MXPA01009306A - Erythromycin derivatives - Google Patents

Abstract

Erythromycin derivatives of general formula (1) or salts of the same, extremely useful as antimicrobial agents:wherein R is H or lower alkyl;R1 is alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or -(CH2)n-X-R4;R2 is H or acetyl;R3 is acyl or -C(=O)-Y-R5;R4 is alkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, aryl, or aralkyl;R5 is alkyl, aryl, or aralkyl;n is an integer of 1 to 6;X is O, S, or -NZ-;Y is O or -NH-;and Z is H or alkyl.

Description

DK ERYTHROMXCINE DERIVATIVES DESCRIPTION OF THE INVENTION The present invention relates to novel erythromycin derivatives or salts thereof as antibacterial agents, which have excellent antibacterial activity especially against atypical acid-resistant mycobacteria including multiple drug-resistant bacteria. The present invention also relates to medicaments comprising the same as an active ingredient. Atypical acid-resistant mycobacteria have low sensitivity to various antibacterial agents including antituberculosis agents, and for this reason, atypical acid-resistant mycobacterioses are extremely intractable diseases. Rifampicin (The Merck Index, 12th edition, 8382) and the like are known as compounds that can be applied to a disease similar to that treated by the compounds of the present invention. In addition, as macrolide derivatives having a chemical structure similar to that of the compounds of the present invention, clarithromycin (The Merck Index, 12th edition, 2400), roxithromycin (The Merck Index, 12th edition, 8433) as a type 9 compound oxime and the like are known as antibacterial agents,. In addition, 4 '' -O-acetylerythromycin A9- (0-methyloxime) and the like are reported in Unexamined Publication of Japanese Patent (KOKAI) No. 63-107921 / 1988 for having an inhibitory action of viral duplication. However, "little is known that these macrolide derivatives have antibacterial activity against atypical acid-resistant mycobacteria." The clinical application of clarithromycin has been proven in the United States and other countries, which It is considered as the most promising agent for the treatment of mycobacteriosis acid resistant atypical among the current macrolide derivatives.However, the antibacterial activity of clarithromycin is not also sufficient as an agent for the treatment of atypical acid-resistant mycobacterioses. Thus, the development of more excellent antibacterial agents has been desired.In recent years, the increase in opportunistic infections has become a major social problem.The causes of the increase in opportunistic infections can include the increase of the number of committed guests with a mechanism of degraded biophylaxis such as patients infected by the human immunodeficiency virus (V IH), cancer and diabetes patients, and elderly people, increase of multiple drug-resistant bacteria whose typical examples are methicillin-resistant Staphylococcus aureus and the like, microbial substitution of patients by these bacteria, and so on. For these reasons, the chemotherapy of opportunistic infections has become more difficult. Atypical acid-resistant mycobacteriosis is one of the opportunistic infections. The atypical acid-resistant mycobacterium, the causative bacterium of atypical acid-resistant mycobacteriosis, proliferates slowly, and even when captured by phagocytes, can survive in the cells for a long period of time. Therefore, prolonged chemotherapy requires treating the infections of these bacteria. In particular, among the atypical acid-resistant mycobacteria, a few effective antibacterial agents are available against the Mycobacterium avium (MAC) complex, and consequently, surgical treatment for the therapeutic treatment of this infection has also been studied at present. In addition, even the aforementioned clarithromycin lacks selectivity to atypical acid-resistant mycobacteria, and MACs that are to be resistant to clarithromycin have already been known. As explained above, various problems arise in the chemotherapy of atypical acid-resistant mycobacterioses, for example, low sensitivity to known antibacterial agents, and conditions of high possibility of microbial substitution or emergence of resistant bacteria. An object of the present invention is to provide a compound having excellent antibacterial and selective activity against atypical acid-resistant mycobacteria. Research has been conducted anxiously to achieve the aforementioned object. As a result, it was found that the novel erythromycin derivatives or salts thereof according to the present invention were useful as antibacterial agents, and that they had excellent antibacterial activity particularly against atypical acid-resistant mycobacteria. The present invention was achieved on the basis of the discoveries. The present invention thus relates to novel erythromycin derivatives represented by the following general formula (I) or salts thereof: wherein R represents a hydrogen atom or a lower alkyl group; R1 represents an alkyl group of Cs_? 2 which can be substituted, a cycloalkyl group that can be substituted, an alkyl (cycloalkyl) group that can be substituted, an aralkyl group that can be substituted, or a group represented by the formula - (CH2) nX-R4; R2 represents a hydrogen atom or an acetyl group; R represents an acyl group that can be substituted, or a group represented by the formula -C (= 0) -Y-R5; R4 represents an alkyl group that can be substituted, an alkoxyalkyl group that can be substituted, an alkylthioalkyl group that can be substituted, an alkylaminoalkyl group that can be substituted, an aryl group that can be substituted or an aralkyl group that can be substituted; R5 represents an alkyl group that can be substituted, an aryl group that can be substituted, or an aralkyl group that can be substituted; n represents an integer from 1 to 6; X represents an oxygen atom, a sulfur atom, or a group represented by -NZ-; Y represents an oxygen atom or a group represented by -NH-; and Z represents a hydrogen atom or an alkyl group that can be substituted. According to the second aspect of the present invention, there are provided compounds represented by the following general formula (II) or salts thereof: wherein R1, R2, and R3 have the same meanings as those defined above, corresponding to the compounds represented by the above-mentioned general formula (I) wherein R is a hydrogen atom. According to the third aspect of the present invention, there is provided the compounds represented by the above-mentioned general formulas (I) and (II) or salts thereof wherein R2 is a hydrogen atom. According to a further aspect of the present invention, there is provided a medicament comprising a compound represented by the above-mentioned general formulas (I) and (II) or a physiologically acceptable salt thereof as an active ingredient. The medicament provided by the present invention can conveniently be used as, for example, an antibacterial agent, in particular, an agent for the treatment of atypical acid-resistant mycobacterioses. The present invention further provides a use of a compound represented by the above-mentioned general formulas (I) and (II) or a physiologically acceptable salt thereof for the manufacture of the aforementioned medicament; and a method for the therapeutic treatment of infectious diseases, in particular a method for the therapeutic treatment of "atypical acid-resistant mycobacterioses" comprising the step of administering to a mammal including a human a therapeutically effective amount of a compound represented by the formulas (I) and (II) mentioned above or a physiologically acceptable salt thereof The novel erythromycin derivatives represented by the above-mentioned general formula (I) according to the present invention will be specifically explained later on. It is apparent to a skilled person that the compounds represented by the aforementioned general formula (II) of the present invention fall within the compounds represented by the above-mentioned general formula (I) In the above-mentioned general formula (I) of the present invention, the lower alkyl group represented by R can be, for example, a methyl group, ethyl group, n-propyl group, n-butyl group or the like. The alkyl group of the optionally substituted Cs-? 2 alkyl group represented by R1 may be a linear or branched alkyl group having from 5 to 12 carbon atoms, for example, an n-pentyl group, isopentyl group, neopentyl group, group ter-pentyl, n-hexyl group, 4-methylpentyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group and the like. The cycloalkyl group of the optionally substituted cycloalkyl group represented by R 1 may be a cycloalkyl group having from 3 to 6 carbon atoms, for example, the cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group. The alkyl (cycloalkyl) group of the optionally substituted alkyl (cycloalkyl) group represented by R 1 is a group consisting of a linear or branched alkyl group having from 1 to 12 carbon atoms substituted with the aforementioned cycloalkyl group at any position. Examples include, for example, the 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, cyclohexyldodecyl group and the like. In the aforementioned general formula (I) of the present invention, the aralkyl group of the optionally substituted aralkyl group represented by R 1, R 4, or R 5 is a group consisting of a linear or branched alkyl group having from 1 to 12 carbon atoms. carbon substituted with an aryl group in any position. Examples include, for example, the benzyl group, naphthylmethyl group, naphthylethyl group, naphthylpropyl group, pyridylmethyl group, pyridylethyl group, pyridylpropyl group, pyrimidylmethyl group, pyrimidylethyl group, pyrimidylpropyl group, pyrazinylmethyl group, pyrazinylethyl group, pyrazinylpropyl group, furylmethyl group, furylethyl group, furylpropyl group, benzofuranylmethyl group, benzofuranylethyl group, benzofuranylpropyl group, thienyl group, thienylethyl group, thienylpropyl group, benzo [b] thienylmethyl group, benzo [b] thienylethyl group, benzo [b] thienylpropyl group, pyrrolylmethyl group, pyrrolylethyl group , pyrrolylpropyl group, indolylmethyl group, indolylethyl group, indolylpropyl group, idazolylmethyl group, idazolylethyl group, imidazolylpropyl group, benzimidazolylmethyl group, benzimidazolylethyl group, benzyl idazolylpropyl group, quinolylmethyl group, quinolylethyl group, quinolylpropyl group, isoquinolylmethyl group, isoquinolylethyl group, group isoquinolylpropyl, phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, phenylheptyl group, phenyloctyl group, phenylnonyl group, phenyldecyl group, phenylundecyl group, phenyldodecyl group and the like. The acyl group of the optionally substituted acyl group represented by R 3 may be a formyl group, or a group consisting of an alkyl group, cycloalkyl group, alkyl (cycloalkyl) group, aryl group or aralkyl group which is substituted with a carbonyl group in any position. Examples include, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, n-valeryl group, isovaleryl group, pivaloyl group, n-hexanoyl group, n-heptanoyl group, n-octanoyl group, n-nonanoyl group, n-decanoyl group, n-undecanoyl group, n-dodecanoyl group, n-tridecanoyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group, cyclopropylacetyl group, cyclobutylacetyl group, cyclopentylacetyl group, cyclohexylacetyl group, cyclohexylpropionyl group, cyclohexylbutyryl group , cyclohexylpentanoyl group, cyclohexylhexanoyl group, cyclohexylheptanoyl group, cyclohexyl octanoyl group, cyclohexylnonanoyl group, cyclohexyldecanoyl group, cyclohexylundecanoyl group, cyclohexyldedecanoyl group, cyclohexyltridecanoyl group, benzoyl group, naphthoyl group, nicotinoyl group, isonicotinoyl group, pyridazoylcarbonyl group, pyrazinylcarbonyl group, furoyl group, group benzofuranylcarb onyl, thienoyl group, benzo [b] thienylcarbonyl group, pyrrolylcarbonyl group, indolylcarbonyl group, imidazolylcarbonyl