JP2000351793A - Erythromycin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new erythromycin compound having an excellent antibacterial activity against Helicobacter pylori, especially Helicobacter pylori showing resistance to other medicines, and also useful as an antiulcer agent. SOLUTION: This erythromycin derivative is expressed by formula I [wherein R1 is H or a lower alkyl; R2 is a (substituted) alkyl, a (substituted) heterocycle or the like; and R3 a (substituted) alkyl, a (substituted) cycloalkyl or the like] or its salt and is e.g. 5-O-desosaminyl-3-O-phenylacetylerythronolide A 9-[O-(1- methoxycyclohexyl)oxime], etc. The compound of formula I is obtained by reacting a compound of formula II (wherein R6 is H or a protecting group for OH group) with a carboxylic acid derivative expressed by the formula: R7-CO2H [wherein R7 is a (substituted) alkyl, a (substituted) heterocycle or the like] and a condensing agent in the presence of or in the absence of a base without or in a solvent and, if necessary, by performing deprotection.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a compound useful as a medicament, in particular, an antibacterial or antiulcer agent, and more particularly to a novel erythromycin derivative or a salt thereof effective against Helicobacter pylori. .

[0002]

BACKGROUND OF THE INVENTION In 1983, Helicobacter pylori was isolated from human gastric mucosa, and the relationship between Helicobacter pylori and gastric and duodenal ulcers was pointed out. In subsequent studies, Helicobacter pylori was considered to be one of the leading causes of ulcers, and is now known as Helicobacter pylori.
Ulcer treatment by so-called chemotherapy, which removes H. pylori with an antibacterial agent, has been performed. Many reports have revealed that this chemotherapy has an excellent therapeutic effect. As a compound having a drug effect similar to that of the present invention, clarithromycin [The Merck Index, 12th edition, 2400] is known, and a clinical test on Helicobacter pylori has been attempted. ing. Also, as a macrolide compound having a chemical structure similar to that of the compound of the present invention, a 9-position oxime type compound, roxithromycin (T)
he Merck Index, 12th edition, 8433) and WO93
/ 13116 and the like, a 3-position ester type compound is disclosed in WO9
No. 3/13115 discloses a 3-position carbamate type compound.

[0003]

Although chemotherapy is an excellent treatment for treating infectious diseases, one of the serious problems in chemotherapy is the emergence of resistant bacteria. For example, methicillin-resistant Staphylococcus aureus (Methicil
The emergence or increase of multidrug-resistant bacteria represented by lin-resistant Staphylococcus aureus) has made treatment with conventional chemotherapy difficult. In recent years, even with chemotherapeutic agents that have been tried in the field of ulcer treatment, the emergence of multidrug-resistant bacteria Helicobacter pylori has already been known. An object of the present invention is to provide a compound which has excellent antibacterial activity against Helicobacter pylori, particularly against Helicobacter pylori which is resistant to other drugs, and is useful as an anti-ulcer agent.

[0004]

The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have found that the novel erythromycin derivative or its salt according to the present invention is useful as an antibacterial agent. -It has been found that the compound has excellent antibacterial activity against H. pylori and is useful as an anti-ulcer agent, and has completed the present invention.

That is, the present invention provides the following general formula (I)

Embedded image(Where R¹Represents a hydrogen atom or a lower alkyl group;^Two
Is an alkyl group which may have a substituent,
Good homo or heterocyclic group, optionally substituted homo
Or a heterocyclic group-substituted alkyl group or a substituent
Styryl group or the formula -XR^FourRepresents a group represented by^Three
Is a substituted alkyl group (carboxyl group,
Having an alkoxycarbonyl group which may have a substituent
Aryloxycarbonyl groups, with substituents
Aralkyloxycarbonyl group or benzyl
Having a substituent selected from amino groups), having a substituent
Optionally substituted cycloalkyl group, optionally substituted saturated
Having a homo- or saturated heterocyclic group-substituted alkyl group or substituent
An alkenyl group or a compound of the formula-(CH_Two)_n-Y-R ^Five
Represents a group represented by^FourIs an optionally substituted al
Represents an aryl group which may have a kill group or a substituent;
^FiveRepresents an aryl group which may have a substituent, and X represents oxygen
Represents an atom or a group represented by the formula -NH-, wherein Y represents a substituent
Methylene group, oxygen atom, sulfur atom, sulf
Ynyl group, sulfonyl group, carbonyl group or formula -NZ-
And Z represents a hydrogen atom or a substituent
And n represents an integer of 1 to 5. )
Novel erythromycin derivative or salt thereof represented by
It is about.

According to a second aspect of the present invention, there is provided an erythromycin derivative or a salt thereof, wherein R ² is a benzyl group which may have a substituent in the compound represented by the general formula (I). .

According to a third aspect of the present invention, in the compound represented by the general formula (I), R ⁵ is a phenyl group which may have a substituent, Pyridyl group,
An erythromycin derivative or a salt thereof, which is a 3-pyridyl group which may have a substituent or a 2-pyridyl group which may have a substituent, is provided.

According to still another aspect of the present invention, there is provided a medicament comprising a compound represented by the above general formula (I) or a salt thereof as an active ingredient. The medicament provided by the present invention can be suitably used, for example, as an antibacterial agent or an anti-ulcer agent.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (I) of the present invention, the lower alkyl group represented by R ¹ includes, for example,
Examples include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group. The alkyl group of the alkyl group which may have a substituent represented by R ² , R ⁴ or Z and the alkyl group having a substituent represented by R ³ are linear or linear having 1 to 12 carbon atoms. Represents a branched alkyl group, such as a methyl group,
Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-
Pentyl group, isopentyl group, neopentyl group, tert-
Examples include a pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, and n-dodecyl group.

In the general formula (I) of the present invention, R ²
The homo- or heterocyclic group of the optionally substituted homo- or heterocyclic group represents a monocyclic or polycyclic saturated or unsaturated homo or heterocyclic group, for example, cyclopropyl Group, cyclobutyl group, cyclopentyl group, cyclohexyl group, bicyclo [3.2.1] octyl group, bicyclo [5.2.0] nonyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, phenyl group, naphthyl group ( 1-naphthyl group, 2-naphthyl group), pyridyl group (2-pyridyl group, 3-pyridyl group, 4-pyridyl group), pyrimidyl group, pyrazinyl group, imidazolyl group,
Furyl, thienyl, pyrrolyl, benzofuranyl, benzo [b] thienyl, benzimidazolyl,
Indolyl, quinolyl, isoquinolyl, 1,2,
3,4-tetrahydronaphthalen-5-yl group, 1,
Examples include a 2,3,4-tetrahydronaphthalen-6-yl group. In the present specification, as the substitution site of the “homologous or heterocyclic group”, “aryl group” and “saturated heterocyclic group”, as partially exemplified above, unless otherwise specified, the ring structure is not limited. It is used as a concept that includes a group that can be substituted at any position as long as it is a substitutable element in the component.
The homo- or heterocyclic-substituted alkyl group which may have a substituent represented by R ² is a straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms. Alkyl group, monocyclic or polycyclic saturated or unsaturated homo or heterocyclic group represents a group substituted at any position, for example,
Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, cyclohexylhexyl Group, cyclohexylheptyl group, cyclohexyloctyl group, cyclohexylnonyl group, cyclohexyldecyl group, cyclohexylundecyl group, cyclohexyldecyl group, tetrahydropyranylmethyl group, tetrahydrothiopyranylmethyl group, benzyl group, phenethyl group, phenylpropyl group, Phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyl , Phenyl decyl group, undecyl group, phenyldodecyl group, naphthylmethyl group,
Pyridylmethyl group, pyrimidylmethyl group, pyrazinylmethyl group, imidazolylmethyl group, furylmethyl group, thenyl group, pyrrolylmethyl group, benzofuranylmethyl group, benzo [b] thienylmethyl group, benzimidazolylmethyl group, indolylmethyl group, quinolylmethyl group, And an isoquinolylmethyl group.

