4)

^ One _R 3 (4)

(Wherein, R ³ represents a hydrogen atom, an alkyl group having 13 carbon atoms, an alkoxycarbonyl group having 16 carbon atoms or a carbamoyl group.) Or a group represented by the formula ( Five )

N—R ⁴ ( ⁵ )

(Wherein, R ⁴ represents a hydrogen atom or a methyl group.). Ar represents an unsubstituted or a C 1-3 alkyl group or a halogen atom. Substituted phenyl group; unsubstituted or a C1-C13 alkyl group or a pyridyl group substituted by a C1-C14 alkyl group selected from halogen atoms; Unsubstituted or a C1-C13 alkyl group Or a pyrimidyl group substituted with 1 to 3 selected from halogen atoms; unsubstituted or 1 to 3 carbon atoms A pyrazyl group substituted by 13 groups selected from an alkyl group or a halogen atom; a unsubstituted or a phenyl group substituted by a group of 113 carbon atoms selected from an alkyl group or a halogen atom having 13 carbon atoms; A substituted or substituted 13-furyl group selected from an alkyl group or a halogen atom having 13 carbon atoms; an unsubstituted or a 1-3 group selected from an alkyl group or a halogen atom having 13 carbon atoms A pyrrolyl group substituted with 1 to 3 carbon atoms; unsubstituted or substituted with 1 to 2 carbon atoms selected from the group consisting of an alkyl group having 13 carbon atoms, an alkoxycarbonyl group having 16 carbon atoms, a carbamoyl group and a halogen atom. Unsubstituted or carbon substituted thiazolyl group; imidazolyl group substituted with 112 selected from alkyl groups or halogen atoms having 13 carbon atoms; 1,2,3_triazolyl group substituted by 12 selected from alkyl groups having 1 to 13 atoms or halogen atoms; unsubstituted or alkyl groups having 1 to 3 carbon atoms or octalogene atoms A selected 1,2,4-triazolyl group substituted by one or two; or an unsubstituted or tetrazolyl group substituted by a C13 alkyl group or a halogen atom. ) Represents a group represented by. ) An erythromycin A derivative represented by the formula or a pharmaceutically acceptable salt thereof.

In a preferred compound of the present invention, in the above formula, A is an alkyl group, alkenyl group, or alkynyl group having 4 carbon atoms, and X ¹ , X ² , X ³ , X ³ in the formula (2) or the formula (3) ^The group represented by a 5-membered aromatic ring composed of ⁴ and carbon atoms is, for example, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a chenyl group, a thiazolyl group, an oxazolyl group, and Ar is a substituent. It is a compound showing a pyridyl group, a pyrimidyl group, a virazyl group, or a thiazolyl group which may be possessed.

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

(Wherein, A, R ′, R ² and X are the same as described above.) That is, a 10,11-anhydro-12-O-imidazolylcarbonyl derivative described in International Patent Publication No. W098 23628 The starting material is used to react an ω-substituted alkylamine derivative in the presence or absence of a base to obtain a 11,12-cyclic cyclic bamate. Subsequently, the compound of the present invention can be obtained by performing deprotection at the 2'-position. The ω-substituted alkylamine derivative can be synthesized with reference to a known production method, for example, the method described in French Patent FR2732684. In the present invention, the alkyl group having 13 carbon atoms means a methyl group, an ethyl group, an η-propyl group or an iso-propyl group. An alkyl group having 2 to 6 carbon atoms is a linear or molecular alkyl group having 2 to 6 carbon atoms, for example, an ethyl group, a propyl group, a butyl group, a pentyl group, a butyl group. Is shown. The alkoxycarbonyl group having 1 to 6 carbon atoms means a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, or the like.

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, glucoheptonic acid, benzoic acid, methanesulfone Acid, ethanesulfonic acid, 2-hydroxybenzenesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, lauryl sulfate, Coricic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcetin, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, pendecane Acids, salts with acids such as acrylic acid polymers and carboxyvinyl polymers can be mentioned. The compounds of the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, powders, troches, ointments, suspensions, suppositories, injections, etc., which can be produced by conventional formulation techniques. The dosage is 100 to 100 mg daily for the treatment of adults, which can be administered 2-3 times a day. This dose can be adjusted appropriately according to the age, weight and condition of the patient. Next, the present invention will be described in more detail with reference to Examples and Test Examples.

Example 1 11-Doxy-11- [4- [4- (pyridine-3-yl)]-1H-imidazole-1-yl] butyl] amino—5-—1-desosaminyl 3-—0- (2— Pyridyl) acetyl-1 6 — O-Methylerythronolide A 11, 12 — Synthesis of cyclic carbamates

International Patent Application No. W09823628 describes 10,11-anhydro-2'-〇-acetyl- 12-O-imidazolylcarbonyl-3-3-0- (2-pyridyl) acetyl-5-O-desosaminyl-1 6-O-methylerythro Noride A 654 mg (0.791 ol), 4- [4- (pyridin-3-yl) -11H-imidazoyl-11-yl] synthesized according to the method described in French Patent FR2732684. Butylamine (800 mg, 3.96 mmol), 1,1,3,3-tetramethylguanidine (91 mg, 0.791) was dissolved in acetonitrile (5 ml), and the mixture was stirred at room temperature for 12 hours. Thereafter, the reaction solution was separated by adding ethyl acetate and water. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The yellow oily substance obtained as a crude product was dissolved in 10 ml of methanol and heated under reflux for 5 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: chloroform: methanol: aqueous ammonia = 25: 1: 0.1) to obtain 460 mg of the title compound.

FABMS m / z: 933 (M + H) ⁺

_{'H-NMR OOMHz, CDC1 3} ) δ (ppm): 0.78 (t, 3Η, J = 7.5Hz, - CH 3), 2.30 (s, 6H, 3' -N (CH 3) 2), 3.00 (s , 3H, 6-0CH ₃ ), 7.27 (m, 1H, pyridine-CH), 7.34 (d, 1H, Jl.2Hz, imidazole-CH), 7.55 (d, 1H, J = l.2Hz, imidazole -CH), 8.07 (dt, 1H, J = 8.0, 2.0Hz, pyrid ine-CH), 8.44 (dd, IH, J = 5.0, 2. OHz, pyridine-CH), 8.95 (m, 1H, pyridine-CH) Example 2 11—Deoxy 11— [3— [4 _ (pyridine-3-yl) — 1 H —imidazole-1-yl] propyl] amino— 5— O—desosaminyl 3-O— (2-pyridyl) acetyl 6—O—methylerythronolide A 11, 12—Cyclic carbamate synthesis

10,11-Anhydro-1'-p-acetyl-1'-O-imidazolylcarbonyl- 3- 3- (2-pyridyl) acetyl-5-O-desosaminyl 6-0-0 Methylerythronolide A 221 mg (0.267 mmol) ) And 3-[4-(pyridine-3-yl)-1 H-imidazole-1 -yl] propylamine 270 mg (l. 33 mmol) in the same manner as in Example 1 to give 130 mg of the title compound. I got

IonSplayMS m / z: 919.5 (M + H) ⁺

'H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.83 (t, 3 H, J = 7.3 Hz' 14-CH ₃ ), 2.28 (s, 6 H, 3 '-N (CH ₃ ) 2), 2.92 (s, 3H, 6-OCH3), 7.26 (ddd, IH, J = 7.9, 4.9, 0.6Hz, pyridine ne-CH), 7.47 (d, IH, J = l.2Hz, imi dazo 1 e-CH ), 7.62 (d, IH, J = l.2Hz, imi dazo 1 e-CH), 8.07 (dt, IH, J = 7.9, 2.0Hz, pyridine-CH), 8.43 (dd, IH, J = 4.9, 2. OHz, pyr pyridine-CH), 8.98 (dd, IH, J = 2.0, 0.6 Hz, pyridine-CH) Example 3 11-Doxy-11- [2-—4- (pyridine-3- 1-H-imidazole-1-yl-ethyl] amino-5-0-desosaminyl 3--0- (2-pyridyl) acetyl-6-O-methylerythronolide A 11, 12-cyclic carbamate Synthesis of

10,11-anhydro-2'-O-acetyl-12-0-midazolyl carboxy-3- (1-pyridyl) acetyl-5-〇-deso-saminilu 6-0-methylerythro described in Example 1 Using 0.325 g (0.393 mmol) of Noride A and 0.370 g (l.97 mmol) of 2- [4- (pyridyl-3-yl) -1H-imidazole-1-yl] ethylamine prepared In the same manner as in Example 1, the title compound (0.270 g) was obtained.

