JPH06192292A - Novel polypeptide compound and salt - Google Patents

Abstract

PURPOSE:To obtain the novel polypeptide compound comprising a cyclic polypeptide, exhibiting a strong antibacterial activity to prevent the growth of broad pathogenic bacteria including gram-positive bacteria and gram-negative bacteria, and effective for preventing and treating carinii pneumonia, etc. CONSTITUTION:A compound of formula I [R<1> is hydroxy, lover alkoxy; R<2> is hydroxy; R<3> is acyl; R<4>, R<5> are hydroxy; R<6> is hydroxy, lower alkanoyloxy, carboxy (lower)alkoxy, etc.; R<8> is H, (substituted)over alkyl, or R<1> and R<2>, R<4> and R<5> are respectively combined with each other to form a group of formula II (R<9>, R<10> are H, lower alkyl); R<7>d. is hydroxysulfonyloxy] or its salt is hydrolyzed in the presence of an alkali such as an alkali metal hydroxide or an acid such as hydrochloric acid in a solvent such as water, alcohol or tetrahydrofuran to provide the novel polypeptide compound (salt) of formula III [R<7> is hydroxy, hydroxysulfonyloxy, carboxy (lover)alkoxy, etc.,] useful as an antibacterial agent, etc.

Description

Detailed Description of the Invention

[0001]

This invention relates to novel polypeptide compounds and salts thereof. More specifically, the present invention has a novel polypeptide having antibacterial activity (particularly antifungal activity), which is expected to be useful for the treatment and prevention of Pneumocystis carinii infection (eg, carini pneumonia) in humans and animals. The present invention relates to a compound and a salt thereof, a method for producing the same, a pharmaceutical composition containing the same, and use for treating or preventing infectious diseases including Pneumocystis carinii infection (eg, carini pneumonia) in humans and animals. Therefore, one object of the present invention is to have high activity against some pathogenic bacteria, and further, it is expected to be useful for the treatment or prevention of Pneumocystis carinii infection (eg, carini pneumonia) in humans and animals. A polypeptide compound and a salt thereof are provided.

Another object of the present invention is to provide a pharmaceutical composition containing a polypeptide compound and its salt as an active ingredient. Still another object of the present invention is to administer a drug to a human body or an animal for the treatment or prevention of infectious diseases including Pneumocystis carinii infections caused by pathogenic bacteria (eg Carini pneumonia). A method of using a polypeptide compound is provided.

[0003]

DETAILED DESCRIPTION OF THE INVENTION Polypeptide compounds targeted by the present invention
The product is novel and is represented by the following general formula [I].[In the formula, R¹Is a hydroxy group or a lower alkoxy group,
R²Is a hydroxy group, R³Is an acyl group, R^Four  And R^FiveIs
Hydroxy group, R⁶Is a hydroxy group, lower alcohol
Canoyloxy group, carboxy (lower) alkoxy group
Or a protected carboxy (lower) alkoxy group, R⁷
 Is a hydroxy group, a hydroxysulfonyloxy group,
Ruboxy (lower) alkoxy group or protected carbo
Xy (lower) alkoxy group, R⁸Is hydrogen or suitable
A lower alkyl group which may have one or more substituents
I mean each.

Here, R ¹ and R ² or R ⁴ and R ⁵ are bonded to each other to form the formula: (In the formula, R ⁹ and R ¹⁰ respectively represent hydrogen or a lower alkyl group) and may form a group. (However, when R ⁶ and R ⁷ are both hydroxy groups, R ³ is not a palmitoyl group)]

The polypeptide compound [I] of the present invention is
It can be produced according to the above reaction formula.Manufacturing method 1 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁶, And R⁸Is
Each has the same meaning as before, R⁷ _dIs hydroxysulfonyl
Means a xy group)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶, And R⁸Is
(The same meaning as before)

Manufacturing method 2 (In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ have the same meanings as described above, and R ¹ _a represents a lower alkoxy group.) (In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ have the same meanings as described above, and R ¹ _a means a lower alkoxy group.)

[0007]Manufacturing method 3 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁷ _d, And R⁸Is
Each has the same meaning as before)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷ _d, And R⁸Is
Each has the same meaning as before, and R⁶ _dIs a lower alkanoyloo
Means a xy group)

[0008]Manufacturing method 4 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁶ _d, R⁷ _d, And
And R⁸Each has the same meaning as before)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶ _d, And R⁸Is
Each has the same meaning as before)

[0009]Manufacturing method 5 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁷ Is it
(Same meaning as before)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶, And R⁷ Is
Each has the same meaning as before, and R⁸ _aIs an appropriate substituent
The above means a lower alkyl group which may have)

[0010]Manufacturing method 6 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁶ And R⁸ _aIs it
Same meaning as before, R⁷ _aIs hydroxysulfonyloxy
Means a group)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ _aIs it
(Same meaning as before)Manufacturing method 7 [In the formula, R¹ , R², R³, R^Four, R^Five, R⁷ And R⁸Haso
The same meaning as before, R¹¹Is carboxy (lower) alk
Group or a protected carboxy (lower) alkyl group,
X means a leaving group][In the formula, R¹ , R², R³, R^Four, R^Five, R⁷And R⁸ Is it
Same meaning as before, R⁶ _aIs carboxy (lower) alkoxy
Si group or protected carboxy (lower) alkoxy group
Means]

[0011]Manufacturing method 8 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁶, R⁸ , R¹¹,
And X have the same meanings as before)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ Haso
The same meaning as before, R⁷ _aIs carboxy (lower) Arco
Xy or protected carboxy (lower) alkoxy
Means a group)

[0012]Manufacturing method 9 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁷And R⁸ Haso
The same meaning as before, R⁶ _bProtected carboxy (low
Class) means an alkoxy group)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷And R⁸ Haso
The same meaning as before, R⁶ _cIs carboxy (lower) Arco
Means a xy group)

[0013]Manufacturing method 10 (In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ Haso
The same meaning as before, R⁷ _bProtected carboxy (low
Class) means an alkoxy group)(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ Haso
The same meaning as before, R⁷ _cIs carboxy (lower) Arco
Means a xy group)

[0014]Manufacturing method 11 (In the formula, R³, R⁶, R⁷And R⁸ Each has the same meaning as before
It's a taste)

[Wherein R³, R⁶, R⁷ , R⁸Each before
Same meaning as R¹ _aAnd R² _aAre hydroxy groups
Or both are combined to give the formula:(In the formula, R⁹And R^TenIs hydrogen or lower
Forming a group represented by (meaning a kill group)
To taste].

Suitable salts of the compound (I) are conventional non-toxic salts such as metal salts such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg calcium salt, magnesium salt). Salt, etc.), ammonium salt, salt with organic base (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.), organic acid addition salt (eg, Formate, acetate,
Trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc. Inorganic acid addition salts (eg hydrochloride, hydrobromide, hydroiodide, sulfuric acid) Salts, phosphates, etc.), salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) and the like. In the above and subsequent description of the present specification, suitable examples and explanations of various definitions included in the scope of the present invention are explained in detail below.
"Lower" means 1 to 6 carbon atoms unless otherwise specified. “Higher” shall mean 7 to 20 carbon atoms unless otherwise indicated.

Suitable "acyl group" includes aliphatic acyl group derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, etc., aromatic acyl group, heterocyclic acyl, and aromatic group or heterocyclic group. Examples thereof include an aliphatic acyl group substituted with a group.

Preferred examples of the acyl are shown below: Halogen (eg, fluorine, chlorine, bromine, iodine, etc.); one or more appropriate substituents such as hydroxy, higher alkoxy described later, aryl mentioned later, and the like ( (Preferably 1 to 3) aryl (eg, phenyl, naphthyl, anthryl, etc.) which may have; lower alkoxy described below; amino; protected amino, preferably lower alkoxycarbonylamino (eg, methoxycarbonylamino, Acylamino such as ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tertiary butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino and the like; di (lower) alkylamino (eg dimethylamino, N- Methylethylamino, die Ruamino, N-propylbutylamino, dipentylamino, dihexylamino, etc.); lower alkoxyimino (eg, methoxyimino, ethoxyimino, propoxyimino, butoxyimino, tertiary butoxyimino, pentyloxyimino, hexyloxyimino, etc.); Phenyl (lower) alkoxyimino optionally having one or more (more preferably 1 to 3) appropriate substituents such as higher alkoxy described below (eg, benzyloxyimino, phenethyloxyimino, benzhi) Alkyl (lower) alkoxyimino such as drilloxyimino; higher alkyl (eg, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, 3,7-dimethyloctyl, undecyl, dodecyl, tridecyl,
Even if it has one or more (more preferably 1 to 3) appropriate substituents such as tetradecyl, pentadecyl, 3-methyl-10-ethyldodecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, etc. A good heterocyclic thio, preferably pyridylthio; a heterocyclic group which may have one or more (more preferably 1 to 3) appropriate substituents such as amino, the above-mentioned protected amino, the above-mentioned higher alkyl and the like. Cyclic group (for example, thienyl, imidazolyl, pyrazolyl, furyl, tetrazolyl, thiazolyl, thiadiazolyl, etc.); etc .; and one or more (more preferably 1 to 3) suitable substituents Alkanoyl [eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, pivaloyl ];

