WO1999021870A1

WO1999021870A1 - Erythromycin a 11, 12-carbamate derivatives

Info

Publication number: WO1999021870A1
Application number: PCT/JP1998/004877
Authority: WO
Inventors: Toshifumi Asaka; Masato Kashimura; Akiko Matsuura; Tomohiro Sugimoto; Tetsuya Tanikawa; Takaaki Ishii
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1997-10-29
Filing date: 1998-10-28
Publication date: 1999-05-06
Also published as: AU9649698A; ZA989830B; JP2004514643A

Abstract

An erythromycin A derivative represented by formula (I), wherein n is an integer of 1 to 7, R1 is a hydrogen atom or an alkyl group, R2 is a quinolyl group, a pyrazinyl group, a benzimidazolyl group, a thiazolyl group, a pyridyl group, a pyrimidyl group, a purinyl group, a triazinyl group, a phenyl group or a naphthyl group, R3 is a hydrogen atom, an alkyl group or a cinnamyl group, R4 is a hydrogen atom, or R?4 and R5¿ together form an oxo group, R5 is a group represented by the formula: -OCO-CH¿2-R?8, -OCO-R8, -OCO-NH-R?8, -O-R8¿ or -OCO-O-R?8; and R6 and R7¿ are each a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof has a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin-resistant bacteria.

Description

DESCRIPTION ERYTHROMYCIN A, 11,12-CARBAMATE DERIVATIVES

TECHNICAL FIELD

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

BACKGROUND ART Erythromycin A is an antibiotic clinically widely used as an agent for treating infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc. However, erythromycin A is decomposed by the gastric acid due to instability to acids, and thereby has a drawback of no constancy of movement in the body. Hitherto many erythromycin A derivatives have been prepared for the purpose of the improvement of the biological or pharmacological properties. For example, it is reported that 6-O-methylerythromycin A derivatives have an improved stability to acids and have a superior in vivo antibacterial activity in comparison with erythromycin A when administered orally (U.S. Patent No. 4331803). Recently, it is also reported that 11,12-cyclic carbamate derivatives are prepared from 6-O-methylerythromycin A as a starting material with the aim of expansion of antibacterial spectrum as well as stability to acids (EP. patent No. 487411 and US. Patent No. 4742049). In addition, the antibacterial activities of the ester derivatives at the 3-position are also reported by some of the present inventors (EP. patent No.619320).

An object of the present invention is to provide post-generational macrolide antibiotics having a strong antibacterial activity against not only known erythromycin-sensitive bacteria but also erythromycin- resistant bacteria which recently are showing a tendency to increase.

DISCLOSURE OF THE INVENTION

The present inventors have found that the compounds which can be produced by introducing certain aromatic rings onto the nitrogen atom of the 11, 12-cyclic carbonate of erythromycin A and converting the 3-position of the erythromycin A have a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin-resistant bacteria, and thus the present invention has been accomplished.

The present invention relates to an erythromycin A derivative represented by the formula:

wherein n is an integer of 1 to 7,

R^ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R2 is a cjuinolyl group, a pyrazinyl group, a benzimidazolyl group, a thiazolyl group, a pyridyl group, a pyridyl group substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group; a dimethyla ino group; an acetylamino group; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group; a pyrrolyl group and a halogen atom, a pyrimidyl group, a pyrimidyl group substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group and a halogen atom, a purinyl group, a purinyl group substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms ; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group and a halogen atom, a triazinyl group, a triazinyl group _.substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group and a halogen atom, a phenyl group, a phenyl group substituted by 1 to 5 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms ; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group and a halogen atom, a naphthyl group, or a naphthyl group substituted by 1 to 5 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group and a halogen atom,

R3 is a hydrogen atom; an alkyl group having 1 to 6 carbon atoms or a cinnamyl group,

R⁴ is a hydrogen atom; or R⁴ and R⁵ together form an oxo group ,

R5 is a group represented by the formula:

-OCO-CH₂-R⁸ a group represented by the formula: -OCO-R⁸ a group represented by the formula:

-OCO-NH-R⁸ a group represented by the formula:

-O-R⁸ or a group represented by the formula:

-OCO-O-R⁸ wherein R⁸ is a pyridylmethyl group, a quinolyl group, a phenyl group, a phenyl group substituted by 1 to 5 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 6 carbon atoms and a halogen atom, a pyridyl group, or a pyridyl group substituted by 1 or 2 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 6 carbon atoms and a halogen atom, and

R^ and R^ are each a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof. In the present invention, examples of the alkyl group having 1 to 6 carbon atoms are a methyl group, an ethyl group, a propyl group, a butyl group, a 3- methylbutyl group and a cyclohexyl group; examples of the alkoxy group having 1 to 6 carbon atoms are a methoxy group, an ethoxy group, a propoxy group and an isopopoxy group, a butoxy group and a cyclohexyloxy group; and the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The pharmaceutically acceptable salt refers to a salt used in chemotherapy or prophylaxis of bacterially infectious diseases, for example, a salt with 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, p- toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid, adipic acid, cysteine, N- acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, polyacrylate or carboxyvinyl polymer. The compounds of the present invention can be prepared, for example, according to the following reaction scheme.

Step 3

Step (1); 2 ^■ -0-Acetyl-5-0-desosaminyl-6-0- methylerythronolide A described in US patent No. 5,523,399 is reacted with triphosgene in an inert solvent in the presence of pyridine under ice-cooling to give a compound of Formula (a) . Examples of the inert solvent to be used here are dichloromethane , dichloroethane, acetone and tetrahydrofuran .

Step (2) ; The compound of Formula (a) is oxidized in an inert solvent using chromic acid, chromic acid-pyridine, pyridinium chlorochromate, pyridinium dichromate or an activated dimethyl sulfoxide at a temperature of from -78°C to 30°C to give a compound of Formula (b) . The inert solvent is the same as used in Step (1) . Examples of the activating agent of dimethyl sulfoxide are acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, phosphorus pentachloride, pyridinium sulfonate, pyridinium trifluoroacetate, 1,3- dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride . Step (3); The compound of Formula (b) is treated with a base in an inert solvent at a temperature of from room temperature to 120°C to give a compound of Formula (c) . Examples of the inert solvent to be used here are N,N-dimethylformamide, dimethyl sulfoxide, N- methylpiperidone, tetrahydrofuran and a mixture thereof, and examples of the base to be used here are 1,1,3,3- tetr.amethylguanidine and potassium carbonate.

Step (4) ; The compound of Formula (c) is reacted with 1, 1 ' -carbonyldiimidazole in an inert solvent under the presence of a base such as sodium hydride to give a compound of Formula (d) . The inert solvent is the same as used in Step (3) . Step (5) ; The compound of Formula (d) is reacted in an inert solvent with an amine compound of the following formula:

R⁶ R¹ I /

H₂N- (CH₂) „-C-N I \ R⁷ R²

wherein n, R^, R^ , R6 and R⁷ are as defined above, and then is deprotected at the 2' -position by an ordinary metanolysis to give a compound of the present invention of Formula (e) . Examples of the inert solvent to be used here are acetonitrile, tetrahydrofuran, N,N- dimethylformamide, dioxane, ethyl acetate, N- methylpyrrolidone, a mixture of the solvent and water and a mixture thereof .

The compounds of the present invention can be administered orally or parenterally in the dosage form such as, for example, tablets, capsules, powders, troches, ointments, suspensions, suppositories and injections, all of which can be prepared according to conventional preparation techniques. The dose of the present compounds for treating an adult is from 100 to 1000 mg/day in single or several divided doses. This dose can be increased or decreased depending on the age, body weight and conditions of the patient.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the following Examples and a Test Example.

Example 1

11- \2 - fN- \2 - (5-Nitro)pyridyllamino1 ethyll amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11,12-cvclic carbamate

(1) To a solution of 53.56 g (0.085 mol) of 2'- 0-acetyl-5-0-desosaminyl-6-0-methylerythronolide A in 500 ml of methylene chloride was added 82.4 ml (1.02 mol) of pyridine. 30.24 g (0.10 mol) of triphosgene was added to the mixture under ice-cooling, followed by stirring for 2 hours . Water was added to the reaction solution to decompose the excess triphosgene, and the mixture was diluted with chloroform, washed with water and a saturated aqueous sodium chloride solution successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in 500 ml of N,N-dimethylformamide, and 21.74 g (0.19 mol) of 1, 1, 3 , 3-tetramethylguanidine was added thereto, followed by stirring at 100°C for 3 hours. After allowing to stand for cooling, the mixture was diluted with ethyl acetate and separated with water. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 50.27 g (yield: 97 %) of the 10,11-anhydro compound.

(2) To a solution of 50.27 g (0.082 mol) of the compound obtained in the above (1) in 500 ml of methylene chloride were successively added 42.65 g (0.25 mol) of 2- pyridylacetate hydrochloride, 46.97 g (0.25 mol) of 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 10.01 g (0.082 mol) of 4-dimethylaminopyridine under ice-cooling, followed by stirring at room temperature for 1.5 hours. The reaction solution was made basic with 2N sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and purification by silica gel column chromatography

(acetone : n-hexane : triethylamine =6:10:0.2) gave 41.95 g (yield: 70 %) of the 3-0- (2-pyridyl ) acetyl compound.

(3) To a solution of 31.01 g (0.042 mol) of the compound obtained in the above (2) in 300 ml of a mixture of N,N-dimethylformamide and tetrahydrofuran (3:2) were successively added 20.58 g (0.127 mol) of carbonyldiimidazole at room temperature and 3.38 g (0.085 mol) of 60 % sodium hydride under ice-cooling, followed by stirring under ice-cooling for 40 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 32.71 g (yield: 93 %) of the 12- O-imidazolylcarbonyl compound.

(4) To a solution of 1.00 g (1.21 mmol) of the compound obtained in the above (3) in 10 ml of N,N- dimethylform-amide was added 2.20 g of 2- (2- aminoethyl) amino-5-nitropyridine at room temperature, followed by stirring for 3 days . To the reaction solution was added an aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of methanol and stirred at room temperature for 16 hours, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform : methanol : aqueous ammonia =19:1:0.1 - 9:1:0.1) to give 0.65 g (yield: 62 %) of the title compound.

IonSprayMS m/z: 899 (M+H)⁺

^- MR (300 MHz, CDCl₃) δ (ppm) : 0.76 (t, 3H, J=7.3 Hz, 14- CH₃), 2.29 (s, 6H, 3'-N(CH₃)₂), 3.06 (s, 3H, 6-OCH₃) , 4.98 (dd, 1H, J=10.8, 2.1 Hz, H-13). 5.07 (d, 1H, J=11.0 Hz, H-3), 6.38 - 6.46 (m, 1H, Ar-H) , 6.51 - 6.62 (m, 1H, NH) , 7.20 - 7.25 (m, 1H, Ar-H), 7.34 - 7.39 (m, 1H, Ar-H), 7.65 - 7.73 ( , 1H, Ar-H), 8.06 - 8.15 (m, 1H, Ar-H), 8.51 - 8.55 (m, 1H, Ar-H), 8.99 - 9.04 (m, 1H, Ar-H) . ¹³C-NMR (75 MHz, CDC1₃) δ (ppm) : 40.3 (3 ' -N(CH₃) ₂) , 50.4 (6-OCH₃) , 170.6(3-OCO-) , 175.6 (C-l) , 216.2 (C-9) .