IonSprayMS m / z = 927.5 [MIH] ⁺

'Η- NMR (300MHz, CDC13) δ (ppm): 0.73 (3H, t, J = 7.5Hz, 14-CH 3), 2. 0 (6H, s, 3' -N (CH 3) 2), 3.08 (3H, s, 6-OCH3), 5.05 (1H, d, J = llHz, 3-CH), 7.48, 7.70 (each 1H, each s, Imidazole-CH) Example 4 11-Doxy_11— [4-1-1 (pyridine-1-3-yl) —1H—imidazo-1-ru 1 —yl] butyl] amino-5—0 —Desosaminyl 3 — O- (3 _pyridyl) acetyl-1 6 — 0 _Methylerythronolide A 11,12- Synthesis of cyclic carbamate

(1) 10,11-anhydro-2'-O-acetyl-5_-O-desosaminyl-6-O-methylerythronolide A 264g (431 mmol), 3-pyridylacetic acid described in International Patent No. 9823628 '' 150g (864mmol) hydrochloride, 1-ethyl-3 (N, N-dimethylamino) propylcarposimid hydrochloride (WSC HC

A mixture of 165 g (861 ol), 53 g (431 mniol) of 4- (dimethylamino) pyridine (hereinafter abbreviated as DMAP) and 2200 ml of methylene chloride was stirred at room temperature for 16 hours. To the reaction mixture were added 1200 ml of chloroform and 2500 ml of water, and the organic layer was separated. The aqueous layer was extracted with chloroform. The organic layers were combined, washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluent: acetone-hexane-triethylamine = 10: 30: 0.3) to give 10,11-anhydro_2'-O-acetyl-5-O —Desosaminyl—3—〇— (3-pyridyl) acetyl—6—O—methylerythronolide A 189 g was obtained.

188 g (257 mol) of this compound was dissolved in a mixed solvent of 1600 ml of tetrahydrofuran and 800 ml of N, N-dimethylformamide (hereinafter, abbreviated as DMF), and 139 g of carbazole N, N'-diimidazole was added under ice cooling. 90%, 771 mmol) and 30.8 g of sodium hydride (oil-based, 60%, 770 ol) were sequentially added and stirred for 90 minutes. Under ice cooling, 2,000 ml of ethyl acetate and 2,000 ml of water were added, and the organic layer was separated. The organic layer was washed with water, a saturated aqueous solution of ammonium chloride and a saturated saline solution in that order, and dried over magnesium sulfate. The crude product obtained after concentration under reduced pressure was recrystallized from a mixed solvent of acetone and n-hexane to give 10,11-anhydro 2'-O-acetyl-5-O-desosaminyl-12-O-imidazolyl. Carbonyl 3 —— (3-pyridyl) acetyl— 6 — O—methylerythrin Noride A 176 g was obtained.

IonSprayMS: m / z = 827.3 [M + H] +

(2) 4- [4-1 (pyridyl-3-yl) -1H-imidazole-1-yl] butylamine prepared with 0.612 g (0.740 mmol) of the compound obtained in the above (1) 0.800 g (3.70minol) and the same operation as in Example 1 to give 0.680 g of the title compound. lonSprayMS m / z = 933.5 [M + H]

'H-NMR (500 MHz, CDC) δ (ppm): 0.77 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.28 (6H, s, 3'-N (CH ₃ ) 2), 3.00 ( 3H, s, 6-OCH3), 5.02 (1H, d, J = 7.5Hz, 3-CH), 7.35 (1H, d, J = 1Hz, imidazole-CH), 7.56 (1H, d, J = lHz, imi dazo 1 e-CH) Example 5 Π-Doxy 11— [4 _ [4— (pyridine-3-yl) —1H—imidazole—1—yl] butyl] amino—5—O—desosaminyl— 3-0- (2-Villaryl) acetyl- 6-〇Methylerythronolide A 11, 12- Synthesis of cyclic calibrate

(1) 10,11-Anhydro 2'- 10, -acetyl-5-11-desosaminyl 6-O-methylerythronolide A described in International Patent No. 9823628, 54.4 g (88.7 odorol) and 2-virazil The same operation as in (1) of Example 4 was carried out using 24.5 g (177 ol) of acetic acid as a raw material to obtain 10,11-anhydro-2'-O-acetyl-5-O-desosaminyl 12 —〇—Imidazolylcarbonyl—3—O— (2-virazyl) acetyl—6—O—methylerythronolide A 37.6 g was obtained.

IonSprayMS: m / z = 828.3 [M + H] ⁺

(2) 4- [4 _ (pyridyl-3-yl) _ 1 H-imidazolyl-1-yl] butylamine prepared with 0.613 g (0.740 mmol) of the compound obtained in the above (1) Using the same procedure as in Example 1 using .SOOg (3.70 minol), 0.670 g of the title compound was obtained.

IonSprayMS m / z = 934.4 [M + H] +

'H-NMR (500MHz, CDC1 3) δ (ppm): 0.78 (3H, t, J = 7.5Hz, 14-CH3), 2.30 (6H, s, 3' -N (CHa) 2), 2.99 (3H , s, 6-OCHa), 5.05 (1H, d, J = 7.5Hz, 3-CH), 7.35 (lH, d, J = 1Hz, imi dazo 1 e-CH), 7.56 (1H, d, J = lHz, imi dazo 1 e-CH) Example 6 11-Doxy-Π— [4 _ [4— (pyridine-1-3-yl) 1-1H—imidazo-1-ru 1 —yl] butyl] amino-5-0 —Desosaminyl— 3— O-(thiazo-41-yl) acetyl 6-〇-methyl erythronolide A

11, 12—Synthesis of cyclic carbamates

(1) 10,11-Anhydro-2'-p-acetyl-5-0-desosaminyl-1-6-0-methylerythronolide A 89g (145mmo1), thiazol-4-yl described in International Patent No. 9823628 Using 62.4 g (436 mmol) of acetic acid as a raw material, (1) of Example 4 Perform the same operation as described above to obtain 10,11-anhydro-2'-0-acetyl-5-O-desosaminyl-12-O-imidazolylcarbonyl-3-3-0_ (thiazole-1-4-yl) acetyl One 6-0-methylerythronolide A 39.9 g was obtained.

IonSprayMS: m / z = 833.2 [M + H]

(2) 1.05 g of 4- [4- (pyridyl-3-yl) -1H-imidazole-1-yl] butylamine prepared with 0.809 g (0.971 mmol) of the compound obtained in the above (1) The same operation as in Example 1 was performed using 4.85 mmol) to obtain 0.840 g of the title compound.

IonSprayMS m / z = 939.4 [M + H] ⁺

'H-NMR (500 MHz, CDCls) δ (ppm): 0.79 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.27 (6H, s, 3'-N (CH ₃ ) 3.02 (3H, s , 6-0CH ₃ ), 7.37 (1H, d, J = 2.5 Hz, thiazole-CH), 8.76 (1H, d, J = 2.5 Hz, thiazole-CH) Example 7 11-Doxy-11— [4 _ (4-Fenil-1H-imidazole-1-1yl) butyl] amino-1 5—〇1-desosaminyl _3—0— (2-pyridyl) acetyl-1 6—0—methylerythronolide A 11, 12—Cyclic power Synthesis of one bamate

10,11-anhydro 2'_0-acetyl-12-0-midazolylcarbonyl 3_O— (2-pyridyl) acetyl—5—〇—deso saminilu 6—0_methylerythro described in Example 1 4— (4—Fenil 1H_imidazole—1yl) prepared with 0.500 g (0.605 ol) of Noride A Butylamine

The same operation as in Example 1 was carried out using 0.650 g (3.02 mmol) to obtain 0.120 g of the title compound.