Higher alkanoyl [eg heptanoyl,
Octanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, 10,12-dimethyltetradecanoyl, heptadecanoyl, steanoyl, nonadecanoyl, icosanoyl, etc.];

One or more (more preferably 1 to 3) suitable substituents such as the higher alkoxy mentioned below and the like such as the above aryl which may have one or more substituents (more preferably 1 to 3). (Preferably 1 to 3) lower alkenoyl which may have [eg acryloyl, methacryloyl, crotonoyl, 3-pentenoyl, 5-hexenoyl, etc.]; higher alkenoyl [eg 4-heptenoyl, 3-octenoyl, 3,6- Decadienoyl, 3,7,11-trimethyl-2,6,10-dodecatrienoyl, 4,1
0-heptadecadienoyl and the like]; lower alkoxycarbonyl [eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-
Butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like]; higher alkoxycarbonyl [eg, heptyloxycarbonyl, octyloxycarbonyl, 2-ethylhexyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, 3,
7-dimethyloctyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl,
Pentadecyloxycarbonyl, 3-methyl-10-ethyldodecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, icosyloxycarbonyl and the like]; aryloxycarbonyl [eg, Phenoxycarbonyl, naphthyloxycarbonyl, etc.];

Arylglyoxyloyl [eg, phenylglyoxyloyl, naphthylglyoxyloyl, etc.]; having one or more substituents such as phenyl (lower) alkoxycarbonyl optionally having nitro or lower alkoxy Optionally substituted ar (lower) alkoxycarbonyl [eg benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl etc.]; lower alkylsulfonyl [eg mesyl, ethylsulfonyl, propylsulfonyl , Isopropylsulfonyl,
Pentylsulfonyl, butylsulfonyl, etc.];

Arylsulfonyl which may have one or more (preferably 1 to 3) substituents such as lower alkyl or higher alkoxy as described below [eg, phenylsulfonyl, tosyl, etc.]; phenyl (lower) Ar (lower) alkylsulfonyl such as alkylsulfonyl and the like [eg benzylsulfonyl, phenethylsulfonyl,
Benzidylsulfonyl, etc.];

The above-mentioned halogen; lower alkyl (for example,
Methyl, ethyl, propyl, butyl, t-butyl, pentyl, hexyl, etc.); the above-mentioned higher alkyl; one or more (preferably, one or more) suitable substituents such as the above-mentioned lower alkoxy, the above-mentioned halogen, the above-mentioned aryl and the like. 1 to 10) optionally substituted lower alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc.); one or more suitable substituents such as the above-mentioned halogens. (Preferably 1 to 17) higher alkoxy which may have (for example, heptyloxy, octyloxy, 2-ethylhexyloxy, nonyloxy, decyloxy, 3,7-dimethyloctyloxy, undecyloxy, dodecyloxy, tri Decyloxy, tetradecyloxy, pentadecyloxy, 3
-Methyl-10-ethyldodecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, etc .; higher alkenyloxy (eg, 3-heptenyloxy, 7-octenyloxy, 2,6-octadienyloxy) , 5-nonenyloxy, 1-decenyloxy, 3,7-dimethyl-6
-Octenyloxy, 3,7-dimethyl-2,6-octadienyloxy, 8-undecenyloxy, 3,6
8-dodecatrienyloxy, 5-tridecenyloxy, 7-tetradecenyloxy, 1,8-pentadecadienyloxy, 15-hexadecenyloxy, 11-heptadecenyloxy, 7- Octadecenyloxy, 10
-Nonadecenyloxy, 18-icosenyloxy, etc.);
Carboxy; the above-mentioned aryl which may have one or more (preferably 1 to 3) suitable substituents such as the above-mentioned higher alkoxy; and one suitable substituent such as the above-mentioned higher-alkoxy. One or more (preferably 1 to 5) appropriate substituents such as aryloxy (eg, phenoxy, naphthyloxy, anthryloxy, etc.) which may be present (preferably 1 to 3), etc. Individual) may have;
Etc .; one or more substituents such as etc. (preferably 1-5)
Aroyl that may have [eg, benzoyl,
Naphthoyl, anthrylcarbonyl, etc.] and the like.

A preferred example of the "acyl group" defined as above is an aroyl group which may have one or more (preferably 1 to 5) higher alkoxy, and more preferred examples thereof are 1-3 (C ₇ ~C ₁₆₎ may benzoyl group optionally having alkoxy, a 1-3 (C ₇ ~C ₁₆₎ may naphthoyl group optionally having alkoxy, And the most preferred examples are 4-n-octyloxybenzyl, 6-n-heptyloxy-2-naphthoyl and 6-n-octyloxy-2-naphthoyl.

Suitable "lower alkyl" moiety of "lower alkyl group optionally having one or more suitable substituents" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, It means a straight chain or branched chain alkane residue having 1 to 6 carbon atoms such as pentyl, neopentyl, hexyl and the like, and a preferable example thereof is a C ₁ -C ₄ alkyl group, and a more preferable example is Examples include a methyl group.

The "lower alkyl group" is hydroxy,
Acyl (eg carboxy, protected carboxy {eg lower alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl etc.)}
Etc.), di (lower) alkylamino (eg, dimethylamino, diethylamino, N-methylethylamino, dipropylamino, dibutylamino, Nt-butylbutylamino, dipentylamino, dihexylamino, etc.), in the ring portion. Cyclic amino optionally having another hetero atom (for example, 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, 1-pyridyl, dihydropyridine-
1-yl and the like) and the like may have one or more (preferably 1 to 3) substituents.

Preferable examples of "lower alkyl group optionally having one or more appropriate substituents" include lower alkyl having hydroxy and carboxy, lower alkyl having di (lower) alkylamino; and include lower alkyl having cyclic amino, the more preferred examples among them, having hydroxy and carboxy (C ₁ ~C ₄₎ alkyl; di (C ₁ ~C ₄₎ having an alkylamino (C ₁ ~ C ₄₎ alkyl; with a piperidino (C ₁ ~C ₄₎ alkyl, and the like, and the most preferred example is 1-hydroxy-1-carboxymethyl, dimethylaminomethyl and piperidinomethyl. Suitable "lower alkoxy" includes straight chain or branched chain such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy and the like.

Suitable "lower alkanoyloxy" includes acetoxy, propionyloxy, butyryloxy,
Hexanoyloxy and the like can be mentioned. Suitable "carboxy (lower) alkoxy group" is carboxymethoxy, carboxyethoxy, carboxypropoxy, carboxybutoxy, 2-carboxy-2-methylethyl,
Examples include groups such as carboxypentyloxy and carboxyhexyloxy.

Suitable “protected carboxy (lower) alkoxy group” includes esterified carboxy (lower) alkoxy group and the like. Preferable examples of the ester include, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropyl. Lower alkyl ester such as ethyl ester; lower alkenyl ester such as vinyl ester and allyl ester; lower alkynyl ester such as ethynyl ester and propynyl ester; such as methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, t-butoxymethyl ester Ester, 1-methoxyethyl ester, 1-
Lower alkoxyalkyl ester such as ethoxyethyl ester; lower alkylthio (lower) such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester
Alkyl ester; for example, 2-iodoethyl ester,
Mono (or di or tri) halo (lower) alkyl esters such as 2,2,2-trichloroethyl ester; eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyl Lower alkanoyloxy (lower) alkyl ester such as oxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester; lower alkanesulfonyl (lower such as mesylmethyl ester, 2-mesylethyl ester) ) Alkyl ester; lower alkoxycarbonyl (lower) alkenyl ester such as 2-isobutoxycarbonyl-2-pentenyl ester such as benzyl ester, 4
-Methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butyl ester Benzyl ester,
Ar (lower) alkyl esters such as mono (or di- or tri) phenyl (lower) alkyl esters which may have one or more suitable substituents such as diphenylmethyl ester; eg phenyl esters, tolyl esters, Having one or more suitable substituents such as substituted or unsubstituted phenyl esters such as tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester and the like. Optionally, aryl ester; tri (lower) alkylsilyl ester; lower alkylthioester such as methylthioester, ethylthioester and the like.

Suitable "leaving group" is, for example, halogen such as chlorine, bromine, iodine and the like, sulfonyloxy group such as benzenesulfonyloxy, tosyloxy and mesyloxy, lower alkanoyloxy group such as acetyloxy and propionyloxy. And acyloxy groups. The method for producing the object compound [I] of the present invention or a salt thereof will be described in detail below.