Example 2

11- \2- FN- Ϊ2- (5-Amino) pyridyl1 aminol ethyll amino- ll-deoxy-3-O- (2-pyridyl) acetγl-5-Q-desosaminyl-6-Q- methylervthronolide A 11,12-cvclic carbamate

To a solution of 0.52 g (0.58 mmol) of the compound obtained in Example 1 in 5 ml of methanol were successively added 0.088 g of sodium borohydride and 0.28 g of nickel (II) chloride hexahydrate under ice-cooling, followed by stirring under ice-cooling for 20 minutes. The reaction solution was made basic with a-queous ammonia and extracted with chloroform, and the chloroform layer was successively washed with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform : methanol : aqueous ammonia =19:1:0.1) to give 0.32 g (yield: 53 %) of the title compound. IonSprayMS m/z : 869 (M+H) ⁺

^TH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.76 (t, 3H, J=7.3 Hz, 14-CH₃), 2.30 (s, 6H, 3'-N(CH₃)₂), 3.04 (s, 3H, 6-OCH₃) , 4.86 - 4.96 (m, 1H, -NH) , 5.08 (d, 1H, J=11.2 Hz, H-3), 5.14 (dd, 1H, J=10.8, 2.0 Hz, H-13), 6.43 (m, 1H, Ar-H), 6.86 - 6.93 (m, 1H, Ar-H), 7.19 - 7.25 (m, 1H, Ar-H) , 7.34 - 7.39 (m, 1H, Ar-H) , 7.65 -^"7.73 (m, 2H, Ar-H) , 8.50 - 8.56 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDC1₃) δ (ppm) : 40.4 (3 ^■ -N(CH₃) ₂) , 50.3 (6-OCH₃) , 170.5 (3-OCO-) , 174.7 (C-l) , 215.6 (C-9) .

Example 3

11- r4- TN- (2 -Pyridyl) .amino1 butyl lamino- ll-deoxy-3-O- (2-pyridγl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11.12-cvclic carbamate Following the same procedure as in Example 1(4) using 0.22 g (0.26 mmol) of the compound obtained in Example 1(3) and 0.45 g of 2- (4-aminobutyl) aminopyridine described in the following Reference Example, there was obtained 0.10 g (yield: 43 %) of the title compound. SIMS m/z: 882 (M+H) ⁺

^-NMR (300 MHz, CDC1₃) δ (ppm) : 0.80 (t, 3H, J=7.3 Hz,

14-CH₃) , 2.29 (s, 6H, 3'-N(CH₃)₂) , 2.98 (s, 3H, 6-0CH₃) , 4.78 - 4.88 (m, 1H, -NH) , 5.05 - 5.09 (m, 2H, H-3 , H-13) , 6.39 - 6.45 (m, 1H, Ar-H) , 6.46 - 6.52 (m, 1H, Ar-H) , 7.19 - 7.25 ( , 1H, Ar-H) , 7.32 - 7.40 (m, 2H,

Ar-H) , 7.65 - 7.72 (m, 1H, Ar-H) , 8.03 - 8.12 ( , 1H, Ar-H) , 8.51 - 8.55 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDC1₃) δ (ppm) : 40.3 (3 ' -N(CH₃) ₂) , 50.1 (6-OCH₃) , 170.5 (3-0C0-) , 174.5 (C-l) , 215.8 (C-9) .

Reference Example

Synthesis of 2- (4-aminobutyl) aminopyridine

To 6.00 g (0.053 mol) of 1, 4-diaminobutane was added 60 ml of 2-chloropyridine, followed by refluxing under heating for 6 hours. The reaction solution was concentrated, and after addition of water, washed with diethyl ether. To the aqueous layer was added sodium chloride, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5.73 g (yield: 66 %) of the title compound. SIMS m/z: 165 (M+H) ⁺

^XH-NMR (300 MHz, CDCl₃) δ (ppm) : 1.40 (brs, 2H, -NH₂) , 1.45 -1.75 (m, 4H, -NHCH₂ (CH₂) ₂CH₂NH₂) , 2.70 - 2.80 (m, 2H, -NHCH₂(CH₂)₂CH₂NH₂) , 3.20 - 3.35 (m, 2H, -NHCH₂(CH₂)₂CH₂NH₂) , 4.65 (brs, 1H, -NH-), 6.35-6.40 (m, 1H, Ar-H), 6.50 - 6.60 (m, 1H, Ar-H), 7.35-7.45 (m, 1H, Ar-H), 8.00 - 8.10 (m, 1H, Ar-H).

Eχ.ample 4

11- r2-TN- (2-Pyridyl) amino1 ethyll amino- ll-deoxγ-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 1(4) using 0.42 g (0.51 mmol) of the compound obtained in

Example 1(3) and 0.70 g of 2- (2-aminoethyl) aminopyridine prepared in the same manner as in Reference Example, there was obtained 0.22 g (yield: 50 %) of the title compound.

IonSprayMS m/z: 854 (M+H)⁺

^XH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.76 (t, 3H, J=7.3 Hz, 14-CH₃) , 2.29 (s, 6H, 3'-N(CH₃)₂) , 3.05 (s, 3H, 6-OCH₃) , 5.08 (d, 1H, J=10.3 Hz, H-3) , 5.11 (dd, 1H, J=11.0, 2.1Hz, H-13), 5.30 - 5.40 (m, 1H, -NH) , 6.44 - 6.53 (m, 2H, Ar-H) , 7.18 - 7.25 (m, 1H, Ar-H) , 7.29 - 7.38 (m, 2H, Ar-H) , 7.65 - 7.73 (m, 1H, Ar-H) , 8.03 - 8.08

(m, 1H, Ar-H) , 8.50 - 8.52 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDCl₃) δ (ppm) : 40.4 (3 ' -N (CH₃) ₂) , 50.3 (6-OCH₃) , 170.5 (3-OCO-) , 174.8 (C-l) , 215.7 (C-9)

Example 5

11- \3- TN- (2-Pyridyl) .amino1 propyl 1 amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 1(4) using 0.65 g (0.78 mmol) of the compound obtained in

Example 1(3) and 1.24 g of 2- (3-aminopropyl) aminopyridine prepared in the same manner as in Reference Example, there was obtained 0.14 g (yield: 20 %) of the title compound. SIMS m/z : 868 (M+H)⁺ ¹H-NMR (300 MHz, CDC1₃) δ (ppm) : 0.81 (t, 3H, J=7.3 Hz,

I4-CH₃), 2.29 (s, 6H, 3'-N(CH₃)₂), 2.99 (s, 3H, 6-OCH3) , 4.99 - 5.14 (m, 3H, -NH, H-3 , H-13), 6.38 - 6.45 (m, 1H, Ar-H), 6.47 - 6.53 (m, 1H, Ar-H), 7.18 - 7.24 (m, 1H, Ar-H), 7.32 - 7.40 (m, 2H, Ar-H), 7.65 - 7.73 (m, 1H, Ar-H), 8.03 - 8.08 (m, 1H, Ar-H), 8.52 - 8.55 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDCI₃) δ (ppm) : 40.4 (3 ' -N(CH₃) ₂) , 50.1 (6-OCH₃), 170.5 (3-OCO-), 174.4 (C-l), 215.8 (C-9). Example 6

11- T5- TN- (2-Pyridyl) amino1 pentyll amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example 1(4) using 0.61 g (0.73 mmol) of the compound obtained in Example 1(3) and 1.46 g of 2- (5-aminopentyl) aminopyridine prepared in the same manner as in Reference Example, there was obtained 0.43 g (yield: 65 %) of the title compound. IonSprayMS m/z : 896 (M+H)⁺

Hi-NMR (300 MHz, CDCl₃) δ (ppm) : 0.80 (t, 3H, J=7.3 Hz,

I4-CH₃) , 2.29 (s, 6H, 3'-N(CH₃)₂) , 3.02 (s, 3H, 6-OCH₃) , 4.55 - 4.64 (m, 1H, -NH) , 5.02 - 5.10 (m, 2H, H-3 , H-13), 6.34 - 6.41 (m, 1H, Ar-H) , 6.48 - 6.54 (m, 1H, Ar-H) , 7.18 - 7.25 ( , 1H, Ar-H) , 7.34 - 7.42 (m, 2H,

Ar-H) , 7.65 - 7.73 (m, 1H, Ar-H) , 8.02 - 8.07 (m, 1H, Ar-H) , 8.50 - 8.56 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDCI₃) δ (ppm) : 40.4 (3 ' -N(CH₃) ₂) , 50.1 (6-OCH₃) , 170.5 (3-OCO-) , 174.3 (C-l) , 215.7 (C-9) .

Example 7

11- T4- TN- (2-Ouinolyl) aminolbutyll .amino- ll-deoxy-3-O- (2-pyridyl) acetγl-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate Following the same procedure as in Example 1(4) using 1.12 g (1.36 mmol) of the compound obtained in Example 1(3) and 3.25 g of 2- (4-aminobutyl) aminoquinoline prepared in the same manner as in Reference Example, there was obtained 0.55 g (yield: 44 %) of the title compound.

FABMS m/z : 932 (M+H)⁺

^XH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.80 (t, 3H, J=7.3 Hz,

I4-CH₃) , 2.29 (s, 6H, 3'-N(CH₃)₂) , 2.96 (s, 3H, 6-OCH₃) , 5.04 - 5.12 (m, 2H, H-3 , H-13) , 5.24 - 5.33 (m, 1H,

-NH) , 6.68 - 6.74 (m, 1H, Ar-H) , 7.12 - 7.19 (m, 1H, Ar-H) , 7.20 - 7.25 ( , 1H, Ar-H) , 7.36 - 7.41 (m, 1H, Ar-H) , 7.45 - 7.56 (m, 2H, Ar-H) , 7.63 - 7.79 (m, 3H, Ar-H) , 8.50 - 8.56 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDCI₃) δ (ppm) : 40.4 (3 ' -N (CH₃) ₂) , 50.1 (6-OCH₃) , 170.5 (3-OCO-) , 174.7 (C-l) , 215.8 (C-9) .

Example 8

11- T4- TN- \2- (3 -Chloro) pyridyll aminoIbutyllamino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 1(4) using 1.23 g (1.49 mmol) of the compound obtained in Example 1(3) and 3.29 g of 2- (4-aminobutyl) amino-3- chloropyridine prepared in the same manner as in Reference Example, there was obtained 0.54 g (yield: 39 %) of the title compound. FABMS m/z : 916 (M+H)⁺

^-NMR (300 MHz, CDC1₃) δ (ppm) : 0.81 (t, 3H, J=7.3 Hz, I4-CH₃), 2.29 (s, 6H, 3'-N(CH₃)₂), 3.01 (s, 3H,

6-OCH₃), 5.01 - 5.10 (m, 2H, H-3 , H-13), 5.12 - 5.20 (m, 1H, -NH) , 6.43 - 6.49 (m, 1H, Ar-H), 7.18 - 7.24 (m, 1H, Ar-H), 7.34 - 7.42 (m, 2H, Ar-H), 7.65 - 7.72 (m, 1H, Ar-H) , 7.97 - 8.02 (m, 1H, Ar-H) ,^" 8.50 - 8.55 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDCl₃) δ (ppm) : 40.4 (3 ' -N (CH₃) ₂) , 50.1 (6-OCH₃) , 170.4 (3-OCO-) , 174.2 (C-l) , 215.7 (C-9) .

Example 9

11- T4- TN- \2- ( 5-Chloro) pyridyl 1 aminolbutyll amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example 1(4) using 0.94 g (1.13 mmol) of the compound obtained in Example 1(3) and 2.50 g of 2- (4-aminobutyl) amino-5- chloropyridine prepared in the same manner as in Reference Example, there was obtained 0.29 g (yield: 27 %) of the title compound.