IonSprayMS m / z = 932.5 [M + H] ⁺

'H-NMR (500MHz, CDCls ) <5 (ppm): 0.78 (3H, t, J = 7.5Hz, 14- CH 3), 2.30 (6H, s, 3' -N (CH 3) 2), 3.01 (3H, s, 6-0CH ₃ ), 7.52 (1H, s, imi dazo 1 e-CH) Example 8 11-Doxy-11- [4 _ (5 —Feneru 1 H-Pyrazol 1 _yl) ) Butyl] amino— 5 — O—desosaminyl— 3 — O— (2 —pyridyl) acetyl 1 6 _ 0—Methylerythronolide A 11,12—Synthesis of cyclic carbamate

10, 11-anhydro 2 'described in Example 1-0-acetyl-12-0- Midazolylcarbonyl-3- (O- (2-pyridyl) acetyl-5-O-desosaminyl-1 6-O-methylerythronolide A Prepared with 0.438 g (0.521 mmol) of 4- (5-phenyl-1- 1 H-Pyrazole-1-yl) The same operation as in Example 1 was carried out using 0.570 g (2.65IM01) of butyramine to obtain 0.270 g of the title compound.

IonSprayMS m / z = 932.5 [M + H] ⁺

'H-NMR (500MHz, CDC1 3) δ (ppm): 0.81 (3H, t, J = 7.5Hz, 14-CH 3), 2.30 (6H, s, 3' -N (CH 3) 2), 2.96 (3H, s, 6-OCH3), 6.51 (1H, d, J = 2.5 Hz, pyrazo 1 e-CH), 7.45 (1H, d, J = 2.5 Hz, pyrazole-CH) Example 9 11-Doxy [4 — [5 — (thiophene — 2 _yl) — 1 H—pyrazole-1 1-yl] butyl] amino-5 — 0—desosaminyl-1 3 — 0- (2-pyridyl) acetyl-1 6 — O—methylerythrono Ride A 11, 12- Synthesis of cyclic carbamate

10,11-Anhydro-2'-0-acetyl-12-O-imidazolylcarbonyl-3-3-O_ (2-pyridyl) acetyl-5 described in Example 1 5-〇-deso-saminyl-6-〇-methyl The same operation as in Example 1 was carried out by using 0.668 g (3.02 mmol) of erythronolide A and 0.568 g (0.605 mmol) of erythronolide A prepared with 0.668 g (3.02 mmol) of 4- (5-thiophenyl-1H-pyrazole-11-yl) butylamine. 0.460 g of the title compound was obtained.

IonSprayMS m / z = 938.4 [MIH] +

'H-NMR (500MHz, CDC13 ) δ (ppm): 0.81 (3H, t, J = 7.5Hz, 14- CH 3), 2.30 (6H, s, 3' -N (CH 3) 2), 2.97 ( 3H, s, 6-OCH3), 6.41 (1H, d, J = 2Hz, pyrazole-CH), 7.45 (1H, d, J = 2Hz, pyrazole-CH) Example 10 11—Doxy_11— [4 — [5 — Methyl — 4 — (Pyridine — 3 — yl) — 1 H—Imidazoyl 1 — yl] butyl] amino-5 — O—desosa miniru 3 — 0 _ (2-pyridyl) acetyl — 6 — 0 _Synthesis of methylerythramide A11,12-cyclic carbamate

10,11-Anhydro-2'-O-acetyl-12-O-midazolylcarponyl-3'-O- (2-pyridyl) acetyl-5-O-deso saminilou 6-0 described in Example 1 —Methylerythronolide A prepared with 1.26 g (l.52 mmol) of 4 — [5-Methyl-4- (pyridine-3-yl) — 1 H—imidazolyl— 0.840 g of the title compound was obtained in the same manner as in Example 1 using 1.75 g (7.60 iMiol) of [yl] butylamine.

IonSprayMS m / z = 974.5 [MIH] ⁺

'H-NMR (500MHz, CDC13 ) <5 (ppm): 0.80 (3H, t, J = 7.5Hz, 14- CH 3), 2.40 (6H, s, 3' -N (CHs) 2), .40 (3H, s, imidazole-CHs), 3.01 (3H, s, 6-OCH3) Example 1 1 11-Doxy-1 11- [4-1 (2— (Pyridine-3-yl) —1H-Imidazo-1 1—yl] butyl] amino-5—0—desosaminyl 3—O- (2—pyridyl) acetyl-6—O—methylerythronolide A 11,12—Synthesis of cyclic carbamates

10,11-anhydro-2'-〇-acetyl-12-O-midazolylcarbonyl 3- (〇- (2-pyridyl) acetyl-5_0-desosaminyl-1 6-〇-methylerythro described in Example 1 Using 0.696 g (0.841 mmol) of Noride A and 0.910 g (4.21 dragonol) of 4 _ [2 — (pyridine-3-yl) _ 1 H-imidazole-1-yl] butylamine prepared The title compound was obtained in the same manner as in Example 1.

0.540 g was obtained.

IonSprayMS m / z = 933.5 [M + H] ⁺

'H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 0 · 80 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.30 (6H, s, 3'-N (CH ₃ ) 2) , 2.92 (3H, s, 6-OCH3), 7.12 (1H, brs, imidazole-CH), 7.15 (1H, brs, imi dazo 1 e-CH) Example 1 2 11—Doxy _ 11— [4 _ [ 4 _ (Pyridine—2 —yl) — 1 H—Imidazoyl 1 —yl] butyl] amino-5 —〇1-desosaminyl—3 — —1 (2-pyridyl) acetyl 6—〇_methylerythronolide A 11,12—Synthesis of cyclic carbamate

10,11-Anhydro_2'-〇-acetyl- 12-O-midazolylcarbonyl 3--3-0- (2-pyridyl) acetyl_5 described in Example 1 O-desosaminyl-6-O-methyl Using 0.488 g (0.832 mmol) of erythronolide A and 0.900 g (4.16 mmol) of 4- [4- (pyridine-2-yl) -11H-imidazole-11-yl] butyramine prepared The title compound was obtained in the same manner as in Example 1.

0.590 g was obtained.

IonSprayMS m / z = 933.5 [M + H] ⁺ _{lH-NMR (500MHz, CDC1 3} ) δ (ppm): 0.80 (3H, t, J = 7.5Hz, 14- CH 3), 2.30 (6H, s, 3 '-N (CH 3) 2), 3.01 ( 3H, s, 6-OCH3), 7.55 (1H, brs, imidazole-CH), 7.63 (lH, brs, imidazole-CH) Example 1 3 11-Doxy-11-1 [4- [4_ (6_methyl) Pyridine-1 2 — yl) _ 1 H—imidazole— 1-yl] butyl] amino— 5 —〇—desosami 2-ru 3 — 0— (2-pyridyl) acetyl-6 — O—methylerythronolide A 11 , 12—Synthesis of cyclic carbamates

10,11-anhydro-2'-0'-acetyl- 12-〇-midazolylcarbonyl- 3 -O- (2-pyridyl) acetyl-5 -O-desosaminyl-6 -0 described in Example 1 —Prepared with 0.553 g (0.669 mmol) of methyl erythronolide A 4 — [4— (6 _methylpyridine-1-yl) — 1 H—imidazole-11-yl] butylamine 0.770 g (3.34 mniol ) To give 0.410 g of the title compound.

IonSprayMS m / z = 947.5 [M + H] ⁺

_{'Η- NMR (500MHz, CDC1 3} ) δ (ppm): 0.80 (3H, t, J = 7.5Hz, 14-CH 3), .30 (6H, s, 3' -N (CH 3) 2), 2.54 (3H, s, imi dazo 1 e-CH 3), 3.01 (3H, s, 6- 0CH 3), 7.12 (1H, brs, imidazole-CH), 7.15 (1H, brs, imidazole-CH) example 1 4 11-Dethoxy-1 11— [4— [4_Methyl_2— (Pyridine—3—yl) —1H—Imidazole-1_Iryl] butyl] amino—5—0—Desosa miniru 3—O— (2 —Pyridyl) acetyl-6 —〇Methylerythramide A11,12—Synthesis of cyclic carbamate

10,11-Anhydro-2'-O-acetyl-12-〇-midazolylcarbonyl 3- (O- (2-pyridyl) acetyl-5-O-deso-saminyl 6-〇-methyl-erythronolai described in Example 1 Example using 0.818 g (3.73 mmol) of 4- [4-methyl-2- (pyridine-3-yl) _1H-imidazole-1-yl] butylamine prepared with 0.618 g (0.747 mmol) of C By a similar operation to 1, 0.420 g of the title compound was obtained.