group, benzimidazolylcarbonyl group, quinolylcarbonyl group, isoquinolylcarbonyl group, phenylacetyl group, naphthylacetyl group, pyridylacetyl group, furylacetyl group, thienylacetyl group, pyrrolylacetyl group, phenylpropionyl group, phenylbutyryl group, phenylpentanoyl group, phenylhexanoyl group, phenylheptanoyl group, phenyloctanoyl group, phenylnonanoyl group, phenyl decanyl group, phenylundecanoyl group, phenyldodecanoyl group, phenyltridecanoyl group, a-methylphenylacetyl group and the like. The alkyl group of the optionally substituted alkyl group represented by R4, R5 or Z can be a linear or branched alkyl group having from 1 to 12 carbon atoms. Examples include, for example, 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, group ter-pentyl, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group and the like. The alkoxyalkyl group of the optionally substituted alkoxyalkyl group represented by R 4 is a group consisting of a linear or branched alkyl group having from 1 to 12 carbon atoms substituted with a linear or branched alkoxyl group having from 1 to 12 carbon atoms in any position. Examples include, for example, methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isoprbpoxymethyl group, n-butoxymethyl group, isobutoxymethyl group, sec-butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group, isopentyloxymethyl group, neopentyloxymethyl group , ter-pentyloxymethyl group, n-hexyloxymethyl group, n-heptyloxymethyl group, n-octyloxymethyl group, n-nonyloxymethyl group, n-decyloxymethyl group, n-undecyloxymethyl group, n-dodecyloxymethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, methoxypentyl group, methoxyhexyl group, methoxyheptyl group, methoxyoctyl group, methoxynononyl group, methoxydecyl group, methoxyundecyl group, methoxydecyl group, ethoxyethyl group, n-hexyloxyethyl group, n-dodecyloxyethyl group, n-propoxypropyl group and the like. The alkylthioalkyl group of the optionally substituted alkylthioalkyl group represented by R 4 is a group consisting of a linear or branched alkyl group having from 1 to 12 carbon atoms substituted with a linear or branched alkylthio group having from 1 to 12 carbon atoms in any position. Examples include, for example, methylthiomethyl group, ethylthiomethyl group, n-propylthiomethyl group, isopropylthiomethyl group, n-butylthiomethyl group, isobutylthiomethyl group, sec-butylthiomethyl group, tert-butylthiomethyl group, n-pentylthiomethyl group, isopentylthiomethyl group, neopentylthiomethyl group , tert-pentylthiomethyl group, n-hexylthiomethyl group, n-heptylthiomethyl group, n- ^ octylthiomethyl group, n-nonylthiomethyl group, n-decylthiomethyl group, n-undecylthiomethyl group, n-dodecylthiomethyl group, methylthioethyl group, methylthiopropyl group, group methylthiobutyl, methylthiopentyl group, methylthiohexyl group, methylthioheptyl group, methylthiooctyl group, methylthiononyl group, methylthiodecyl group, methylthioundecyl group, methylthiododecyl group and the like. The alkylaminoalkyl group of the optionally substituted alkylaminoalkyl group represented by R 4 is a group consisting of a linear or branched alkyl group having from 1 to 12 carbon atoms substituted with an amino group further substituted with one or two linear or branched alkyl groups having from 1 to 12 carbon atoms in any position. Examples include, for example, the methylaminomethyl group, ethylaminomethyl group, n-propylamino ethyl group, isopropylaminomethyl group, n-butylaminomethyl group, isobutylamino ethyl group, sec-butylaminomethyl group, tert-butylaminomethyl group, n-pentylaminomethyl group, isopentylaminomethyl group, neopentylaminomethyl group, ter-pentylaminomethyl group, n-hexylaminomethyl group, n-heptylaminomethyl group, n-octylaminomethyl group, n-nonylaminomethyl group, n-decylaminomethyl group, n-undecylaminomethyl group, n-dodecylaminomethyl group, methylaminoethyl group, methylaminopropyl group, methylaminobutyl group, methylaminopentyl group, methylaminohexyl group, methylaminoheptyl group, methylaminooctyl group, methylaminononyl group, methylaminodecyl group, methylaminodecyl group, methylaminododecyl group, dimethylaminomethyl group, dimethylaminoethyl group and the like. In the above-mentioned general formula (I) of the present invention, the aryl group of the optionally substituted aryl group represented by R 4 or R 5 can be, for example, the phenyl group, naphthyl group, pyridyl group, pyrimidyl group, pyrazinyl group, group furyl, benzofuranyl group, thienyl group, benzo [b] thienyl group, pyrrolyl group, indolyl group, imidazolyl group, benzimidazolyl group, quinolyl group, isoquinolyl group and the like. In the aforementioned general formula (I) of the present invention, when a functional group is defined as "a group that can be substituted", the substituent is not limited as long as it can exist on the functional group. The number and type of the substituent is not particularly limited. When two or more substituents are present, they may be the same or different. The position of the substituent is not limited either. Examples of substitutable groups include, for example, a hydroxyl group which may be protected, an alkoxyl group, an amino group which may be substituted, a carbamoyl group which may be substituted, a halogen atom, an alkyl group, a trifluoromethyl group, an acyl group, a cycloalkyl group, an aryl group, an aryloxy group, a cyano group, a nitro group, a guanidino group, an amidino group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group and the like. The protecting group of the hydroxyl group can be any protecting group while a protected group is substantially inactive in a reaction system in which the hydroxyl group should not be involved in the reaction, and the protected group is easily unfolded under a certain condition for vulnerability. Examples of the protecting group include, for example, an acyl group, trialkylsilyl group such as the trimethylsilyl group and the triethylsilyl group, the benzyl group and the like. The alkoxy group can be a straight or branched alkoxy group, and examples include, for example, a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, ter group -butoxy, n-pentyloxy group, isopentyloxy group, neopentyloxy group, ter-pentyloxy group, n-hexyloxy group and the like. Examples of the amino group which may be substituted include, for example, an 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, ter-pentylamino group, n-hexylamino group, dimethylamino group, diethylamino group and the like. Examples of the carbamoyl group that may be substituted include, for example, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, N-butylcarbamoyl group, N-isobutylcarbamoyl group, N- group sec-butylcarbamoyl, N-tert-butylcarbamoyl group, Nn-pentylcarbamoyl group, N-isopentylcarbamoyl group, N-neopentylcarbamoyl group, N-ter-pentylcarbamoyl group, N-hexylcarbamoyl group, N, N-dimethylcarbamoyl group, N group, N- diethylcarbamoyl and the like. Examples of the halogen atom include, for example, fluorine atom, chlorine atom, bromine atom or iodine atom. Examples of the aryloxy group include, for example, phenoxy group, naphthyloxy group, pyridyloxy group, pyrimidyloxy group, pyrazinyloxy group, benzofuranyloxy group, thienyloxy group, indolyloxy group, benzimidazolyloxy group, quinolyloxy group, isoquinolyloxy group and the like. Examples of the alkoxycarbonyl group include, for example, 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, ter group -pentyloxycarbonyl, n-hexyloxycarbonyl group and the like. Examples of the aryloxycarbonyl group include, for example, phenoxycarbonyl group, naphthyloxycarbonyl group, pyridyloxycarbonyl group, pyrimidyloxycarbonyl group, benzofuranyloxycarbonyl group, thienyloxycarbonyl group, indolyloxycarbonyl group, benzimidazolyloxycarbonyl group, quinolyloxycarbonyl group, isoquinolyloxycarbonyl group, and the like. Examples of the aralkyloxycarbonyl group include, for example, the benzyloxycarbonyl group, naphthylmethyloxycarbonyl group, pyridylmethyloxycarbonyl group, furylmethyloxycarbonyl group, benzofuranylmethyloxycarbonyl group, thienyloxycarbonyl group, indolylmethyloxycarbonyl group, imidazolylmethyloxycarbonyl group, benzimidazolyl-methyloxycarbonyl group, quinolylmethyloxycarbonyl group, isoquinolylmethyloxycarbonyl group and the like. As examples of the aforementioned alkyl group, acyl group, cycloalkyl group and aryl group which may be substituted, those groups exemplified above may be used. In the specification, the substitution or linking position on the "aryl group" of the "aralkyl group", the "acyl group", the "aryl group", the "aryloxy group", the "aryloxycarbonyl group" and the "aralkyloxycarbonyl group" "it can be in any position in that the elements constituting the ring in the position are substitutable or capable of forming a bond. The compounds represented by the aforementioned general formula (I) of the present invention have asymmetric carbons and therefore may exist as stereoisomers such as optical isomers, diastereoisomers, and geometric isomers. Any of these isomers and any mixture thereof or racemates thereof and salts thereof also fall within the scope of the present invention. The compounds represented by the aforementioned general formula (I) of the present invention can be converted into salts, preferably physiologically acceptable salts, if desired, and the resulting salts can also be converted into compounds in free forms. Examples of salts of the compounds represented by the aforementioned general formula (I) of the present invention include, for example, acid addition salts or alkali addition salts. Examples of acid addition salts include, for example, mineral acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, yodohidratos and phosphates, and organic acid salts such as acetates, propionates, butyrates, isobutyrates, formates, valerates, isovalerates , pivalates, trifluoroacetates, acrylates, maleates, tartrates, citrates, oleates, laurates, stearates, myristates, succinates, lactobionates, glutarates, sebacates, gluconates, benzoates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, phthalates, terephthalates, cinnamates, p -toluenesulfonates, lauryl sulfates, gluceptates, maleates, malonates, aspartates, glutamates, adipates, oxalates, nicotinates, picrates, thiocyanates, undecanoates, mandelates, fumarates, 10-camphorsulfonates, lactates, 5-oxotetrahydrofuran-2-carboxylates, 2-hydroxyglutarates. Examples of the alkaline addition salts include, for example, inorganic alkali metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts, and organic base salts such as ethanolamine salts and salts thereof. N, N-dialkylethanolamine, and salts of the optically active substances thereof. The compounds represented by the general formula (I) mentioned above or salts thereof according to the present invention can exist in the forms of any crystal or any solvate with water or organic solvents depending on the manufacturing conditions. These crystals, hydrates, solvates, and mixtures thereof also fall within the scope of the present invention. Preferred compounds of the present invention include the compounds listed below. However, the present invention is not limited to these examples. In the tables, Me represents the methyl group, Et represents the ethyl group, n-Pr represents the n-propyl group, i-Pr represents the isopropyl group, n-Bu represents the n-butyl group, i-Bu represents the group isobutyl, s-Bu represents the sec-butyl group, t-Bu represents the tert-butyl group, n-Pent represents the n-pentyl group, i-Pent represents the isopentyl group, neo-Pent represents the neopentyl group, t-Pent represents the ter-pentyl group, n-Hx represents n-hexyl group, n-Hept represents the n-heptyl group, n-Oct represents the n-octyl group, n-Non represents the n-nonyl group, n-Dec represents the n-decyl group, n-Undec represents the n-undecyl group, n-Dodec represents the n-dodecyl group, and Ac represents the acetyl group.