In the general formula (I) of the present invention, R ³
Examples of the alkoxycarbonyl group substituted with the alkyl group represented by are methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl Group, tert-
Butoxycarbonyl group, n-pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, n-hexyloxycarbonyl group, n-heptyloxycarbonyl group, n-octyloxycarbonyl group , N-nonyloxycarbonyl group, n-decyloxycarbonyl group,
n-undecyloxycarbonyl group, n-dodecyloxycarbonyl group and the like. Examples of the aryloxycarbonyl group substituted with the alkyl group represented by R ³ include, for example, a phenoxycarbonyl group, a pyridyloxycarbonyl group, and a pyrimidyl group. Oxycarbonyl group, pyrazinyloxycarbonyl group, imidazolyloxycarbonyl group, naphthyloxycarbonyl group, furyloxycarbonyl group, benzofuranyloxycarbonyl group, benzo [b]
Thienyloxycarbonyl, benzimidazolyloxycarbonyl, indolyloxycarbonyl, thienyloxycarbonyl, pyrrolyloxycarbonyl, quinolyloxycarbonyl, isoquinolyloxycarbonyl, (1,2,3,4-tetrahydro Naphthalen-5-yl) oxycarbonyl group, (1,2,3,
4-tetrahydronaphthalen-6-yl) oxycarbonyl group and the like. Examples of the aralkyloxycarbonyl group that substitutes for the alkyl group represented by R ³ include:
Benzyloxycarbonyl, pyridylmethyloxycarbonyl, pyrimidylmethyloxycarbonyl, pyrazinylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, naphthylmethyloxycarbonyl, furylmethyloxycarbonyl, benzofuranylmethyloxy Carbonyl group, benzo [b] thienylmethyloxycarbonyl group, benzimidazolylmethyloxycarbonyl group, indolylmethyloxycarbonyl group, thienylmethyloxycarbonyl group, pyrrolylmethyloxycarbonyl group, quinolylmethyloxycarbonyl group, isoquinolylmethyl An oxycarbonyl group, (1,
2,3,4-tetrahydronaphthalen-5-yl) methyloxycarbonyl group, (1,2,3,4-tetrahydronaphthalen-6-yl) methyloxycarbonyl group,
Phenethyloxycarbonyl, phenylhexyloxycarbonyl, phenyldodecyloxycarbonyl and the like.

In the general formula (I) of the present invention, R ³
The cycloalkyl group of the cycloalkyl group optionally having a substituent represents a cycloalkyl group having 3 to 6 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group,
Cyclopentyl group, a cyclohexyl group, R ³
The saturated homo- or saturated heterocyclic group-substituted alkyl group which may have a substituent represented by a saturated homo- or saturated heterocyclic group-substituted alkyl group is a straight-chain or branched chain having 1 to 12 carbon atoms. Represents a group obtained by substituting a saturated allo- or saturated heterocyclic group at an arbitrary position in an alkyl group such as cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopropylethyl group, Cyclobutylethyl group, cyclopentylethyl group, cyclohexylethyl group, cyclohexylpropyl group, cyclohexylbutyl group, cyclohexylpentyl group, cyclohexylhexyl group, cyclohexylheptyl group, cyclohexyloctyl group, cyclohexylnonyl group, cyclohexyldecyl group, cyclohexylundecyl group, Cyclohe Shirudodeshiru group, (azetidin -1
-Yl) ethyl group, (pyrrolidin-1-yl) ethyl group, (piperidin-1-yl) ethyl group, (homopiperidin-1-yl) ethyl group, (piperazin-1-yl)
Ethyl group, (morpholin-4-yl) ethyl group, (thiomorpholin-4-yl) ethyl group, (pyrrolidin-1-
Yl) propyl group, (pyrrolidin-1-yl) butyl group, (pyrrolidin-1-yl) pentyl group, (pyrrolidin-1-yl) hexyl group, (pyrrolidin-1-yl)
Heptyl group, (pyrrolidin-1-yl) octyl group,
(Pyrrolidin-1-yl) nonyl group, (pyrrolidin-1
-Yl) decyl group, (pyrrolidin-1-yl) undecyl group, (pyrrolidin-1-yl) dodecyl group and the like. The alkenyl group of the alkenyl group which may have a substituent represented by R ³ represents a linear or branched alkenyl group having 3 to 7 carbon atoms, for example, an allyl group, a butenyl group, a pentenyl group. , A hexenyl group, a heptenyl group, an isopropenyl group and the like.

In the general formula (I) of the present invention, R ⁴
Or the aryl group of the optionally substituted aryl group represented by R ⁵ represents a monocyclic or polycyclic aromatic ring group, for example, a phenyl group, a naphthyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, Imidazolyl group, furyl group, thienyl group, pyrrolyl group, benzofuranyl group, benzo [b] thienyl group, benzimidazolyl group, indolyl group, quinolyl group, isoquinolyl group, 1,2,3,4-tetrahydronaphthalen-5-yl group, Examples thereof include a 1,2,3,4-tetrahydronaphthalen-6-yl group.

In the general formula (I) of the present invention, when a functional group is "may have a substituent", any functional group may be used as long as it can be substituted on these groups. The number and type of the substituents are not particularly limited, and when two or more substituents are present, they may be the same or different. For example, a hydroxyl group optionally having a protecting group, an alkoxy group, an alkylthio group, an amino group optionally having a substituent, a carbamoyl group optionally having a substituent,
Halogen atom, alkyl group, trifluoromethyl group, acyl group, cycloalkyl group, aryl group, aryloxy group, arylthio group, cyano group, nitro group, guanidino group, amidino group, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl And aralkyloxycarbonyl groups. Any hydroxyl-protecting group may be used as long as it is substantially inert in a system in which the hydroxyl group should not participate in the reaction and can be easily cleaved under the conditions of the specific deprotection reaction. Examples thereof include an acyl group, a trialkylsilyl group, and a benzyl group. Examples of the acyl group that is a protecting group for a hydroxyl group include formyl group, acetyl group, propionyl group, butyryl group, and pivaloyl group. Examples of the trialkylsilyl group that is a protecting group for a hydroxyl group include trimethylsilyl group and triethylsilyl. And the like. The alkoxy group represents a linear or branched alkoxy group, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy. Group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, n-hexyloxy group, n-
Examples include a heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decyloxy group, n-undecyloxy group, and n-dodecyloxy group. The alkylthio group represents a linear or branched alkylthio group, for example, a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-
Butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, tert-
Pentylthio, n-hexylthio, n-heptylthio, n-octylthio, n-nonylthio, n-decylthio, n-undecylthio, n-dodecylthio and the like. Examples of the amino group which may have a substituent include, for example, amino group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino Group, tert
-Butylamino group, n-pentylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, n-hexylamino group, dimethylamino group, diethylamino group, acetylamino group, propionylamino group and the like. And a carbamoyl group which may have a substituent include, for example, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, Nn-propylcarbamoyl group, N-isopropylcarbamoyl group,
n-butylcarbamoyl group, N-isobutylcarbamoyl group, N-sec-butylcarbamoyl group, N-tert-butylcarbamoyl group, Nn-pentylcarbamoyl group, N-
Isopentylcarbamoyl group, N-neopentylcarbamoyl group, N-tert-pentylcarbamoyl group, Nn-
Hexylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and examples of the aryloxy group include a phenoxy group, a pyridyloxy group, a pyrimidyloxy group, a pyrazinyloxy group, an imidazolyloxy group, and a naphthyloxy group. , Furyloxy, benzofuranyloxy, benzo [b] thienyloxy, benzimidazolyloxy, indolyloxy, thienyloxy, pyrrolyloxy, quinolyloxy, isoquinolyloxy, (1,2,3 , 4-
Tetrahydronaphthalen-5-yl) oxy group, (1,
2,3,4-tetrahydronaphthalen-6-yl) oxy group and the like. As the arylthio group, for example,
Phenylthio, pyridylthio, pyrimidylthio,
Pyrazinylthio, imidazolylthio, naphthylthio, furylthio, benzofuranylthio, benzo [b] thienylthio, benzimidazolylthio, indolylthio, thienylthio, pyrrolylthio, quinolylthio, isoquinolylthio, (1,2, 3,4
-Tetrahydronaphthalen-5-yl) thio group, (1,
2,3,4-tetrahydronaphthalen-6-yl) thio group and the like. Also, the above-mentioned substitutable alkyl group,
Examples of the acyl group, cycloalkyl group, aryl group, alkoxycarbonyl group, aryloxycarbonyl group, and aralkyloxycarbonyl group include the groups exemplified above.

The compound represented by the above general formula (I) of the present invention has an asymmetric carbon and may exist in stereoisomers such as optically active isomers, diastereoisomers, and geometric isomers. And mixtures thereof and salts thereof are also included in the scope of the present invention.

The compound represented by the above general formula (I) of the present invention can be converted into a salt, preferably a pharmacologically acceptable salt, if desired. It can also be converted. Examples of the salt of the compound represented by the general formula (I) of the present invention include an acid addition salt and an alkali addition salt. Examples of the acid addition salt include:
Minerals such as hydrochloride, hydrobromide, nitrate, sulfate, hydroiodide, phosphate, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, Tartrate, citrate, stearate, succinate, lactobionate, gluconate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate, lauryl sulfate, gluceptate, malate, aspartate, glutamate, adipate, oxalate, nicotinate, picrate, thiocyanate, undecanoate, Mandelate, fumarate, 10-camphorsulfonate, lactate, 5-oxotetrahydrofuran-2-carboxylate, 2-hydroxyglutarate and the like As the acid salt, the alkali addition salt includes, for example, inorganic alkali salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, and organic bases such as ethanolamine salt and N, N-dialkylethanolamine salt. Salts.

The compound represented by the above general formula (I) or a salt thereof according to the present invention can be converted into an arbitrary crystal form depending on production conditions.
In addition, any hydrate or solvate of an organic solvent can exist, and these crystal forms, hydrates, solvates and mixtures thereof are also included in the scope of the present invention.