IonSprayMS m / z = 947.5 [M + H] ⁺

'Η-NMR (500 MHz, CDCh) δ (ppm): 0.80 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.25 (3H, s, imidazole-CH ₃ ), 2.30 (6H, s, 3 _{_{'-N (CH 3) 2)}} , 2.92 (3H, s, 6-0CH 3). Example 15 11-Doxy-11- [4_ [2-methyl-4_ (pyridine-3-yl) 1-1H-imidazoyl-1-yl] butyl] amino] 5-〇_desosaminyl _ 3 — O— (2 — pyridyl) acetyl- 1 6 _ O—Methylerythramide A 11, 12—Synthesis of cyclic carbamate

10,11-anhydro-2'-O-acetyl-12-0-midazolylcarbonyl 3- (O- (2-pyridyl) acetyl-5-O-deso saminyl 6-O-methyl described in Example 1 Prepared with 0.898 g (l.09 mmol) of erythronolide A, 1.25 g of 4- [2-methyl-41- (pyridine-3-yl)-1 H-imidazolyl-11-yl] butylamine In the same manner as in Example 1 using 5.43 mmol), 0.800 g of the title compound was obtained.

IonSprayMS m / z = 947.5 [M + H] ⁺

'H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.76 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.30 (6H, s, 3'-N (CH ₃ )), 2.43 ( 3H, s, imidazole-CH ₃ ), 3.01 (3H, s, 6-0CH ₃ ) Example 1 6 11-Doxy-11- [4-I [3_ (Pyridine-3-I-yl) —1H-1 , 2,4—triazo-1-yl [butyl] amino-5—O—desosa miniru 3—O— (2—pyridyl) acetyl—6 methyl erythride A 11,12_cyclic carbamate Synthesis of

10,11-Anhydro-2'-P-acetyl-12-O-midazolylcarbonyl-3'-O- (2-pyridyl) acetyl--5-O-deso saminilu 6-O-methylerythro described in Example 1 1.32 g (6.17 mmol) of 4- [3- (pyridine-3-yl) -1H-1, 2,4-triazole-1-yl] butylamine prepared with 1.02 g (l.23 mmol) of Noride A ) To give the title compound in the same manner as in Example 1 to obtain 23 g.

IonSprayMS m / z = 934.4 [M + H] ⁺

'H-NMR (500 MHz, CDCls) δ (ppm): 0.80 (3H, t, J = 7.3 Hz, 14-CH ₃ ), 2.30 (6H, s, 3'-N (CH ₃ ) ₂ ), 2.99 ( 3H, s, 6-0CH ₃ ), 5.03 (1H, d, J = ll.3Hz, 3-CH), 7.22 (1H, dd, J = 7.6, 5.8Hz, pyridine-CH), 7.33-7.38 (2H , m, yr id ine-CH), 7.69 (1H, ddd, J = 7.6, 7.6, 1.8Hz, pyridine-CH), 8.17 (1H, s, pyrid ine-CH), 8.36-8.34 (lH, m , pyridine-CH), 8.53-8.52 (1H, m, yridine-CH), 8.61 (lH, dd, 1 = 4.9, 1.8Hz, pyridine-CH), 8.61 (1H, dd, J = 4.9, 1.8Hz, pyridine-CH), 9.31 (1H, d, J = l.5Hz, triazole-CH) Example 1 7 11-Doxy_11— [4— [3— (pyridine-3-yl) —1H—1,2,4-1triazole—1—yl] butyl] amino—5—O—desosa Synthesis of Minyl 1- 3-0- (2-pyridyl) acetyl 6-〇-Methylerythropenlide A11,12-Cyclic carbamate

10,11-Anhydro-2'- 0-acetyl- 12- 0-midazolylcarbonyl- 3 -0_ (2-pyridyl) acetyl- 5 -〇-deso-saminyl 6-O- described in Example 1 Methylerythronolide A prepared with 0.37 g (0.44 mmol) of 4- [3 — (pyridine-3-yl) — 1 H—1,2,4-triazolyl-11 yl] butylamine 0.38 g (1.75 mmol) and 337 mg of the title compound were obtained in the same manner as in Example 1.

IonSprayMS m / z = 934.2 [M + H] +

'H-NMR (500MHz, CDC1 3) δ (pm): 0.80 (3H, t, J = 7.3Hz, 14-CH 3), 2.28 (6H, s, 3' -N (CH 3) 2), 2.98 (3H, s, 6-OCH3), 5.01 (1H, d, J = 1.0 Hz, 3-CH), 7.31 (1H, dd, J = 7.9, 4.9 Hz, pyridine-CH), 7.35 (1H, dd , J = 7.9, 4.9Hz, pyridine-CH), 7.74-7.75 (lH, m, pyridine-CH), 8.17 (1H, s, pyridine-CH), 8.35 (1H, ddd, J = 7.9 , 1.8, 1.8Hz, pyridine-CH), 8.56 (lH, m, pyridine-CH), 8.61 (1H, dd, J = 4.9, 1, 8Hz, pyridine-CH), 9.32 (1H, d, J = 2.4 Hz, triazole-CH) Example 1 8 11-Doxy 11— [4-—3— (pyridine_3_yl) —1H—1,2,4-triazole-1—yl] butyl] Amino-5—O—desosa miniru 3—O— (2-Villaryl) acetyl-6—O—Methylerythnolide A 11,12—Synthesis of cyclic carbamate

Example 5, 10,11-Hydro_2'_0-acetyl—12—0_imidazolylcarbonyl—3—O_ (2-virazyl) acetyl—5—0—desosa miniru 6 obtained in (1) — O-Methylerythronolide A prepared with 0.35 g (0.43 mmol) of 4- [3 — (pyridine-3-yl) — 1 H—1,2,4—triazolyl-1—yl] The same operation as in Example 5 (2) was performed using 0.37 g (1.70 mmol) of butylamine to obtain 305 mg of the title compound.

IonSprayMS m / z = 935.2 [M + H] +

'H-NMR (500 MHz, CDCls) δ (ppm): 0.81 (3H, t, J = 7.3 Hz, 14-CH3), 2.30 (6H, s, 3'-N (CH3) 2), 2.98 (3H, s, 6-OCH3), 5.04 (1H, d, J = 1.0Hz, 3-CH), 7.35 (1H, dd, J = 7.9, 4.9Hz, pyridine-CH), 8.17 (1H, s, pyridine- CH), 8.35 (1H, ddd, J = 7.9, 1.8, 1.8Hz, pyridine-CH), 8.61 (IH, dd, J = 4.9, 1.8Hz, pyridine-CH), 8.52 (2H, s, pyrazine-CH), 8.64 (1H, s, pyrazine-CH), 9.31 (1H, d, J = l. Hz, triazole-CH) Example 1 9 11-Doxy-11- [4-1- [3- (pyridine-3-yl) -1-H-1, 2,4-triazo- 1-yl] butyl] amino-1 5 —〇—desosa miniru 3 — O— (thiazoluyl 4-yl) acetyl— 6 — O—methylerythronolide A 11,12—Synthesis of cyclic carbamates

Example 6, 10,11-anhydro- 2'-O-acetyl- 0-imidazolylcarbonyl 3_〇- (thiazole-41-yl) acetyl-5-O-desosaminyl 6-O obtained in (1) —Methylerythronolide A 0.37 g (0.44 bandol) prepared with 4- [3— (pyridine-3-yl) -1 1H—1,2,4—triazol-1-yl] butylamine The same operation as in Example 1 was performed using 0.29 g (0.35 mmol) to obtain 378 mg of the title compound.

lonSprayMS m / z = 940.1 [M + H] ⁺

'H-NMR (500MHz, CDC1 3) δ (pm): 0.81 (3H, t, J = 7.3Hz, 14 - CH 3), 2.27 (6H, s, 3'-N (CH 3) 2), 3.00 (3H, s, 6-OCH3), 5.05 (IH, d, J = l 1.6Hz, 3-CH), 7.34-7.37 (2H, m, pyridine-CH and thiazole-CH), 8.17 (1H, s, pyridine-CH), 8.35 (1H, ddd, J = 7.9, 1.8, 1.8Hz, pyridine-CH), 8.61 (IH, dd, J = 4.9, 1.2Hz, pyridine-CH), 8.76 (lH, d, J = l.8Hz, thiazole-CH), 9.32 (lH, d, J = 2.5Hz, triazole-CH) Example 2 0 11-Doxy-11- [4- [3- (pyridine-3-yl) — 1 H—pyrroyl 1-yl] butyl] amino-1 5 — O—desosaminyl— 3 — O—

