JPH05117291A - New macrolide derivative - Google Patents

Abstract

PURPOSE: To obtain a new compd. having excellent antifungal activity and useful as an antifungal agent.

CONSTITUTION: This compd. is expressed by formula I, wherein R¹ is amino, a mono or di-lower alkylamino; R², R³ are each H or bonded to form carbonyl. The compd. is for example, 16[(6-deoxy2,3-dio-methylβ-Dallo-hexopyranocyl) oxy]4[(2,6dideoxy-3C-methyl-d-L-ribohexopyranocyl)oxy]14-ethyl9-hydroxy12-(isovaleryloxy)3,5,7,9, 11,13,15heptamethyl-6[(3,4,6trideoxy-3(methylamino)-βD- ribohexopyranocyl)oxy]1-oxacyclotetradecane2,10-dione. The compd. is obtd., for example, by allowing an amine expressed by R⁴NH₂ (R⁴ is H, etc.), such as methyl amine hydrochloride to react with a new YL-02107Q substance expressed by formula II produced by Kibdelosporangium bacteria, and then reducing the obtd. substance.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a macrolide derivative or a salt thereof which is useful as a medicine, especially as an antibacterial agent.

[0002]

2. Description of the Related Art Conventionally, among various macrolide compounds produced by microorganisms, those belonging to a basic macrolide and those belonging to a neutral macrolide are known in a narrow sense. Among these, those belonging to basic macrolides belong to 12-membered ring macrolides such as metymycin and neomethymycin, and belong to 14-membered ring macrolides such as erythromycin, oleandomycin, picromycin and megaromycin. Thing, josamycin, leucomycin, spiramycin, carbomycin, tylosin, angoramycin, mycinamicin, rosamicin,
Those belonging to a 16-membered ring macrolide such as juvenimicin are known. Neutral macrolides include those belonging to 14-membered ring macrolides such as lancamycin and cudymycin, and 16 such as charcomycin and aldagamycin.
Those belonging to the membered ring macrolide are known.

The present inventors previously collected a new 14-membered ring macrolide compound, YL-02107Q substance, from a culture solution of a microorganism belonging to the genus Gibbederosporangium. It was clarified to have activity (Japanese Patent Application No. 143804 / 2-143804).

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The inventors have found that a series of novel macrolide derivatives obtained by chemically modifying the L-02107Q substance have excellent antibacterial activity and completed the present invention.

[0005]

Means for Solving the Problems That is, the present inventor is a novel macrolide derivative represented by the following general formula (I) or a salt thereof.

[0006]

[Chemical 2]

(Wherein R ¹ is an amino group or a mono- or di-lower alkylamino group, R ² or R ³ is a hydrogen atom respectively, or R ² and R ³ together form a carbonyl group. means.)

The compound of the above general formula (I) will be further described as follows. In the definition of the general formula of the present invention, the "lower alkylamino group" has 1 to 6 carbon atoms.
Means an amino group substituted by a straight-chain or branched alkyl group.

The typical ones are as follows.
Methylamino group, ethylamino group, propylamino group,
Isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, pentyl (amyl) amino group, dimethylamino group, diethylamino group.

The compound (I) of the present invention forms a salt with an acid.
As salts, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
Mineral acids such as nitric acid and phosphoric acid, formic acid, acetic acid, propionic acid,
Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid be able to.

Since the compound (I) has an asymmetric carbon, it has optical isomers. The target compound of the present invention includes a mixture of these isomers and an isolated one.

(Production Method) The compound of the present invention can be produced by applying the following synthetic method. First manufacturing method

[0013]

[Chemical 3]

(In the formula, R ² or R ³ is as defined above, and R ⁴ is a hydrogen atom or a lower alkyl group.)

In this production method, first, the amine (III) is reacted with the macrolide compound (II) to introduce the carbonyl group of the sugar at the 5-position of the macrolactone ring into a Schiff base, and then this group is reduced to respond. An aminated macrolide (IV) having an amino group is obtained.

In the reaction leading to the Schiff base, the compound (II) and the corresponding amount of the compound (III) are reacted in an inert solvent at room temperature or under heating.

Examples of the inert solvent include methanol,
Examples include ethanol, tetrahydrofuran, benzene, chloroform, toluene, xylene and the like.

Next, the reduction of the Schiff base is carried out by using a reducing agent as a reducing agent.
For example, it is carried out using a catalytic reduction using a metal hydride such as sodium cyanoborohydride or sodium borohydride, or Pd / c.