Preferred compounds of the present invention include the compounds described below, but the present invention is not limited thereto. Me shown in the table is a methyl group,
Et is ethyl group, n-Pr is n-propyl group, n-Bu is n-butyl group, n-Pent is n-pentyl group, n-Hex is n-hexyl group, nH
ept is n-heptyl group, n-Oct is n-octyl group, n-Non is n-
Nonyl group, n-Dec is n-decyl group, n-Undec is n-undecyl group, n-Dodec is n-dodecyl group, and Ac is acetyl group.

[0019]

Embedded image

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

[0025]

[Table 6]

[0026]

[Table 7]

[0027]

[Table 8]

[0028]

[Table 9]

[0029]

[Table 10]

[0030]

[Table 11]

[0031]

[Table 12]

[0032]

[Table 13]

[0033]

[Table 14]

[0034]

[Table 15]

[0035]

[Table 16]

[0036]

[Table 17]

[0037]

[Table 18]

[0038]

[Table 19]

[0039]

[Table 20]

[0040]

[Table 21]

[0041]

[Table 22]

[0042]

[Table 23]

[0043]

[Table 24]

[0044]

[Table 25]

[0045]

[Table 26]

[0046]

[Table 27]

[0047]

[Table 28]

[0048]

[Table 29]

[0049]

[Table 30]

[0050]

[Table 31]

The novel erythromycin derivative represented by the general formula (I) of the present invention can be produced, for example, by the following method, but the production method of the compound of the present invention is not limited to these methods. .

According to the first mode of the method for producing the compound of the present invention, the compound represented by the general formula (I) is represented by the following general formula (II)

Embedded image (Wherein, R ¹ and R ³ have the same meanings as described above, and R ⁶ represents a hydrogen atom or a hydroxyl-protecting group), and a compound represented by the following general formula (III): R ⁷ —CO ₂ H (III) (wherein, R ⁷ is an alkyl group which may have a substituent, a homo- or heterocyclic group which may have a substituent, a homo- or heterocyclic group which may have a substituent A carboxylic acid derivative represented by a substituted alkyl group or a styryl group which may have a substituent) and a condensing agent, in the presence or absence of a base, in the absence of a solvent or in a solvent. Or the following general formula (IV): R ⁷ —CO ₂ U (IV) (wherein R ⁷ has the same meaning as described above, and U is an acid anhydride residue) Or an acid anhydride represented by the following general formula (V): R ⁸ -COW (V) (wherein R ⁸ may have a substituent. Alkyl groups, homo- or heterocyclic groups which may have a substituent, homo- or heterocyclic groups which may have a substituent, substituted alkyl groups, styryl groups which may have a substituent or represents a group represented by O-R ^4, R ⁴ represents the same meaning as above, W is an acid halide or halogenated carbonate derivative represented by the representative.) a halogen atom, or the following general formula (VI) R ⁴ -N = C = O (VI) (wherein R ⁴ has the same meaning as described above), and is reacted in the presence or absence of a base in the absence or presence of a solvent, and It can be produced by deprotecting if necessary.

Examples of the condensing agent used in this production method include 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl)
Examples include carbodiimide hydrochloride, 1,1′-carbonyldiimidazole, Woodward reagent K (2-ethyl-5-phenylisoxazolium-3′-sulfonic acid), and examples of the base used include: Triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -7
Organic bases such as -undecene, 1,2,2,6,6-pentamethylpiperidine, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. The solvent used may be any solvent which is inert in the reaction itself and does not inhibit the reaction, for example, dichloromethane,
Halogenated hydrocarbon solvents such as 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, Aprotic polar solvents such as tetramethylene sulfolane, tetramethylene sulfoxide, and hexamethylene phosphoric triamide; ester solvents such as methyl acetate and ethyl acetate; ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane;
Organic base solvents such as pyridine, picoline, lutidine, collidine and the like, and a mixed solvent thereof are exemplified. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C.

The deprotection reaction in this production method can be carried out by various methods depending on the type of the hydroxyl-protecting group R ^{6. For} example, the following method can be used. For example, when the hydroxyl protecting group R ⁶ is an alkanoyl group,
In the case of a protecting group which forms an ester such as a halogenoalkanoyl group or an arylcarbonyl group, it can be produced by hydrolysis without a solvent or in a solvent in the presence or absence of an acid or alkali. Ester hydrolysis is a method known per se.
For example, acids such as hydrochloric acid and sulfuric acid can be used. For the alkaline hydrolysis, for example, sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxy, ethoxy sodium, tert-butoxy Alkali such as sodium and potassium tert-butoxide can be used. These acids or alkalis can be used as an aqueous solution, but methanol, ethanol, n-propanol, isopropanol,
alcoholic solvents such as n-butanol, sec-butanol, tert-butanol, acetone, acetonitrile, N, N
Dimethylformamide, dimethylsulfoxide, tetramethylenesulfolane, tetramethylenesulfoxide,
An aprotic polar solvent such as hexamethylenephosphoric triamide, an ether solvent such as tetrahydrofuran or 1,4-dioxane, or a hydrated solvent thereof can be used. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C.

When the protecting group R ^{6 for the} hydroxyl group is a protecting group forming a carbonate such as an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, etc., the presence of a cation scavenger in a solvent or in a solvent is omitted. The compound can be produced by reacting an acid in the presence or absence of an acid, or by subjecting it to hydrogenolysis and deprotection in the presence of a catalyst in a solvent. The solvent used may be any solvent which is inert in the reaction itself and does not inhibit the reaction, for example, water, acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol, alcohol solvents such as sec-butanol and tert-butanol, dichloromethane,
Halogenated hydrocarbon solvents such as 2-dichloroethane and chloroform; aromatic hydrocarbon solvents such as benzene and toluene; acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, and tetramethylene Aprotic polar solvents such as sulfolane, tetramethylene sulfoxide, hexamethylene phosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, or a mixture thereof. Examples of the solvent include a cation scavenger, and examples thereof include anisole, thioanisole, and ethanethiol. Examples of the acid used include hydrochloric acid, hydrobromic acid, trifluoroacetic acid, acetic acid, and sulfuric acid. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C. Further, as a catalyst used for hydrogenolysis, 5% palladium / carbon,
Palladium-based catalysts such as 10% palladium / carbon and 20% palladium hydroxide / carbon, and platinum oxide are exemplified. As a hydrogen source, in addition to hydrogen gas, cyclohexene,
1,3-cyclohexadiene, formic acid, ammonium formate and the like can be used. The solvent used may be any solvent that is inert in the reaction itself and does not inhibit the reaction, for example, water, acetic acid,
Alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, dichloromethane, 1,2-
Halogenated hydrocarbon solvents such as dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfolane, Aprotic polar solvents such as tetramethylene sulfoxide and hexamethylene phosphoric triamide; ester solvents such as methyl acetate and ethyl acetate; ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane; and mixed solvents thereof Is mentioned. The reaction is carried out at room temperature to 200 ° C., and when hydrogen gas is used as the hydrogen source, the hydrogen pressure is carried out at normal pressure to 200 kgf / cm ² .

When the hydroxyl-protecting group R ⁶ is a trialkylsilyl-type protecting group, it can be produced by reacting with an acid or tetrabutylammonium fluoride in the absence or in the presence of a solvent, followed by deprotection. it can. The solvent used may be any solvent which is inert in the reaction itself and does not inhibit the reaction, for example, water, acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol, alcohol solvents such as sec-butanol and tert-butanol, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, acetone, acetonitrile, N, N
Aprotic polar solvents such as -dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, tetramethylenesulfolane, tetramethylenesulfoxide, hexamethylenephosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, tetrahydrofuran, Examples thereof include ether solvents such as diethyl ether and 1,4-dioxane, and mixtures thereof. Examples of the acid used include mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and sulfuric acid. Trifluoroacetic acid, acetic acid, p-
Organic acids such as toluenesulfonic acid, citric acid, oxalic acid and the like can be mentioned. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C.

According to the second mode of the process for producing the compound of the present invention, the compound represented by the above general formula (I) is represented by the following general formula (VII)

Embedded image (Wherein R ¹ , R ² and R ⁶ have the same meanings as described above) and the following general formula (VIII) R ³ -Q (VIII) (wherein R ³ is as defined above) Having the same meaning, Q represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group) and tetrabutylammonium iodide in the presence or absence of sodium iodide or a base, It can be produced by reacting without a solvent or in a solvent, and further deprotecting if necessary.

As the base used in the present production method, for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,2,2
Organic bases such as 2,6,6-pentamethylpiperidine, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, sodium hydroxide, potassium hydroxide and the like can be mentioned.
The solvent used may be any solvent as long as it is inert in the reaction itself and does not inhibit the reaction, for example, a halogenated hydrocarbon solvent such as dichloromethane, 1,2-dichloroethane and chloroform; Aromatic hydrocarbon solvents such as benzene and toluene, acetone, acetonitrile, N, N-dimethylformamide,
N-methyl-2-pyrrolidone, dimethyl sulfoxide,
Aprotic polar solvents such as tetramethylene sulfolane, tetramethylene sulfoxide, hexamethylene phosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, tetrahydrofuran, diethyl ether, 1,
Examples thereof include ether solvents such as 4-dioxane, organic base solvents such as pyridine, picoline, lutidine, and collidine, and mixed solvents thereof. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C.