Production Method 1 The object compound (Ia) or a salt thereof can be produced by subjecting the compound (II) or a salt thereof to a hydrolysis reaction. The hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include alkali metals (eg sodium, potassium, etc.),
Alkaline earth metals (eg magnesium, calcium etc.), hydroxides, carbonates or hydrogen carbonates of these metals, trialkylamines (eg trimethylamine,
Triethylamine), picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]. -Inorganic bases or organic bases such as Undec-7. Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid,
And trifluoroacetic acid) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).
The elimination using a Lewis acid such as trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.) is preferably carried out in the presence of a cation scavenger (eg, anisole, phenol, etc.). The reaction is usually carried out in a solvent such as water, alcohol (for example, methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, N, N dimethylformamide, or a mixture thereof, but the reaction is adversely affected. It can be carried out in any other solvent as long as it does not exceed the above. A liquid base or acid can also be used as a solvent. The reaction temperature is not particularly limited and is usually under cooling or heating.

Production Method 2 The object compound (Ib) or its salt is the compound (III)
Alternatively, it can be produced by reacting the salt with compound (IV). This reaction is usually an acid (eg p
-Toluenesulfonic acid, etc.). Compound (IV) may be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.
The case where the hydroxysulfonyloxy group in R ⁷ is changed to a hydroxy group during the reaction is also included in the scope of the present invention.

Production Method 3 The object compound (Ic) or a salt thereof can be produced by subjecting the compound (V) or a salt thereof to an acylation reaction. Suitable acylating agent used in this acylation reaction, _{^{wherein: R 6 b -OH [VII]}} [ wherein R ³ _b is lower alkanoyl] or acylating agents or a reactive derivative conventionally represented by The salt is mentioned.

Suitable "lower alkanoyl" of the compound [VII] may be the same as the above "lower alkanoyl" moiety of "lower alkanoyloxy".
Suitable reactive derivative at the carboxy group of the compound [VII] includes acid halide, acid anhydride, activated amide, activated ester and the like. Suitable examples thereof include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, and sulfurous acid. , Thiosulfuric acid, sulfuric acid, sulfonic acid (eg methanesulfonic acid etc.), alkyl carbonic acid, aliphatic carboxylic acid (eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-
Mixed acid anhydrides with acids such as ethyl butyric acid or trichloroacetic acid) or aromatic carboxylic acids (such as benzoic acid); symmetrical acid anhydrides (such as acetic anhydride); imidazoles, 4-substituted imidazoles, dimethylpyrazole, Triazole, tetrazole or 1-hydroxy-1H-
Activated amides with benzotriazoles; activated esters (eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH
-] Ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester,
p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc., or N-hydroxy compound (for example, N, N-dimethylhydroxylamine, 1-
Hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.)
And the like. These reactive derivatives can be appropriately selected from these depending on the kind of the compound [VII] to be used.

Suitable salts of the compound [VII] and its reaction derivative may be the same as those exemplified for the salt of the compound (I).

The reaction is usually carried out in a conventional manner such as water, alcohol (eg methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. In any other organic solvent that does not adversely affect the reaction. These conventional solvents may be used as a mixture with water.

When the compound [VII] is used in this reaction in the form of a free acid or a salt thereof, the reaction is carried out by N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-
N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl)
Carbodiimide; N, N'-diethylcarbodiimide,
N, N'-diisopropylcarbodiimide; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis- (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene -N-cyclohexylimine;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; eg ethyl chloroformate, chloroformate Lower alkyl haloformates such as isopropyl acid; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2
-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; N, N-dimethylformamide and thionyl chloride, It is desirable to carry out in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by reaction with phosgene, phosphorus oxychloride and the like. The reaction also includes alkali metal carbonates, alkali metal hydrogen carbonates, tri (lower) alkylamines (eg triethylamine etc.), pyridine, di (lower) alkylaminopyridines (eg 4-dimethylaminopyridine etc.), N- (lower ) It is desirable to carry out in the presence of an inorganic or organic base such as alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. The reaction temperature is not particularly limited and is usually under cooling or heating.

Production Method 4 The object compound (Id) or a salt thereof can be produced by subjecting the compound (Ic) or a salt thereof to a hydrolysis reaction. Since this reaction can be carried out by substantially the same method as described in Production method 1, the description of Production method 1 can be applied to the reaction method and reaction conditions (for example, solvent, reaction temperature, etc.).

Production Method 5 The object compound (Ie) or a salt thereof can be produced by subjecting the compound (VI) or a salt thereof to an alkylation reaction. Suitable alkylating agents used in this reaction include: 1) as a substituent of one or more (preferably 1 to 3) “lower alkyl group optionally having one or more suitable substituents” Lower alkanals optionally having suitable substituents as exemplified (eg formaldehyde, ethanal, propanal, butanal, t-butanal, pentanal, hexanal, etc.),

2) Expression [Wherein R ¹² and R ¹³ are each lower alkyl as exemplified above]
A compound represented by: 3) formula (In the formula, the formula: Examples of the group represented by are cyclic aminium groups which may have other heteroatoms in the ring portion (eg, pyrirollidinium, piperidinium, piperazinium, morpholinium, etc.) and the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol (for example, methanol, ethanol, propanol, etc.), methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N-dimethylformamide, acetone. Alternatively, it is carried out in any other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited and is usually under cooling or heating.

Production Method 6 The object compound (Ig) or a salt thereof can be produced by subjecting the compound (If) or a salt thereof to a hydrolysis reaction. Since this reaction can be carried out by substantially the same method as described in Production method 1, the description of Production method 1 can be applied to the reaction method and reaction conditions (for example, solvent, reaction temperature, etc.).

Production Method 7 The object compound (Ii) or its salt can be produced by reacting the compound (Ih) or its salt with the compound (VIII). This reaction is carried out by tri (lower) alkylamine (eg trimethylamine, triethylamine etc.), pyridine, di (lower) alkylaminopyridine (eg 4-dimethylaminopyridine etc.), N- (lower) alkylmorpholine, N, N-di ( It is desirable to carry out in the presence of an inorganic or organic base such as (lower) alkylbenzylamine. The reaction will usually adversely affect conventional solvents or reactions such as alcohols (eg, methanol, ethanol, propanol, etc.), methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, N, N-dimethylformamide, acetone. Done in any other solvent that does not affect. The reaction temperature is not particularly limited and is usually under cooling or heating.

Production Method 8 The object compound (Ik) or its salt can be produced by reacting the compound (Ij) or its salt with the compound (VIII). Since this reaction can be carried out in substantially the same manner as in production method 7, the reaction conditions (for example, reaction temperature, solvent etc.) described in production method 7 can be applied correspondingly.

Production Method 9 The object compound (Im) or a salt thereof can be produced by subjecting the compound (Il) or a salt thereof to a reaction for eliminating a carboxy protecting group. This reaction is carried out by a conventional method such as hydrolysis or reduction. The hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include alkali metals (eg sodium,
Potassium, etc.), alkaline earth metals (eg magnesium, calcium etc.), hydroxides or carbonates or hydrogen carbonates thereof, trialkylamines (eg trimethylamine, triethylamine etc.), picoline, 1,5-
Diazabicyclo [4.3.0] non-5-ene, 1,4
There may be mentioned inorganic bases or organic bases such as -diazabicyclo [2.2.2] octane and 1,8-diazabicyclo [5.4.0] -undec-7. Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid,
Hydrogen chloride, hydrogen bromide, ammonium chloride and the like). The elimination reaction using a Lewis acid such as trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.) is preferably carried out in the presence of a cation scavenger (eg, anisole, phenol, etc.). The reaction is usually water, alcohol
In a solvent such as methanol (e.g. methanol, ethanol, etc.), tetrahydrofuran, methylene chloride, mixtures thereof, or any other solvent that does not adversely influence the reaction. A liquid base or acid can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Examples of the reduction method that can be used in the elimination reaction include chemical reduction and catalytic reduction.
Suitable reducing agents used for chemical reduction include metals (eg tin, zinc, iron etc.) or metal compounds (eg chromium chloride, chromium acetate etc.) and organic or inorganic acids (eg formic acid, acetic acid, propionic acid, trifluoro). A combination of acetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts used for catalytic reduction include platinum catalysts (eg platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg palladium sponge, palladium black, palladium oxide, palladium). -Carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, etc.), nickel catalyst (eg, reduced nickel, nickel oxide, Raney-nickel, etc.), cobalt catalyst (eg, reduced cobalt, Raney-cobalt, etc.), iron catalyst ( Reduced iron,
Raney iron, etc.), a copper catalyst (for example, reduced copper, Raney copper, Ullmann copper, etc.) and the like. The reduction is usually carried out in conventional solvents which do not adversely influence the reaction, such as water, methanol.
It is carried out in a solvent such as toluene, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof. Further, when the acid used for chemical reduction is liquid, these can be used as a solvent. The reaction temperature for reduction is not particularly limited, but the reaction is usually performed under cooling or heating.

Production Method 10 The object compound (Io) or a salt thereof can be produced by subjecting the compound (In) or a salt thereof to a reaction for eliminating a carboxy protecting group. Since this reaction can be carried out in substantially the same manner as in production method 9, the reaction conditions (for example, reaction temperature, solvent etc.) described in production method 9 can be applied correspondingly.