The aminated macrolide thus obtained is usually a mixture of two diastereomers. The above reductive amination can also be carried out simultaneously. Second manufacturing method

[0020]

[Chemical 4]

(In the formula, R ² , R ^{3 and} R ⁴ have the above-mentioned meanings.) This production method is a reductive N-alkylation of an aminated macrolide. In this production method, the reaction operation differs depending on whether R ⁴ is a hydrogen atom or a lower alkyl group.

When R ⁴ is a hydrogen atom, the compound (I
V) and corresponding amount or excess amount of aldehyde compound (V)
Can be used in the same manner as in the first production method.

When R ⁴ is a lower alkyl group, compound (IV) is added in an equimolar amount of aldehyde compound (V).
And an acid formic acid treatment in an inert solvent to form a compound (VI) having an oxazolidine ring, which is then reduced in the same manner as in the first production method to give a dialkylated macrolide (VI).
I) can be obtained. Third method

[0024]

[Chemical 5]

(In the formula, R ¹ has the above-mentioned meaning, and n is 2
3 to 3 are shown. ) This production method is applied to R ² and R ³ in the compound (I) of the present invention.
Is a method for producing a target compound which means a carbonyl group in combination.

In this method, the adjacent hydroxyl groups in the sugar moiety bonded to the 3-position of the macrolactone ring are cyclic carbonated to produce a macrolide compound represented by the general formula (IX). It can be carried out by reacting the compound (VIII) with an amount of the alkylene carbonate (X) corresponding to the reaction in an inert solvent at room temperature or under heating.

The following reaction accelerators are preferably added to accelerate this reaction.

For example, potassium carbonate, potassium butoxide, potassium hydroxide, sodium carbonate, sodium hydroxide, sodium hydride, sodium metal, sodium methoxide, lithium carbonate, pyridine, triethylamine, triethanolamine, anhydrous potassium carbonate, potassium cyanide, cyanide. Examples thereof include potassium acid salt, potassium thiocyanate, potassium chloride, potassium bromide, potassium iodide, sodium thiocyanate and sodium iodide.

The compound of the present invention thus produced is isolated as a free salt or a salt thereof and purified.

Isolation and purification include extraction, concentration, evaporation, crystallization,
It is carried out by applying ordinary chemical operations such as filtration, recrystallization and various kinds of chromatography.

[0031]

INDUSTRIAL APPLICABILITY The present invention has a strong activity against various bacteria. Therefore, it is useful as an antibacterial agent. General formula (I)
The compound represented by or a salt thereof is administered orally or parenterally. The preparation for oral administration may be any of tablets, pills, capsules, granules or liquids. As a preparation for parenteral administration, injections such as intravenous injection and intramuscular injection, suppositories, and transdermal agents are used. The carrier or excipient for the preparation may be solid or liquid, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter or ethylene glycol, and others. The usual ones are mentioned. The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the administration subject, and sex.

The compound of the present invention and the method for producing the same have been described above, but the present invention will be described in more detail with reference to the following examples. In addition, the raw material compound (YL-021
07Q substance) is a novel compound, and its production method is shown in Reference Example.

Glucose 2.0%, potato starch 2.
A medium (pH 7.0) containing 0%, yeast extract 0.5%, polypeptone 0.5%, and calcium carbonate 0.4% was prepared, and each 60 ml was dispensed into a 500 ml Erlenmeyer flask, and 120 ° C. Sterilized for 20 minutes with seed culture medium, and inoculate it by scraping the mycelium of Kibderlosporangium S.P.YL-02107Q strain (Microtechnology Research Institute, No. 11467) grown well on Venetian agar. Then
Shaking culture was performed at 28 ° C. for 48 hours to prepare a seed culture solution, and a two-stage culture method was performed. The first stage and the second stage were each cultivated for 2 days, and 400 ml of the seed culture was finally obtained.

Next, in the main culture, a medium (pH 7) containing glucose 1.0%, potato starch 2.0%, soybin meal 0.5%, feather meal 0.5% and calcium carbonate 0.4% in a 30 l culture tank. 0.0) 18 l is prepared and sterilized in advance at 120 ° C. for 30 minutes. Bacillus of the target compound YL-02107Q substance was obtained by inoculating the whole amount of 400 ml of the seed culture solution that had been cultivated earlier, and culturing at an aeration rate of 30 l / min at 200 rpm for 3 days.
The antibacterial activity against the Subtilis ATCC6633 strain was maximized.