The novel erythromycin derivatives represented by the aforementioned general formula (I) of the present invention can be prepared by, for example, the methods explained below. However, the method for preparing the compounds of the present invention is not limited to these methods. According to the first embodiment of the method for preparing the compounds of the present invention, the compounds wherein R2 and R3 are acetyl groups falling within the compounds represented by the above-mentioned general formula (I) can be prepared by allowing a compound represented by the following general formula (III): wherein R and R1 have the same meanings as those defined above, to react with acetyl chloride or acetic anhydride in the presence or absence of a base without solvent or in a solvent. Examples of the bases used in the method for preparing include, . for example, organic bases such as triethylamine, pyridine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -7-undecene and 1, 2, 2, 6, 6-pentamethylpiperidine and the like, or inorganic bases such as sodium carbonate, potassium carbonate, sodium acid carbonate and potassium acid carbonate and the like. The solvent used in the method for preparing can be any solvent while per se is inert in the reaction and does not inhibit the reaction. Examples of such solvents include, for example, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, polar aprotic solvents such as acetone, acetonitrile, N, N-di-ethylformamide. , N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulpholane, tetramethylene sulfoxide and hexamethylene phosphoric triamide, ether solvents such as methyl acetate and ethyl acetate, solvent solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, organic based solvents such as pyridine, picoline, lutidine and collidine, or mixed solvents thereof. The reaction is carried out in a temperature range from below the ice cooling to 200 ° C. According to the second embodiment of the method for preparing the compounds of the present invention, the compounds wherein R2 is an acetyl group falling within the compounds represented by the aforementioned general formula (I) can be prepared by allowing a compound represented by the following general formula (IV): wherein R and R1 have the same meanings as those defined above, and Ac represents an acetyl group, to react with formic acid in the presence or absence of perchloric acid without solvent or in a solvent, or to react with an acidic anhydride represented by the following general formula (V): R6-C (= 0) -OW (V) wherein R6 represents a hydrogen atom, an alkyl group that can be substituted, a cycloalkyl group which can be substituted, an alkyl (cycloalkyl) that can be substituted, an aryl group that can be substituted, or an aralkyl group that can be substituted, and W represents a residue of acid anhydride, or to react with an acid halide or halogenated carbonate derivatives represented by the following general formula (VI): R7-C (= 0) -Q (VI) wherein R7 represents a hydrogen atom, an alkyl group that can be substituted, a cycloalkyl group that can be substituted, an alkyl (cycloalkyl) group that can be substituted, an aryl group that can be substituted, an aralkyl group that can be substituted, substituted, an alkoxy group that can be substituted, an aryloxy group that can be substituted, or an aralkyloxy group that can be substituted, and Q represents a halogen atom, in the presence or absence of a base without solvent or in a solvent, or to react with an isocyanate derivative represented by the following general formula (VII): R8-N = C = 0 (VII) wherein R8 represents an alkyl group that can be substituted, an aryl group that can be substituted or an aralkyl group which can be substituted, in the presence or absence of a base without solvent or in a solvent. Examples of the bases used in the method to prepare include, for example, organic bases such as triethylamine, pyridine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -7-undecene and 1, 2, 2, 6, 6-pentamethylpiperidine, or inorganic bases such as sodium carbonate, potassium carbonate, sodium acid carbonate, and potassium hydrogen carbonate. The solvent used in the method for preparing can be any solvent while per se is inert in the reaction and does not inhibit the reaction. Examples of such solvents include, for example, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, polar aprotic solvents such as acetone, acetonitrile, N, N-dimethylformamide, N -methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylenesulfolane, tetramethylene sulfoxide and ethylene phosphate triamide, ester solvents such as methyl acetate and ethyl acetate, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, organic based solvents such as pyridine, picoline, lutidine and collidine, or mixed solvents thereof. The reaction is carried out in a temperature range from below cooling with ice to 200 ° C. According to the third embodiment of the method for preparing the compounds of the present invention, the compounds represented by the aforementioned general formula (I) can be prepared by allowing a compound represented by the following general formula (VIII): wherein R, R2 and R3 have the same meanings as those defined above, to react with a compound represented by the following general formula (IX): R1-! 1 (IX) wherein R1 have the same meaning as those defined above, and T represents a halogen atom, mesyloxy group, tosyloxy group or trifluoromethylsulfonyloxy group, and tetrabutylammonium iodide in the presence or absence of sodium iodide or a base without solvent or in a solvent. Examples of the bases used in the method to prepare include, for example, organic bases such as triethylamine, pyridine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -7-undecene and 1, 2, 2, 6, 6-pentamethylpiperidine, or inorganic bases such as sodium carbonate, potassium carbonate, sodium acid carbonate and potassium acid carbonate, sodium hydride, sodium hydroxide and potassium hydroxide. The solvent to be used can be any solvent while per se is inert in the reaction and does not inhibit the reaction. Examples of such solvents include, for example, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, polar aprotic solvents such as acetone, acetonitrile, N, N-dimethylforman-ida. , N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulpholane, tetramethylene sulphoxide and hexamethylene phosphoric triazide, ester solvents such as methyl acetate and ethyl acetateether solvents such as tetrahydrofuran ether, diethyl ether and 1,4-dioxane, organic base solvents such as pyridine, picoline, lutidine and collidine, or mixed solvents thereof. The reaction is carried out in a temperature range from below the ice cooling to 200 ° C. According to the fourth embodiment of the method for preparing the compounds of the present invention, the compounds wherein R 1 is a cycloalkyl group substituted with an alkoxy group falling within the compounds represented by the above-mentioned general formula (I) can be prepared by allowing a compound represented by the above-mentioned general formula (VIII), for reacting with a cycloalkyl compound represented by the following general formula (X): wherein R9 and R10 independently represent an alkoxy group, and m represents an integer from 1 to 4 , or to react with a cycloalkene compound represented by the following general formula (XI): , H? K (XI) wherein R, 11 represents an alkoxy group, and k represents an integer from 1 to 4, in the presence or absence of an acid catalyst without solvent or in a solvent. Examples of the acids used in the method for preparation include, for example, pyridine hydrochloride, pyridine trifluoroacetate, pyridine p-toluenesulfonate and the like. The solvent to be used can be any solvent while per se is inert in the reaction and does not inhibit the reaction. Examples of the solvent include, for example, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, polar aprotic solvents such as acetone, acetonitrile, N, N-dimethylformamide, N -methyl-2-pyrrolidone, dimethyl sulfoxide, tetraethylenesulfolane, tetramethylene sulfoxide and hexamethylenephosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane or mixed solvents thereof. The reaction is carried out in a temperature range from below the ice cooling to 200 ° C. According to the fifth embodiment of the method for preparing the compounds of the present invention, the compounds wherein R 2 is a hydrogen atom falling within the compounds represented by the aforementioned general formula (I) can be prepared by hydrolyzing a compound represented by the general formula (I) mentioned above wherein R2 is an acetyl group without a solvent or in a solvent in the presence or absence of an acid or a base. Examples of the acid used in the method to prepare include, for example, hydrochloric acid, sulfuric acid and the like. Examples of the base to be used include, for example, sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, -potassium butoxide and the like. Although these acids or alkalis can be used as an aqueous solution, they can also be used as a solution in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec-butyl alcohol and tert-butyl alcohol, solvents aprotic polar such as acetone, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, tetraethylene sulfolane, tetramethylene sulfoxide and hexamethylene phosphoric triamide, ether solvents such as tetrahydrofuran and 1,4-dioxane, or water-containing solvents comprising any of these solvents and the like. The reaction is carried out in a temperature range from below the ice cooling to 200 ° C. Some of the compounds represented by the above-mentioned general formulas (III), (IV) and (VIII), which are used as the starting materials of the methods for preparing the compounds of the present invention, are known compounds which are described in Unexamined Publications of Japanese Patents (KOKAI) Nos. 56-100799 / 1981, 63-107921 / 1988, 3-204893 / 1991 and the like. They can be prepared, for example, as explained later. The details of the preparation of the novel compounds will be shown as reference examples.