(2—Pyridyl) acetyl-6_0_Methylerythronolide A 11,12—Synthesis of cyclic carbamate

10,11-anhydro-2'-O-acetyl- 12-0-midazolylcarbonyl 3-O- (2-pyridyl) acetyl-5- 0-deso-saminyl-6-0-methylerythro described in Example 1 Example using 0.290 g (1.35 mmol) of Noride A prepared with 0.300 g (0.363 mmol) of 4 — [3 — (pyridin-3-yl) — 1 H-pyrrole— 1 _ iryl] ptyramine By the same operation as 1, 0.250 g of the title compound was obtained.

lonSprayMS m / z = 932.4 [M + H] +

'H-NMR (300 MHz, CDCls) δ (ppm): 0.78 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.28 (6H, s, _{_{3 '-N (CH 3) 2}} ), 2.98 (3H, s, 6- 0CH 3), 5.03 (1H, d, J = llHz, 3 - CH) Example 2 1 11 Dokishi 11- [4 _ [3 —Methoxycarbonyl— 4 — (Pyridine—3 —yl) 1 1 H—Pyrrole 1 —yl] butyl] amino-1 5 _ O—desosaminyl 3 _ O _ (2 _ pyridyl) acetyl — 6 — O— Methylerythronolide A 11, 12—Synthesis of cyclic carbamate

10,11-anhydro-2'-0-acetyl-12-0-midazolylcarbonyl 3- (O- (2-pyridyl) acetyl-5-O-deso-saminyl 6--1-methylerythrono described in Example 1 Prepared with 0.600 g (0.181 mmol) of ride A 4- [3-methoxycarbonyl 4- (pyridine-3-yl) 1-1H-pyrroyl-1-yl] butylamine 1.090 g (3.99 mmol) ) To give 0.501 g of the title compound.

IonSprayMS m / z = 990.7 [M + H] +

* H-NMR (300MHz, CDC1 3) δ (ppm): 0.75 (3H, t, J = 7.5Hz, 14-CH3), 2.28 (6H, s, 3 '-N (CH 3) 2), 3.00 ( _{3H, s, 6- 0CH 3)} , 3.70 (3H, s, C0 2 CH 3), 5.25 (lH, d, J = llHz, 3-CH), 6.70, 7.08 (each 1H, each s, pyrrole-CH Example 2 2 11—Doxy 11— [4— [3— (thiophene 1—yl) —1H-pyrrole—1—yl] butyl] amino—5—0—desosaminyl—3—〇ichi (2 —Pyridyl) acetyl- 6 _ O—Methylerythronolide A 11, 12- Synthesis of cyclic carbamate

10,11-Anhydro-2'-0-acetyl- 12-0-dimidazolylcarbonyl 3 -0_ (2-pyridyl) acetyl-5 described in Example 1 5 -O-desosaminyl-1 6 -O-methylerythrono Performed with 0.150 g (0.181 mmol) of ride A and 0.200 g (0.908 mmol) of 4- [3- (thiophen-2-yl) _ 1 H-pyrroyl-1-yl] butylamine By the same operation as in Example 1, 0.146 g of the title compound was obtained.

IonSprayMS m / z = 937.4 [M + H] 10

'H-NMR (300 MHz, CDCla) δ (ppm): 0.79 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.29 (6H, s, 3'-N (CH ₃ ) ₂ ), 3.00 ( 3H, s, 6-0CH ₃ ), 5.05 (1H, d, J = llHz, 3-CH), 6.32 (1H, t, J = l.8 Hz, pyrrole-H), 6.64 (1H, t, J = 2.4Hz, pyr ro 1 eH), 6.90 (lH, m, pyrrole— H) Example 2 3 11-Doxy 11- [4_ [3-Methoxycarbinyl 4- (thiophen-1-yl) _1H-pyrrol-1- 1-yl] butyl] amino-1 5-0-desosaminyl 3 —〇— (2-pyridyl) acetyl- 6 — 0—Methyl erythronolide AU, 12—Synthesis of cyclic carbamate

10,11-anhydro-2′-0-acetyl-12-◦-midazolylcarbonyl 3- (O)-(2-pyridyl) acetyl-5 described in Example 1 5-〇-desosaminyl-1 6—O-methylerythro 0.95 g of 4- [3—Methoxycarbonyl-14- (thiophene-2-yl) -1H-pyrrole-1—yl] butylamine prepared with 0.600 g (0.726 ol) of Noride A Using the same procedure as in Example 1 except for using 3.41 mmol), 0.370 g of the title compound was obtained.

lonSprayMS m / z = 995.6 [M + H] ⁺

'.Eta. thigh (300MHz, CDCla) δ (ppm ): 0.78 (3H, t, J = 7.5Hz, 14 - CH 3), 2.29 (6H, s, 3'-N (CH 3) 2), 3.00C3H , s, 6-0CH ₃ ), 3.74 (3H, s, CO2CH3), 5.04 (1H, d, J = llHz, 3-CH) Example 2 4 11-Doxy 11— [4— [3—Methoxycarbonyl — 4— (5—Methylfuran— 2 —yl) — 1 H—Pyrroyl-1 1 —yl] butyl] amino 5 —〇—desosaminyl 3 — 0— (2 —pyridyl) acetyl 6 — 0— Synthesis of Methylerythronolide A 11, 12—Cyclic Carbamate

10,11-anhydro-2'-〇-acetyl- 12-O-midazolylcarbonyl, as described in Example 1 3-O- (2-pyridyl) acetyl-5-0-deso-saminyl-6-0-methylerythro Prepared with 0.800 g (0.967 mmol) of Noride A 41- [3-Methoxycarbonyl-1- (5-methylfuran-2-yl) -11H-pyrroyl-1-yl] butylamine 0.830 The same operation as in Example 1 was performed using g (4.71 mmol) to obtain 0.680 g of the title compound.

lonSprayMS m / z = 993.7 [MIH] +

'H-NMR (300 MHz, CDC13) δ (ppm): 0.80 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.28 (9H, s, 3' -N (CHs) 2 and furan-CH ₃ ), 3.00 (3H, s, 6-OCH3), 3.78 (3H, s, C0 2 Me), 5.05 (1H, d, J = llHz, 3-CH), 5.98 (1H, d, J = 3.1Hz, Ar-CH), 6.94 (1H, d, J-3.7Hz, Ar-CH), 6.97 (1H, d, J = 2.4Hz, Ar-CH) Example 2 5 11-Doxy-11- [4— [3—Power Lubamoir 4 — (Pirigi 3- (yl) — 1 H-pyrroyl-1 1-yl] butyl] amino-5-O-deso saminyl 3- (1-pyridyl) acetyl-6-O-methylerythronolide A 11, 12—Cyclic carbamate synthesis

10,11-Anhydro-2'-O-acetyl-12-pymidazolylcarbonyl 3- (O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0-methyl described in Example 1 Prepared with 0.500 g (0.605 mmol) of erythronolide A, 0.790 g of 4- [3-carbamyl-4- (pyridin-3-yl) -11H-pyrrol-1--1-yl] butylamine The same procedure as in Example 1 was performed using 3.06 mmol) to obtain 0.360 g of the title compound.

IonSprayMS m / z = 975.6 [M + H] ⁺

'H-NMR (500 MHz, CDC) δ (ppm): 0.79 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.30 (6H, s, 3'-N (CH ₃ ) ₂ ), 2.95 ( 3H, s, 6-OCH3), 5.00 (1H, d, J = l 1Hz, 3-CH), 5.62 (2H, br, CONH2), 6.71 (1H, d, J = l.8Hz, pyrrole- CH) Example 2 6 11-Doxy-11- [4- [4- (thiazol-2-yl) thiazol-2-yl] butyl] amino-5-〇—desosaminyl 3-0— ( 2-Pyridyl) acetyl-6-O-methylerythronolide A 11,12—Synthesis of cyclic carbamate

10,11-Anhydro-2'-O-acetyl-12-O-midazolylcarbonyl 2--0- (2-pyridyl) acetyl-5-0-desosaminyl-6-O-methylerythro described in Example 1 As in Example 1 using 0.56 g (2.38 mmol) of 4- [4- (thiazolu-2-yl) thiazo-1-ru-2-yl] butylamine prepared with 0.66 g (0.79 mmol) of Noride A By the operation described above, 627 mg of the title compound was obtained.