Radiolite # 600 (manufactured by Showa Chemical Industry Co., Ltd.) was added to the thus obtained culture solution, and the mixture was stirred and then filtered. The obtained culture filtrate (pH 8.2) was adjusted to pH 7.0 with hydrochloric acid, and then 1 l of Diaion HP-2 was added.
0 was passed through a column packed in a glass tube having an outer diameter of 8 cm and a height of 30 cm to adsorb the target compound. Then 10
After thoroughly rinsing with 1 liter of distilled water, add 25% acetone water to 1
The mixture was washed with 5 liters of water, and finally 15 liters of 70% aqueous acetone was used to elute the target compound.

The eluate was concentrated under reduced pressure to 200 ml to obtain an extract of the target YL-02107Q substance. Next, adjust the pH of this extract to 7.0, add 500 ml of ethyl acetate, shake well and extract with ethyl acetate,
The layers were separated and the aqueous layer was removed. Glauber's salt was added to the thus-obtained extract, and after being well dehydrated, Glauber's salt was removed by filtration and concentrated under reduced pressure to obtain 4.03 g of a crude candy-like extract of YL-02107Q substance.

To further purify the crude extract, 20
Dissolve in 3 ml of chloroform and separate 3 cm in outer diameter and 11 in length
550 m filled with chloroform in a 0 cm chromatographic tube
1 column of silica gel (Wakogel C-300, Wako Pure Chemical Industries, Ltd.), chloroform: methanol (1
Elution was performed with the developed eluate of 00: 1). This eluate was collected by fractionation into 20 g of each fraction with a fraction collector.

[0038] using silica gel plates to confirm the desired compound (Kieselgel 60F _254, 20 cm × 20 cm, Merck), chloroform: methanol (90: 1
Chromatography was performed using the solvent of 0),
% Sulfuric acid solution was sprayed and heated at 110 ° C. for 20 minutes to develop a color, and the target compound YL-02107Q substance (Rf = 0.
43) was confirmed.

Since the desired YL-02107Q substance was eluted between the fraction numbers 210 to 300, it was collected, concentrated to dryness under reduced pressure, and dried overnight in a vacuum desiccator to have a purity of 92%. YL-0210
696 mg of white powder of 7Q substance was obtained.

The obtained YL-02107Q having a purity of 92%.
106.4 mg of the substance was dissolved in 1 ml of methanol, divided into 0.2 ml portions, and subjected to high performance liquid chromatography to purely separate the target YL-02107Q substance. Conditions for high performance liquid chromatography are STR-O
2cm x 25c of DS-H (manufactured by Shimadzu Techno Research Co.)
m column, acetonitrile: tetrahydrofuran: methanol: water as eluent (31: 12: 19: 38)
Was used at a flow rate of 8 ml / min and was detected using UV absorption at 220 nm.

As a result, the desired YL-02107Q substance was eluted at a retention time of 20 minutes and 40 seconds, so this fraction was collected. The purity of the YL-02107Q substance contained in this fraction was determined by high performance liquid chromatography STR-ODS-H.
(Preparative-ODS-H) 4.6 mm x
Using a 250 mm column, using the same solvent as the eluent for the fractionation at an elution rate of 0.8 ml per minute,
As a result of detection by UV absorption at 220 nm, retention time was 10
A pure peak of YL-02107Q material was confirmed at 51 minutes 51 minutes.

Pure YL-0210 thus obtained
The total amount of the fractions containing the 7Q substance was 63 ml.
This was concentrated to 20 ml, 50 ml of ethyl acetate was added, and the mixture was shaken well to extract the target substance in the ethyl acetate layer. After extraction, liquid separation was performed to remove the aqueous layer, and sodium sulfate was added to the obtained ethyl acetate extract to thoroughly dehydrate it, and the sodium sulfate was removed by filtration and concentrated to dryness under reduced pressure. For better drying, it was dried in a vacuum dessicator overnight to give 62.5 mg of pure YL-02107Q material.

Next, in order to crystallize this, 0.2 ml
Ethyl acetate was added and dissolved, and 0.6 ml of hexane was gradually added and stirred, and then the mixture was allowed to stand in an ice chamber overnight to precipitate crystals. The crystals thus obtained are filtered,
After drying in a vacuum desiccator overnight, 53 mg of pure crystalline white powder was obtained.

YL-02 extracted, separated and purified as described above
The 107Q substance has the following physicochemical properties.