SIMS m/z : 916 (M+H)⁺

^-NMR (300 MHz, CDC1₃) δ (ppm) : 0.80 (t, 3H, J=7.3 Hz, I4-CH₃) , 2.29 (s, 6H, 3'-N(CH₃)₂), 2.97 (s, 3H, 6-OCH₃), 4.94 - 5.01 (m, 1H, -NH) , 5.01 - 5.10 (m, 2H, H-3, H-13), 6.36 - 6.42 (m, 1H, Ar-H), 7.19 - 7.404

( , 3H, Ar-H), 7.66 - 7.78 (m, 1H, Ar-H), 7.97 - 8.00 (m, 1H, Ar-H), 8.51 - 8.55 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDC1₃) δ (ppm) : 40.4 (3 ' -N(CH₃) ₂) , 50.1 (6-OCH₃), 170.5 (3-OCO-), 174.6 (C-l), 215.8 (C-9).

Example 10

11- ^"4- TN- \2- (5-Trifluoromethγl)pyridvπamino1 - butyll amino- ll-deoxy-3-O- (2 -pyridyl) acetyl-5-O- desosaminγl-6-O-methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 1(4) using 1.10 g (1.33 mmol) of the compound obtained in Example 1(3) and 3.00 g of 2- (4-aminobutyl) amino-5- trifluoromethylpyridine prepared in the same manner as in Reference Example, there was obtained 0.51 g (yield: 41 %) of the title compound. SIMS m/z : 950 (M+H)⁺ ^XH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.79 (t, 3H, J=7.3 Hz,

14-CH₃), 2.29 (s, 6H, 3'-N(CH₃)₂), 2.94 (s, 3H, 6-OCH₃) , 5.00 - 5.06 (m, 2H, H-3 , H-13), 5.37 - 5.48 (m, 1H, -NH) , 6.43 - 6.50 (m, 1H, Ar-H), 7.19 - 7.26 (m, 1H, Ar-H), 7.35 - 7.41 (m, 1H, Ar-H), 7.49 - 7.56 (m, 1H, Ar-H), 7.66 - 7.74 (m, 1H, Ar-H), 8.27 - 8.31 (m, 1H, Ar-H), 8.50 - 8.56 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDCl₃) δ (ppm) : 40.3 (3 ' -N(CH₃) ₂) , 50.1 (6-OCH₃), 170.5 (3-OCO-), 174.8 (C-l), 215.9 (C-9).

Example 11

11- T4- TN- r2- (6-Methyl)pyridyll amino1 butyl lamino- ll-deoxγ-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 1(4) using 0.83 g (1.00 mmol) of the compound obtained in Example 1(3) and 2.00 g of 2- (4-aminobutyl) amino-6- methylpyridine prepared in the same manner as in Reference Example, there was obtained 0.56 g (yield: 62 %) of the title compound.

SIMS m/z: 896 (M+H)⁺

^XH-NMR (300 MHz, CDCl₃) (ppm) : 0.80 (t, 3H, J=7.3 Hz,

14-CH₃), 2.29 (s, 6H, 3'-N(CH₃)₂) , 2.99 (s, 3H, 6-OCH₃) , 4.67 - 4.77 (m, 1H, -NH) , 5.02 - 5.10 (m, 2H, H-3 ,

H-13) , 6.18 - 6.24 (1H, m, Ar-H) , 6.36 - 6.41 (m, 1H,

Ar-H) , 7.18 - 7.39 (m, 3H, Ar-H) , 7.65 - 7.72 (m, 1H,

Ar-H) , 8.51 - 8.56 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDC1₃) δ (ppm) : 40.4 (3 ' -N (CH₃) ₂) , 50.1 (6-OCH₃) , 170.5 (3-OCO-) , 174.4 (C-l) , 215.7 (C-9) .

Example 12

11- T4- TN- (2-Pyrimidyl) amino1 butyl 1 amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 1(4) using 1.00 g (1.21 mmol) of the compound obtained in Example 1(3) and 2.23 g of 2- (4-aminobutyl) aminopyrimidine prepared in the same manner as in Reference Example, there was obtained 0.11 g (yield: 10 %) of the title compound. SIMS m/z : 883 (M+H) ⁺ ^- MR (300 MHz, CDC1₃) δ (ppm) : 0.81 (t, 3H, J=7.4 Hz,

I4-CH₃), 2.29 (s, 6H, 3'-N(CH₃)₂), 3.00 (s, 3H, 6-OCH₃) , 5.01 - 5.09 (m, 2H, H-3 , H-13), 5.38 - 5.47 (m, 1H, -NH) , 6.44 - 6.48 (m, 1H, Ar-H), 7.18 - 7.24 (m, 1H, Ar-H), 7.34 - 7.39 (m, 1H, Ar-H), 7.64 - 7.72 (m, 1H, Ar-H), 8.22 - 8.29 (m, 2H, Ar-H), 8.50 - 8.55 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDC1₃) δ (ppm) : 40.4 (3 ' -N(CH₃) ₂) , 50.1 (6-OCH₃), 170.5 (3-OCO-), 174.2 (C-l), 215.9 (C-9).

Example 13 11- r4- ΓN- (2-Pyridyl) a inolbutyll amino-3 , 11- dideoxy-5-Q-desosaminyl-3-oxo-6-0-methγlerγthronolide A 11.12-cyclic carbamate

(1) To a solution of 66 g (105 mmol) of 2 ' -0- acetyl-5-0-desosaminyl-6-0-methylerγthronolide A in 500 ml of methylene chloride was added 82 ml (1.02 mol) of pyridine. A solution of 30.2 g (102 mmol) of triphosgene in 60 ml of methylene chloride was added to the mixture under ice-cooling, followed by stirring at room temperature for 1.5 hours. The reaction solution was cooled on ice, and excess triphosgene was decomposed by cooled water. The mixture was separated with water, and the organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 72 g of the 11,12-cyclic carbonate compound.

(2) To a solution of 72 g of the compound obtained in the above (1) in 500 ml of methylene chloride was added 66 ml (850 mmol) of dimethyl sulfoxide, and after ice-cooling, 49 g (255 mmol) of l-ethyl-3- (3- dimethylammopropyl) carbodiimide hydrochloride and 49 g (255 mmol) of pyridinium trifluoroacetate were successively added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with chloroform and separated with water. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 67 g of the 3-oxo compound. (3) To a solution of 67 g of the compound obtained in the above (2) in 300 ml of N,N- dimethylformamide was added 16 ml (127 mmol) of 1,1,3,3- tetramethylguanidine, followed by stirring at 100°C for an hour. After cooling, the reaction solution was diluted with ethyl acetate, washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting crystals were washed with ether to give 19.8 g (yield: 32 %) of the 10, 11-anhydro compound. (4) To a solution of 19.8 g (32 mmol) of the compound obtained in the above (3) in a mixture of 150 ml N,N-dimethylformamide and 300 ml of tetrahydrofuran was added 16 g (97 mmol) of 1, 1 ' -carbonyldiimidazole under ice-cooling, and then 3.9 g (97 mmol) of 60 % sodium hydride was added thereto, followed by stirring for 30 minutes. After the reaction, the reaction solution was diluted with ethyl acetate and separated with water. The organic layer was successively washed with water twice and with a saturated aqueous sodium chloride solution once, followed by drying over anhydrous magnesium sulfate.

After evaporation of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (acetone : hexane : triethylamine =10:20:0.2) to give 15.5 g (yield: 68 %) of the 12-0- imidazolylcarbonyl compound.

(5) To a solution of 0.60 g (0.85 mmol) of the compound obtained in the above (4) in 20 ml of acetonitrile was added 1.4 g (8.5 mmol) of 2- (4- aminobutyl ) aminopyridine prepared in the manner as in Reference Example, followed by stirring for 5 days. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution twice, water and a saturated aqueous sodium chloride solution successively. After evaporation of the solvent under reduced pressure, the residue was dissolved in 20 ml of methanol and refluxed under heating for 2 hours. After allowing to stand for cooling, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform : methanol : aqueous ammonia =25:1:0.1) to give 0.49 g (yield: 76 %) of the title compound. IonSprayMS m/z: 761.4 (M+H) ⁺ ^XH-NMR (500 MHz,CDCl₃) δ (ppm) '. 0.85(t, 3H, J=7.5 Hz,

14-CH₃), 2.26 (s, 6H, 3'-N(CH₃)₂), 2.62 (s, 3H, 6-OCH3) , 4.23 (d, 1H, J=8.8 Hz, H-5), 4.28 (d, 1H, J=7.3 Hz, H-l'), 4.82 (t, 1H, J=5.5 Hz, N-H) , 4.96 (dd, 1H, J=11.0, 2.5 Hz, H-13) ¹³C-NMR (125 MHz, CDCI₃) δ (ppm) I 40.1 (3 ' -N(CH₃) ₂) , 49.7

( 6-OCH₃ ) , 103 . 9 (C-l ' ) , 157 . 2 ( carbamate ) , 169 . 7 (C-l ) , 203 . 6 ( C-3 ) , 216 . 1 ( C-9 ) Example 14

11- r4- TN- \2- ( 5-Chloro) yridyl 1 aminoIbutyllamino- 3 , ll-dideoxγ-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11, 12-cyclic carbamate Following the same procedure as in Example 1(5) using 0.70 g (0.99 mmol) of the compound obtained in Example 13(4) and 2.0 g (9.9 mmol) of 2- (4-aminobutyl) - amino-5-chloropyridine prepared in the same manner as in Reference Example, there was obtained 0.41 g (yield: 52 %) of the title compound.

IonSprayMS m/z: 795.4 (M+H) ⁺

^-NMR (500 MHz, CDCl₃) δ (ppm) : 0.84 (t, 3H, J=7.5 Hz,

14-CH₃) , 2.26 (s, 6H, 3'-N(CH₃)₂) , 2.61 (s, 3H, 6-OCH₃) , 4.23 (d, 1H, J=8.9 Hz, H-5) , 4.27 (d, 1H, J=7.3 Hz, H-l') , 4.90 (t, 1H, J=5.5 Hz, N-H) , 4.94 (dd, 1H,

J=10.6, 2.1 Hz, H-13) ¹³C-NMR (125 MHz, CDCl₃) δ (ppm) ^'. 40.2 (3 ' -N(CH₃) ₂) , 49.8

(6-OCH₃) , 103.9 (C-l') , 157.2 (carbamate) , 169.8 (C-l), 203.6 (C-3) , 216.1 (C-9) .

Example 15

11- f4- TN- \2- (3 -Chloro) pyridyl 1 aminolbutyll amino- 3 , ll-dideoxγ-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11,12-cvclic carbamate Following the same procedure as in Example 1(5) using 0.70 g (0.99 mmol) of the compound obtained in Example 13(4) and 2.0 g (9.9 mmol) of 2- (4-aminobutyl) - amino-3-chloropyridine prepared in the same manner as in Reference Example, there was obtained 0.26 g (yield: 33 %) of the title compound. IonSprayMS m/z: 795.4 (M+H)⁺

^XH-NMR (500 MHz, CDCl₃) δ (ppm) : 0.85 (t, 3H, J=7.3 Hz, 14-CH₃), 2.26 (s, 6H, 3'-N(CH₃)₂), 2.64 (s, 3H, 6-OCH₃) ,

4.24 (d, 1H, J=8.8 Hz, H-5), 4.28 (d, 1H, J=7.3 Hz,

H-l'), 4.96 (dd, 1H, J=10.7, 2.4 Hz, H-13), 5.12

(t, 1H, J=5.3 Hz, N-H) ¹³C-NMR (125 MHz, CDC1₃) δ (ppm) : 40.1 (3 ' -N(CH₃) ₂) , 49.8 (6-OCH₃), 103.9 (C-l'), 157.2 (carbamate), 169.4 (C-l),

203.7 (C-3) , 216.0 (C-9) .