Various methods can be used for the deprotection reaction in the present production method depending on the type of the hydroxyl-protecting group R ⁶ , and can be carried out according to the method of the first production mode described above.

According to the third mode of the process for producing the compound of the present invention, among the compounds represented by the above general formula (I), R ³
Is a cycloalkyl group substituted with an alkoxy group, the compound represented by the above general formula (VII) and the following general formula (IX)

Embedded image (Wherein, R ⁹ and R ¹⁰ each independently represent an alkoxy group, and m represents an integer of 1 to 5), or the following general formula (X)

Embedded image (Wherein R ¹¹ represents an alkoxy group, and p represents an integer of 1 to 5), and reacted with or without an acid catalyst in the absence or presence of a solvent,
Further, it can be produced by deprotection if necessary.

Examples of the acid used in the present production method include pyridine hydrochloride, pyridine trifluoroacetate, pyridine p-toluenesulfonate and the like.
Any solvent may be used as long as it is inert in the reaction itself and does not inhibit the reaction. For example, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform may be used. , Benzene, toluene, etc., aromatic hydrocarbon solvents, acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, tetramethylenesulfolane, tetramethylenesulfoxide, hexamethylenephosphoric triamide, etc. Aprotic polar solvents, ester solvents such as methyl acetate and ethyl acetate, tetrahydrofuran, diethyl ether,
Examples thereof include ether solvents such as 1,4-dioxane, and mixed solvents thereof. The reaction is performed under ice-cooling for 20 minutes.
It is performed in a range up to 0 ° C.

The deprotection reaction in this production method can use various methods depending on the type of the hydroxyl-protecting group R ⁶ , and can be carried out according to the method of the first production mode described above.

According to a fourth mode of the process for producing the compound of the present invention, the compound represented by the general formula (I) is represented by the following general formula (XI)

Embedded image (Wherein R ¹ , R ² and R ⁶ have the same meanings as described above) and the following general formula (XII) R ³ —O—NH ₂ (XII) (wherein R ³ is A hydroxylamine derivative represented by the formula (1) or a salt thereof, in the presence or absence of a base, in the absence of a solvent or in a solvent, and then, if necessary, deprotected. Can be.

The base used in the present production method includes, for example, triethylamine, imidazole, diisopropylethylamine, 4-dimethylaminopyridine,
Organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene, 1,2,2,6,6-pentamethylpiperidine, or sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Inorganic base. The solvent used may be any solvent that is inert in the reaction itself and does not inhibit the reaction, for example, methanol, ethanol,
n-propanol, isopropanol, n-butanol, se
alcohol solvents such as c-butanol and tert-butanol; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform; aromatic hydrocarbon solvents such as benzene and toluene; acetone, acetonitrile, N, N -Dimethylformamide, N-methyl-2
Aprotic polar solvents such as pyrrolidone, dimethyl sulfoxide, tetramethylene sulfolane, tetramethylene sulfoxide, hexamethylene phosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, tetrahydrofuran, diethyl ether, 1,4-dioxane and the like And organic base solvents such as pyridine, picoline, lutidine, collidine and the like, and mixed solvents thereof. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C.

The deprotection reaction in this production method can use various methods depending on the type of the hydroxyl-protecting group R ⁶ , and can be carried out according to the method of the first production mode described above.

According to the fifth mode of the process for producing the compound of the present invention, R ^{2 in the} general formula (I) is represented by -XR ⁴ , X is an oxygen atom, and R ⁴ is a substituent. The compound which is an alkyl group which may be an aryl compound wherein X is an oxygen atom and R ⁴ is an aryl group which may have a substituent, which is produced by the first, second or fourth mode, or A compound in which the hydroxyl group at the 2′-position of the desosamine moiety of these aryl compounds is protected, and a compound represented by the following general formula (XIII) R ¹² —OH (XIII) (where R ¹² is an alkyl which may have a substituent) The compound can be produced by reacting an alcohol derivative represented by the formula (1) with or without a solvent and, if necessary, deprotecting.

The solvent used in the present production method may be any solvent as long as it is inert in the reaction itself and does not inhibit the reaction. Examples thereof include dichloromethane, 1,2-dichloroethane and chloroform. Halogenated hydrocarbon solvents, aromatic hydrocarbon solvents such as benzene and toluene, acetone, acetonitrile,
Aprotic polar solvents such as N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, tetramethylenesulfolane, tetramethylenesulfoxide, hexamethylenephosphoric triamide, and ester solvents such as methyl acetate and ethyl acetate And organic solvents such as pyridine, picoline, lutidine, collidine and the like, and mixed solvents thereof. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C.

The deprotection reaction in this production method can use various methods depending on the type of the hydroxyl-protecting group R ⁶ , and can be carried out according to the method of the first production mode described above.

According to the sixth mode of the process for producing the compound of the present invention, the compound having an acylamino group or an amino group in the substituent represented by R ² or R ³ in the general formula (I) is
The compound having a nitro group in the substituent represented by R ² or R ³ produced by the first method is converted into a metal in a solvent in the presence or absence of an acylating agent, in the presence or absence of an acid, or in a solvent. Or hydrogenation in the presence of a catalyst.

The acylating agent used in the present production method includes, for example, acid chlorides such as acetyl chloride, propionyl chloride, benzoyl chloride, phenylacetyl chloride, acetic anhydride, propionic anhydride, benzoic anhydride, phenylacetic anhydride and the like. Acid anhydrides. Examples of the acid used include hydrochloric acid, sulfuric acid, and acetic acid. Examples of the metal used include metals such as tin, iron, and zinc and salts thereof. As a catalyst used for hydrogenation, 5% palladium / carbon, 10% palladium /
Carbon, a palladium catalyst such as 20% palladium hydroxide / carbon, or platinum oxide may be used. As the hydrogen source, besides hydrogen gas, cyclohexene, 1,3-cyclohexadiene, formic acid, ammonium formate and the like can be used. The solvent used may be any solvent which is inert in the reaction itself and does not inhibit the reaction, for example, water, acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol, alcohol solvents such as sec-butanol and tert-butanol; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform; benzene;
Non-protons such as aromatic hydrocarbon solvents such as toluene, acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfolane, tetramethylene sulfoxide, hexamethylene phosphoric triamide Examples thereof include a polar solvent, an ester solvent such as methyl acetate and ethyl acetate, an ether solvent such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and a mixed solvent thereof. The reaction is carried out at room temperature to 200 ° C., and when hydrogen gas is used as the hydrogen source, the hydrogen pressure is carried out at normal pressure to 200 kgf / cm ² .

According to the seventh mode of the process for producing the compound of the present invention, R ^{3 in the} general formula (I) is a group represented by the formula — (CH ₂ ) _n —Y—.
In the compound represented by R ⁵ , Y is a sulfur atom or a group —NZ—
Is a compound represented by the following general formula (XI) wherein R ³ is a halogenoalkyl group produced by the first, second or fourth mode.
V)

Embedded image (Wherein, R ¹ and R ² have the same meanings as described above, T represents a halogen atom, and q represents an integer of 1 to 4) and a compound represented by the following general formula (XV) R ⁵ − NH-Z (XV) (wherein, R ⁵ and Z have the same meanings as described above), or the following general formula (XVI) R ⁵ -SH (XVI) (wherein R ⁵ Have the same meanings as described above.) In the presence or absence of a base in the absence or presence of a solvent.

The base used in the present production method includes, for example, triethylamine, imidazole, diisopropylethylamine, 4-dimethylaminopyridine,
Organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene, 1,2,2,6,6-pentamethylpiperidine, or sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Inorganic base. The solvent used may be any solvent which is inert in the reaction itself and does not inhibit the reaction, for example, dichloromethane, 1,2-
Halogenated hydrocarbon solvents such as dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfolane, Aprotic polar solvents such as tetramethylene sulfoxide and hexamethylene phosphoric triamide; ester solvents such as methyl acetate and ethyl acetate; ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane; pyridine, picoline and lutidine And organic base solvents such as collidine, and a mixed solvent thereof. The reaction is carried out at a temperature ranging from under ice cooling to 200 ° C.

The compounds represented by the general formulas (II), (VII) and (XI), which were used as starting materials in the process for producing the compound of the present invention, are partially described in JP-A-63-264495.
No., JP-A-8-104640 or WO93 / 1311
It is a known compound already disclosed in No. 6, etc., and can be produced, for example, as follows. Further, in the following production process, among the compounds represented by the general formulas (II), (VII) and (XI), the compound in which R ⁶ is a protecting group for a hydroxyl group is a compound in which R ⁶ is a hydrogen atom. It can also be produced by introducing a protecting group as needed. Among these, the novel compounds are described in detail as reference examples.