Production Method 11 The object compound (Iq) or a salt thereof can be produced by subjecting the compound (Ip) or a salt thereof to a ketalization reaction. This reaction can be carried out by a method usually used for ketalization (for example, the method described in Examples below). The starting compound [II] can be produced by the fermentation and synthetic methods disclosed in European Patent EP0462531A2. The strain Coleophoma sp. Used in the above fermentation method. F-
11899 is No. 19 as FERM BP-2635.
It has been deposited at the Institute of Microbial Technology, Institute of Industrial Technology (Postal code 305, 1-3 1-3 Higashi, Tsukuba, Ibaraki, Japan) on October 26, 1989.

The biological data of typical compounds are shown below to show the usefulness of the polypeptide compound (I) of the present invention. Test method : antibacterial activity The in vitro antibacterial activity of the compound of Example 3 (hereinafter referred to as compound I) described below was measured by the following agar plate multiple dilution method. Each test strain was cultivated overnight in Sabouraud broth containing 2% glucose, and 1 platinum loop (viable cell count 10 ⁵ cells / ml) was added to each test strain containing Compound (I) at each concentration step. -Stonitrogen base Dextrose agar (YNBD agar) was inoculated and incubated at 30 ° C for 24 hours, after which the minimum inhibitory concentration (MIC)
Was expressed in μg / ml. As is clear from the above test results, the polypeptide compound (I) of the present invention has antibacterial activity (particularly antifungal activity).

The pharmaceutical composition of the present invention comprises rectal inhalation, pulmonary inhalation (inhalation from nasal cavity or mouth), nasal administration, eye administration, external administration (local administration), oral administration, parenteral administration (subcutaneous, subcutaneous, Conventional pharmaceutical preparations containing the polypeptide compound (I) and salts thereof as active substances in admixture with organic or inorganic carriers or excipients suitable for (intravenous, intramuscular injection) solid forms,
It can be used in a semi-solid or liquid form. The active ingredient is mixed with a conventional non-toxic pharmaceutically acceptable carrier and is in a suitable dosage form such as tablets, pellets, troches, capsules, suppositories, ointments, aerosols, powders for inhalation or solutions, emulsions, It may be used in the form of a suspension or the like. If necessary, auxiliary agents, stabilizers, thickening agents and coloring agents, and fragrances may be used in the above formulations.

The amount of the polypeptide compound (I) and its salt contained in this pharmaceutical composition is an amount sufficient to exert a desired antibacterial effect on a disease process and state. When applied to humans, it is preferably performed by intravenous injection, intramuscular injection, inhalation into the lung, or oral administration. The dose of the polypeptide compound (I) varies depending on conditions such as the age of the patient to be treated and the degree of disease. Generally, polypeptide compound 1 for intravenous injection
The daily dose is about 0.01 to 20 mg / kg, and the intramuscular injection is a polypeptide compound. The daily dose is about 0.1 to 20 mg / k.
g, in the case of oral administration, a daily dose of the polypeptide compound of about 0.5 to 50 mg / kg may be used for treating or preventing infectious diseases. For administration by inhalation, the compounds of this invention are conveniently used in the form of an aerosol spray from a compressed container or nebulizer. This compound may be formed and used as a powder. The powder composition may be inhaled with the aid of an inhaler for inhalable powders. The preferred inhalation method is a calibrated inhalation aerosol.
It may be formed as a suspension or solution of a compound in a suitable propellant such as fluorocarbon or hydrocarbon. Inhalation is also a desirable method, especially when the infection has spread to the ears and other body cavities. In addition, intravenous administration by infusion is used as parenteral administration. Hereinafter, the present invention will be described in more detail with reference to manufacturing examples and examples.

Production Example 1 1 -Ethoxymethylpiperidine (1 g) was added to an acetonitrile solution of methyltrichlorosilane (0.82 ml) under ice cooling, and the mixture was stirred at the same temperature for 5 minutes. Diethyl ether
Tellurium, the precipitate formed is filtered off, dried and
Methylene piperidinium chloride (0.88 g) is obtained. IR (Nujol): 3100, 2700,
1420, 1110, 920 cm ^-1 EI-MS: e / z = 133 (M +).

[0053]Production example 2 10 of 6-hydroxy-2-naphthoic acid (1.04 g)
% Aqueous sodium hydroxide solution (4.44 ml) and dimethy
Solution of a mixture of lusulfoxide (18 ml) at 80 ° C.
Stir for half an hour. Heptyl bromide (0.872 ml)
And stirred at 60 ° C. for 5 hours. The reaction mixture with water
(50 ml), adjust the mixture to pH 3 with concentrated hydrochloric acid
To do. The precipitate formed is filtered off and dried to give 6-heptyl.
Oxy-2-naphthoic acid (1.39 g) is obtained. IR (Nujol): 1660, 1620, 121
0 cm^-1  NMR (DMSO-d₆, Δ): 0.88 (3H,
t, J = 6.6 Hz), 1.2-1.6 (8H,
m), 1.7-1.9 (2H, m), 4.10
(2H, t, J = 6.5Hz), 7.18 (1
H, dd, J = 8.9 Hz and 2.4H
z), 7.35 (1H, d, J = 2.4 Hz),
 7.79 (1H, d, J = 8.6Hz), 7.
9-8.1 (2H, m), 8.45 (1H, s)

Preparation Example 3 1-Ethyl-3- (3
Add dimethylaminopropyl) carbodiimide hydrochloride (1.21 g) and stir at room temperature for 3 hours. The reaction mixture is taken up in water (100 ml). Separate the organic layer,
It is dried over magnesium sulfate, magnesium sulfate is filtered off, and the solvent of the filtrate is distilled off under reduced pressure to obtain 6-heptyloxy-2-naphthoic acid succinimide (1.48 g). IR (Nujol): 1760, 1740, 1
620 cm ^-1 NMR (CDCl ₃ , δ): 0.91 (3H,
t, J = 6.6 Hz), 1.2-1.6 (8H,
m), 1.7-2.0 (2H,
m), 2.93 (4H, s), 4.10 (2H,
t, J = 6.5 Hz), 7.
1-7.3 (2H, m), 7.77 (1H,
d, J = 8.6 Hz), 7.84 (1H, d, J
= 8.6 Hz), 8.03 (1H, dd, J =
8.9 Hz and 2.4 Hz), 8.65 (1H,
s)

[0055]Production Example 4 Bromoacetic acid (10 g) in tetrahydrofuran (300 m
l) Add diphenyldiazomethane (28 g) to the solution and add
Stir at warm temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue
The distillate is purified by silica gel chromatography and
Molybdenum benzhydryl ester (5.4 g) is obtained.  NMR (CDCl_Three) Δ: 3.91 (s, 2H),
6.91 (s, 1H), 7.2-7.5 (m, 10H) IR (neat): 3020, 1720, 1260, 1
140 cm^-1

The starting compounds used in the following Production Examples and Examples and the target compounds obtained are shown in the following tables, the formulas of the starting compounds are shown in the upper row, and the formulas of the target compounds are shown in the lower row. . In the table below, Ph means a phenyl group.

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

Production Example 5 Starting compound (2.8 g) and 6-heptyloxy-2-
A solution of naphthoic acid succinimide (1.46 g) in N, N-dimethylformamide (28 ml) was added with 4- (N, N).
-Dimethylamino) pyridine (0.393 g) was added,
Stir for 12 hours at room temperature. The reaction mixture is triturated with ethyl acetate (140ml). The precipitate is filtered off and the solvent is dried under reduced pressure. The powder obtained was placed in water (50 ml) and the DOWEX 50WX4 (trademark:
It is subjected to ion exchange column chromatography (Dow Chemical Company) and eluted with water. Fractions containing the target compound are combined and subjected to column chromatography of ODS (YMC-gelODS-AMS-50) (trademark: manufactured by Yamamura Chemical Laboratory), and eluted with 50% aqueous methanol solution. The fractions containing the target compound are combined and the methanol is distilled off under reduced pressure. The residue is freeze-dried to obtain the target compound (1.94 g).

IR (Nujol): 3300,
1620 cm ^-1 NMR (CD ₃ OD, δ): 0.92 (3H,
t, J = 6.6 Hz), 1.06 (3H, d,
J = 6. 8Hz), 1.24 (3H,
d, J = 6.1 Hz), 1.3-1.7 (8H,
m), 1.7-2.3 (5H, m),
2.3-2.7 (3H, m), 2.8-2.9 (1
H, m), 3.39 (1H, m), 3.7-
4.7 (16H, m), 4.99 (1H, m
d, J = 2 Hz), 5.10 (1H, d, J
= 3.7 Hz), 5.36 (1d, J = 2.9H)
z), 6.86 (1H, d, J = 8.3H
z), 7.05 (1H, dd, J = 8.3 Hz)
and 2 Hz), 7.17 (1H, d
d, J = 8.9 Hz and 1.9 Hz), 7.
23 (1H, d, J = 2 Hz), 7.32 (1
H, d, J = 1.9 Hz), 7.7-7.9 (3
H, m), 8.31 (1H, s) FRB-MS e / z = 1249 (M + Na).