(In the formulas, R and R1 have the same meanings as those defined above, and Ac represents an acetyl group). According to the compounds that are related to the compounds of the present invention represented by the above-mentioned general formula (I), the novel compounds represented by the following general formula (XII): wherein R and R have the same meanings as those defined above and R12 represents an alkyl group of C2_ which can be substituted, can be prepared according to the aforementioned preparations of the compounds of the present invention. The details of the preparations of these compounds will also be described as reference examples. The medicament comprising at least one of the novel erythromycin derivatives represented by the above-mentioned general formula (I) or salts thereof as an active ingredient are normally administered as preparations for oral administration such as capsules, tablets, refined granules, granules, powders and syrups, or preparations such as injections, suppositories, eye drops, ophthalmological ointments, ear drops, nasal drops and dermatological preparations. These preparations can be manufactured in a conventional manner by mixing with physiologically and pharmaceutically acceptable additives. For preparations for oral administration and suppositories, pharmaceutical additives such as, for ele, excipients such as lactose, sucrose, D-mannitol, corn starch and crystalline cellulose; disintegrating agents such as carboxymethylcellulose, calcium carboxymethylcellulose, partially pregelatinized starch, croscarmellose sodium, and crospovidone; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone; lubricants such as magnesium stearate, talc, hydrogenated oil, dimethyl polysiloxane, hydrated silicon dioxide, colloidal silicon dioxide and carnauba wax; coating agents such as hydroxypropylmethylcellulose, sucrose and titanium oxide; plasticizers such as triethyl citrate, polyethylene glycol and fatty acid glycerin esters; bases such as polyethylene glycol and hard fat and the like can be used. For injections, eye drops and ear drops, pharmaceutical additives such as, for example, dissolving agents and dissolving aids which may constitute aqueous preparations or preparations to be dissolved during use such as distilled water for injection, saline solution physiological and propylene glycol; pH modifiers such as inorganic or organic acids and bases, isotonic agents such as sodium chloride, glucose and glycerin, stabilizers and the like can be used. For ophthalmic ointments and dermatological preparations, suitable pharmaceutical additives can be used for ointments, creams and patches such as soft white paraffin, macrogol, glycerin, liquid paraffin and cotton cloth. When the medicament comprising the compound of the present invention as an active ingredient is administered to a patient, the doses may vary, depending on the symptoms of the patient. The dose for an adult may generally be from 10 to 2000 mg per day for oral administration, or from 1 to 1000 mg per day for parenteral administration, whose daily doses may be administered once or several times as divided portions. It is desirable that the doses be adequately increased or decreased depending on the purpose of the administration, that is, therapeutic or preventive treatment, a region of infection and the type of pathogenic bacteria, the age and symptoms of a patient and the like. EXAMPLES The present invention will be further explained with reference to the following examples of reference examples. However, the present invention is not limited to these examples. In the following tables, Me represents the methyl group, Et represents the ethyl group, n-Pr represents the n-propyl group, i-Pr represents the isopropyl group, nB represents the n-butyl group, n-Hex represents the n group -hexyl, n-Oct represents the n-octyl group, n-Dode represents the n-dodecyl group, and Ac represents the acetyl group. The descriptions in parentheses in the description of physicochemical properties indicate recrystallization solvents. Reference Example 1: Erythromycin A9- [0- (3-phenoxypropyl) oxime] Powdered potassium hydroxide (0.43 g) was added to a mixture of 4.00 g of erythromycin A9-oxime, 0.10 g of tetrabutylammonium iodide, 0.12 g of sodium iodide and 1.30 ml of 3-phenoxypropyl bromide in 40 ml of tetrahydrofuran at room temperature with stirring, and the mixture was stirred at room temperature for 16.5 hours. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was made alkaline with saturated aqueous sodium acid carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was added with diethyl ether and diisopropyl ether for solidification to give 2.80 g of a colorless solid. NMR spectrum (CDCl3) ppm: 0.85 (3H, t, J = 7.5Hz), 1.02 (3H, d, J = 6.5Hz), 1.08-1.80 (31H, m), 1.87-2.05 (2H, m) , 2.08-2.18 (2H, m), 2.21 (1H, d, J = 10.5Hz), 2.29 (6H, s), 2.33-2.48 (1H, m), 2.36 (1H, d, J = 15.5Hz), 2.63-2.72 (1H, m), 2.85-2.96 (1H, m), 3.02 (1H, t, J = 10Hz), 3.10 (1H, s), 3.22 - (1H, dd, J = 10, 7.5Hz) , 3.32 (3H, s), 3.41 (1H, s), 3.44-3.53 (1H, m), 3.57 (1H, d, J = 7.5Hz), 3.64-3.76 (2H, m), 3.96-4.10 (4H , m), 4.16-4.27 (2H, m), 4.38 (1H, s), 4.42 (1H, d, J = 7.5Hz), 4.92 (1H, d, J = 5Hz), 5.12 (1H, dd, J = ll, 2Hz), 6.84-6.96 (3H, m), 7.21-7.32 (2H, m). The compounds of Reference Examples 2 through 18 were obtained in the same manner as that described in Reference Example 1.