[0074]

Embedded image (Wherein, R ¹ , R ² , R ³ and R ⁶ have the same meanings as described above;
Ac represents an acetyl group. )

Pharmaceuticals containing the novel erythromycin derivative represented by the above general formula (I) or at least one salt thereof as an active ingredient are usually capsules, tablets, fine granules, Granules, powders,
It is administered as an oral preparation such as a syrup, or as an injection, suppository, eye drop, eye ointment, ear drop or dermis.
These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, for oral preparations and suppositories, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.), binders (hydroxypropylcellulose, hydroxypropyl) Methylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), plasticizers (polyethylene glycol, etc.), base materials (polyethylene glycol, hard fat, etc.) ) Is an aqueous solution or a solubilizing agent or a solubilizing agent (a distilled water for injection, physiological saline, propylene glycol) which can constitute a dissolvable dosage form when used in injections, eye drops or ear drops. Glycol, etc.), pH
Ingredients for preparations such as regulators (inorganic or organic acids or bases), tonicity agents (salts, glucose, glycerin, etc.), stabilizers, and ointments for external ointments and external preparations Agent,
Appropriate ingredients for formulation (white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.) are used as creams and patches.

When the compound of the present invention is administered to a patient, it depends on the condition of the patient, but in the case of an adult, it is usually about 10 to 2000 mg by oral administration and 1 to 10 mg by parenteral administration in a daily dose.
About 00 mg can be administered once or several times a day. However, it is desirable to appropriately increase or decrease according to the purpose of treatment or prevention, the site of infection or the type of pathogenic bacteria, the age and symptoms of the patient, and the like.

[0077]

EXAMPLES The present invention will be described below with reference to Examples and Examples, but the present invention is not limited to these Examples. In the table, Me is a methyl group, Et is an ethyl group, n-
Pr is n-propyl group, i-Pr is isopropyl group, n-Bu is n-butyl group, n-Pent is n-pentyl group, n-Hept is n-heptyl group, n-Non is n-nonyl group, Ac is an acetyl group, Anal.Calc
d. represents an elemental analysis value.

Reference Example 1 Erythromycin A 9- [O- [3- (4-pyridyl) propyl] oxime] Erythromycin A 9-oxime 130 g, tetrabutylammonium iodide 3.20 g and 3- (4-pyridyl) propylmethane To a mixed solution of 56.0 g of sulfonate and 1300 ml of tetrahydrofuran was added 14.0 g of powdered potassium hydroxide with stirring at room temperature, and the mixture was stirred at room temperature for 23 hours. Further, 14.0 g of powdered potassium hydroxide was added, and the mixture was stirred at room temperature for 21 hours. The reaction solution was evaporated under reduced pressure to remove a half of the solvent, poured into ice water, and the precipitated solid was collected by filtration. The solid was washed with water and diisopropyl ether to obtain 112 g of a colorless solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.85 (3H, t, J = 7.5Hz),
1.01-1.70 (33H, m), 1.78 (1H, brs), 1.87-2.04 (4H, m), 2.20
(1H, d, J = 10.5Hz), 2.29 (6H, s), 2.36 (1H, d, J = 15.5Hz), 2.3
9-2.46 (1H, m), 2.64-2.72 (3H, m), 2.87-2.95 (1H, m), 3.02
(1H, t, J = 10Hz), 3.08 (1H, s), 3.22 (1H, dd, J = 10.5,7.5Hz),
3.32 (3H, s), 3.43 (1H, brs), 3.45-3.53 (1H, m), 3.60 (1H, d,
J = 8Hz), 3.63-3.72 (2H, m), 3.97-4.09 (4H, m), 4.35 (1H, s),
4.43 (1H, d, J = 7.5Hz), 4.91 (1H, d, J = 5Hz), 5.10 (1H, dd, J = 1
1,2.5Hz), 7.10-7.15 (2H, m), 8.47-8.52 (2H, m)

The compounds of Reference Examples 2 to 40 were obtained in the same manner as in Reference Example 1.

[0080]

[Table 32]

[0081]

[Table 33]

[0082]

[Table 34]

[0083]

[Table 35]

[0084]

[Table 36]

[0085]

[Table 37]

[0086]

[Table 38]

[0087]

[Table 39]

[0088]

[Table 40]

[0089]

[Table 41]

Reference Example 41 5-O-desosaminylerythronolide A 9- [O-
[3- (4-Pyridyl) propyl] oxime] 107 g of erythromycin A 9- [O- [3- (4-pyridyl) propyl] oxime] was added to 1000 ml of 1N hydrochloric acid with stirring at room temperature, and the mixture was stirred at room temperature for 3 hours. . After the reaction, the reaction solution was poured into 500 g of ice, made alkaline with a 4N aqueous sodium hydroxide solution, and the precipitated solid was collected by filtration and washed with water to obtain 79.0 g of a colorless solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.85 (3H, t, J = 7.5Hz),
1.07 (3H, d, J = 7.5Hz), 1.09 (3H, d, J = 7.5Hz), 1.15-1.75 (21
H, m), 1.88-2.03 (3H, m), 2.04-2.12 (1H, m), 2.25 (6H, s), 2.
37 (1H, s), 2.43-2.51 (1H, m), 2.60-2.74 (4H, m), 3.15 (1H,
s), 3.24 (1H, dd, J = 10.5,7.5Hz), 3.47-3.62 (3H, m), 3.67-
3.76 (2H, m), 3.83 (1H, brs), 4.01-4.11 (2H, m), 4.30 (1H, m
s), 4.39 (1H, d, J = 7.5Hz), 5.22 (1H, dd, J = 11,2.5Hz), 7.08-
7.15 (2H, m), 8.47-8.54 (2H, m)

The compounds of Reference Examples 42 to 81 were obtained in the same manner as in Reference Example 41.

[0092]

[Table 42]

[0093]

[Table 43]

[0094]

[Table 44]

[0095]

[Table 45]

[0096]

[Table 46]

[0097]

[Table 47]

[0098]

[Table 48]

[0099]

[Table 49]

[0100]

[Table 50]

[0101]

[Table 51]

Reference Example 82 5-O-desosaminyl-6-O-methylerythronolide A 9- [O- (1-methoxycyclohexyl) oxime] 5-O-desosaminyl-6-O-methylerythronolide A 9 Oxime 1.10 g and pyridine hydrochloride 0.3
To a mixture of 2 g of dichloromethane (11 ml) was stirred at room temperature for 1,
A solution of 1.4 ml of 1-dimethoxycyclohexane in 4 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 19 hours.
Heated to reflux for an hour. Water was added to the reaction solution, which was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with diethyl ether. The extract was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel, ethyl acetate: methanol: aqueous ammonia = 20: 1: 0.1 → 10: 1: 0.
Purification was performed in 1), and the obtained solid was washed with diisopropyl ether to obtain 0.37 g of a colorless amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.84 (3H, t, J = 7.5Hz),
0.99 (3H, d, J = 7.5Hz), 1.10 (3H, d, J = 7.5Hz), 1.07-2.02 (31
H, m), 2.09-2.20 (1H, m), 2.25 (6H, s), 2.43-2.52 (1H, m), 2.
57-2.72 (2H, m), 3.00 (3H, s), 3.21 (3H, s), 3.24 (1H, dd, J = 1
0.5,7.5Hz), 3.33 (1H, s), 3.48-3.60 (3H, m), 3.68-3.93 (4
H, m), 4.38 (1H, d, J = 7.5Hz), 4.54 (1H, s), 5.23 (1H, dd, J = 1
(1,2.5Hz)

The compounds of Reference Examples 83 to 86 were obtained in the same manner as in Reference Example 82.

[0104]

[Table 52]

Reference Example 87 2'-O-acetyl-5-O-desosaminylerythronolide A 9- [O- [3- (4-pyridyl) propyl] oxime] 5-O-desosaminylerythronolide Ride A 9- [O-
[3- (4-Pyridyl) propyl] oxime] 71.0
g of acetone in a solution of 700 ml of acetone at room temperature with stirring,
1.0 ml was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed sequentially with an aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown amorphous solid. After treating the obtained solid with activated carbon in ethyl acetate, the solvent was distilled off under reduced pressure, and then washed with a mixed solution of ethyl acetate and diisopropyl ether to obtain 41.0 g of a colorless solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.85 (3H, t, J = 7.5Hz),
0.94 (3H, d, J = 7.5Hz), 1.05 (3H, d, J = 7.5Hz), 1.10-1.75 (21
H, m), 1.87-2.01 (4H, m), 2.06 (3H, s), 2.07-2.16 (1H, m), 2.
26 (6H, s), 2.61-2.75 (5H, m), 3.13 (1H, s), 3.42-3.57 (3H,
m), 3.58-3.70 (2H, m), 4.00-4.10 (2H, m), 4.39 (1H, s), 4.58
(1H, d, J = 7.5Hz), 4.76 (1H, dd, J = 10.5,7.5Hz), 5.23 (1H, d
d, J = 11,2.5Hz), 7.07-7.15 (2H, m), 8.46-8.54 (2H, m)

The compounds of Reference Examples 88 to 132 were obtained in the same manner as in Reference Example 87.