Example 1 A solution of the starting compound (0.2 g) in N, N-dimethylformamide (2 ml) and acetone (2 ml) was added,
Glyoxylic acid (0.155 g) is added at room temperature in the presence of molecular sieves 4Å. The mixture is stirred at the same temperature for 5 hours. The reaction mixture is triturated with ethyl acetate (20ml). The precipitate is collected by filtration and the solvent is dried under reduced pressure to obtain the target compound (0.14g). NMR (CD ₃ OD, δ): 0.90
(T, 3H, J = 6, 6Hz), 1.05
(D, 3H, J = 6.7 Hz), 1.24 (d,
3H, J = 6.0 Hz), 1.2-1.6
(M, 10H), 1.7-1.9 (m, 2H),
1.9-2.2 (m, 3H), 2.3-2.6
(M, 3H), 2.7-2.9 (m, 1
H), 3.40 (m, 1H), 3.7-4.7.
(M, 16H), 4.98 (s, 1H),
5.09 (brs, 1H), 5.31 (br
s, 1H), 5.40 (s, 1H), 6.8
-7.2 (m, 4H), 7.33 (s, 1
H), 7.85 (d, 2H, J = 8.4H
z). FAB-MS: e / z = 1287 (M +
Na)

Example 2 The target compound is obtained in the same manner as in Example 1. NMR (CD ₃ OD, δ): 0.90
(T, 3H, J = 6, 6Hz), 1.05
(D, 3H, J = 6.7 Hz), 1.24 (d,
3H, J = 6.1 Hz), 1.2-1.6
(M, 10H), 1.7-1.9 (m, 2H),
1.9-2.2 (m, 3H), 2.3-2.6
(M, 3H), 2.7-2.9 (m, 1
H), 3.42 (m, 1H), 3.7-4.7.
(M, 16H), 4.98 (s, 1H),
5.09 (d, 1H, J = 3.8Hz), 5.
31 (d, 1H, J = 2.8 Hz), 5.44
(S, 1H), 6.60 (dd, 1H, J =
8.1, 1.9 Hz), 6.72 (d, 1H,
J = 8.1 Hz), 6.82 (d, 1H, J =
1.9 Hz), 6.95 (d, 2H, J = 8.8)
Hz) 7.84 (d, 2H, J = 8.8H
z). IR (Nujol): 3250, 1610
cm ^-1 FAB-MS: e / z = 1185 (M +
Na) Elemental analysis As C ₅₂ H ₇₃ N ₈ O ₂₂ Na.7H ₂ O, calculated value: C 47.63, H 6.76, N
8.54 Found: C 47, 56, H 6.66, N
8.35

Example 3 A solution of the crude starting compound (3.1 g) in N, N-dimethylformamide (31 ml) was added glyoxylic acid (1.25 g) at room temperature in the presence of molecular sieves 4Å. The mixture is stirred at the same temperature for 5 hours. The reaction mixture is triturated with ethyl acetate (150ml). The precipitate is filtered off and the solvent is dried under reduced pressure. The powder was put in water (70 ml), and Dowex 50WX4 (trademark: manufactured by Dow Chemical Co.) (15
ml) ion-exchange column chromatography,
Elute with water. Combine the fractions containing the target compound, and c18
μ Bondapak resin (water)
Associates, Milf, Massachusetts
D)) and the LC-8A pump (manufactured by Shimadzu Corporation) at a flow rate of 80 ml for 1 minute,
Acetonitrile-pH3 phosphate buffer (44:56)
Elute with a solvent system consisting of. The column is 240 nm
Then, monitor with a UV detector. Fractions containing the target compound (main) with a retention time of 14.8 minutes are combined, and acetonitrile is distilled off under reduced pressure. The residue is converted to ODS (YMC-gelODS
-AMS-50) (trademark: manufactured by Yamamura Chemical Laboratory), washed with water, and eluted with 80% aqueous methanol solution. The fractions containing the target compound are combined and the methanol is distilled off under reduced pressure. The residue is freeze-dried to obtain the target compound (main). NMR (CD ₃ OD, δ): 0.91
(T, 3H, J = 6.7 Hz), 1.05
(D, 3H, J = 6.7 Hz), 1.25 (d,
3H, J = 5.9 Hz), 1.2-1.6
(M, 10H), 1.7-2.0 (m, 2H),
2.0-2.3 (m, 3H), 2.3-2.8
(M, 3H), 2.98 (m, 1H),
3.37 (m, 1H), 3.7-4.8 (m,
16H), 4.97 (m, 1H), 5.11
(M, 1H, 5.38 (d, 1H, J = 2
Hz), 5.70 (s, 1H), 6.61 (d
d, 1H, J = 8.1, 1.7 Hz), 6.72
(D, 1H, J = 8.1 Hz) 6.81
(D, 1H, J = 1.7 Hz) 7.15 (dd,
1H, J = 8.7, 1.7 Hz), 7.21
(D, 1H, J = 1.7 Hz) 7.75 (d,
1H, J = 8.7 Hz) 7.88 (d, 2H,
J = 8.7 Hz), 8.39 (s, 1H) FAB-MS: e / z = 1235 (M +
Na) as the element analysis _{C 56 H 75 N 8 NaO 22} · 6H 2 O, Calculated: C 50.22, H 6.54, N 8.
36 Found: C 50.26, H 6.39, N 8.
38

The target compound (the smaller one) with a retention time of 9.87 minutes is obtained in the same manner as the target compound (main). NMR (CD ₃ OD, δ): 0.91
(T, 3H, J = 6.7 Hz), 1.06
(D, 3H, J = 6.7 Hz), 1.2-1.6
(M, 13H), 1.7-2.3 (m, 5
H), 2.3-3.0 (m, 4H), 3.34.
(M, 1H), 3.6-4.7 (m, 16H),
4.98 (m, 1H), 5.11 (m, 1
H), 5.35 (d, 1H, J = 2Hz),
5.51 (s, 1H), 6.86 (d, 1H,
J = 8.3 Hz), 7.04 (d, 1H, J
= 8.3 Hz) 7.1-7.25 (m, 2H),
7.33 (s, 1H), 7.6-8.0
(M, 3H), 8.35 (s, 1H) Elemental analysis As C ₅₆ H ₇₅ N ₈ O ₂₅ SNa · 7H ₂ 0, calculated value: C 46.66, H 6.22, N
7.77 Found: C 46.63, H 6.01, N
7.74

Example 4 To a solution of the starting compound (1g) in N, N-dimethylformamide (10ml) was added 1-methylenepiperidinium chloride (0.169g) at room temperature in the presence of 4Å molecular sieves. The mixture is stirred at the same temperature for 5 hours. The reaction mixture is triturated with ethyl acetate (50 ml). The precipitate is filtered off and the solvent is dried under reduced pressure. The end of the water (20m
1), and the mixture is subjected to ion exchange column chromatography using Dowex 50WX4 (trademark: manufactured by Dow Chemical Co.) (15 ml) and eluted with water. Fractions containing the target compound were combined and combined with ODS (YMC-gelODS-AMS-
50) Subject to column chromatography (trademark: manufactured by Yamamura Chemical Laboratory Co., Ltd.) and elute with 40% aqueous methanol solution. Fractions containing the target compound were combined and concentrated under reduced pressure.
Distill Le.

The residue was lyophilized to give the desired compound (0.90
g) is obtained. NMR (DMSO-d₆, Δ): (Sulfurization of the target compound
The acid ester has not been deesterified in the NMR measurement state.
There is a possibility. ) 0.86 (t, 3H, J = 6.7 Hz), 0.
96 (d, 3H, J = 6.7 Hz), 1.0
3, (d, 3H, J = 6.0 Hz), 1.2-
1.5 (m, 10H), 1.5-2.0 (m,
 11H), 2.1-2.5 (m, 4H), 2.
6-3.0 (m, 4H), 3.17 (m, 1
H), 3.6-4.5 (m, 18H), 4.7.
8 (d, 2H, J = 5.9 Hz), 4.8-5.
3 (m, 8H), 5.48 (d, 1H, J =
5.9 Hz), 6.72 (d, 1H, J = 8.
2Hz), 6.81 (d, 1H, J = 8.2H
z), 6.98 (d, 2H, J = 8.8 Hz),
 7.04 (s, 1H), 7.35 (d, 1
H, J = 6.7 Hz), 7.45 (d, 1
H, J = 8 Hz), 7.86 (d, 2H,
J = 8.8 Hz), 8.12 (d, 1H, J
= 8 Hz) 8.24 (d, 1H, J = 8H
z), 8.64 (m, 2H), 8.85
(S, 1H), 9.8 (s, 1H) IR (Nujol): 3300, 1620,
 1240, 1040 cm^-1