Example 16

11- T4- TN- T2- (6-Methyl) yridyl 1 aminolbutyll amino- 3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-0-methylerγthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 1(5) using 0.60 g (0.85 mmol) of the compound obtained in Example 13(4) and 1.5 g (8.5 mmol) of 2- (4-aminobutyl) - amino-6-methylpyridine prepared in the same manner as in Reference Example, there was obtained 0.41 g (yield: 66 %) of the title compound. SIMS m/z : 775 (M+H)⁺

^XH-NMR (300 MHz, CDCI₃) δ (ppm) : 0.85 (t, 3H, J=7.3 Hz, I4-CH₃), 2.26 (s, 6H, 3'-N(CH₃)₂), 2.34 (s, 3H,

Pyridyl-CH₃) , 2.63 (s, 3H, 6-OCH₃), 4.24 (d, 1H, J=8.7 Hz, H-5), 4.28 (d, 1H, J=7.3 Hz, H-l'), 4.73 (t, 1H, J=5.5 Hz, N-H), 4.96 (dd, 1H, J=10.6, 2.3 Hz, H-13). Example 17

11- f4- TN- 12 - (5-Trifluoromethyl ) yridyl1.amino1 - butyll amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cvclic carbamate Following the same procedure as in Example 1(5) using 0.42 g (0.60 mmol) of the compound obtained in Example 13(4) and 1.4 g (6.0 mmol) of 2- (4-aminobutyl) - amino-5-trifluoromethylpyridine prepared in the same manner as in Reference Example, there was obtained 0.33 g (yield: 67 %) of the title compound. SIMS m/z: 829 (M+H) ⁺ ^XH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.84 (t, 3H, J=7.3 Hz,

14-CH₃), 2.27 (s, 6H, 3 ' -N(CH₃)₂) , 2.60 (s, 3H, 6-OCH₃) , 4.19 (d, 1H, J=8.9 Hz, H-5), 4.28 (d, 1H, J=7.3 Hz, H-l'), 4.95 (dd, 1H, J=10.6, 2.3 Hz, H-13), 5.40 (t, 1H, J=5.5 Hz, N-H) .

Eχ.ample 18

11- f4- .TN- (2-Ouinolyl) amino1 butyll amino-3 , 11- dideoxy-5-0-desosaminyl-3-oxo-6-Q-methylervthronolide A

11,12-cγclic carbamate

Following the same procedure as in Example 1(5) using 0.60 g (0.85 mmol) of the compound obtained in

Example 13(4) and 1.8 g (8.5 mmol) of 2- (4-aminobutyl) - aminoquinoline prepared in the same manner as in Reference

Example, there was obtained 0.61 g (yield: 88 %) of the title compound.

IonSprayMS m/z: 811.5 (M+H) ⁺ ^XH-NMR (500 MHz, CDC1₃) δ (ppm) : 0.84 (t, 3H, J=7.3 Hz,

14-CH₃) , 2.25 (s, 6H, 3'-N(CH₃)₂) , 2.62 (s, 3H, 6-OCH₃) , 4.23 (d, 1H, J=8.8 Hz, H-5) , 4.27 (d, 1H, J=7.3 Hz, H-l') , 4.98 (dd, 1H, J=10.8, 2.5 Hz, H-13), 5.25 (brs, 1H, N-H)

¹³C-NMR (125 MHz, CDC1₃) δ (ppm) : 40.2 (3 ' -N(CH₃) ₂) , 49.8

(6-OCH₃) , 103.9 (C-l') , 157.3 (carbamate) , 169.9 (C-l),

203.5 (C-3) , 216.1 (C-9) .

Example 19

11- \2- TN- (2-Pyridyl) amino1 ethyll amino-3.11- dideoxy-5-0-desosaminyl-3-oxo-6-Q-methylervthronolide A 11.12-cvclic carbamate

Example 13(4) and 1.2 g (8.5 mmol) of 2- (2-aminoethyl) - aminopyridine prepared in the same manner as in Reference Example, there was obtained 0.37 g (yield: 59 %) of the title compound. SIMS m/z: 733 (M+H)⁺

^-NMR (500 MHz, CDC1₃) δ (ppm) : 0.81 (t, 3H, J=7.3 Hz,

14-CH₃) , 2.27 (s, 6H, 3'-N(CH₃)₂), 2.67 (s, 3H, 6-OCH₃) , 4.26 (d, 1H, J=8.6 Hz, H-5), 4.29 (d, 1H, J=7.3 Hz, H-l'), 5.01 (dd, 1H, J=10.5, 2.2 Hz, H-13), 5.21 (t, 1H, J=5.8 Hz, N-H)

¹³C-NMR (125 MHz, CDC1₃) δ (ppm) : 40.1 (3 ' -N(CH₃) ₂) , 49.8

(6-OCH₃) , 103.8 (C-l') , 157.6 (carbamate), 170.0 (C-l) ,

203.6 (C-3) , 216.1 (C-9) . Example 20

11- T2- ΓN- \2- (5-Nitro) pyridyl1 aminolethyllamino- 3. ll-dideoxy-5-0-desosaminγl-3-oxo-6-0-methylervthronolide A 11.12-cyclic carbamate Following the same procedure as in Example 1(5) using 2.5 g (3.7 mmol) of the compound obtained in Example 13(4) and 6.8 g (37 mmol) of 2- (2-aminoethyl) amino-5- nitropyridine prepared in the same manner as in Reference Example, there was obtained 0.66 g (yield: 23 %) of the title compound.

SIMS m/z: 778 (M+H)⁺

¹H-NMR (300 MHz, CDC1₃) δ (ppm) : 0.81 (t, 3H, J=7.4 Hz,

14-CH₃), 2.27 (s, 6H, 3 ' -N(CH₃)₂) , 2.67 (s, 3H, 6-OCH₃), 4.26 (d, 1H, J=6.6 Hz, H-5), 4.29 (d, 1H, J=5.0 Hz, H-l'), 4.91 (dd, 1H, J=10.6, 2.3 Hz, H-13), 6.38 (t, 1H, J=5.0 Hz, N-H) .

Example 21

11- T3- TN- (2-Pyridyl) amino1 ropyl1 amino-3 , 11- dideoxy-5-0-desosaminyl-3-oxo-6-0-rπethylervthronolide A

11.12-cyclic carbamate

Example 13(4) and 1.3 g (8.5 mmol) of 2- (3-aminopropyl) - aminopyridine prepared in the same manner as in Reference

Example, there was obtained 0.49 g (yield: 78 %) of the title compound.

IonSprayMS m/z : 747.5 (M+H) ⁺ ^XH-NMR (500 MHz, CDC1₃) δ (ppm) '. 0.85 (t, 3H, J=7.4 Hz,

14-CH₃), 2.26 (s, 6H, 3'-N(CH₃)₂) , 2.61 (s, 3H, 6-OCH₃) , 4.23 (d, 1H, J=8.8Hz, H-5) , 4.27 (d, 1H, J=7.3 Hz, H-l') , 4.94 (dd, 1H, J=10.6, 2.2 Hz, H-13) , 5.04 (t, 1H, J=5.5 Hz, N-H)

¹³C-NMR (125 MHz, CDCl₃) δ (ppm) : 40.1 (3 ' -N(CH₃) ₂) , 49.7

(6-OCH₃), 103.9 (C-l')_; 157.3 (carbamate), 169.6 (C-l), 203.6 (C-3) , 216.2 (C-9) .

Example 22

11- T4- TN- Ϊ2- ( 5-Cvanolpyridyl 1 aminoIbutyll amino- ll-deoχy-3-O- (2-pyridyl ) acetγl-5-Q-desosaminyl-6-Q- methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 1(4) using 0.43 g (0.52 mmol) of the compound obtained in Example 1(3) and 1.10 g of 2- (4-aminobutyl) amino-5- cyanopyridine prepared in the same manner as in Reference Example, there was obtained 0.039 g (yield: 8 %) of the title compound. SIMS m/z : 907 (M+H) ⁺

^XH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.80 (t, 3H, J=7.3 Hz,

14-CH₃) , 2.29 (s, 6H, 3'-N(CH₃)₂) , 2.94 (s, 3H, 6-OCH₃) , 4.98 - 5.10 (m, 2H, H-3 , H-13) , 5.68 - 5.77 (m, 1H, -NH) , 6.42 - 6.49 (1H, , Ar-H) , 7.18 - 7.28 (m, 1H, Ar-H), 7.34 - 7.42 (m, 1H, Ar-H) , 7.46 - 7.54 (m, 1H,

Ar-H) , 7.66 - 7.75 (m, 1H, Ar-H) , 8.30 - 8.36 (m, 1H, Ar-H) , 8.50 - 8.57 (m, 1H, Ar-H) ¹³C-NMR (75 MHz, CDC1₃) δ (ppm) : 40.3 (3 ' -N(CH₃) ₂) , 50.1 (6-OCH₃), 119.0 (-CN), 170.6 (3-OCO-), 175.0 (C-l), 216.0 (C-9) .

Example 23 11- [4- TN- (2-Pyrimidyl) aminol butyll amino-3.11- dideoxy-5-0-desosaminyl-3-oxo-6-0-methylerγthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 1(5) using 0.60 g (0.85 mmol) of the compound obtained in Example 13(4) and 1.4 g (8.5 mmol) of 2- (4-aminobutyl) - aminopyrimidine prepared in the same manner as in Reference Example, there was obtained 0.49 g (yield: 15 %) of the title compound. FABMS m/z: 762 (M+H) ⁺ ^XH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.85 (t, 3H, J=7.4 Hz,

14-CH₃), 2.26 (s, 6H, 3'-N(CH₃)₂), 2.64 (s, 3H, 6-OCH₃) , 4.24 (d, 1H, J=8.7 Hz, H-5), 4.29 (d, 1H, J=7.3 Hz, H-l'), 4.95 (dd, 1H, J=10.6, 2.5 Hz, H-13), 5.48 (t, 1H, J=5.6 Hz, N-H), 6.47 (t, 1H, J=4.8 Hz, pyrimidyl- H) , 8.24 (d, 2H, J=4.8 Hz, pyrimidyl-H) .

Example 24

11- T4- TN- \2 - ( 5-Cvano) pyridyl 1 aminolbutyll amino- 3. ll-dideoxy-5-Q-desosaminyl-3-oxo-6-0-methylerythronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 1(5) using 0.40 g (0.57 mmol) of the compound obtained in Example 13(4) and 1.1 g (5.7 mmol) of 2- (4-aminobutyl) - amino-5-cyanopyridine prepared in the same manner as in

Reference Example, there was obtained 0.03 g (yield: 7 %) of the title compound.

IonSprayMS m/z: 786.5 (M+H) ⁺ ^XH-NMR (300 MHz, CDC1₃) δ (ppm) : 0.86 (t, 3H, J=7.4 Hz,

14-CH₃) , 2.27 (s, 6H, 3'-N(CH₃)₂), 2.59 (s, 3H, 6-0CH₃) , 4.23 (d, 1H, J=9.0 Hz, H-5) , 4.28 (d, 1H, J=7.3 Hz, H-l') , 4.94 (dd, 1H, J=10.6, 2.3 Hz, H-13) , 5.61 (t, 1H, J=5.0 Hz, N-H) , 6.48 (t, 1H, J=8.9 Hz, pyridyl -H ) , 7.53 (dd, 1H, J=8.9, 2.3 Hz, pyridyl -H ) , 8.33 (d, 1H,

J=2.3 Hz, pyridyl -H ) .