[0107]

[Table 53]

[0108]

[Table 54]

[0109]

[Table 55]

[0110]

[Table 56]

[0111]

[Table 57]

[0112]

[Table 58]

[0113]

[Table 59]

[0114]

[Table 60]

[0115]

[Table 61]

[0116]

[Table 62]

[0117]

[Table 63]

[0118]

[Table 64]

Example 1 5-O-desosaminyl-3-O-phenylacetylerythronolide A 9- [O- (1-methoxycyclohexyl) oxime] To a solution of 1.11 g of phenylacetic acid and 1.2 ml of triethylamine in 40 ml of dichloromethane. Under ice cooling and stirring, 1.0 ml of pivaloyl chloride was added dropwise, followed by stirring at the same temperature for 1 hour. 2.2 ml of pyridine and 2'-O-
Acetyl-5-O-desosaminylerythronolide A
9- [O- (1-methoxycyclohexyl) oxime]
2.00 g of a 15 ml dichloromethane solution was sequentially added dropwise.
Stirred at room temperature for 1 day. Ice water was added to the reaction solution, the mixture was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with dichloromethane. After the extract was washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel, dichloromethane: methanol = 3).
Purification by 3: 1) gave 1.38 g of a yellow-brown viscous liquid.
A solution of 1.20 g of this yellow-brown viscous liquid in 50 ml of methanol was stirred at room temperature for 1 day. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, dichloromethane: methanol = 100: 1 → 50: 3) to obtain 0.72 g of a colorless amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.80 (3H, t, J = 7.5Hz),
0.86 (3H, d, J = 6.5Hz), 1.03 (3H, d, J = 6.5Hz), 1.12-1.98 (32
H, m), 2.22-2.31 (1H, m), 2.30 (6H, s), 2.33-2.42 (1H, m), 2.
60 (1H, brs), 2.64-2.72 (1H, m), 2.75-2.85 (1H, m), 3.04-3.
21 (3H, m), 3.19 (3H, s), 3.50 (1H, d, J = 4.5Hz), 3.64-3.78 (2
H, m), 3.65 (1H, d, J = 14.5Hz), 3.71 (1H, d, J = 14.5Hz), 3.96
(1H, d, J = 7.5Hz), 4.57 (1H, s), 5.14 (1H, d, J = 10.5Hz), 5.20
(1H, dd, J = 11,2.5Hz), 7.24-7.38 (5H, m)

In the same manner as in Example 1, the compounds of Examples 2 and 3 were obtained.

[0121]

[Table 65]

Example 4 5-O-desosaminyl-3-O-phenylacetyl-6
-O-methylerythronolide A 9- [O- (1-methoxycyclohexyl) oxime] N, N-dimethylformamide 1 was added to a solution of 0.05 g of phenylacetic acid and 0.03 ml of oxalyl chloride in 0.6 ml of dichloromethane while stirring at room temperature. Drops were added, and after stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. A 2.5 ml solution of the residue in dichloromethane was stirred at room temperature for 2'-O-acetyl-5-
O-desosaminyl-6-O-methylerythronolide A
The mixture was added dropwise to a solution of 0.10 g of 9- [O- (1-methoxycyclohexyl) oxime] and 0.09 ml of pyridine in 0.8 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, the mixture was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with diethyl ether. After the extract was washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure. A solution of the obtained residue in 4 ml of methanol was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, the mixture was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with diethyl ether. After the extract was washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 20: 1) to give 0.05 g of a colorless amorphous solid.
I got NMR spectrum δ (CDCl ₃ ) ppm: 0.80 (3H, t, J = 7.5Hz),
0.89 (3H, d, J = 6.5Hz), 0.97 (3H, d, J = 7.5Hz), 1.00-2.00 (31
H, m), 2.10-2.39 (2H, m), 2.28 (6H, s), 2.52-2.64 (1H, m), 2.
76-2.88 (1H, m), 2.90-3.35 (4H, m), 3.07 (3H, s), 3.21 (3H,
s), 3.37-3.50 (1H, m), 3.67 (1H, d, J = 15Hz), 3.68-3.82 (2H,
m), 3.73 (1H, d, J = 15Hz), 3.90 (1H, d, J = 7.5Hz), 4.58 (1H,
s), 5.07 (1H, d, J = 11Hz), 5.20 (1H, dd, J = 11,2Hz), 7.17-7.4
0 (5H, m)

The compounds of Examples 5 to 22 were obtained in the same manner as in Example 4.

[0124]

[Table 66]

[0125]

[Table 67]

[0126]

[Table 68]

[0127]

[Table 69]

[0128]

[Table 70]

[0129]

[Table 71]

[0130]

[Table 72]

Example 23 3-O- (4-chlorophenyl) acetyl-5-O-desosaminylerythronolide A 9- [O- [3- (4
-Pyridyl) propyl] oxime] 2'-O-acetyl-5-O-desosaminylerythronolide A 9- [O- [3- (4-pyridyl) propyl] oxime] 25.0 g, 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride 19.0
g, 17.0 g of 4-chlorophenylacetic acid and 4.90 g of 4-dimethylaminopyridine in tetrahydrofuran 25
The 0 ml mixture was stirred at room temperature for 4 hours. The reaction solution was decanted, tetrahydrofuran was added to the insoluble viscous substance, and the mixture was decanted again. The decanted supernatants were combined, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed with water, and back-extracted with hydrochloric acid. The aqueous layer was made alkaline with a 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. After passing the ethyl acetate solution of the obtained residue through silica gel, the solvent was distilled off under reduced pressure to obtain a colorless amorphous solid.
A solution of the obtained amorphous solid in 150 ml of methanol was stirred at room temperature for 33 hours. The reaction solution was concentrated under reduced pressure to obtain 14.9 g of a pale yellow amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.82 (3H, t, J = 7.5Hz),
0.90 (3H, d, J = 6.5Hz), 1.03 (3H, d, J = 6.5Hz), 1.07-1.62 (21
H, m), 1.82 (1H, s), 1.88-2.02 (3H, m), 2.21-2.50 (2H, m), 2.
35 (6H, s), 2.63-2.74 (3H, m), 2.79-2.87 (1H, m), 2.97-3.05
(1H, m), 3.10 (1H, brs), 3.20 (1H, dd, J = 10,7.5Hz), 3.45 (1
(H, d, J = 4.5Hz), 3.58-3.74 (2H, m), 3.62 (1H, d, J = 15Hz), 3.6
7 (1H, d, J = 15Hz), 3.91 (1H, d, J = 7.5Hz), 4.06 (2H, t, J = 6.5H
z), 4.37 (1H, brs), 5.16 (1H, d, J = 11Hz), 5.20 (1H, d, J = 11H
z), 7.13 (2H, d, J = 5.5Hz), 7.20-7.40 (4H, m), 8.51 (2H, d, J =
5.5Hz)

The compounds of Examples 24 to 236 were obtained in the same manner as in Example 23.

[0133]

[Table 73]

[0134]

[Table 74]

[0135]

[Table 75]

[0136]

[Table 76]

[0137]

[Table 77]

[0138]

[Table 78]

[0139]

[Table 79]

[0140]

[Table 80]

[0141]

[Table 81]

[0142]

[Table 82]

[0143]

[Table 83]

[0144]

[Table 84]

[0145]

[Table 85]

[0146]

[Table 86]

[0147]

[Table 87]

[0148]

[Table 88]

[0149]

[Table 89]

[0150]

[Table 90]

[0151]

[Table 91]

[0152]

[Table 92]

[0153]

[Table 93]

[0154]

[Table 94]

[0155]

[Table 95]

[0156]

[Table 96]

[0157]

[Table 97]

[0158]

[Table 98]

[0159]

[Table 99]

[0160]

[Table 100]

[0161]

[Table 101]

[0162]

[Table 102]

[0163]

[Table 103]

[0164]

[Table 104]

[0165]

[Table 105]

[0166]

[Table 106]

[0167]

[Table 107]

[0168]

[Table 108]

[0169]

[Table 109]

[0170]

[Table 110]

[0171]

[Table 111]

[0172]

[Table 112]

[0173]

[Table 113]

[0174]

[Table 114]

[0175]

[Table 115]

[0176]

[Table 116]

[0177]

[Table 117]

[0178]

[Table 118]

[0179]

[Table 119]

[0180]

[Table 120]

[0181]

[Table 121]

[0182]

[Table 122]

[0183]

[Table 123]

[0184]

[Table 124]

[0185]

[Table 125]

[0186]

[Table 126]

[0187]

[Table 127]

[0188]

[Table 128]

[0189]

[Table 129]

[0190]

[Table 130]

[0191]

[Table 131]

[0192]

[Table 132]

[0193]

[Table 133]

[0194]

[Table 134]

[0195]

[Table 135]

[0196]

[Table 136]

[0197]

[Table 137]

[0198]

[Table 138]

[0199]

[Table 139]

[0200]

[Table 140]

[0201]

[Table 141]

[0202]

[Table 142]

[0203]

[Table 143]