[0081]Example 5 The target compound is obtained in the same manner as in Example 4. NMR  (DMSO-d₆, Δ): (of the target compound
Sulfate ester is deesterified under NMR measurement
There is a possibility that ) 0.86 (t, 3H, J = 6.7 Hz), 0.
96 (d, 3H, J = 6.8 Hz), 1.0
3, (d, 3H, J = 6.0 Hz), 1.2-
1.5 (m, 10H), 1.6-2.0 (m,
 5H), 2.1-2.5 (m, 4H), 2.
69 (s, 6H), 3.24 (s, 1H),
 3.73 (m, 2H), 3.9-4.7
(M, 16H), 4.8 (m, 2H), 4.9
-5.5 (m, 9H), 6.71 (d, 1
H, J = 8.2 Hz), 6.81 (d, 1H,
 J = 8.2 Hz) 6.99 (d, 2H, J =
8.8 Hz), 7.11 (s, 1H), 7.2
-7.5 (m, 2H), 7.85 (d, 2
H, J = 8.8 Hz), 8.14 (d, 1H,
 J = 8 Hz), 8.29 (d, 1H, J =
7.3 Hz), 8.6-8.8 (m, 2H),
8.84 (s, 1H), 9.38 (s, 1H) IR (Nujol): 3300, 1620,
 1500, 1240 cm^-1 FAB-MS: e / z = 1248 (M +
Na) Elemental analysis C₅₃H₇₉N₉O_{twenty two}S ・ 6H₂As O 2, calculated values: C 47.70, H 6.87, N 9.
44 Found: C 47.47, H 6.83, N 9.
34

Example 6 To a solution of the starting compound (0.5 g) in N, N-dimethylformamide (10 ml) was added acetic anhydride (0.119 ml) in the presence of molecular sieve 4Å, and then under ice cooling. Add triethylamine (0.175 ml) at. The mixture is stirred under ice cooling for 5 hours. The reaction mixture is triturated with ethyl acetate (50 ml). The precipitate is filtered off and the solvent is dried under reduced pressure. The powder is put in water (20 ml) and the Dowex 50WX4 (trademark: Dow Chemical Co.) (15 m
l) Ion exchange column chromatography-ion exchange. Then, it is eluted with water. Fractions containing the target compound were combined and combined with ODS (YMC-gelODS-AMS
-50) (Trademark: manufactured by Yamamura Chemical Laboratory Co., Ltd.), and eluted with 40% aqueous methanol solution. Fractions containing the target compound were combined and concentrated under reduced pressure.
Distill Le.

The residue was lyophilized to give the desired compound (104 m
g) is obtained. NMR (CD ₃ OD, δ): 0.90
(T, 3H, J = 6.7 Hz), 1.07
(D, 3H, J = 6.8 Hz), 1.20
(D, 3H, J = 6.1 Hz), 1.3-1.6
(M, 10H), 1.7-1.9 (m, 2
H), 1.9-2.2 (m, 3H), 2.29.
(S, 3H), 2.2-2.6 (m, 3
H), 2.7-2.9 (m, 1H), 3.39.
(M, 1H), 3.7-4.7 (m, 16
H), 4.98 (s, 1H), 5.10.
(D, 1H, J = 3.5 Hz), 5.32
(D, 1H, J = 2.8 Hz) 6.93 (d,
2H, J = 8.9 Hz), 7.09 (d, 1
H, J = 8.3 Hz), 7.19 (dd, 1
H, J = 8.3, 1.7 Hz), 7.60 (d,
1H, J = 1.7 Hz), 7.80 (d,
2H, J = 8.9 Hz) IR (Nujol): 3300, 1740,
1600, 1040 cm ^-1 FAB-MS: e / z = 1255 (M +
Na) Elemental analysis As C ₅₂ H ₇₃ N ₈ NaO ₂₃ S.6H ₂ 0, calculated value: C 46.56, H 6.38, N 8.
35 Found: C 46.62, H 6.38, N 8.
23

Example 7 The target compound is obtained in the same manner as in Example 9. NMR (DMSO-d6, δ): 0.86
(T, 3H, J = 6.6Hz), 0.95
(D, 3H, J = 6.7 Hz), 1.06
(D, 3H, J = 5.9 Hz), 1.2-2.0
(M, 15H), 2.1-2.7 (m, 4
H), 3.15 (dd, 1H, J = 6.6H)
z), 3.73 (m, 2H), 3.8-4.5.
(M, 14H), 4.7-5.2 (m, 10
H), 5.49 (d, 1H, J = 5.5H
z), 6.41 (d, 1H, J = 8.1H
z), 6.61 (d, 1H, J = 8.1H
z), 6.70 (s, 1H), 6.85 (s,
1H), 6.96 (d, 2H, J = 8.8H
z), 7.2-7.5 (m, 3H), 7.8
6 (d, 2H, J = 8.8 Hz), 8.04
(D, 1H, J = 8 Hz), 8.32 (d,
1H, J = 7.3 Hz), 8.54 (d, 1H,
J = 6.7 Hz), 8.79 (s, 2H) IR (Nujol): 3300, 1620.
cm ^-1 FAB-MS: e / z = 1112 (M +
Na) as the elemental analysis _{C 50 H 72 N 8 O 19} · 4H 2 0, Calcd: C 51.71, H 6.94, N 9.
64 Found: C 51.67, H 6.96, N 9.
54

Example 8 The target compound is obtained in the same manner as in Example 9. NMR (DMSO-d ₆ , δ): 0.86
(T, 3H, J = 6.7 Hz), 0.96
(D, 3H, J = 6.8 Hz), 1.06
(D, 3H, J = 5.9 Hz), 1.2-2.0
(M, 15H), 2.23 (s, 3H),
2.1-2.7 (m, 4H), 3.17 (dd,
1H, J = 6.6 Hz), 3.73 (m, 2
H), 3.8-4.5 (m, 14H), 4.7.
-5.4 (m, 10H), 5.49 (d, 1
H, J = 5.5 Hz), 6.7-7.1 (m, 5
H), 7.2-7.5 (m, 3H), 7.86
(D, 2H, J = 8.8 Hz), 8.09
(D, 1H, J = 8 Hz), 8.30 (d,
1H, J = 7.3 Hz), 8.59 (d, 1H
J = 6.7 Hz), 9.57 (s, 1H) IR (Nujol): 3300, 1620,
1250 cm ^-1 FAB-MS: e / z = 1153 (M +
Na) as the element analysis _{C 52 H 74 N 8 O 20} · 5H 2 0, Calcd: C 51.14, H 6.93, N 9.
17 Found: C 51.05, H 7.00, N 9.
06

Example 9 Trifluoroacetic acid (30.9 μl) was added to a solution of the starting compound (0.5 g) in N, N-dimethylformamide (5 ml).
And water (5 μl) are added at room temperature, and the mixture is stirred at the same temperature for 6 hours. The reaction mixture is triturated with ethyl acetate (50 ml). The precipitate is filtered off and the solvent is dried under reduced pressure. Put the powder in water and add ODS (YMC-gelODS-AMS-5
0) (trademark: manufactured by Yamamura Chemical Laboratory), and eluted with a 45% aqueous methanol solution.
The fractions containing the target compound are combined and the methanol is distilled off under reduced pressure. The residue was lyophilized to give the desired compound (99.0 m
g) is obtained. NMR (DMSO-d ₆ , δ): 0.86
(T, 3H, J = 6.6 Hz), 0.96
(D, 3H, J = 6.6 Hz), 1.02
(D, 3H, J = 5.9 Hz), 1.2-1.5
(M, 10H), 1.6-2.0 (m, 5
H), 2.1-2.7 (m, 4H), 2.68.
(S, 6H), 3.2 (m, 1H), 3.7
3 (m, 2H), 3.8-4.6 (m, 16
H), 4.7-5.5 (m, 11H), 6.7.
4 (d, 1H, J = 8Hz), 6.76
(D, 1H, J = 8 Hz), 6.99 (d,
2H, J = 8.7 Hz), 7.11 (s, 1
H), 7.2-7.5 (m, 2H), 7.85.
(D, 2H, J = 8.7 Hz) 8.09 (d,
1H, J = 8Hz), 8.32 (d, 1H,
J = 7.3 Hz), 8.67 (m, 2H),
8.84 (s, 1H), 9.40 (s, 1
H) IR (Nujol): 3300, 1600
cm ^-1 FAB-MS: e / z = 1147 (M +
1) Elemental analysis _{C 53 H 79 N 9 O 19} · CF 3 COOH · 9H 2 0
As calculated value: C 46.44, H 6.94, N 8.
86 Found: C 46.71, H 6.82, N 9.
Thirteen

Example 10 The object compound is obtained in the same manner as in Example 9. NMR (CD ₃ OD, δ): 0.91
(T, 3H, J = 6.7 Hz), 1.05
(D, 3H, J = 6.8 Hz), 1.23
(D, 3H, J = 4.9 Hz), 1.2-1.6
(M, 10H), 1.7-2.0 (m, 2
H), 2.0-2.35 (m, 3H), 2.4.
-2.7 (m, 3H), 2.91 (m, 1
H), 3.37 (m, 1H), 3.82
(D, 1H, J = 10 Hz), 3.92 (d,
1H, J = 10 Hz), 4.1-4.8 (m,
14H), 5.00 (m, 1H), 5.10
(D, 1H, J = 3.8 Hz), 5.39
(D, 1H, J = 2.3 Hz), 6.62
(D, 1H, J = 8.1 Hz) 6.74 (d,
1H, J = 8.1 Hz), 6.80 (s, 1
H), 8.29 (s, 1H) IR (Nujol): 3300, 1620,
1500, 1210 cm ^-1 FAB-MS: e / z = 1161 (M +
Na)

Example 11 A solution of the starting compound (1 g) in methanol (10 ml) was added with p.
-Toluenesulfonic acid (0.08g) was added at room temperature,
Stir for 12 hours at the same temperature. The reaction mixture is triturated with ethyl acetate (50 ml). The precipitate is filtered off and the solvent is dried under reduced pressure. Add the powder to a 50% aqueous solution of methanol,
Preparative HPLC using c18μ Bondapak resin (Water Associates, Inc., Milfad, Mass.), Shimadzu LC-8.
Elute with a solvent system consisting of acetonitrile-pH3 phosphate buffer (42:58) at a flow rate of 80 ml for 1 minute using the A pump. The column is monitored at 240 nm with a UV detector. Fractions containing the target compound are combined, and acetonitrile is distilled off under reduced pressure. The residue is ODS (YMC-
gel ODS-AMS-50) (trademark: manufactured by Yamamura Chemical Laboratory), subjected to column chromatography, washed with water,
Elute with 80% aqueous methanol solution. The fractions containing the target compound are combined and the methanol is distilled off under reduced pressure.