Reference Example 19: 2'-O-Acetylethythromycin A9- [0- (3-phenoxypropyl) oxime] To a solution of 8.00 g of erythromycin A9- [0- (3-phenoxypropyl) oxime] in 80 ml of acetone, added 1.00 ml of acetic anhydride per drop, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was added with diisopropyl ether, and then the mixture was heated and filtered under heating. The filtrate was cooled, and the precipitated crystals were collected by filtration to obtain 6.00 g of a colorless solid. The solid was recrystallized from a mixture of acetone and diisopropyl ether to give a colorless solid having a melting point of 99-101 ° C. Spectrum of NMR d (CDCl3) ppm: 0.84 (3H, t, J = 7.5Hz), 0.93 (3H, d, J = 7.5Hz), 1.03 (3H, d, J = 7.5Hz), 1.10-1.80 (28H , m), 1.87-1.98 (2H, m), 2.02-2.20 (3H, m), 2.06 (3H, s), 2.28 (6H, s), 2.35 (1H, d, J = 15.5Hz), 2.55- 2.69 (2H, m), 2.83-2.93 (1H,), 3.04 (1H, t, J = 9.5Hz), 3.11 (1H, s), 3.35 (3H, s), 3.43-3.55 (2H, m), 3.61-3.73 (2H, m) 3.90-4.08 (4H, m), 4.15-4.26 (2H, m), 4.39 (1H, s), 4.57 (1H, d,, J = 8Hz), 4.70-4.81 (1H , m) 4.92 (1H, d, J = 5Hz), 5.11 (1H, d,, J = 9Hz), 6.84-6.96 (3H, m), 7.22-7.31 (2H, m) The compounds of the Reference Examples 20 to 25 were obtained in the same manner as that described in Reference Example 19.