Example 237 5-O-desosaminyl-3-O- (1-imidazolyl)
Carbonylerythronolide A 9- [O- (1-methoxycyclohexyl) oxime] 2'-O-acetyl-5-O-desosaminylerythronolide A 9- [O- (1-methoxycyclohexyl)
Oxime] in a dichloromethane (30 ml) solution containing 2.00 g of 1,1'-carbonyldiimidazole 2.1
8 g and 0.36 g of 4-dimethylaminopyridine were sequentially added, and the mixture was heated under reflux for 4 days. After cooling the reaction solution, ice water was added, the mixture was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with dichloromethane. After the extract was washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 33: 1) to give a pale yellow amorphous solid 2.39.
g was obtained. 1.32 g of the obtained solid in 50 ml of methanol
The solution was stirred at room temperature for 1 day. The reaction solution was concentrated under reduced pressure to obtain 1.20 g of a pale yellow amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.85 (3H, t, J = 7.5Hz),
1.05 (3H, d, J = 7.5Hz), 1.06 (3H, d, J = 6.5Hz), 1.12-2.00 (31
H, m), 2.08 (1H, s), 2.18 (6H, s), 2.37-2.44 (1H, m), 2.49-2.
58 (1H, m), 2.67-2.77 (1H, m), 3.00-3.08 (2H, m), 3.18-3.24
(1H, m), 3.21 (3H, s), 3.31 (1H, s), 3.53 (1H, d, J = 3.5Hz), 3.
63-3.77 (3H, m), 3.80 (1H, d, J = 6.5Hz), 4.64 (1H, s), 5.25-
5.33 (2H, m), 7.11 (1H, s), 7.50 (1H, s), 8.22 (1H, s)

Example 238 5-O-desosaminyl-3-O-phenylacetylerythronolide A 9- [O- (2-methoxyphenethyl) oxime] 5-O-desosaminyl-3-O-phenylacetylerythronolide A mixture of 0.40 g of A9-oxime, 11 mg of tetrabutylammonium iodide, 0.20 g of 2-methoxyphenethylmethanesulfonate and 45 mg of powdered potassium hydroxide in 4 ml of tetrahydrofuran was stirred at room temperature for 5 days. Water was added to the reaction solution, which was extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel, dichloromethane: methanol:
Ammonia water = 100: 3: 1.5) to give 0.50 g of a colorless amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.81 (3H, t, J = 7.5Hz),
0.87 (3H, d, J = 6.5Hz), 0.97 (3H, d, J = 7.5Hz), 1.10-1.67 (21
H, m), 1.88-1.99 (1H, m), 2.22-2.30 (1H, m), 2.27 (6H, s), 2.
31-2.38 (1H, m), 2.59-2.68 (1H, m), 2.77-2.85 (1H, m), 2.87
-3.04 (2H, m), 3.06-3.20 (3H, m), 3.28 (1H, brs), 3.41 (1H,
d, J = 5Hz), 3.54-3.63 (1H, m), 3.66 (1H, d, J = 14.5Hz), 3.70
(1H, d, J = 14.5Hz), 3.73 (1H, s), 3.84 (3H, s), 3.95 (1H, d, J =
7.5Hz), 4.20-4.28 (2H, m), 4.51 (1H, s), 5.14 (1H, d, J = 11H
z), 5.22 (1H, dd, J = 11.5,2Hz), 6.81-6.93 (2H, m), 7.08-7.1
4 (1H, m), 7.17-7.40 (6H, m)

In the same manner as in Embodiment 238, Embodiment 239
To Example 241 were obtained.

[0207]

[Table 144]

Example 242 5-O-desosaminyl-3-O-methoxycarbonylerythronolide A 9- [O- (3-phenylpropyl) oxime] 2'-O-acetyl-5-O-desosaminylerythro 1.3 ml of phenyl chloroformate was added dropwise to a solution of 0.80 g of Nolide A 9- [O- (3-phenylpropyl) oxime] in 8 ml of pyridine, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, which was extracted with diethyl ether. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to give 0.38 g of a colorless amorphous solid.
I got A solution of 0.38 g of the obtained solid in 5 ml of methanol was stirred at room temperature for 160 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) to obtain 0.22 g of a colorless amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.84 (3H, t, J = 7.5Hz),
1.04 (3H, d, J = 6.5Hz), 1.19-1.80 (23H, m), 1.90-2.03 (4H,
m), 2.20-2.40 (7H, m), 2.47-2.60 (1H, m), 2.60-2.75 (3H,
m), 2.85-2.95 (1H, m), 3.12 (1H, s), 3.15-3.30 (2H, m), 3.30
-3.40 (1H, m), 3.52 (1H, d, J = 3.5Hz), 3.62-3.72 (2H, m), 3.8
0 (3H, s), 4.06 (2H, t, J = 6.5Hz), 4.19 (1H, d, J = 7.5Hz), 4.45
(1H, s), 4.89 (1H, d, J = 11Hz), 5.26 (1H, dd, J = 11,2Hz), 7.10
-7.31 (5H, m)

In the same manner as in Example 242, Example 243
Was obtained.

Example 243 5-O-desosaminyl-3-O-methoxycarbonylerythronolide A 9- [O- (2-phenoxyethyl) oxime] Property Colorless amorphous solid NMR spectrum δ (CDCl ₃ ) ppm: 0.85 (3H, t, J = 7.5Hz),
1.00 (3H, d, J = 6.5Hz), 1.05-1.70 (23H, m), 1.90-2.00 (1H,
m), 2.12 (1H, s), 2.20-2.35 (1H, m), 2.27 (6H, s), 2.40-2.50
(1H, m), 2.62-2.75 (1H, m), 2.85-2.95 (1H, m), 3.12 (1H, s),
3.15 (1H, dd, J = 10.5,7.5Hz), 3.24 (1H, brs), 3.30-3.40 (1
H, m), 3.46 (1H, d, J = 4.5Hz), 3.65-3.85 (2H, m), 3.79 (3H,
s), 4.13-4.20 (3H, m), 4.37-4.43 (3H, m), 4.87 (1H, d, J = 10H
z), 5.26 (1H, dd, J = 11,2.5Hz), 6.90-7.00 (3H, m), 7.25-7.3
5 (2H, m)

Example 244 5-O-desosaminyl-3-O- (N-phenylcarbamoyl) erythronolide A 9- [O- (3-phenylpropyl) oxime] 2'-O-acetyl-5-O- A solution of 0.40 g of desosaminylerythronolide A 9- [O- (3-phenylpropyl) oxime], 0.34 ml of phenylisocyanate and 0.12 ml of pyridine in 4 ml of tetrahydrofuran was stirred at room temperature for 28 hours. Water was added to the reaction solution, which was extracted with diethyl ether. Wash the extract with saturated saline,
After drying over sodium sulfate, the solvent was distilled off under reduced pressure. A solution of the residue in 15 ml of methanol was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) to give a colorless amorphous solid.
31 g were obtained. NMR spectrum δ (CDCl ₃ ) ppm: 0.85 (3H, t, J = 7.5Hz),
0.97-1.68 (27H, m), 1.90-2.03 (4H, m), 2.13-2.38 (2H, m),
2.19 (6H, s), 2.62-2.77 (3H, m), 2.82-2.95 (1H, m), 3.05-3.
25 (3H, m), 3.55 (1H, d, J = 3.5Hz), 3.63-3.79 (2H, m), 3.98-
4.17 (3H, m), 4.48 (1H, s), 5.03 (1H, d, J = 10.5Hz), 5.27 (1H,
dd, J = 11.5,2Hz), 7.05 (1H, t, J = 7.5Hz), 7.11 (1H, brs), 7.1
6-7.22 (3H, m), 7.25-7.34 (4H, m), 7.40-7.48 (2H, m)

In the same manner as in Example 244, Example 245
~ The compound of Example 247 was obtained.

[0213]

[Table 145]

Example 248 3-O- (4-Aminophenyl) acetyl-5-O-desosaminylerythronolide A 9- [O- (phenethyl) oxime] A solution of 0.86 ml of acetyl chloride in 25 ml of methanol was prepared. 5
-O-desosaminyl-3-O- (4-nitrophenyl)
A solution of 0.40 g of acetylerythronolide A 9- [O- (phenethyl) oxime] in 20 ml of methanol was added dropwise, 0.91 g of zinc dust was added, and the mixture was stirred at room temperature for 3 hours.
The mixture was made alkaline with an aqueous sodium hydroxide solution under ice-cooling and stirred at room temperature for 5 minutes. After the precipitated solid was removed by filtration, the filtrate was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate: aqueous ammonia = 100: 1) gave 0.14 g of a colorless amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.82 (3H, t, J = 7.5Hz),
0.93 (3H, d, J = 6Hz), 0.97 (3H, d, J = 6.5Hz), 1.00-1.76 (24H,
m), 1.88-1.98 (1H, m), 2.20-2.68 (3H, m), 2.38 (6H, brs), 2.
76-2.86 (1H, m), 2.90-3.06 (3H, m), 3.10-3.27 (2H, m), 3.39
(1H, d, J = 4.5Hz), 3.44-3.80 (2H, m), 3.53 (1H, d, J = 14.5H
z), 3.57 (1H, d, J = 14.5Hz), 3.82-3.92 (1H, m), 4.20-4.30 (2
H, m), 4.46 (1H, s), 5.10 (1H, d, J = 11Hz), 5.22 (1H, d, J = 11H
z), 6.66 (2H, d, J = 8.5Hz), 7.13 (2H, d, J = 8.5Hz), 7.16-7.34
(5H, m)

Example 249 was performed in the same manner as in Example 248.
Was obtained.