Eχ.ample 25

11- \2- (N-Phenylamino) ethyll amino-3 , ll-dideoxγ-5- 0-desosaminyl-3-oxo-6-0-methylervthronolide A 11.12-cvclic carbamate

Carrying out the same reaction as in Example

13(5) using 1.0 g (1.4 mmol) of the compound obtained in

Example 13(4) and 2.0 g (15 mmol) of N-phenylethylenediamine, there was obtained 0.4 g of the title compound.

FABMS m/z: 732 (M+H)⁺

Example 26 H-r4-fN-r2- ( 5-Nitro) pyridyl1 amino1 butyll amino-

3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-0-methylerythronolide A 11, 12-cyclic carbamate

Following the same procedure as in Example 1(5) using 1.0 g (1.42 mmol) of the compound obtained in Example 13(4) and 2.98 g (14.2 mmol) of 2- (4- aminobutylamino) -5-nitropyridine prepared in the same manner as in Reference Example, there was obtained 0.34 g (yield: 30 %) of the title compound. FABMS m/z: 806 (M+H)⁺.

¹ H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.6Hz, 14-CH₃), 2.27(s, 6H, 3'-N(CH ₃) ₂) , 2.59(s, 3H, 6-OCH₃), 4.22(d, 1H, J=9.2Hz, H-5) , 4.28(d, 1H, J=7.3Hz, H-l'), 4.94(dd, 1H, J=11.0, 2.4Hz, H-13), 6.02 (brs, 1H, N-H) .

Example 27 ll-r4-^'N- (3-Pyridyl) aminoIbutyll amino-3 , 11- dideoxy-5-0-desosaminyl-3 -0- ( 2-pyridyl ) acetyl-6-O- methylervthronolide A 11,12-cyclic carbamate

(1) Following the same procedure as in Example 1(4) using 5.0 g (6.05 mmol) of the compound obtained in Example 1(3) and 5.1 g (60.5 mmol) of 4-aminobutanol, there was obtained 2.62 g (yield: 51 %) of the ll-N-(4- hydroxy) butyl compound.

(2) To a solution of 2.6 g (3.07 mmol) of the compound obtained in the above (1) in a mixture of 100 ml of dimethyl sulfoxide and 11 ml of triethylamine was added 2.44 g (15.3 mmol) of sulfur trioxide pyridine complex, followed by stirring for 2 hours . To the reaction solution was added a saturated aqueous ammonium chloride solution, and then ethyl acetate and water were added thereto for separation. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (acetone : hexane : triethyla ine =10:10:0.2) to give 1.60 g (yield: 62 %) of the aldehyde compound.

(3) To a solution of 0.3 g (0.36 mmol) of the compound obtained in the above (2) and 0.05 g (0.533 mmol) of 3 -aminopyridine in methylene chloride was added 0.15 g (0.71 mmol) of sodium triacetoxyborohydride, followed by stirring for 15 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and then chloroform and water were added thereto for separation.

The organic layer was successively washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (acetone : hexane : triethylamine =20:10:0.2), and the resulting product was dissolved in methanol, followed by stirring for 15 hours. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (acetone : hexane : triethylamine =10:10:0.2) to give 0.17 g (yield: 52 %) of the title compound. FABMS m/ z : 882 (M+H) ⁺ .

¹ H-NMR(500MHz, CDCl ₃ ) δ (ppm) : 0.80 ( t , 3H, J=7.3Hz, 14-CH₃), 2.30(s, 6H, 3'-N(CH₃)₂), 2.98(s, 3H, 6-OCH₃), 4.07(d, 1H, J=7.3Hz, H-l'), 4.22 (brs, 1H, N-H), 5.06 (dd, 1H, J=11.0, 2.4Hz , H-13), 5.07(d, 1H, J=11.0Hz, H-3) .

Example 28

H-r4-rN- (3-Ouinolyl) amino1 butyll amino-3, 11- dideoxγ-5-Q-desosaminyl-3-0- (2-pyridyl) acetyl-6-0- methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 27(3) using 0.3 g (0.36 mmol) of the compound obtained in Example 27(2) and 0.077 g (0.53 mmol) of 3-aminoquinoline, there was obtained 0.21 g (yield: 63 %) of the title compound.

IonSprayMS m/z: 932.4 (M+H)⁺.

' H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.77 ( t , 3H, J=7.4Hz, I4-CH₃), 2.30(s, 6H, 3'-N(CH ₃) ₂) , 3.00(s, 3H, 6-OCH₃), 4.07 (d, 1H, J=7.3Hz, H-l'), 4.54(brt, 1H, J=5.3Hz, N-H), 5.05-5.08(m, 2H, H-3, H-13).

Example 29

11- T3- TN- (3-Pyridyl) amino1 propyl1 amino- 3 , ll-dideoxy-5-Q-desosaminyl-3-oxo-6-0-methylervthronolide A 11, 12-cyclic carbamate

(1) Following the same procedure as in Example 27(1) using 5.0 g (7.1 mmol) of the compound obtained in Example 13(4) and 5.3 g (71 mmol) of 3-aminopropanol, there was obtained 5.1 g (yield: 100 %) of the ll-N-(3- hydroxy) propy1 compound.

(2) Following the same procedure as in Example 27(2) using 5.0 g (7.0 mmol) of the compound obtained in the above (1), there was obtained 5.0 g (yield: 100 %) of the aldehyde compound.

(3) Following the same procedure as in Example 27(3) using 0.50 g (0.70 mmol) of the compound obtained in the above (2) and 0.099 g (1.1 mmol) of 3-aminopyridine, there was obtained 0.21 g (yield: 63 %) of the title compound.

FABMS m/z: 747 (M+H)⁺.

¹ H-NMR( 300MHz, CDCl ₃ ) δ (ppm) : 0.82 ( t , 3H, J=7.5Hz, 14-CH₃), 2.27(s, 6H, 3 ' - (CH ₃ ) ₂ ) , 2.63(s, 3H,

6-OCH₃), 4.24(d, 1H, J=8.5Hz, H-5) , 4.28(d, 1H, J=7.3Hz, H-l'), 4.96(dd, 1H, J=11.0, 2.4Hz, H-13).

Example 30 11- T3- fN- (3-Ouinolyl) amino1 propyl 1 amino-

3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-0-methylervthronolide

A 11, 12-cyclic carbamate

Following the same procedure as in Example 27(3) using 0.50 g (0.70 mmol) of the compound obtained in Example 29(2) and 0.15 g (1.1 mmol) of 3-aminoquinoline, there was obtained 0.11 g (yield: 20 %) of the title compound.

FABMS m/z: 797 (M+H)⁺. ¹ H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.82 ( , 3H, J=7^~.5Hz, 14-CH ₃) , 2.27(s, 6H, 3'-N(CH ₃)₂) , 2.63(s, 3H, 6-OCH ₃) , 4.23(d, 1H, J=9.2Hz, H-5) , 4.28(d, 1H, J=7.3Hz, H-l'), 4.78(brt, 1H, J=5.3Hz, N-H), 4.96(dd, 1H, J=11.0, 2.4Hz, H-13)

Eχ.ample 31

11- F3- TN- (2-Thiazolyl)aminolpropyllamino- 3 , ll-dideoxy-5-Q-desosaminyl-3-oxo-6-Q-methγlerythronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 27(3) using 0.50 g (0.70 mmol) of the compound obtained in Example 29(2) and 0.11 g (1.1 mmol) of 2-aminothiazole, there was obtained 0.050 g (yield: 9 %) of the title compound.

IonSprayMS m/z:753.2 (M+H)⁺.

¹ H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.86 ( t , 3H, J=7.6Hz, I4-CH₃), 2.27(s, 6H, 3'-N(CH₃)₂), 2.63(s, 3H, 6-OCH₃), 4.24(d, 1H, J=8.5Hz, H-5), 4.28(d, 1H, J=7.3Hz, H-l'), 4.93(dd, 1H, J=10.4, 2.4Hz, H-13), 5.78 (brs, 1H, N-H) .

Example 32

11- T4- TN- (3-Pyridyl) aminolbutyll amino- 3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11,12-cyclic carbamate

(1) Following the same procedure as in Example 27(1) using 5.0 g (7.1 mmol) of the compound obtained in Example 13(4) and 5.3 g (71 mmol) of 4-aminobutanol, there was obtained 3.8 g (yield: 73 %) of the ll-N-(4- hydroxy) butyl compound.

(2) Following the same procedure as in Example 27(2) using 3.0 g (4.1 mmol) of the compound obtained in the above (1), there was obtained 0.76 g (yield: 25 %) of the aldehyde compound.

(3) Following the same procedure as in Example 27(3) using 0.30 g (0.41 mmol) of the compound obtained in the above (2) and 0.058 g (0.62 mmol) of 3 -aminopyridine, there was obtained 0.14 g (yield: 44 %) of the title compound.

FABMS m/z: 761 (M+H)⁺.

¹ H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.3Hz, 14-CH₃), 2.27(s, 6H, 3'-N(CH₃)₂), 2.63(s, 3H,

6-OCH₃), 4.12 (brt, 1H, J=5.3Hz, N-H), 4.24 (d, 1H, J=8.5Hz, H-5), 4.28(d, 1H, J=7.3Hz, H-l'), 4.97(dd, 1H, J=10.7, 2.4Hz, H-13) .

Example 33

11- f4- fN- (3-Ouinolyl) aminolbutyll amino- 3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 27(3) using 0.30 g (0.41 mmol) of the compound obtained in

Example 32(2) and 0.090 g (0.62 mmol) of 3-aminoquinoline, there was obtained 0.15 g (yield: 45 %) of the title compound. FABMS m/z: 811 (M+H)⁺.

¹ H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.82 ( t , 3H, J=7.6Hz, 14-CH ₃), 2.26(s, 6H, 3'-N(CH ₃)₂), 2.65(s, 3H, 6-OCH ₃) , 4.24(d, IH, J=8.5Hz, H-5) , 4.28(d, IH, J=7.3Hz, H-l') , 4.49(brt, IH, J=5.2Hz, N-H), 4.98(dd,

IH, J=11.0, 2.4Hz, H-13) .

Eχ.ample 34

11- T4- fN- 12- (5-Nitro) pyridyl1 aminolbutyll amino- ll-deoxy-3-O- (2-pγridyl) acetyl-5-Q-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 1(4) using 2.00 g (2.42 mmol) of the compound obtained in Example 1(3) and 5.65 g of 2- (4-aminobutylamino) -5- nitropyridine prepared in the same manner as in Reference Example, there was obtained 0.59 g (yield: 26 %) of the title compound. IonSprayMS m/z : 927.5 (M+H) ⁺.

¹ H-NMR(300MHz, CDCl ₃ ) δ (ppm) : 0.80 ( t , 3H, J=7.3Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.95(s, 3H,

6-OCH₃), 6.10-6.20(m, IH, N-H), 6.42-6.50(m, IH, Ar-H), 7.20-7.26(m, IH, Ar-H), 7.36-7.42 (m, IH, Ar-H), 7.68-7.76(m, IH, Ar-H), 8.07-8.19(m, IH, Ar-H), 8.50-8.57 (m, IH, Ar-H), 8.97-9.02(m, IH, Ar-H). ' ³C-NMR( 75MHz, CDCl ₃ ) δ (ppm) : 40.3 (3 ' -N(CH ₃ ) ₂ ) ,

50.K6-OCH ₃) , 170.6(3-OCO-) , 175.KC-1), 216.0(C-9). Example 35

11- f4- TN- f2- (3 -Aminocarbonyl) pyridyl1 amino! - butyll amino-11-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methγlervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 1(4) using 1.00 g (1.21 mmol) of the compound obtained in Example 1(3) and 3.35 g of 2- (4-aminobutylamino) - nicotinamide prepared in the same manner as in Reference Example, there was obtained 0.26 g (yield: 23 %) of the title compound. FABMS m/z : 925 (M+H) ⁺.