Reference Example 26: 2 ', 4"-0-Diacetylthrythromycin A9- (0-ethyl-oxime) To a solution of 0.50 g of erythromycin A9- (O-ethyl-oxime) in 5 ml of pyridine, 0.61 ml of acetic anhydride was added dropwise and the mixture was stirred at room temperature for 64 hours. The reaction mixture was added with water, and the mixture was made alkaline with saturated aqueous sodium acid carbonate solution and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to give 0.27 g of a colorless amorphous solid. Spectrum of NMR d (CDCl3) ppm: 0.84 (3H, t, J = 7.5Hz), 0.95 (3H, d, J = 8Hz), 1.04 (3H, d, J = 6.5Hz), 1.08-1.78 (30H, ), 1.80-2.00 (3H, m), 2.05 (3H, s), 2.10 (3H, s), 2.30 (6H, s), 2.41 (1H, d, J = 14.5Hz), 2.60-2.80 (2H, ), 2.84-2.95 (1H, m), 3.12 (1H, s), 3.34 (3H, s), 3.50 (1H, d, J = 6.5Hz), 3.59-3.80 (3H, m), 3.96 (1H, d, J = 10Hz), 4.06 (2H, q, J = 7Hz), 4.25-4.36 (1H, m), 4.46 (1H, s), 4.64-4.84 (3H, m), 4.99 (1H, d, J = 5Hz), 5.13 (1H, dd, J = ll, 2Hz). The compounds of Reference Examples 27 and 28 were obtained in the same manner as that described in Reference Example 26.

Reference Example 29: 4"-0-Acetylethylthromycin A9- (0-ethyl-oxime) A solution of 0.15 g of 2 ', 4" -0-diacetylcythromycin A9- (O-ethyl oxime) in 3 ml of methanol was stirred at room temperature for 64 hours. The reaction mixture was concentrated under reduced pressure to give 0.10 g of a pale brown amorphous solid.