Example 249 3-O- (4-acetylaminophenyl) acetyl-5
-O-desosaminylerythronolide A 9- [O-
[3- (4-Pyridyl) propyl] oxime] Property Light brown amorphous solid NMR spectrum δ (CDCl ₃ ) ppm: 0.82 (3H, t, J = 7.5 Hz),
0.90 (3H, d, J = 6.5Hz), 0.98-2.03 (25H, m), 1.02 (3H, d, J = 7.
5Hz), 2.02 (3H, s), 2.20-2.50 (2H, m), 2.33 (6H, s), 2.62-2.
73 (3H, m), 2.77-2.87 (1H, m), 3.00-3.12 (2H, m), 3.18 (1H, d
d, J = 10,7Hz), 3.30 (1H, brs), 3.47 (1H, d, J = 5Hz), 3.53 (1H,
d, J = 14.5Hz), 3.57 (1H, d, J = 14.5Hz), 3.60-3.74 (2H, m), 3.
94 (1H, d, J = 7.5Hz), 4.06 (2H, d, J = 6.5Hz), 4.38 (1H, s), 5.1
3 (1H, d, J = 11Hz), 5.20 (1H, dd, J = 11.5,2Hz), 6.64 (2H, d, J =
8.5Hz), 7.12 (2H, d, J = 8.5Hz), 7.13 (2H, d, J = 6Hz), 8.51 (2
(H, d, J = 6Hz)

Example 250 3-O- (4-aminophenyl) acetyl-5-O-desosaminylerythronolide A 9- [O- [3- (4
-Pyridyl) propyl] oxime] To a solution of 1.90 ml of acetyl chloride in 50 ml of methanol was added 5
-O-desosaminyl-3-O- (4-nitrophenyl)
Acetylerythronolide A 9- [O- [3- (4-
A solution of 0.90 g of pyridyl) propyl] oxime] in 40 ml of methanol was added dropwise, and 2.02 g of zinc dust was added, followed by stirring at room temperature for 4 hours. The reaction solution was made alkaline with an aqueous sodium hydroxide solution and stirred at room temperature for 20 minutes. After the precipitated solid was removed by filtration, the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 20 ml of methanol was added to the residue, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel,
(Ethyl acetate) to give 0.43 g of a yellow amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.81 (3H, t, J = 7.5Hz),
0.88 (3H, d, J = 6.5Hz), 1.02 (3H, d, J = 6.5Hz), 1.07-1.65 (21
H, m), 1.81 (1H, s), 1.87-2.02 (4H, m), 2.20-2.47 (2H, m), 2.
28 (6H, s), 2.60-2.73 (3H, m), 2.75-2.88 (1H, m), 3.05-3.20
(1H, m), 3.10 (1H, s), 3.16 (1H, dd, J = 10.5,7.5Hz), 3.29 (1
H, brs), 3.44-3.74 (2H, m), 3.52 (1H, d, J = 14.5Hz), 3.57 (1
H, d, J = 14.5Hz), 3.72 (1H, s), 3.98 (1H, d, J = 7.5Hz), 4.06 (2
H, d, J = 6.5Hz), 4.37 (1H, s), 5.13 (1H, d, J = 11Hz), 5.20 (1H, s
dd, J = 11.5,2Hz), 6.63 (2H, d, J = 8Hz), 7.12 (2H, d, J = 8Hz),
7.13 (2H, d, J = 6Hz), 8.51 (2H, d, J = 6Hz)

Example 251 5-O-desosaminyl-3-O-phenylacetylerythronolide A 9- [O- [2- (phenylamino)
Ethyl] oxime] 5-O-desosaminyl-3-O-phenylacetylerythronolide A A solution of 0.50 g of 9- [O- (2-bromoethyl) oxime] in 20 ml of aniline was placed in a sealed tube under a nitrogen atmosphere at 50 ° C. It reacted for 19 hours. Diethyl ether was added to the reaction solution, and the mixture was washed successively with an aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Column chromatography (silica gel,
The residue was purified by ethyl acetate to give 0.29 g of a colorless amorphous solid. NMR spectrum δ (CDCl ₃ ) ppm: 0.82 (3H, t, J = 7.5Hz),
0.89 (3H, d, J = 6.5Hz), 1.00 (3H, d, J = 6.5Hz), 1.05-1.80 (22
H, m), 1.88-2.00 (1H, m), 2.03 (1H, brs), 2.20-2.50 (2H, m),
2.35 (6H, brs), 2.64-2.71 (1H, m), 2.77-2.85 (1H, m), 3.02-
3.13 (2H, m), 3.15-3.24 (1H, m), 3.39 (2H, t, J = 5Hz), 3.43 (1H
(H, d, J = 5Hz), 3.62-3.78 (2H, m), 3.66 (1H, d, J = 15Hz), 3.70
(1H, d, J = 15Hz), 3.92 (1H, d, J = 6.5Hz), 4.20-4.31 (2H, m),
4.35 (1H, s), 5.12 (1H, d, J = 11Hz), 5.20 (1H, dd, J = 11.5,2H
z), 6.63-6.67 (3H, m), 7.17-7.38 (7H, m)

Example 252 was performed in the same manner as in Example 251.
~ The compound of Example 253 was obtained.

[0220]

[Table 146]

Hereinafter, in order to confirm the excellent effects of the compound of the present invention, the antibacterial spectrum against Helicobacter pylori was measured. Clarithromycin was used as a control compound.

[0222]

Embedded image

Antibacterial activity against Helicobacter pylori
The measurement of the antibacterial activity of the vector (minimum inhibitory concentration: MIC) is carried out according to the standard method of the Japanese Society of Chemotherapy [Japanese Journal of Chemotherapy, Vol.
(1981)], using a clinical isolate Helicobacter pylori at a viable cell count of 10 ⁶ CFU / ml. The results are shown in Table 147. The compound of the present invention comprises clarithromycin-resistant Helicobacter pylori (H. pylori TK1).
147, etc.) showed superior antibacterial activity as compared to the control compound.

[0224]

[Table 147]

[0225]

EFFECT OF THE INVENTION The erythromycin derivative or its salt according to the present invention has excellent antibacterial activity against Helicobacter pylori containing multidrug-resistant bacteria, and is extremely useful as an antibacterial agent or an antiulcer agent.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hiroyuki Nishino 37-1, Inoguchi, Katsuyama City, Fukui Prefecture Hokuriku Seiyaku Co., Ltd. (72) Inventor Akemi Nishimoto 37-1, Inoguchi 37, Katsuyama City, Fukui Prefecture Hokuriku Pharmaceutical Co., Ltd. F-term (reference) 4C057 BB02 CC03 DD01 KK13 4C086 AA01 AA02 AA03 EA13 MA04 NA14 ZA68 ZB35

Claims (6)

[Claims] 1. The following general formula:(Where R¹Represents a hydrogen atom or a lower alkyl group;^Two
Is an alkyl group which may have a substituent,
Good homo or heterocyclic group, optionally substituted homo
Or a heterocyclic group-substituted alkyl group or a substituent
Styryl group or the formula -XR^FourRepresents a group represented by^Three
Is a substituted alkyl group (carboxyl group,
Having an alkoxycarbonyl group which may have a substituent
Aryloxycarbonyl groups, with substituents
Aralkyloxycarbonyl group or benzyl
Having a substituent selected from amino groups), having a substituent
Optionally substituted cycloalkyl group, optionally substituted saturated
Having a homo- or saturated heterocyclic group-substituted alkyl group or substituent
An alkenyl group or a compound of the formula-(CH_Two)_n-Y-R ^Five
Represents a group represented by^FourIs an optionally substituted al
Represents an aryl group which may have a kill group or a substituent;
^FiveRepresents an aryl group which may have a substituent, and X represents oxygen
Represents an atom or a group represented by the formula -NH-, wherein Y represents a substituent
Methylene group, oxygen atom, sulfur atom, sulf
Ynyl group, sulfonyl group, carbonyl group or formula -NZ-
And Z represents a hydrogen atom or a substituent
And n represents an integer of 1 to 5. )
An erythromycin derivative represented by the formula or a salt thereof. ^2. The compound according to claim 1, wherein R ² is a benzyl group which may have a substituent, or a salt thereof. 3. A phenyl group wherein R ⁵ may have a substituent,
The compound according to claim 1 or 2, which is a 4-pyridyl group optionally having a substituent, a 3-pyridyl group optionally having a substituent or a 2-pyridyl group optionally having a substituent. Its salt. 4. A medicament comprising the compound according to any one of claims 1 to 3 or a salt thereof as an active ingredient. 5. An antibacterial agent comprising the compound according to claim 1 or a salt thereof as an active ingredient. 6. An anti-ulcer agent comprising the compound according to any one of claims 1 to 3 or a salt thereof as an active ingredient.