¹ H-NMR(300MHz, CDCl ₃ ) δ (ppm) : 0.80 ( t , 3H, J=7.3Hz, 14-CH₃), 2.29(s, 6H, 3'-N(CH₃)₂), 2.95(s, 3H, 6-OCH₃), 5.77 (brs, IH, N-H), 6.35-6.53 (m, IH, Ar-H), 7.17-7.25 (m, IH, Ar-H), 7.33-7.40(m, IH, Ar-H), 7.65- 7.74(m, IH, Ar-H), 8.10-8.21 (m, 2H, Ar-H), 8.50-8.56 (m, IH, Ar-H) . ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40. (3 ' -N(CH ₃ ) ₂ ) , 49.9(6-OCH ₃) , 170.6 (3-OCO-) , 173.9(C-1), 215.6(C-9).

Example 36

11- T4- fN- (2-Benzimidazolyl) amino1 butyll amino-11- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 1(4) using 0.50 g (0.61 mmol) of the compound obtained in Example 1(3) and 1.87 g of 2- (4-aminobutylamino) - benzimidazole prepared in the same manner as in Reference

Example, there was obtained 0.17 g (yield: 31 %) of the title compound.

FABMS m/z : 921 (M+H) ⁺. ¹ H-NMR(300MHz, CDCl ₃ ) δ (ppm) : 0.73 ( t, 3H, J=7.3Hz, 14-CH₃), 2.29(s, 6H, 3'-N(CH₃)₂), 2.94(s, 3H, 6-OCH₃), 5.29 (brs, IH, N-H), 6.92-6.98 (m, 2H, Ar-H), 7.14-7.28(m, IH, Ar-H), 7.36-7.41 (m, IH, Ar-H), 7.68- 7.76(m, IH, Ar-H), 8.53-8.58(m, IH, Ar-H). ' ³C-NMR(75MHz, CDCl ₃ ) δ (ppm) : 40.3 (3 ' -N (CH ₃ ) ₂ ) ,

50.K6-OCH ₃) , 171.K3-OCO-) , 175.7(C-1), 215.7(C-9).

Example 37

11- \ 2 - TN- (2-Pyrimidyl) amino1 ethyll amino-11- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 1(4) using 1.00 g (1.21 mmol) of the compound obtained in Example 1(3) and 1.86 g of 2- (2-aminoethylamino) - pyrimidine prepared in the same manner as in Reference Example, there was obtained 0.85 g (yield: 82 %) of the title compound. IonSprayMS m/z : 855.3 (M+H) ⁺.

¹ H-NMR( 300MHz, CDCl ₃ ) δ (ppm) : 0.82 ( t , 3H, J=7.4Hz, I4-CH₃), 2.29(s, 6H, 3'-N(CH ₃) ₂) , 3.10(s, 3H,

6-OCH₃), 5.96-6.06(m, IH, N-H), 6.45-6.50(m, IH, Ar-H), 7.19-7.25(m, IH, Ar-H), 7.33-7.39(m, IH, Ar-H), 7.65-7.77 (m, IH, Ar-H), 8.21-8.27 (m, 2H, Ar-H), 8.50- 8.55 (m, IH, Ar-H) . ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N(CH ₃) ₂) ,

50.4(6-OCH ₃) , 170.5(3-OCO-) , 174.6(C-1), 215.7(C-9).

Example 38

11- \2 - TN- \2- ( 5-Cvano) pyridyl1 amino1 ethyl amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 1(4) using 0.19 g (0.23 mmol) of the compound obtained in Example 1(3) and 0.42 g of 2- (2-aminoethylamino) -5- cyanopyridine prepared in the same manner as in Reference Example, there was obtained 0.14 g (yield: 70 %) of the title compound. IonSprayMS m/z : 879.5 (M+H) ⁺.

¹ H-NMR( 300MHz, CDCl ₃ ) δ (ppm) : 0.74 ( t , 3H, J=7.3Hz, 14-CH₃), 2.29(s, 6H, 3'-N(CH₃)₂), 3.04(s, 3H, 6-OCH₃), 6.15-6.23(m, IH, N-H), 6.42-6.48(m, IH, Ar-H), 7.20-7.26(m, IH, Ar-H), 7.34-7.39(m, IH, Ar-H), 7.45-7.52(m, IH, Ar-H), 7.66-7.73(m, IH, Ar-H), 8.34- 8.37 (m, IH, Ar-H), 8.51-8.55 (m, IH, Ar-H). ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N(CH ₃ ) _ ) ,

50.4(6-OCH ₃) , 170.6(3-OCO-) , 175.4(C-1), 215.9(C-9).

Example 39

11- r2-rN-(2-Pyrimidyl)aminol ethyll amino-3.11- dideoxγ-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example 13(5) using 1.00 g (1.42 mmol) of the compound obtained in Example 13(4) and 2.18 g of 2- (2-aminoethylamino) - pyrimidine prepared in the same manner as in Reference Example, there was obtained 0.68 g (yield: 66 %) of the title compound. IonSprayMS m/z : 734.3 (M+H) ⁺.

¹ H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.86 ( t , 3H, J=7.3Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.70(s, 3H, 6-OCH₃), 5.80-5.86(m, IH, N-H), 6.47-6.50(m, IH, Ar-H), 8.22-8.28(m, 2H, Ar-H). ¹³C-NMR( 125MHz, CDCl ₃) δ (ppm) :40.2 (3 '-N(CH ₃) ₂) , 50.0(6-OCH ₃) , 104.0(C-1'), 157.6 (carbamate) , 169.9(0-1), 203.6(C-3), 216.1(C-9).

Example 40

11- 2 - TN- \2 - ( 5-Cvano) pyridyl 1 aminol ethyll amino- 3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example 13(5) using 1.00 g (1.42 mmol) of the compound obtained in Example 13(4) and 2.55 g of 2- (2-aminoethylamino) -5- cyanopyridine prepared in the same manner as in Reference Example, there was obtained 0.61 g (yield: 57 %) of the title compound.

SIMS m/z : 758 (M+H) ⁺.

¹ H-NMR(300MHz, CDCl ₃ ) δ (ppm) : 0.80 (t , 3H, J=7.4Hz, I4-CH₃), 2.27(s, 6H, 3'-N(CH₃)₂), 2.66(s, 3H, 6-OCH ₃) , 5.96-6.10(m, IH, N-H) , 6.44-6.51 (m, IH, Ar- H) , 7.47-7.54(m, IH, Ar-H) , 8.34-8.37(m, IH, Ar-H) . ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N (CH ₃) ₂) , 49.9(6-OCH ₃) , 104.KC-1') , 157.9 (carbamate) , 170.5(C-1) , 203.4(C-3) , 216.4(C-9) .

Example 41

11- T4- TN- (2-Pyrazinyl) aminolbutyll amino-3 , 11- dideoxy-5-0-desosaminyl-3-oxo-6-Q-methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 13(5) using 1.00 g (1.42 mmol) of the compound obtained in Example 13(4) and 2.62 g of 2- (4-aminobutylamino)pyrazine prepared in the same manner as in Reference Example, there was obtained 0.70 g (yield: 64 %) of the title compound. FABMS m/z : 762 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.3Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.61(s, 3H, 6-OCH₃), 5.12-5.20(m, IH, N-H), 7.72-7.74(m, IH, Ar-H), 7.92-7.97 ( , 2H, Ar-H).

¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N (CH ₃ ) ₂ ) , 49.9(6-OCH ₃) , 104.KC-1'), 157.4 (carbamate) , 170.KC-1), 203.5(C-3), 216.3(C-9).

Ex-ample 42

11- \4- FN- \2- (3-Pyrrol-l-yl)pyridyl1 amino1 - butyll amino-3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cvclic carbamate Following the same procedure as in Example 13(5) using 0.50 g (0.71 mmol) of the compound obtained in Example 13(4) and 1.81 g of 2- (4-aminobutylamino) -3- pyrrol-1-ylpyridine prepared in the same manner as in Reference Example, there was obtained 0.073 g (yield: 12 %) of the title compound. FABMS m/z : 826 (M+H) ⁺.

¹ H-NMR( 300MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.3Hz, 14-CH₃), 2.27(s, 6H, 3'-N(CH₃)₂), 2.61(s, 3H, 6-OCH₃), 4.53-4.62(m, IH, N-H), 6.32-6.36(m, 2H,

Ar-H), 6.55-6.61(m, IH, Ar-H), 6.78-6.82 (m, 2H, Ar-H), 7.26-7.31(m, IH, Ar-H), 8.08-8.14 (m, IH, Ar-H). ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) ₂ ) , 49.8(6-OCH ₃) , 103.9(0-1'), 157.2 (carbamate) , 169.4(C-1), 203.9(C-3), 216.0(C-9).

Example 43

11-Γ4-ΓN-Γ2-Γ6-(2 '-Pyridyl) 1 pyridyl 1 amino1- butyll amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 13(5) using 0.50 g (0.71 mmol) of the compound obtained in

Example 13(4) and 1.53 g of 2- (4-aminobutylamino) -6- (2 ' - pyridyl ) pyridine prepared in the same manner as in Reference Example, there was obtained 0.098 g (yield:

17 %) of the title compound.

FABMS m/z : 838 (M+H) ⁺.

¹ H-NMR(300MHz, CDCl ₃ ) δ (ppm) : 0.85 (t , 3H, J=7.3Hz, 14-CH ₃) , 2.26(s, 6H, 3'-N(CH ₃) ₂) , 2.64(S, 3H, 6-OCH ₃) , 4.82-4.89(m, IH, N-H) , 6.45-6.50(m, IH, Ar-H) , 7.20-7.27 (m, IH, Ar-H) , 7.49-7.56(m, IH, Ar-H) , 7.62-7.66(m, IH, Ar-H) , 7.76-7.82(m, IH, Ar-H) , 8.33- 8.38(m, IH, Ar-H) , 8.61-8.66 (m, IH, Ar-H) .

¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) ₂ ) , 49.8(6-OCH ₃) , 103.9 (C-l') , 157.3 (carbamate) , 169.8(C-1) , 203.7(C-3), 216.KC-9) .

Example 44

11- r4-TN-r4-r2-(2 '-Pyridyl) 1 pyridyl 1.amino1 - butyll amino-3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-Q- methylerythronolide A 11,12-cvclic carbamate

Example 13(4) and 1.53 g of 4- (4-aminobutylamino) -2- (2 ' - pyridyl )pyridine prepared in the same manner as in Reference Example, there was obtained 0.28 g (yield: 48 %) of the title compound. FABMS m/z: 838 (M+H) ⁺.

¹ H-NMR(300MHz, CDCl ₃ ) δ (ppm) : 0.87 (t , 3H, J=7.3Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.63(s, 3H, 6-OCH₃), 4.76-4.84(m, IH, N-H), 6.50-6.55(m, IH, Ar-H), 7.23-7.29(m, IH, Ar-H), 7.57-7.60(m, IH, Ar-H), 7.73-7.80(m, IH, Ar-H), 8.24-8.28(m, IH, Ar-H), 8.30-8.36(m, IH, Ar-H), 8.63-8.67 (m, IH, Ar-H). ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) ₂ ) , 49.9(6-OCH ₃) , 104.0 (C-l"), 157.4 (carbamate) , 170 . 0 ( C-1 ) , 203 . 5 ( C-3 ) , 216 . 2 ( C-9 ) .