NMR spectrum (CDCl3) ppm: 0.84 (3H, t, J = 7.5Hz), 0.97-2.07 (39H, m), 2.11 (3H, s), 2.31 (6H, s); 2.42 (1H, d, J = 14.5Hz), 2.50-2.60 (1H, m), 2.63-2.70 (1H, m), 2.87-2.97 (1H, m), 3.10 (1H, s), 3.22 (1H, dd, J = 10.5, 7.5Hz), 3.31 (3H, s), 3.47 (1H, s), 3.59 (1H, d, J = 6.5Hz), 3.62-3.80 (3H, m), 4.00-4.11 (3H , m), 4.30-4.41 (1H, m), 4.46 (1H, s), 4.57 (1H, d, J = 7.5Hz), 4.68 (1H, d, J = 10Hz), 4.99 (1H, d, J = 5Hz), 5.13 (1H, dd, J = 11, 2Hz) The compounds of Reference Examples 30 and 31 were obtained in the same manner as that described in Reference Example 29.

Example 1: 2 ', 4"-0-Diacetylthrythromycin A9- [0 (3-phenoxypropyl) oxime] Method a) To a solution of 0.50 g of erythromycin A9- [0- (3-phenoxypropyl) oxime] in 2.3 ml of pyridine, 0.53 ml of acetic anhydride was added per drop, and the mixture was stirred at room temperature for 29 hours.The reaction mixture was added with water, and the mixture was made alkaline with saturated aqueous sodium acid carbonate solution and The extract was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure.The residue was purified by column chromatography (silica gel, ethyl acetate). to give 0.21 g of a colorless amorphous solid: NMR spectrum d (CDCl 3) ppm: 0.84 (3 H, t, J = 7.5 Hz), 0.95 (3 H, d, J = 7.5 Hz), 1.03 (3 H, d, J = 7.5Hz), 1.06-1.83 (28H,), 1.87-2.18 (4H, m), 2.05 (3H, s), 2.10 (3H, s), 2.29 (6H, brs), 2.40 (1H, d, J = 14.5Hz), 2.61-2.80 (2H, m), 2.83-2.95 (1H, m), 3.10 (1H, s), 3.34 (1H, s), 3.49 (1H, d, J = 6Hz), 3. 60-3.80 (3H, m), 3.95 (1H, d, J = 10Hz), 4.00-4.08 (2H, m), 4. 13-4.34 (3H,), 4.37 (1H, s), 4.62-4.82 (3H, m), 4.98 (1H, d, J = 5Hz), 5.13 (1H, dd, J = ll, 2.5Hz), 6.86 -6.96 (3H, m), 7.22-7.30 (2H, m). Method b) To a solution of 25.0 g of 2'-O-acetylethythromycin A9- [O- (3-phenoxypropyl) oxime] in 250 ml of pyridine, 9.50 ml of acetyl chloride was added dropwise under cooling with ice, and the reaction mixture was stirred at the same temperature for 4 hours and then at room temperature for 2 hours. The reaction mixture was poured into ice water, and the mixture was made alkaline with saturated aqueous sodium acid carbonate solution and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give a colorless amorphous solid. The TLC (Rf value) and the NMR spectrum of the resulting solid was identical to the solid obtained in Method a. The compounds of Examples 2 to 52 were obtained in the same manner as that described in Example 1.

Example 53: 2'-O-acetyl-4"-0-phenylaminocarbonylethythromycin A9- [O- (3-phenoxypropyl oxime] To a solution of 1.20 g of 2'-O-acetylethythromycin A9- [O- (3-phenoxypropyl ) oxime] in 6 ml of pyridine, 0.63 ml of phenylisocyanate was added dropwise, and the mixture was stirred at room temperature for 25 hours.The reaction mixture was added with water and the mixture was made alkaline with acidic acid carbonate solution. saturated aqueous sodium and extracted with diethyl ether The extract was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure.The residue was purified by column chromatography ( silica, ethyl acetate) and again purified by column chromatography (silica gel, n-heptane: acetone: triethylamine = 7: 3: 0.15) to give 0.95 g of a colorless amorphous solid.D NMR spectrum (CDCl3 ) ppm: 0.85 (3H, t, J = 7.5Hz), 0.95 (3H, d, J = 7.5Hz), 1.03 (3H, d, J = 6.5Hz), 1.07-1.86 (28H, m), 1.88-2.00 (2H, m) , 2.02-2.19 (2H, m), 2.08 (3H, s), 2.34 (6H, s), 2.44 (1H, d, J = 15.5Hz), 2.61-2.69 (1H, m), 2.72-2.94 (2H , m), 3.11 (1H, s), 3.37 (3H, s), 3.52 (1H, d, J = 6.5Hz), 3.60-3.75 (3H, m), 3.99 (1H, d, J = 9Hz), 4.01-4.08 (2H, m), 4.16-4.25 (2H, m), 4.28-4.36 (1H, m), 4.38 (1H, s), 4.59-4.69 (2H,), 4.73-4.83 (1H, m) , 4.97 (1H, d, J = 5Hz), 5.13 (1H, dd, J = ll, 2Hz), 6.73 (1H, brs), 6.87-6.95 (3H, m), 7.09 (1H, t, J = 7.5 Hz), 7.23-7.29 (2H, m), 7.32 (2H, t, J = 8Hz), 7.40 (2H, d, J = 8Hz) Example 54: 4"-0-Acetylethythromycin A9- [0- (3-phenoxypropyl) oxime] A solution of 0.13 g of 2 ', 4" -0-diacetylthrythromycin A9- [O- (3-phenoxypropyl) oxime] in 10 ml of methanol was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure to give 0.12 g of a colorless solid. The solid was recrystallized from a mixture of methanol and water to give colorless prisms having a melting point of 127-130 ° C. NMR spectrum (CDCl3) ppm: 0.85 (3H, t, J = 7.5Hz), 0.97-1.83 (35H, m), 1.86-2.18 (4H,), 2.10 (3H, s), 2.20-2.48 (7H , m), 2.50-2.71 (2H,), 2.87-2.98 (1H, m), 3.09 (1H, s), 3.18-3.34 (1H, m), 3.31 (3H, s), 3.57 (1H, d, J = 6.5Hz), 3.62-3.80 (3H, m), 3.97-4.09 (3H, m), 4.16-4.25 (2H, m), 4.27-4.40 (2H, m), 4.57 (1H, d, J = 7.5Hz), 4.68 (1H, d, J = 10Hz), 4.98 (1H, d, J = 5Hz), 5.13 (1H, d, J = 8.5Hz), 6.86-6.96 (3H, m), 7.21-7.30 (2H, m). The compounds of Examples 55 to 108 were obtained in the same manner as that described in Example 54.