[0045]

[Chemical 6]

Compound name of YL-02107Q substance 16-[(6-deoxy-2,3-di-O-methyl-β
-D-Allo-hexopyranosyl) oxy] -6-
[(4,6-dideoxy-β-D-erythro-hexopy
Ranose-3-ulose-1-yl) oxy] -4-
[(2,6-Dideoxy-3-C-methyl-α-L-ly
Bo-hexopyranosyl) oxy] -14-ethyl-9-
Hydroxy-12- (isovaleryloxy) -3,5
7,9,11,13,15-heptamethyl-1-oxa
Cyclotetradecane-2,10-dione Melting point: 145.5 ° C. to 147.5 ° C. Specific optical rotation: [α] _D ²⁰= -76.07 (C = 1%,
(In methanol) Molecular weight: 963.164

Mass spectrum: 985 (M + Na)
(FAB) Molecular formula: C ₄₈H₈₂O₁₉

Elemental analysis value: C ₄₈H₈₂O₁₉・ 0.3H₂As O C (%) H (%) N (%) Actual value 59.43 8.49 0.00 Calculated value 59.52 8.60 0.00

Example 1 YL-02107Q substance (1006 mg) was dissolved in methanol (20 ml) and methylamine hydrochloride (1375 m) was added.
g) was added and the mixture was stirred for 3 hours, and sodium cyanoborohydride (400.1 mg) was divided into 5 portions, and the mixture was slowly added over 2 hours. The reaction was stopped by further stirring for 14 hours and adding water adjusted to pH 10 with a 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate.

By distilling off the solvent under reduced pressure and purifying by medium pressure row bar column chromatography, YL-
D-4,6 at 5-position of macrolactone ring of 02107Q substance
-3'-deoxo-α-methylamino derivative of dideoxy-3-ketoalose, 16-[(6-deoxy-
2,3-di-O-methyl-β-D-allo-hexopyranosyl) oxy] -4-[(2,6-dideoxy-3-C
-Methyl-α-L-ribo-hexopyranosyl) oxy]
-14-Ethyl-9-hydroxy-12- (isovaleryloxy) -3,5,7,9,11,13,15-heptamethyl-6-[[3,4,6-trideoxy-3-
(Methylamino) -β-D-ribo-hexopyranosyl]
Oxy] -1-oxacyclotetradecane-2,10-
Dione (417 mg, 43%) and 3'-deoxo-
β-methylamino derivative, 16-[(6-deoxy-2,3
-Di-O-methyl-β-D-allo-hexopyranosyl)
Oxy] -4-[(2,6-dideoxy-3-C-methyl-α-L-ribo-hexopyranosyl) oxy] -14
-Ethyl-9-hydroxy-12- (isovaleryloxy) -3,5,7,9,11,13,15-heptamethyl-6-[[3,4,6-trideoxy-3- (methylamino) -Β-D-Xylo-hexopyranosyl] oxy] -1-oxacyclotetradecane-2,10-dione (500 mg, 51%) was obtained. Table 1 below shows the chemical structure
Shown in.

Physicochemical properties of 3'-deoxo-α-methylamino compound (i) ¹ H NMR (CD ₃ OD): δppm 0.90 (d, 3)
H), 1.01 ~ 1.36 (m), 1.65 (q, 2H), 1.80 ~ 1.88 (m), 2.0
3 to 2.15 (m), 2.21 (d, 2H), 2.26 to 2.30 (m), 2.38 (s, 3
H), 2.85 (t, 1H), 2.29 (d, 1H), 2.96 (d, 1H), 3.01 (q, 1
H), 3.14 (q, 1H), 3.25 ~ 3.34 (m), 3.41 (q, 2H), 3.45
(q, 1H), 3.51 (s, 3H), 3.57 (s, 3H), 3.63 (m, 1H), 3.
76 ~ 3.82 (m), 3.95 ~ 3.98 (m, 1H), 4.09 (d, 1H), 4.55
(d, 1H), 4.64 (d, 1H), 4.88 (d, 1H), 4.90 (d, 1H), 5.
17 (d, 1H)

(Ii) ¹³ C NMR (CD ₃ OD): 10.5 23.6 37.7 46.9 71.7 81.5 102.7 11.2 26.7 38.9 60.0 72.9 81.7 174.0 15.7 27.0 40.4 61.0 73.0 81.9 177.9 15.9 27.6 40.8 62.6 73.2 83.6 216.3 18.7 35.2 42.2 67.6 75.3 86.8 19.2 35.3 45.0 67.8 77.1 100.3 21.9 36.6 46.1 71.4 78.7 102.4