Example 45

11- T4- ΓN- \2- (4, 6-Dimethoxy) pyrimidyl 1 amino1 - butyll amino-3 , ll-dideoxy-5-Q-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 13(5) using 0.54 g (0.77 mmol) of the compound obtained in Example 13(4) and 1.93 g of 2- (4-aminobutylamino) -4 , 6- dimethoxypyrimidme prepared in the same manner as in

Reference Example, there was obtained 0.17 g (yield: 27 %) of the title compound. FABMS m/z : 822 (M+H) ⁺.

¹ H-NMR( 500MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.3Hz, 14-CH₃), 2.26(s, 6H, 3 ' -N(CH ₃ ) ₂ ) , 2.64(s, 3H,

6-OCH₃), 3.85(ε, 6H, Ar-OCH ₃ ) , 5.10-5.15 (m, IH, N-H), 5.36(s, IH, Ar-H) . ¹³C-NMR( 125MHz, CDCl ₃) δ (ppm) :40.2 (3 ' -N(CH ₃) ₂) , 49.8(6-OCH ₃) , 103.9(C-1'), 157.2 (carbamate) , 169.6(C-1), 203.7(C-3), 216.KC-9).

Example 46

11- - ΓN- \ 2 - (4 , 6-Diamino) -1,3.5- triazinyll a inol butyll amino-3. ll-dideoxy-5-O- desosaminyl-3-oxo-6-0-methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 13(5) using 0.50 g (0.71 mmol) of the compound obtained in Example 13(4) and 1.55 g of 2- (4-aminobutylamino) -4, 6- diamino-1, 3 , 5-triazine prepared in the same manner as in Reference Example, there was obtained 0.097 g (yield: 17 %) of the title compound. FABMS m/z: 793 (M+H) ⁺.

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.3Hz,

14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.65(s, 3H,

6-OCH₃), 4.81 (brs, 2H, Ar-NH _ ) , 5.06 (brs, 2H,

Ar-NH₂), 5.14-5.20 (m, IH, N-H). ¹³C-NMR (125MHz, CDCl ₃ ) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) _ ) ,

49.8(6-OCH ₃) , 104.0(C-1'), 157.2 (carbamate) ,

169.8(C-1), 203.8(C-3), 216.2(C-9).

Example 47 11- T4- TN- \ 6- (2.4-Diamino) pyrimidyl1 amino1 - butyll amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 13(5) using 0.53 g (0.76 mmol) of the compound obtained in Example 13(4) and 1.65 g of 6- (4-aminobutylamino) -2, 4- diaminopyrimidine prepared in the same manner as in

Reference Example, there was obtained 0.14 g (yield: 24 %) of the title compound.

SIMS m/z : 792 (M+H) ⁺. ' H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.4Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.63(s, 3H, 6-OCH₃), 4.76-4.82 (m, IH, N-H), 5.06(s, IH, Ar-H).

¹³C-NMR (75MHz, CDCl ₃) δ (ppm) :40.2 (3 '-N(CH ₃) ₂) , 49.8(6-OCH ₃) , 104.0(C-1'), 157.3 (carbamate) , 169.8(C-1), 203.8(C-3), 216.2(C-9).

Example 48 11- T4- TN- \ 2 - (3-Cyano) pyridyl1 aminol butyll amino-

3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-Q-methylerythronolide A 11.12-cyclic carbamate

(1) Following the same procedure as in Example 13(5) using 10.0 g (0.014 mol) of the compound obtained in Example 13(4) and 12.5 g of 1, 4-diaminobutane, there was obtained 6.69 g (yield: 69 %) of the 11- (4- aminobutyl ) amino compound. FABMS m/z : 684 (M+H) ⁺.

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) : 0.86 ( t , 3H, J=7.3Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.66(s, 3H,

6-OCH₃), 4.24(d, IH, J=8.5Hz, H-5), 4.29(d, IH, J=7.3Hz, H-l'), 4.96(dd, IH, J=10.7, 2.5Hz , H-13). ¹³C-NMR( 125MHz, CDCl ₃) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) _ ) , 49.8(6-OCH ₃) , 103.9(C-1'), 157.2 (carbamate) , 169.5(C-1), 203.9(C-3), 216.KC-9).

(2) To a solution of 0.50 g (0.73 mmol) of the compound obtained in the above (1) in 5 ml of N,N- dimethylformamide was added 0.21 g of 2-chloro-3- cyanopyridine, followed by stirring at 120°C for an hour. The reaction solution was, after addition of an aqueous sodium hydroxide solution, extracted with ethyl acetate, and the ethyl acetate layer was successively washed with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform : methanol : aqueous ammonia =19:1:0.1) to give 0.20 g (yield: 35 %) of the title compound. FABMS m/z: 786 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.86 ( t , 3H, J=7.3Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.64(s, 3H, 6-OCH₃), 5.35-5.44(m, IH, N-H), 6.51-6.57 (m, IH,

Ar-H), 7.58-7.63 ( , IH, Ar-H), 8.22-8.28(m, IH, Ar-H). ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) :40.3 (3 '-N(CH ₃) ₂) , 49.8(6-OCH ₃) , 104.0 (C-l'), 157.3 (carbamate) , 169.6(C-1), 203.8(C-3), 216.3(C-9).

Example 49

11- T4- TN- Ϊ2 - (3 -Nitro) pyridyl 1 aminolbutyll amino- 3. ll-dideoχy-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11.12-cvclic carbamate Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.23 g of 2-chloro-3-nitropyridine, there was obtained 0.42 g (yield: 70 %) of the title compound. FABMS m/z : 806 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.83 ( t , 3H, J=7.3Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.61(s, 3H, 6-OCH₃), 6.57-6.64(m, IH, N-H), 8.24-8.34(m, IH, Ar-H) , 8.36-8.43 (m, 2H, Ar-H) . ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N(CH ₃ ) _ ) , 49.7(6-OCH ₃) , 104.0(C-1') , 157.3 (carbamate) , 169.5(C-1) , 203.8(C-3) , 216.2(C-9) .

Example 50

H-Γ4-ΓN-Γ2-(3.5-

Dinitro) pyridyll amino1 butyll amino-3 , ll-dideoxy-5-O- desosaminyl-3-oxo-6-Q-methylerythronolide A 11.12-cvclic carbamate .

Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.30 g of 2-chloro-3 , 5-dinitro-pyridine, there was obtained 0.35 g (yield: 56 %) of the title compound.

FABMS m/z : 851 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.78 ( t , 3H, J=7.4Hz, 14-CH ₃) , 2.26(s, 6H, 3'-N(CH ₃) ₂) , 2.54(s, 3H, 6-OCH ₃) , 8.80-8.94(m, IH, N-H) , 9.19-9.25 (m, 2H, Ar-H) .

¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N (CH ₃) ₂) , 49.6(6-OCH ₃) , 104.KC-1') , 157.3 (carbamate) , 169.7(C-1) , 203.4(C-3) , 216.4(C-9) .

Example 51

11- f4- ΓN- r2-(6-Chloro-3-nitro)Pyridyl1amino1 - butyll amino-3. ll-dideoxy-5-0-desosaminγl-3-oxo-6-0- methylervthronolide A 11.12-cvclic carbamate Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.31 g of 2 , 6-dichloro-3 -nitropyridme, there was obtained 0.45 g (yield: 73 %) of the title compound.

FABMS m/z : 840 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.3Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.60(s, 3H, 6-OCH₃), 6.55-6.60 (d, IH, J=8.7Hz, Ar-H), 8.32-8.36(d, IH, J=8.7Hz, Ar-H), 8.36-8.45(m, IH, N-H) ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N(CH ₃ ) ₂ ) , 49.7(6-OCH ₃) , 104.0 (C-l'), 157.3 (carbamate) , 169.6(C-1), 203.7(C-3), 216.2(C-9).

Example 52

11- T4- TN- \ 2 - (4-Methyl-5-nitro) pyridyl1 - amino! butyll amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.25 g of 2-chloro-4-methyl-5- nitropyridine, there was obtained 0.42 g (yield: 69 %) of the title compound. IonSprayMS m/z : 820.4 (M+H) ⁺. ' H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.3Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.59(s, 3H, 6-OCH₃), 4.91-4.98(m, IH, N-H), 6.31 (brs, IH, Ar-H), 8.93 (s, IH, Ar-H) . ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N(CH ₃ ) ^'_ ) , 49.9(6-OCH ₃) , 104.KC-1') , 157.4 (carbamate) , 170.2(C-1) , 203.4(C-3), 216.4(C-9) .

Example 53

11- T4- TN- \2- (4-Methyl-3 -nitro) yridyl! amino! - butyll amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 48(2) using a solution of 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) in 5 ml of N,N-dimethylformamide and 0.25 g of 2-chloro-4-methyl-3 -nitropyridme, there was obtained 0.30 g (yield: 51 %) of the title compound. IonSprayMS m/z : 820.4 (M+H) ⁺. ¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.4Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.63(s, 3H, 6-OCH₃), 6.43 (d, IH, J=4.8Hz, Ar-H), 7.57-7.68 (m, IH, N-H), 8.10 (d, IH, J=4.8Hz, Ar-H). ¹³C-NMR( 75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N (CH ₃ ) ₂ ) , 49.8(6-OCH ₃) , 104.0(C-1'), 157.3 (carbamate) , 169.5(C-1), 203.7(C-3), 216.KC-9).

Example 54

11- T4- TN- (6-Purinyl) aminolbutyl! amino-3.11- dideoxy-5-0-desosaminyl-3-oxo-6-0-methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.23 g of 6-chloropurine, there was obtained 0.16 g (yield: 27 %) of the title compound. FABMS m/z : 802 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.3Hz, 14-CH₃), 2.27(s, 6H, 3'-N(CH₃)₂), 2.62(s, 3H,

6-OCH₃), 6.22-6.44 (m, IH, N-H), 7.95 (brs, IH, Ar-H), 8.41 (brs, IH, Ar-H) . ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) : 40.2 (3 ' -N(CH ₃) ₂) , 49.9(6-OCH ₃) , 104.0(C-1'), 157.3 (carbamate) , 169.6(C-1), 203.9(C-3), 216.2(C-9). Example 55

11- T4- TN- T4- (2-Chloro)pyrimidyl!amino1butyl1 - amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.22 g of 2 , 4-dichloropyrimidine, there was obtained 0.23 g (yield: 39 %) of the title compound. FABMS m/z : 796 (M+H) ⁺. ¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.4Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.60(s, 3H, 6-OCH₃), 5.92 (brs, IH, N-H), 6.37 (brs, IH, Ar-H), 7.97 (brs, IH, Ar-H) . ' ³C-NMR(75MHz, CDCl ₃) δ (ppm) :40.3 (3 '-N(CH ₃) ₂) , 49.9(6-OCH ₃) , 104.KC-1'), 157.4 (carbamate) , 170.3(C-1), 203.4(C-3), 216.4(C-9). Example 56

11- r4- ΓN-T2- (4, 6-Dichloro)pyrimidyllamino! - butyl! amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-Q- methylervthronolide A 11.12-cvclic carbamate (1) and 11-Γ4-ΓN-Γ4-(2.6-dichloro) pyrimidyl! amino1 butyl1 amino-

3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-Q-methylervthronolide A 11.12-cyclic carbamate (2)

Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.27 g of 2 , 4 , 6-trichloropyrimidine, there were obtained 0.11 g (yield: 18 %) of the title compound (1) and 0.19 g (yield: 31 %) of the title compound (2) .