The residue was lyophilized to give the desired compound (0.13
g) is obtained. NMR (CD ₃ OD, δ): 0.90
(T, 3H, J = 6.7 Hz), 1.06
(D, 3H, J = 6.9 Hz), 1.20 (d,
3H, J = 6.0 Hz), 1.3-1.6
(M, 10H), 1.6-1.9 (m, 2H),
1.9-2.2 (m, 3H), 2.3-2.
7 (m, 3H), 2.8-3.0 (m, 1
H), 3.34 (s, 3H), 3.38.
(M, 1H), 3.7-4.7 (m, 16H),
4.99 (m, 1H), 5.05-5.15
(M, 2H), 6.61 (dd, 1H, J =
8.1, 1.7 Hz), 6.72 (d, 1H, J
= 8.1 Hz), 6.80 (d, 1H, J =
1.7 Hz), 6.92 (d, 2H, J = 8.
9 Hz), 7.78 (d, 2H, J = 8.9H
z) IR (Nujol): 3250, 1620,
1500, 1250 cm ^-1 FAB-MS: e / z = 1125 (M +
Na)

Example 12 The target compound is obtained in the same manner as in Example 1. NMR (DMSO-d ₆ , δ): 0.88 (t, 3
H, J = 6.6 Hz), 0.96 (d, 3H,
J = 6.7 Hz), 1.12 (d, 3H, J = 5.
9 Hz), 1.2-2.0 (m, 13H), 2.
1-2.7 (m, 4H), 3.15 (m, 1
H), 3.5-4.5 (m, 18H), 4.7-
5.7 (m, 1H), 6.74 (d, 1H, J
= 8.2 Hz), 6.84 (d, 1H, J = 8.
5 Hz), 7.03 (s, 1H), 7.22
(D, 1H, J = 8.9 Hz), 7.36 (s,
1H), 7.5 (m, 1H), 7.83 (d,
1H, J = 8.8 Hz), 7.9-8.0 (m, 2
H), 8.0-8.3 (m, 3H), 8.49.
(S, 1H), 8.65 (m, 1H), 8.8
5 (brs, 1H) FAB-MS e / z = 1324 (M) Elemental Analysis: Elemental analysis C ₅₅ H ₇₂ N ₈ Na ₂ O ₂₅ S; 7H ₂ O, calculated value: C45.57, H5.98, N7.73 Found: C45.72, H5.87, N7.69.

Example 13 A solution of the starting compound (3.15 g) in N, N-dimethylformamide (32 ml) was added with trifluoroacetic acid (0.37 m).
A mixture of 1) and p-toluenesulfonic acid hydrate (0.5 g) is added at room temperature, and the mixture is stirred at the same temperature for 12 hours. The reaction mixture is triturated with ethyl acetate (300 ml). The precipitate was filtered off and the solvent was dried under reduced pressure to give the crude product (3.3
g) is obtained. The crude product (0.6 g) was added to water (100 ml)
In addition, the sample was subjected to preparative HPLC using c18μ Bondapak resin (Water Associates, Inc., Millfad, Mass.) For 1 minute using a Shimadzu LC-8A pump. Acetonitrile-pH 3 phosphate buffer (38: 6 at a flow rate of 80 ml).
Elute with the solvent system consisting of 2). The column is 240n
m, monitor with UV detector. Fractions containing the target compound with a retention time of 20 and 6 minutes are combined, and acetonitrile is distilled off under reduced pressure. The residue was adjusted to Ph6.5 with a saturated aqueous sodium hydrogen carbonate solution, and ODS (YMC-gelODS-
AMS-50) (trademark: manufactured by Yamamura Chemical Laboratory), subjected to column chromatography, washed with water, and eluted with 80% aqueous methanol solution. The fractions containing the target compound are combined and the methanol is distilled off under reduced pressure.

The residue was lyophilized to give the desired compound (147 m
g) is obtained.  NMR (DMSO-d₆, Δ); 0.88 (t, 3
H, J = 6.6 Hz), 0.94 (t, 2H,
J = 6.7 Hz), 1.09 (d, 3H, J = 5.
9 Hz), 1.2-2.0 (m, 13H), 2.
1-2.7 (m, 4H), 3.20 (m, 1
H), 3.6-4.5 (m, 18H), 4.7-
5.2 (m, 10H), 5.4-5.6 (m, 2
H), 6.44 (d, 1H, J = 8.2 Hz),
 6.6 (d, 1H, J = 8.2 Hz), 6.7
0 (s, 1H), 7.1-7.5 (m, 3
H), 7.7-8.2 (m, 6H), 8.3-
8.9 (m, 5H) IR (Nujol) 3300, 1
620 cm^-1

[0093]Example 14 The target compound is obtained in the same manner as in Example 4.  NMR (DMSO-d₆) Δ: 0.88 (t, 3H,
J = 6.8 Hz), 0.967 (d, 3H, J = 6.8)
Hz), 1.06 (d, 3H, J = 5.5 Hz), 1.
22-1.55 (m, 8H), 1.7-2.1 (m, 5)
H), 2.1-2.5 (m, 4H), 2.70 (s, 6)
H), 3.20 (m, 1H), 3.74 (m, 2H),
3.87-4.7 (m, 16H), 4.7-5.56
(M, 11H), 6.72 (d, 1H, J = 8.2H
z), 6.78 (d, 1H, J = 8.2 Hz), 7.1
0 (s, 1H), 7.24 (d, 1H, J = 8.9H
z), 7.3-7.5 (m, 3H), 7.8-8.0.
(M, 3H), 8.14 (d, 1H, J = 8Hz),
8.29 (d, 1H, J = 7.3 Hz), 8.43
(S, 1H), 8.67 (m, 1H), 8.83 (s,
1H), 8.75-8.85 (m, 1H), 9.38
(S, 1H) IR (Nujol): 3250, 1600 cm^-1 Elemental analysis C₅₆H₇₉N₉O₂₂As S, calculated value: C; 50.40, H; 6.57, N; 9.44 Measured value: C; 50.62, H; 6.79, N; 9.54

[0094]Example 15 The target compound is obtained in the same manner as in Example 9.  NMR (DMSO-d₆) Δ: 0.88 (t, 3H,
J = 6.8 Hz), 0.96 (d, 3H, J = 6.9H
z), 1.09 (d, 3H, J = 5.5 Hz), 1.2
-1.6 (m, 8H), 1.68-2.75 (m, 9
H), 2.12 (s, 6H), 3.20 (m, 1H),
3.74 (m, 2H), 3.8-4.6 (m, 16)
H), 4.7-5.23 (m, 10H), 5.51
(D, 1H, J = 5.8 Hz), 6.44 (d, 1H,
J = 8.9 Hz), 7.24 (d, 1H, J = 8.9H)
z), 6.70 (s, 1H), 7.1-7.5 (m, 4)
H), 7.8-8.2 (m, 6H), 8.3-8.5.
(M, 2H), 8.7-8.9 (m, 3H) IR (Nujol): 3200, 1600 cm^-1 Elemental analysis C₅₆H₇₉N₉O₁₉・ 6H_TwoO
Calculated value: C; 52.11, H; 7.10, N; 9.76 Measured value: C; 51.77, H; 7.04, N; 9.69

Example 16 The starting compound (25 g) was added to a mixed solvent of tetrahydrofuran (500 ml) and N, N-dimethylformamide (125 ml), and chlorotrimethylsilane (107 ml) and triethylamine (175.
5 ml) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound [A] (15.
57 g) was obtained. Potassium carbonate (0.249 g) and bromoacetic acid benzhydryl ester (1.10 g) were added to an N, N-dimethylformamide (25 ml) solution of compound [A] (5 g) under ice-cooling stirring, and the mixture was stirred for 3 hours as it was. . The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give two isomeric compounds [B] (1.
05 g) and compound [C] (1.619 g) were obtained. Compound [B] (1.05 g) was added to a mixed solvent of methanol (10.5 ml) and acetic acid (2.63 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to ether and pulverized, and the powder was collected by filtration and dried under reduced pressure. The powder is purified by silica gel chromatography to obtain the target compound (a).
(0.3 g) was obtained. The compound [C] was treated in the same manner as the compound [B] to obtain the target compound (II) (0.27 g).