(Iii) FAB-MS: m / z 978
(M⁺+ H), 834, 660, 144

The principle of 3'-deoxo-β-methylamino compound
Chemical properties (i)¹1 H NMR (CD₃OD): δppm 0.91 (d, 3
H), 1.02 ~ 1.32 (m), 1.70 (m), 1.82 (q, 2H), 1.90 ~ 2.17
(m), 2.22 (d, 2H), 2.27 (m), 2.38 (s, 3H), 2.55 (m, 2
H ), 2.84 (t, 1H), 2.98 (d, 1H), 3.01 (q, 1H), 3.10 ~
3.15 (m), 3.27 ~ 3.32 (m), 3.41 (q, 2H), 3.47 (d, 1H),
3.51 (s, 3H), 3.57 (s, 3H), 3.64 (m, 1H), 3.76 ~ 3.82
(m), 3.95 (m, 1H), 4.07 (d, 1H), 4.26 (d, 1H), 4.55
(d, 1H), 4.87 (d, 1H), 4.92 (d, 1H), 5.12 (d, 1H)

( i i )¹³C NMR (CD₃OD): 10.5 21.0 40.2 62.1 73.1 83.6 216.4 11.3 22.0 40.7 62.6 75.3 87.3 11.5 23.6 42.4 67.6 75.7 100.9 15.7 27.9 45.2 70.3 77.1 102.4 16.1 34.9 46.3 71.4 78.4 105.8 18.7 38.6 46.9 71.7 81.9 174.1 19.2 38.9 59.9 73.0 82.0 177.8

(Iii)  FAB-MS: m / z 978
(M⁺+ H), 834, 660, 144

Example 2 The 3'-deoxo-β-methylamino compound (1096 mg) obtained in Example 1 was dissolved in chloroform (10 ml), 37% formalin (2 ml) was added, and the mixture was vigorously stirred for 1 hour. Sodium cyanoborohydride (250 mg) was added to this suspension, and the mixture was further stirred for 1 hr.
Chloroform was added to the reaction solution, washed with saturated saline adjusted to pH 10, and the chloroform layer was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure to give 3'-deoxo-
β-dimethylamino derivative, 16-[(6-deoxy-2,
3, -di-O-methyl-β-D-allo-hexopyranosyl) oxy] -4-[(2,6-dideoxy-3-C-
Methyl-α-L-ribo-hexopyranosyl) oxy]-
14-Ethyl-9-hydroxy-12- (isovaleryloxy) -3,5,7,9,11,13,15-heptamethyl-6-[[3,4,6-trideoxy-3- (dimethylamino) ) -Β-D-Xylo-hexopyranosyl]
Oxy] -1-oxacyclotetradecane-2,10-
Dione (1106 g, 99%) was obtained. The chemical structural formulas are shown in Table 1 below. The physicochemical properties of this product are as follows.

Of the 3'-deoxo-β-dimethylamino form
Physicochemical properties (i)¹1 H NMR (CD₃OD): δppm 0.91 (d, 3H),
1.02 ~ 1.33 (m,), 1.70 (q, 2H), 1.73 (m, 2H), 1.81 (q,
2H), 1.90 (t, 1H), 2.01 ~ 2.17 (m), 2.22 (d, 2H), 2.27
~ 2.35 (m), 2.35 (s, 3H), 2.67 (m, 1H ), 2.86 (m, 1H),
2.97 (d, 1H), 3.01 (q, 1H ), 3.14 (q, 1H), 3.28 ~ 3.32
(m), 3.41 (q, 2H), 3.47 (q, 1H), 3.51 (s, 3H), 3.57
(s, 3H), 3.59 (m), 3.63 (q, 1H), 3.76 ~ 3.77 (m), 3.80
(q, 2H), 3.96 (m, 1H), 4.07 (d, 1H), 4.25 (d, 1H), 4.5
5 (d, 1H), 4.85 ~ 4.88 (m, 1H), 4.92 (d, 1H), 5.12 (d,
1H)

(Ii) ¹³ C NMR (CD ₃ OD): 10.4 21.0 37.7 46.3 71.4 78.4 106.4 11.4 22.1 38.9 46.9 71.7 81.8 174.1 11.5 23.6 40.2 59.9 72.9 82.0 177.8 15.7 26.6 40.6 62.6 73.0 83.6 216.1 16.1 27.0 41.4 66.3 73.1 87.2 18.7 28.0 42.4 67.6 75.3 100.9 19.2 34.9 45.1 70.4 77.1 102.4 FAB-MS: m / z 992 (M ⁺ + H), 158

(Iii)  Specific rotation: [α] _D ²⁰= -59.
79 (C = 1.000, in methanol)

Example 3 3'-deoxo-β-dimethylamino compound (135 m
g), ethylene carbonate (145 mg) and potassium carbonate 50 mg were dissolved in benzene 6 ml, and the mixture was heated under reflux for 24 hours.