Compound (1)

FABMS m/z : 830 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.4Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.64(s, 3H, 6-OCH₃), 5.80-5.88 (m, IH, N-H), 6.55 (s, IH, Ar-H). ^{■ 3}C-NMR(75MHz, CDCl ₃ ) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) _ ) ,

49.9(6-OCH ₃) , 104.0(C-1'), 157.2 (carbamate) , 169.7(C-1), 203.7(C-3), 216.5(C-9).

Compound (2 ) SIMS m/z: 830 (M+H) ⁺.

Η-NMR(300MHz, CDCl ₃) δ (ppm) :0.85 (t, 3H, J=7.3Hz, I4-CH₃), 2.27(s, 6H, 3'-N(CH₃)₂), 2.60(s, 3H, 6-OCH₃), 6.15 (brs, IH, N-H), 6.48 (brs, IH, Ar-H). ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) :40.3 (3 '-N(CH ₃) ₂) , 49.9(6-OCH ₃) , 104.1(C-1'), 157.4 (carbamate) , 203.7(C-3) , 216.5(C-9) .

Example 57

11- F4- fN- \ 2 - (4,5, 6-Trichloro) pyrimidyl! amino! - butyl! amino-3 , ll-dideoxy-5-0-desosaminyl-3-oxo-6-Q- methylervthronolide A 11.12-cvclic carbamate

Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in

Example 48(1) and 0.32 g of 2 , 4, 5, 6-tetrachloro-pyrimidine, there was obtained 0.24 g (yield: 39 %) of the title compound.

FABMS m/z : 864 (M+H) ⁺. ' H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.3Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH ₃) ₂) , 2.63(s, 3H, 6-OCH₃), 6.01-6.09 ( , IH, N-H). ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) :40.2 (3 ^■ -N(CH ₃) ₂) , 49.9(6-OCH ₃) , 104.0(C-1'), 157.4 (carbamate) , 169.8(C-1), 203.5(C-3), 216.4(C-9).

Example 58

11- T4- TN- \2- (4-Chloro-6-methyl)pyrimidyl! - aminolbutyl! amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cyclic carbamate (1) and 11- T4- TN- T4- (2-chloro-6-methyl) yrimidyl! aminolbutyl! -amino- 3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0-methylerythronolide A 11.12-cyclic carbamate (2) Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.24 g of 2 , 4-dichloro-6- methylpyrimidine, there were obtained 0.096 g (yield: 16 %) of the title compound (1) and 0.20 g (yield: 34 %) of the title compound (2) . Compound (1) FABMS m/z : 810 (M+H) ⁺.

' H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.3Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.28(s, 3H,

Ar-CH₃), 2.64(s, 3H, 6-OCH₃), 5.40-5.50(m, IH, N-H), 6.40(s, IH, Ar-H) . ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) ₂ ) , 49.9(6-OCH ₃) , 103.9(C-1'), 157.2 (carbamate) , 169.6(C-1), 203.8(C-3), 216.3(C-9).

Compound (2 ) FABMS m/z : 810 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.3Hz, I4-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.33(s, 3H,

Ar-CH₃), 2.60(s, 3H, 6-OCH₃), 5.65 (brs, IH, N-H), 6.21 (brs, IH, Ar-H) . ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) :40.3 (3 '-N(CH ₃) ₂) , 49.9(6-OCH ₃) , 104.KC-1'), 157.4 (carbamate) , 170.2(C-1), 203.4(C-3), 216.4(C-9).

Example 59

11- T4-ΓN- Γ4- (6-Chloro) pyrimidyl! amino! butyll - amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-Q- methylervthronolide A 11,12-cyclic carbamate

Following the same procedure as in Example 48(2) using 0.50 g (0.73 mmol) of the compound obtained in Example 48(1) and 0.22 g of 4 , 6-dichloropyrimidine, there was obtained 0.16 g (yield: 27 %) of the title compound. FABMS m/z : 796 (M+H) ⁺.

¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.84 ( t , 3H, J=7.4Hz, 14-CH₃), 2.26(s, 6H, 3'-N(CH₃)₂), 2.61(s, 3H, 6-OCH₃), 5.30 (brs, IH, N-H), 6.45 (brs, IH, Ar-H), 8.32 (s, IH, Ar-H) . ¹³C-NMR(75MHz, CDCl ₃) δ (ppm) :40.2 (3 ' -N(CH ₃) ₂) , 49.9(6-OCH ₃) , 104.0(C-1'), 157.4 (carbamate) , 170.2(C-1), 203.4(C-3), 216.5(C-9).

Example 60

11-Γ4-ΓN-Γ6-(2-Chloro) purinyl 1 amino1 butyl 1 - amino-3. ll-dideoxy-5-0-desosaminyl-3-oxo-6-0- methylervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example 48(2) using 0.59 g (0.86 mmol) of the compound obtained in Example 48(1) and 0.34 g of 2 , 6-dichloropurine, there was obtained 0.31 g (yield: 43 %) of the title compound. SIMS m/z: 836 (M+H) ⁺. ' H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.3Hz, I4-CH₃), 2.27(s, 6H, 3'-N(CH₃)₂), 2.62(s, 3H, 6-OCH₃), 6.59 (brs, IH, N-H). ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.2 (3 ' -N(CH ₃ ) ₂ ) , 49.9 (6-OCH ₃) , 104.0(C-1'), 157.3 (carbamate) , 169.6(C-1), 203.8(C-3), 216.2(C-9).

Example 61 11- T4- rN- 2 - (4, 6-Dimethoxy) -1,3,5- triazinyl! aminolbutyl! amino-3 , ll-dideoxy-5-O- desosaminyl-3-oxo-6-Q-methylerythronolide A 11,12-cvclic carbamate

Following the same procedure as in Example 48(2) using 0.27 g (0.39 mmol) of the compound obtained in

Example 48(1) and 0.14 g of 2-chloro-4 , 6-dimethoxy-l , 3 , 5- triazine, there was obtained 0.15 g (yield: 46 %) of the title compound. FABMS m/z : 823 (M+H) ⁺. ¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm) : 0.85 ( t , 3H, J=7.4Hz, I4-CH₃), 2.26(ε, 6H, 3'-N(CH₃)₂), 2.63(s, 3H, 6-OCH₃), 3.93(s, 3H, Ar-OCH ₃ ) , 3.96(s, 3H, Ar-OCH ₃ ) , 5.65-5.73 ( , IH, N-H) . ¹³C-NMR (75MHz, CDCl ₃) δ (ppm) : 40.3 (3 ' -N (CH ₃ ) _ ) , 49.9(6-OCH ₃) , 104.0 (C-l'), 157.3 (carbamate) , 169.7(C-1), 203.7(C-3), 216.3(C-9).

Example 62

11- T4- TN- (2-Pyrimidyl) aminolbutyl! amino-11- deoxy-3-O- \ (3-pyridylmethyl) amino1 carbonyl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cyclic carbamate

(1) To a solution of 1.6 g (2.4 mmol) of the compound obtained in Example 13 (1) in 10 ml of pyridine was added dropwise a solution of 0.74 g (2.5 mmol) of triphosgene in 10 ml of methylene chloride under ice- cooling, followed by stirring for 30 minutes. 1.25 ml (12.3 mmol) of 3- (aminomethyl) pyridine was added to the mixture, followed by stirring for 1.5 hours. After completion of the reaction, an ordinary working-up gave 1.3 g of the 3-0- [ (3-pyridylmethyl) amino] carbonyl compound. (2) Carrying out the same reactions as in Examples 13(3), 13(4) and 23 successively using 1.3 g (1.6 mmol) of the compound obtained in the above (1) , there was obtained 44 mg of the title compound. FABMS m/z: 898 (M+H)⁺

Example 63

11- T4- TN- (2-Pyrimidyl) aminolbutyl! amino-11- deoxy-3-O- (3-pyridyloxy) carbonyl-5-O-desosaminyl-6-0- methylervthronolide A 11,12-cvclic carbamate

(1) To a solution of 1.6 g (2.4 mmol) of the compound obtained in Example 13(1) in 10 ml of pyridine was added dropwise a solution of 0.74 g (2.5 mmol) of triphosgene in 10 ml of methylene chloride under ice- cooling, followed by stirring for 30 minutes. 1.18 g (12.4 mmol) of 3 -hydroxypyridine was added to the mixture, followed by stirring for 1.5 hours. After completion of the reaction, an ordinary working-up gave 0.91 g of the 3- 0- (3-pyridyloxy) carbonyl compound.

(2) Carrying out the same reactions as in Examples 13(3), 13(4) and 23 successively using 3.0 g (3.9 mmol) of the compound obtained in the above (1) , there was obtained 44 mg of the title compound. FABMS m/z: 885 (M+H)⁺

Test Example

The in vitro antibacterial activity of the compound obtained in Example 1 as an example of the compound of the present invention against various experimental bacteria was measured using sensitive disc media (produced by Eiken Chemical Co.) according to the MIC measuring method specified by the Japan Society of Chemotherapy. The results are expressed as MIC value (Minimum Inhibitory Concentration, μg/ml) , and shown in Table 1.

[Table 1] In Vitro Antibacterial Activity: MIC (μg/ml)

INDUSTRIAL APPLICABILITY

The compounds of the present invention have a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin- resistant bacteria. Therefore, the compounds of the present invention are useful as antibacterial agents for the treatment of bacterially infectious diseases in human beings and animals (including farm animals) .

Claims

1. An erythromycin A derivative represented by the formula:

wherein n is an integer of 1 to 7 ,

R! is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms ,

R^ is a quinolyl group, a pyrazinyl group, a benzimidazolyl group, a thiazolyl group, a pyridyl group, a pyridyl group substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ,- an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group; a pyrrolyl group and a halogen atom, a pyrimidyl group, a pyrimidyl group substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group; a dimethylamino group; an acetylamino group ; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group and a halogen atom, a purinyl group, a purinyl group substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms ; a nitro group; an amino group, a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group and a halogen atom, a triazinlyl group, a triazinlyl group substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group, a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group; a pyridyl group; a carbamoyl group and a halogen atom, a phenyl group, a phenyl group substituted by 1 to 5 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 6 carbon atoms ; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group and a halogen atom, a naphthyl group, or a naphthyl group substituted by 1 to 5 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a nitro group; an amino group; a dimethylamino group; an acetylamino group; a cyano group; a trifluoromethyl group and a halogen atom, R3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cinnamyl group,

R^ is a hydrogen atom, or R^ and R^ together form an oxo group, R5 is a group represented by the formula: -OCO-CH -R⁸ a group represented by the formula: -OCO-R⁸ a group represented by the formula: -OCO-NH-R⁸ a group represented by the formula: -O-R⁸ or a group represented by the formula: -OCO-O-R⁸ wherein R⁸ is a pyridylmethyl group, a quinolyl group, a phenyl group, a phenyl group substituted by 1 to 5 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 6 carbon atoms and a halogen atom, a pyridyl group, or a pyridyl group substituted by 1 or 2 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 6 carbon atoms and a halogen atom, and R^ and R⁷ are each a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising an effective amount of the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1.

3. An antibacterial preparation comprising the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1 as an effective component.

4. A method for the treatment of a bacterially infectious disease which comprises administering a pharmaceutically effective amount of the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1 to a patient.

5. Use of the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1 for the treatment of a bacterially infectious disease .