IonSprayMS m / z = 956.4 [M + H] ⁺

'H-NMR (500MHz, CDC1 3) δ (ppm): 0.81 (3H, t, J = 7.3Hz, 14-CHs), 2.30 (6H, s, 3' -N (CH 3) 2), 3 · 04 (3H, s, 6-OCH3), 5.03-5.06 (2H, m, 3-CH and 13-CH), 7.22 (1H, ddd, J = 7.9, 4.9, 1.2Hz, pyridine-CH), 7.33- 7.21 (2H, m, th azo 1 e-CH), 7.69 (1H, ddd, J = 7.9, 7.9, 1.8Hz, pyridine-CH), 7.81-7.82 (2H, m, thi azo 1 e-CH) , 8.52-8.53 (lH, m, pyridine-CH) Example 2 7 11-Doxy-11- [4- [4- (thiazol-2-yl) thio Fazol-2-yl [butyl] amino-5-O-desosaminyl-3-O— (thiazol-4-yl) acetyl-6-O-methylerythronolide A11,12—Cyclic power Synthesis

Example 6 10, 11-Anhydro-2'-O-acetyl- 12- 0-imidazolylcarbonyl 2-O- (thiazo-l-lu 4-yl) acetyl- 5-0-desosaminyl obtained in (1) 0.37 g (l.5 minol) of 4_ [4- (thiazol-2-yl) thiazo-1-yl-2-butyl] amine prepared with 0.32 g (0.39 mmol) of 6-O-methylerythronolide A Using the same procedures as in Example 6 (2), 0.25 g of the title compound was obtained.

lonSprayMS m / z = 962.3 [M + H] +

'H-NMR (300MHz, CDC13 ) δ (pm): 0.82 (3H, t, J = 7.5Hz, 14-CH3), 2.28 (6H, s, 3' -N (CH 3) 2), 3.06 (3H , s, 6-OCH3), 5.07 (1H, d, J = l 1Hz, 3-CH), 7.31 (1H, d, J = 3Hz, thiazole-CH), 7.38 (1H, d, J = 3Hz, thiazole -CH), 7.81 (1H, s, tiazo 1 e-CH), 7.82 (1H, s, thiazole-CH), 8.76 (1H, s, thiazole-CH) Example 2 8 11—Doxy_111-1 [ 4 _ [4 _ (thiazolyl-2-yl) thiazol-2-yl] butyl] amino-5-〇_desosaminyl 3-〇— (2-virazyl) acetyl 6-0-methylerythronolide A 11, 12—Cyclic carbamate synthesis

Example 5 10,11-Anhydro-2'-O-acetyl-12-O-imidazolylcarbonyl 2- (1-virazyl) acetyl-5 ____ desosaminyl-1-6-O obtained in (1) —Example using 0.25 g (l.Onnnol) of 4- [4- (thiazol-2-yl) thiazo-1-yl-2-butyl] amine prepared with 0.22 g (0.26 mmol) of methylerythronolide A 5 By the same operation as in (2), 0.21 g of the title compound was obtained. lonSprayMS m / z = 957.3 [M + H] +

'H-NMR (300MHz, CDCls ) δ (ppm): 0.81 (3H, t, J = 7.5Hz, 14- CH 3), 2.28 (6H, s, 3' -N (CH 3) 2), 3.03 ( 3H, s, 6-OCH3), 5.05 (1H, d, J = llHz, 3-CH), 8.52 (2H, s, pyrazine-CH), 8.64 (1H, s, pyrazine-CH) 11—Doxy—11— [4 _ [4-1 (thiazolu-1-yl) thiazol—2—yl] butyl] amino-5—0—desosaminyl 3—O— (2—pyridyl) acetyl 6— {1-Methylerythronolide A}, 12—cycle Synthesizing a liquid carbamate

10,11-anhydro-2'-〇-acetyl-12-O-midazolylcarbonyl-3-3-0- (2_pyridyl) acetyl-5-0-5-deso-saminyl described in Example 1 Example 1 was repeated using 0.46 g (0.51 mmol) of monomethylerythronolide A and 0.36 g (1.50 iMol) of [4- (thiazol-5-yl) thiazol-2-yl] butylamine prepared with 0.42 g (0.51 mmol) of monomethylerythronolide A. By the same operation, 374 mg of the title compound was obtained.

IonSprayMS m / z = 956.3 [M + H] ⁺

'Η-Awake (500MHz, CDC13) δ (ppm): 0.81 (3H, t, J = 7.3Hz, 14-CH ₃ ), 2.30 (6H, s, 3'-N (CH ₃ ) 2), 3.01 ( 3H, s, 6-OCH3), 5.03-5.06 (2H, m, 3-CH and 13-CH), 7.21 (1H, dd, J = 6.7, 4.9Hz, yridine-CH), 7.29 (1H, s , Thiazole-CH), 7.37 (1H, d, J = 7.9Hz, pyridine-CH), 7.69 (1H, ddd, J = 7.3, 7.3, 1.8Hz, Pyridine-CH), 8.19 (1H, s, thiazole-CH), 8.51 (lH, d, J = 4.3Hz, pyridine-CH), 8.72 (1H, s, thiazole-CH) Example 3 0 11—Doxy-1 11— [4— [4-1 (Thiazo-1 Lou 5 — yl) thiazole 1 2 — yl] butyl 1 amino 1 _ 0—desosaminyl 1 3 — O— (thiazole 1 -4-yl) acetyl 1 6—〇_methylerythronolide A 11 , 12—Cyclic carbamate synthesis

Example 6 10,11-Hydro-2'_0-acetyl- 12-〇-imidazolylcarbonyl 2'_3_0_ (thiazol-4-yl) acetyl-5-0—desosaminyl-1 6— obtained in (1) Performed using 0.44 g (1.93 mmol) of 4- [4 _ (thiazoyl 5-yl) thiazol-2-yl] butylamine prepared with 0.54 g (0.65 mmol) of O-methylerythronolide A The same operation as in Example 6 (2) gave 419 mg of the title compound.

IonSprayMS m / z = 962.3 [M + H] ⁺

'H-NMR (500 MHz, CDC13) δ (ppm): 0.82 (3H, t, J = 7.3 Hz, 14-CH ₃ ), 2.7 (6H, s, 3'-N (CH ₃ ) ₂ ), 3.02 (3H, s, 6-0CH3), 5.06 (1H, d, J = ll. OHz, 3-CH), 7.29 (1H, s, thiazole-CH), 7.37 (1H, d, J = l.8Hz , thiazole-CH), 8.19 (1H, s, thiazole-CH), 8.72 (1H, s, thiazole-CH), 8.76 (1H, d, J = l.8Hz, thiazole-CH) Deoxy—11-1 [4— [4— (thiazol-5—yl) thiazolu2—yl] butyl] amino—5—0—desosaminyl—3—0— (2—virazil) acetyl—6_0 —Methylerythronolide A 11, 12—Cycle Synthesis of Rick Carbamate

Example 5 10,11-Ahydro-1,2'_0-acetyl-12-O-imidazolylcarbonyl 3-O- (2-virazyl) acetyl-5-O-desosaminyl-6- obtained from (1) Example using 0.47 g (1.96 mmol) of 4- [4- (thiazol-5-yl) thiazol-2-yl] butylamine prepared with 0.54 g (0.65 mmol) of O-methylerythronolide A 5 A similar procedure to (2) yielded 403 mg of the title compound:

IonSprayMS m / z = 957.3 [M + H] ⁺

'H-NMR (500 MHz, CDCl ₃ ) 6 (ppm): 0.82 (3H, t, J-7.3 Hz, 14-CH ₃ ), 2.29 (6H, s, 3'-N (CH ₃ ) ₂ ), 3.01 (3H, s, 6-OCH3), 5.05 (1H, d, J = 1.0 Hz, 3-CH), 7.28 (1H, s, thiazole-CH), 8.19 (1H, s, thiazo 1 e- CH), 8.52 (2H, s, pyrazine-CH), 8.64 (1H, s, pyrazine-CH), 8.72 (1H, s, thiazole-CH) Example 3 2 11-Doxy-11- [4-1-1 [ 2 _ (pyridine-2-yl) thiazol—4-yl] butyl] amino-5_〇—desosaminyl 3—O— (2-pyridyl) acetyl-1 6—O—methylerythronolide A Π , 12—Cyclic carbamate synthesis

10,11-Anhydro-2'-acetyl- 12-〇-midazolylcarbonyl 2- 3- (1-pyridyl) acetyl-5 -—- deso-saminyl-6-Ο-methylerythro described in Example 1 As in Example 1 using 0.54 g (0.65 mmol) of Noride A and 0.46 g (1.97 mmol) of 4- [2- (pyridine-2-yl) thiazole-4-yl] butylamine prepared By the operation described above, 0.52 g of the title compound was obtained.