After cooling, potassium carbonate was filtered off and the filtrate was concentrated to give a colorless syrup. The obtained syrup is separated and purified by medium pressure row bar chromatography (normal phase) (solvent system chloroform-methanol-ammonia water).
Cyclic Carbonation of Mycarose at the 3-Position of Macrolactone Ring of YL-02107Q Substance 3'-deoxo-β-
Dimethylamino form, 16-[(6-deoxy-2,3-
Di-O-methyl-β-D-allo-hexopyranosyl) oxy] -14-ethyl-9-hydroxy-12- (isovaleryloxy) -3,5,7,9,11,13,15
-Heptamethyl-4-[(2,3,4,6-tetradeoxy-3,4-carbonyldioxy-3-C-methyl-
α-L-ribo-hexopyranosyl) oxy] -6-
[[3,4,6-Trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranosyl] oxy]-
1-oxacyclotetradecane-2,10-dione (1
16 mg) was obtained as a colorless syrup. The chemical structural formulas are shown in Table 1 below. The physicochemical properties of this product are as follows.

(I) ¹ H NMR (CD ₃ OD): δppm
0.904 (d, 3H), 1.02 to 1.28 (m), 1.33 (s, 3H), 1.39 (d,
3H), 1.56 (s, 3H), 1.68 ~ 1.77 (m, 2H), 1.89 ~ 1.94
(m, 1H), 2.08 ~ 2.39 (m), 2.34 (s, 6H), 2.59 ~ 2.64 (m,
1H), 2.83 to 2.90 (m, 1H), 3.01 (q, 1H), 3.14 (q, 1H),
3.24 to 3.32 (m), 3.39 (q, 1H), 3.51 (s, 3H), 3.57 (s,
3H), 3.51 ~ 3.66 (m), 3.76 ~ 3.83 (m), 4.05 (d), 4.04 ~
4.06 (m), 4.12 ~ 4.19 (m, 1H), 4.27 (d, 1H), 4.55 (d, 1
H), 5.08 ~ 5.12 (m), 5.10 (q, 1H)

(Ii) ¹³ C NMR (CD ₃ OD): δppm 10.5 22.2 32.9 41.5 67.8 76.7 86.6 216.1 11.4 23.6 36.8 45.0 70.6 79.5 97.9 15.1 23.7 37.5 45.1 70.8 79.9 102.3 15.9 26.5 38.0 46.0 71.4 81.8 106.2 18.8 26.9 38.4 59.9 72.8 82.5 156.0 19.7 27.1 40.2 62.6 72.9 83.6 173.9 19.9 27.7 40.9 66.3 75.3 85.0 177.9

(Iii)  FAB-MS: 1018 (M⁺+
1), 158

(Iv) [α] _D ²⁰-41.60 (C =
0.500 in methanol)

[0068]

[Table 1]

Front Page Continuation (72) Inventor Akio Koda 4-3-5 North Hibarigaoka, Hoya City, Tokyo (72) Inventor Kiyoshi Washizaki 1-11-30 Fujimi, Ageo City, Saitama Prefecture (72) Inventor Ryan Suhuan People's Republic of China Shi Yang Hai 2000 31 Yu Yang Road 319 Si Yang Hai Institute Of Materia Medica Academia Cinica (72) Inventor Wang Fu Qin China Si Yang Hai 2000 31 Yu Yang Road 319 Si Yang Hai Institute Of Materia Medica Academia Shin Ka In U In U In U People's Republic of Shenhai City 2000 31 Yuyang Road 319 Sheyanghai Institute of Materia Medica Academia Sinica (72) Inventor Liu Cheway Wai People's Republic of China Yangyang Road 2000 31 Yuan Road 319 Sheyanhai Institute In blanking materialized Medeikaa Kademia Sinica

Claims (1)

[Claims] 1. A novel macrolide derivative represented by the following chemical formula 1 or a salt thereof. [Chemical 1] (In the formula, R ¹ represents an amino group or a mono- or di-lower alkylamino group, R ^{2 and} R ³ each represent a hydrogen atom, or R ² and R ³ together represent a carbonyl group. )