H.s) .3.18 - H, H.d, (1 J = 5Hz), 5.1 (3 H, Example 109: 4"-0-Acetylethythromycin A9- [0- (n-octyl) oxime] A 0.50 g portion of the colorless amorphous solid obtained in Example 66 was crystallized from methanol to give 0.35 g of colorless crystals having a melting point of 157.5-160 ° C. The NMR spectrum of the compound obtained was identical to that of the compound obtained in Example 66. Example 110: 4"-0-Acetylethylthromycin A9- [0- (3-cyclohexylpropyl) oxime] A 0.90 g portion of the colorless amorphous solid obtained in Example 71 was crystallized from n-heptane to give 0.47 g of colorless crystals having a melting point of 130-132.5 ° C. The NMR spectrum of the compound obtained was identical to that of the compound obtained in Example 71. To evaluate the excellent efficiency of the compounds of the present invention, their antibacterial spectrum was measured against atypical acid-resistant mycobacteria. Reference compounds clarithromycin, rifampicin, and 4"-0-acetylerythromycin A9- (0-methyloxime) [a compound described in Publication? Or Examined Japanese Patent (KOKAI)? Or 63-107921 / 1988] were used as reference compounds. Ac in the formula represents the acetyl group.

Reference Compound 1 (clarithromycin) Reference Compound 2 (rifampicin) Reference Compound 3 Antibacterial activity against atypical acid-resistant mycobacteria Antibacterial activities (minimal inhibitory concentrations) against clinical isolates of atypical acid-resistant mycobacteria were measured by the agar dilution method according to the standard method of the Japan Chemotherapy Society. Approximately 5 μl of bacterial suspension (adjusted to 10 6 CFU / ml) was stained on the 7H11 agar plates containing the test compounds. The minimum inhibitory concentrations were determined by the growth or non-growth of the bacteria after incubation at 37 ° C for 7 days. The results are shown in the following table. The compounds of the present invention had more excellent antibacterial activity than the reference compounds against atypical acid-resistant mycobacteria including atypical acid-resistant mycobacteria resistant to clarithromycin (M. avi um 20092 and other bacteria). The names of the bacteria in the table are as follows: Mycobacterium avium [M. avium) Mycobacterium intracellulare (M. intracellulare) Antibacterial activity (minimum inhibitory concentration μg / ml) Industrial Applicability The novel erythromycin derivatives and salts thereof according to the present invention have excellent antibacterial activity against atypical acid-resistant mycobacteria including multiple drug resistant bacteria and are useful as antibacterial agents.

Claims (8)

1. CLAIMS 1. An erythromycin derivative represented by the following general formula or a salt thereof: characterized in that R represents a hydrogen atom or a lower alkyl group; R1 represents an alkyl group of C5-12 which may be substituted, a cycloalkyl group which may be substituted, an alkyl (cycloalkyl) group which may be substituted, an aralkyl group which may be substituted, or a group represented by the formula (CH2) nX-R4; R "represents a hydrogen atom or an acetyl group, R3 represents an acyl group that can be substituted, or a group represented by the formula -C (= 0) -Y-R5; R4 represents an alkyl group that can be substituted, an alkoxyalkyl group that can be substituted, an alkylthioalkyl group that can be substituted, an alkylaminoalkyl group that can be substituted, an aryl group that can be substituted or an aralkyl group that can be substituted, R6 represents an alkyl group that can be substituted, an aryl group that can be substituted, or an aralkyl group that can be substituted, n represents an integer from 1 to 6, X represents an oxygen atom, a sulfur atom, or a group represented by -NZ-; Y represents an oxygen atom or a group represented by -NH-; and Z represents a hydrogen atom or an alkyl group that can be substituted 2. An erythromycin derivative represented by the following general formula or a salt thereof: characterized in that R1 represents an alkyl group of C5_2 which can be substituted, a cycloalkyl group which can be substituted, an alkyl (cycloalkyl) group which can be substituted, an aralkyl group which can be substituted, or a group represented by formula - (CH2) n-XR4; R2 represents a hydrogen atom or an acetyl group; R3 represents an acyl group that can be substituted, or a group represented by the formula -C (= 0) -Y-R5; R4 represents an alkyl group that can be substituted, an alkoxyalkyl group that can be substituted, an alkylthioalkyl group that can be substituted, an alkylaminoalkyl group that can be substituted, an aryl group that can be substituted, or an aralkyl group that can be substituted; R5 represents an alkyl group that can be substituted, an aryl group that can be substituted, or an aralkyl group that can be substituted; n represents an integer from 1 to 6; X represents an oxygen atom, a sulfur atom, or a group represented by -NZ-; Y represents an oxygen atom or a group represented by -NH-; and Z represents a hydrogen atom or an alkyl group that can be substituted. 3. The compound or salt thereof according to any of claims 1 or 2, characterized in that R2 is a hydrogen atom. 4. The medicament is characterized in that it comprises the compound or physiologically acceptable salt thereof according to any of claims 1 to 3 as an active ingredient. 5. An antibacterial agent characterized in that it comprises the compound or physiologically acceptable salt thereof according to any of claims 1 to 3 as an active ingredient. The medicament for the treatment of an atypical acid-resistant microbacteriosis characterized in that it comprises the compound or the physiologically acceptable salt thereof according to any of claims 1 to 3 as an active ingredient. The use of the compound or physiologically acceptable salt thereof according to any of claims 1 to 3, for the manufacture of the medicament according to claim 4. 8. The method for the treatment of an infectious disease characterized in that it comprises the step of administering a therapeutically effective amount of the compound or physiologically acceptable salt thereof according to any one of claims 1 to 3 to a mammal including a human. SUMMARY A novel erythromycin derivative represented by the following general formula or a salt thereof: wherein R represents a hydrogen atom or a lower alkyl group; R1 represents an alkyl group, a cycloalkyl group, an alkyl (cycloalkyl) group, an aralkyl group, or a group represented by the formula - (CH2) n-X-P.4; R2 represents a hydrogen atom or an acetyl group; R3 represents an acyl group or a group represented by the formula -C (= 0) -Y-R5; R 4 represents an alkyl group, an alkoxyalkyl group, an alkylthioalkyl group, an alkylaminoalkyl group, an aryl group, or an aralkyl group; R5 represents an alkyl group, an aryl group, or an aralkyl group; n represents an integer from 1 to 6; X represents an oxygen atom, a sulfur atom, or a group represented by -NZ-; Y represents an oxygen atom or a group represented by -NH-; and Z represents a hydrogen atom or an alkyl group. The derivative has excellent antibacterial activity against atypical acid-resistant mycobacteria that include multiple drug-resistant bacteria and is extremely useful as an antibacterial agent.