IonSprayMS m / z = 950.3 [M + H] +

'H-NMR (500MHz, CDC1 3) δ (ppm): 0.82 (3H, t, J-7.3Hz, 14- CH 3), 2.29 (6H, s, 3' - N (CH 3) 2), 3.03 (3H, s, 6-OCH3), 5.05 (1H, d, J = l 1.0Hz, 3-CH), 7.04 (1H, s, thia zole-CH), 7.21 (lH, dd, J = 6.7, 4.9 Hz, pyr pyridine-CH), 7.6-7.29 (1H, m, pyridine-CH), 7.37 (1H, d, J = 7.9Hz, pyr idine-CH), 7.69 (1H, ddd, J = 7.9 , 7.9, 1.8Hz, pyridine-CH), 7.77 (1H, ddd, J = 7.9, 7.9, 1.8Hz, pyridine-CH), 8.18 (1H, d, J = 7.9Hz, pyridine-CH), 8.52 ( 1H, dd, J = 4.9, 1.8Hz, pyridine-CH), 8.58 (1H, dd, J = 4.9Hz, pyridine-CH) Example 3 3 11-Doxy-11-1 [4 _ [2— ( Pyridine-3-yl) thiazolu-4-yl] butyl] amino—5-0—desosaminyl-1-O— (2— Pyridyl) acetyl-6_O-methylerythronolide A 11,12_Cyclic synthesis of cyclic force

10,11-anhydro-2'-O-acetyl-12-O-midazolylcarbonyl-3-O- (2-pyridyl) acetyl-5-O-desosaminyl_6_0 described in Example 1 Performed using 0.52 g (0.63 mmol) of methyl erythronolide A and 0.73 g (3.13 related 01) of 4- [2- (pyridine-3-yl) thiazol-4-yl] butylamine prepared with 0.52 g (0.63 mmol). By the same operation as in Example 1, 0.36 g of the title compound was obtained.

IonSprayMS m / z = 950.4 [M + H] 10

'H-NMR (500 MHz, CDCh) δ (ppm): 0.80 (3H, t, J = 7.3 Hz, 14-CH ₃ ), 2.30 (6H, s, 3'-N (CH ₃ ) ₂ ), 2.99 ( 3H, s, 6-0CH ₃ ), 5.05 (1H, d, J-ll.OHz, 3-CH), 7.00 (1H, s, thiazole-CH), 7.21-7.23 (1H, m, pyr idine-CH ), 7.34-7.38 (2H, m, pyr idi ne-CH), 7.69 (1H, ddd, J-7.6, 7.6, 1.8Hz, pyr idi ne-CH), 8.25 (1H, ddd, J = 7.9, 1.8 , 1.8Hz, pyridine-CH), 8.52-8.53 (1H, m, yr idine-CH), 8.61 (1H, dd, J = 4.9, 1.8Hz, pyridine-CH), 9.12 (1H, dd, J = 2.4, 0.9Hz, pyridine-CH) Example 3 4 11-Doxy-11- [4-1- [2 _ (pyridine-14-yl) thiazol- 4-yl] butyl] amino-5- 0—Desosaminyl 3-O— (2-pyridyl) acetyl-1 6 _〇_Methylerythronolide A 11,12_Synthesis of cyclic carbamate

10,11-anhydro 2'-O-acetyl- 12-O-midazolylcarbonyl 2- (3-O_ (2-pyridyl) acetyl- 5--O-deso-saminyl 6-O-methylerythrono described in Example 1 Example 1 was prepared using 0.59 g (0.70 mmol) of ride A and 0.49 g (2.1 marl ol) of 4- [2- (pyridine-4-yl) thiazolyl-4-yl] butylamine. 508 mg of the title compound were obtained in the same manner as in the above.

IonSprayMS m / z = 950. [M + H] +

'H-NMR (500MHz, CDC1 3) δ (ppm): 0.79 (3H, t, J-7.3Hz, 14-CH 3), 2.29 (6H, s, 3' -N (CH 3) 2), 2.96 (3H, s, 6-OCH3), 5.03-5.06 (2H, m, 3-CH and 13-CH), 7.07 (1H, s, thiazole-CH), 7.22 (1H, dd, J = 6.7, 4.9Hz , yridine-CH), 7.37 (1H, d, J = 7.9Hz, pyridine-CH), 7.69 (1H, ddd, J = 7.3, 7.3, 1.8Hz, pyridine-CH), 7.80 (1H, dd) , J = 4.3, 1.2Hz, pyridine-CH), 8.53 (1H, dd, J = 4.9, 1.2Hz, pyridine-CH), 8.66 (1H, dd, J = 4.9, 1.2Hz, pyridine-CH) CH) Example 3 5 11-Doxy-11- [4_ [2— (thiazole-4-yl) thiazole—41-yl] butyl] amino-5—0—desosaminyl 3- 3-〇 (2-pyridyl) acetyl 6 _〇Methylerythronolide A 11, 12—Synthesis of cyclic carbamate

10,11-anhydro-2'-〇-acetyl-12-0-midazolylcarbonyl 3-O- (2-pyridyl) acetyl-5-O-desosaminyl-1 6-0-methyl described in Example 1 Example 1 was repeated using 0.260 g (0.301IMO1) of erythronolide A and 0.360 g (l.50 mmol) of 4- [2 — (thiazo-l- 4-yl) thiazol-4-yl] butyramine. By the same operation, 0.270 g of the title compound was obtained.

IonSprayMS m / z = 956.4 [M + H] +

'H-NMR (500MHz, CDC ) δ (pm): 0.80 (3H, t, J = 7.5Hz, 14 - CH 3), 2 · 30 (6H, s, 3' -N (CH 3) 2), 3.02 (3H, s, 6-0CH., 6.98 (1H, s, thia azo 1 e-CH), 8.02 (1H, d, 1Hz, thiazole-CH), 8.83 (1H, d,〗 = lHz, thiazole -CH) Example 3 6 11-Doxy-11- [4_ [2- (thiazol-2-yl) thiazol-4-yl] butyl] amino-5-0—desosaminyl-3—O— ( 2-Pyridyl) acetyl-6-0-Methylerythronolide A 11,12-Synthesis of cyclic carbamate

10,11-anhydro 2'_0-acetyl_12-O-midazolylcarbonyl 3_0— (2-pyridyl) acetyl—5—O-desosaminyl-1 6—0-methyl described in Example 1 Erythronolide A 0.622 g (0.752 mmol) prepared with 4 — [2 — (thiazol-2-yl) thiazol-4-yl] butylamine 0.900 g (3.76 minol) By the same operation as in Example 1, 0.550 g of the title compound was obtained.

IonSprayMS m / z = 956.4 [M + H] +

'H-NMR (500MHz, CDC ) δ (ppm): 0.80 (3H, t, J = 7.5Hz, 14- CH 3), 2 · 30 (6H, s, 3' -N (CH 3) 2), 3.03 (3H, s, 6-OCH3), 7.05 (1H, s, thiazole-CH), 7.39 (1H, d, J = 3Hz, thiazole-CH), 7.85 (1H, d, J = 3Hz, thiazole-CH) ) Example 3 7 11-Deoxy 11-[4-[4 _ (pyridine-3-yl)-1 H-imidazole-2-yl] butyl] amino-5 〇-desosaminyl-3- O-(2-pyridyl) acetyl-6-O-methyl erythronolide A 11, 1 2-Synthesis of cyclic carbamate

10,11-Anhydro-2'-0-acetyl-12-12-imidazolylcarbonyl 3-O- (2-pyridyl) acetyl-5 __- desosaminyl-1 6-0-methyl described in Example 1 0.314 g (0.379 mmol) of erythronolide A and 0.410 g (l.90 mmol) of 4- [4- (pyridine-3-yl) -11H-imidazo-l-2-yl] butylamine prepared The same procedure as in Example 1 was carried out to obtain 0.230 g of the title compound.

IonSprayMS m / z = 933.4 [M + H] +

'Η-NMR (500 MHz, CDC 13) δ (ppm): 0.81 (3H, t, J = 7.5 Hz, 14-CH ₃ ), 2.29 (6H, s, 3'-N (CH ₃ ) ₂ ), 2.90 (3H, s, 6-OCH3), 7.23 (1H, d, J = 8, 4 Hz, pyridine-CH), 7.25 (1H, dd, J = 7, 5 Hz, pyridine-CH), 7 1H, s, imidazo 1 e-CH), 7.38 (1H, d, J = 8.0Hz, pyridine-CH), 7.70 (1H, ddd, J = 8, 8, 1Hz, pyridine-CH), 8.10 ( lH, brd, J = 8Hz, pyridine-CH), 8.43 (1H, dd, J = 5, 1Hz, yridine-CH), 8.53 (1H, brd, J = 4Hz, pyridine-CH), 8.96 (1H, brs, imidazo 1 e-CH), 10.36 (1H, brs, imi dazo 1 e-NH) Example 3 8 11-Doxy _ 11-1 [4— [3 _ (pyridine-3-yl) — 1 H— 1,2,4,1 Triazole-5-yl] butyl] amino-5-0-desosa miniru 3-〇-1- (2-pyridyl) acetyl-6_〇-methyl erythride A 11,12—Cyclic carbamate Synthesis of

10,11-anhydro 2'-0-acetyl-12-py midazolylcarbonyl 2- 3-O- (2-pyridyl) acetyl-5-O-desosaminyl-1 6-0-methyl described in Example 1 Erythronolide A prepared with 0.29 g (0.34 mmol) of 4- [3- (pyridine-3-yl) -1H_1,2,4-triazo-1-yl 5-butylamine 0.37 g (l The same procedure as in Example 1 was performed using .70 ol) to obtain 94 mg of the title compound.

IonSprayMS m / z = 934.2 [M + H] ⁺

'H-NMR (500MHz, CDCh ) δ (ppm): 0.79 (3H, t, J = 7.3Hz, 14-CH 3), 2.30 (6H, s, 3' -N (CH 3) 2), 2.87 ( 3H, s, 6-OCH3), 5.03 (1H, d, J = ll.0Hz, 3-CH), 7.22 (1H, dd, J =

6.7, 4.9Hz, pyridine-CH), 7.33-7.37 (2H, m, pyridine-CH), 7.68 (1H, ddd, J = 7.9,

7.9, 1.8Hz, pyridine-CH), 8.35 (1H, ddd, J = 7.9, 1.8, 1.8Hz, pyridine-CH), 8.51 -8.52 (lH, m, pyridine-CH), 8.60 (1H, dd , J = 4.9, 1.8Hz, pyr idi ne-CH), 9.32 (1H, d, J = 1.8 Hz, pyridine-CH) Example 3 9 11-Doxy-11- [4- [5- (Pyridine-1-yl) thiophen-1-2-yl] —3-butynyl] amino — 5— O—desosaminyl 3--0- (2_pyridyl) acetyl- 6 〇-methylerythronolide A 11, 12- Synthesis of cyclic carbamate

(1) 10, 11-anhydro-2'_0-acetyl-12-〇-imidazolylcarbonyl-3 _O_ (2-pyridyl) acetyl-5_0-desosaminilu 6-6-0-methylerythro described in Example 1 Using 17.0 g (20.5 mmol) of Noride A and 14.2 g (205 mmol) of 4-amino_1-butyne, 2′_O-acetyl-11-doxy-11— (3— Putinyl) amino-5-0-desosaminyl_3-O- (2_pyridyl) acetyl-6-O-methylerythronolide A 11,12-cyclic carbamate 17. Og was obtained.

(2) 0.500 g (0.604ΜΙΟ1) of the compound obtained in (1) above, triphenylphosphine

0.063 g (0.242 mmol), palladium acetate (Π) 0.014 g (0.0604 mmol), 2-bromo-5- (pyridine-2-yl) thiophene 0.217 g (0.906 Ο1), copper iodide 0.006 g (0.0302 mmol) Was dissolved in a mixed solution of triethylamine and dimethoxane, and the mixture was refluxed for 1 hour. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained crude product was purified by silica gel column chromatography-eluent (eluent: chloroform-form-methanol-25% aqueous ammonia = 30: 1: 0.1) to obtain 0.150 g of the title compound. Was.

IonSprayMS m / z = 945.3 [M + H] +

'H-NMR (500MHz, CDCls ) <5 (ppm): 0.71 (3H, t, J = 7.5Hz, 14 - CH 3), 2.33 (6H, s, 3' -N (CH 3) 2), 3.09 (3H, s, 6-OCH3), 7.13 (1H, d, J = 4Hz, thiophene-CH), 7.40 (1H, d, 4Hz, thiophene-CH) Test Example 1 (in vitro antibacterial activity)

Using a medium for susceptibility disks (manufactured by Eiken Chemical Co., Ltd.), the in vitro antibacterial activity of the compound of the present invention against various test bacteria was measured according to the MIC measurement method of the Japanese Society of Chemotherapy. As the specimen, the compound of the present invention: the compound of Example 1, Comparative Drug 1: Clarice Mouthmycin and Comparative Drug 2: Azithromycin were used. MIC Values (minimum inhibitory concentration of microbial growth mcg / ml) are shown in the table.

Table 1 MIC value (mcg / ml)

As a result of the test, the compound of the present invention showed stronger antibacterial activity than Comparative Drug 1 and Comparative Drug 2. Therefore, the compounds of the present invention were shown to be extremely useful as antibiotics. Industrial applicability

The compound of the present invention has an extremely strong antibacterial activity not only against erythromycin-sensitive bacteria but also against erythromycin-resistant bacteria. Accordingly, the compounds of the present invention are useful as antibacterial substances for the treatment of bacterial infections in humans and animals (including farm animals).

Claims

The scope of the claims

(In the formula, A represents an alkyl group having 2 to 6 carbon atoms, an alkenyl group, or an alkynyl group; R ′ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; R ² represents a pyridyl group; X represents a thiazolyl group, and X is a group represented by the formula (2)

Represents a carbon atom, XX ³ and X ³ represent a sulfur atom, a nitrogen atom, an oxygen atom, and the formula (4)

Three

(Four)

C—R

(Wherein, R ³ represents a hydrogen atom, an alkyl group having 13 to 13 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms or a carbamoyl group.) Or a group represented by the formula ( Five )

( Five)

N—R

(Wherein, R ⁴ represents a hydrogen atom or a methyl group.), And Ar represents an unsubstituted or selected from an alkyl group having 13 carbon atoms or a halogen atom. Substituted phenyl group; unsubstituted or pyridyl substituted with 1-4 carbon atoms selected from alkyl groups having 1 to 3 carbon atoms or halogen atoms A group; an unsubstituted or 13-substituted pyrimidyl group selected from an alkyl group or a halogen atom having 13 carbon atoms; an unsubstituted or 1 group selected from an alkyl group or a halogen atom having 13 carbon atoms _____________________________________________ either-either substituted or unsubstituted or a C 13 -Cnenyl group selected from an alkyl group or a halogen atom having 13 to 13 carbon atoms; 13-substituted furyl group selected from alkyl groups or halogen atoms; unsubstituted or 13-substituted pyrrolyl group selected from 13 carbon atoms or halogen atoms; unsubstituted Or substituted with one or two selected from an alkyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a carbamoyl group or a halogen atom. A thiazolyl group; an unsubstituted or an imidazolyl group substituted by a group of 123 selected from an alkyl group having 13 carbon atoms or an octylogen atom; an alkyl group or a halogen atom which is unsubstituted or has 13 carbon atoms 1,2,3-triazolyl group substituted with one or two selected from the group consisting of: 1,2,3-substituted unsubstituted or 1,2-substituted with one or two selected from an alkyl group having 1 to 3 carbon atoms or a halogen atom , 4-triazolyl group; or unsubstituted or tetrazolyl group substituted by an alkyl group having 13 carbon atoms or a halogen atom. ) Represents a group represented by. An erythromycin A derivative represented by the formula or a pharmaceutically acceptable salt thereof.