Target compound [a]  NMR (DMSO-d₆) Δ: 0.86 (t, 3H,
J = 6.6 Hz), 0.95 (d, 3H, J = 6.6H)
z), 1.07 (d, 3H, J = 5.9 Hz), 1.2
-1.53 (m, 10H), 1.55-2.10 (m,
5H), 2.10-2.70 (m, 4H), 3.17.
(Dd, 1H, J = 6.6 Hz), 3.71 (m, 2
H), 3.8-4.6 (m, 15H), 4.7-5.7.
(M, 12H), 6.60-6.92 (m, 5H),
6.97 (d, 2H, J = 8.7 Hz), 7.2-7.
6 (m, 13H), 7.86 (d, 2H, J = 8.7H
z), 8.09 (d, 1H, J = 8 Hz), 8.31
(D, 1H, J = 7.3 Hz), 8.59 (d, 1H,
J = 6.7 Hz), 9.11 (brs, 1H) IR (Nujol): 3250, 1600 cm^-1 FAB-MS: e / z = 1335 (M + Na)

Target compound [b]  NMR (DMSO-d₆) Δ: 0.86 (t, 3H,
J = 6.6 Hz), 0.95 (d, 3H, J = 6.8H)
z), 1.07 (d, 3H, J = 5.9 Hz), 1.2
-1.55 (m, 10H), 1.6-2.1 (m, 5
H), 2.1-2.7 (m, 4H), 3.16 (dd,
1H, J = 6.6 Hz), 3.73 (m, 2H), 3.
8-4.6 (m, 15H), 4.7-5.6 (m, 12)
H), 6.52 (dd, 1H, J = 8.2, 1.5H
z), 6.74 (d, 1H, J = 8.2 Hz), 6.7.
9 (d, 1H, J = 1.5 Hz), 6.87 (m, 2
H), 6.97 (d, 2H, J = 8.9 Hz), 7.2
-7.6 (m, 13H), 7.86 (d, 2H, J =
8.9 Hz), 8.04 (d, 1H, J = 8 Hz),
8.32 (d, 1H, J = 7.3 Hz), 8.55
(D, 1H, J = 6.7 Hz), 9.12 (s, 1H) IR (Nujol): 3250, 1610, 1240,
1060 cm^-1 FAB-MS: e / z = 1335 (M + Na)

[0098]Example 17 The starting compound (0.3 g) was added to methanol (12 ml).
Add radium black (0.15g), under hydrogen, room temperature
For 15 minutes. The reaction mixture is filtered and the filtrate is depressurized.
Concentrate below and purify the residue by preparative liquid chromatography.
The target compound (102 mg) was obtained.  NMR (DMSO-d₆) Δ: 0.86 (t, 3H,
J = 6.6 Hz), 0.95 (d, 3H, J = 6.7H)
z), 1.06 (d, 3H, J = 5.9 Hz), 1.2
-1.6 (m, 10H), 1.6-2.15 (m, 5
H), 2.15-2.7 (m, 4H), 3.17 (d
d, 1H, J = 6.6 Hz), 3.74 (m, 2H),
3.9-4.7 (m, 13H), 4.52 (s, 2)
H), 4.7-5.6 (m, 12H), 6.60 (s,
1H), 6.73 (s, 2H), 6.84 (s, 1
H), 6.97 (d, 2H, J = 8.8 Hz), 7.2
-7.6 (m, 3H), 7.86 (d, 2H, J = 8.
8 Hz), 8.04 (d, 1H, J = 8 Hz), 8.3
1 (d, 1H, J = 7.3 Hz), 8.59 (d, 1
H, J = 6.7 Hz) IR (Nujol): 3250, 1610, 1240c
m^-1 FAB-MS: e / z = 1169 (M + Na) Elemental analysis C₅₂H₇₄N₈O₂₁Calculated value: C; 49.75, H; 6.90, N; 8.92 Measured value: C; 49.74, H; 6.98, N; 8.91

[0099]Example 18 The target compound is obtained in the same manner as in Example 17.  NMR (DMSO-d₆) Δ: 0.86 (t, 3H,
J = 6.6 Hz), 0.96 (d, 3H, J = 6.8H)
z), 1.07 (d, 3H, J = 5.9 Hz), 1.2
-1.6 (m, 10H), 1.6-2.2 (m, 5)
H), 2.2-2.7 (m, 4H), 3.17 (dd,
1H, J = 6.6 Hz), 3.7-4.6 (m, 17)
H), 4.7-5.6 (m, 12H), 6.54 (d,
1H, J = 8.5 Hz), 6.76 (d, 1H, J =
8.5 Hz), 6.74 (s, 1H), 6.84 (s,
1H), 6.96 (d, 2H, J = 8.8Hz), 7.
2-7.6 (m, 3H), 7.86 (d, 2H, J =
8.8 Hz), 8.04 (d, 1H, J = 8 Hz),
8.31 (d, 1H, J = 7.3 Hz), 8.59
(D, 1H, J = 6.7 Hz) IR (Nujol): 3300, 1620, 1250,
1050 cm^-1 FAB-MS: e / z = 1145 (M-Na-1) Elemental analysis C₅₂H₇₃N₈NaO₂₁Calculated value: C; 48.89, H; 6.70, N; 8.77 Actual value: C; 49.13, H; 6.81, N; 8.89

Example 19 A starting compound (0.2 g), 2, in a mixed solvent of N, N-dimethylformamide (2 ml) and acetone (2 ml).
2-Dimethoxypropane (0.206 ml), p-toluenesulfonic acid monohydrate (0.0319 g) and molecular sieves 4Å (3 grains) were added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with ethyl acetate (5
0 ml) and the resulting powder was collected by filtration and dried under reduced pressure. In addition to the powder and water (10 ml), DOWEX-5
Purified by ion exchange column chromatography using 0W × 4, then ODS (YMC-gelODS
-AMS-50) for purification by column chromatography. Fractions containing the desired product are collected, lyophilized,
The target compound (20 mg) was obtained. FAB-MS: e / z = 1293 (M + + Na)

Example 20 The synthesis method was performed in the same manner as in Example 19 except that the reaction was performed under ice cooling. IR (Nujol): 3300, 1620 cm ^-1 FAB-MS: e / z = 1253 (M ⁺ + Na).

It should be noted that the known compound [A] of the following formula or a salt thereof can be converted to the compound [B] of the following formula or a salt thereof by a method similar to the production methods 2, 3, and 5. is there. (In the formula, R ^a is an acyl group R ^b , R ^c , R ^f , and R ^g are each independently hydrogen or hydroxy R ^d is hydroxy, acyloxy, phosphoryloxy or sulfonyloxy R ^e is hydrogen or methyl R ^f ₁ is Hydrogen or lower alkoxy R ^h means each lower alkyl optionally having one or more suitable substituents)

Compound [A] is described in JP-A-1-163179,
3-163096, 4-217694, 4-21769
5,4-217696, 4-217697, 4-217
698, 4-217699.

Claims (3)

[Claims] 1. The formula:[In the formula, R¹Is a hydroxy group or a lower alkoxy group, R²Is a hydroxy group, R³Is an acyl group, R^Four  And R^FiveAre each hydroxy
Group, R⁶Is a hydroxy group, a lower alkanoyloxy group,
Carboxy (lower) alkoxy group or protected cal
Boxy (lower) alkoxy group, R⁷  Is a hydroxy group,
Hydroxysulfonyloxy group, carboxy (lower)
Lucoxy group or protected carboxy (lower) alk
Xy group, R⁸Has one or more hydrogen or suitable substituents
And a lower alkyl group which may be present. here
Where R¹And R²Or R^FourAnd R^FiveAre each
Combine and formula:(In the formula, R⁹And R^TenIs hydrogen or lower
(Meaning a kill group) may be formed.
Yes. (However, R⁶And R⁷When both are hydroxy groups
Is R³Is not a palmitoyl group)]
Thing and its salt. 2. The formula:[In the formula, R¹Is a hydroxy group or a lower alkoxy group, R²Is a hydroxy group, R³Is an acyl group, R^Four  And R^FiveAre each hydroxy
Group, R⁶Is a hydroxy group, a lower alkanoyloxy group,
Carboxy (lower) alkoxy group or protected cal
Boxy (lower) alkoxy group, R⁷  Is a hydroxy group,
Hydroxysulfonyloxy group, carboxy (lower)
Lucoxy group or protected carboxy (lower) alk
Xy group, R⁸Has one or more hydrogen or suitable substituents
And a lower alkyl group which may be present. here
Where R¹And R²Or R^FourAnd R^FiveAre each
Combine and formula:(In the formula, R⁹And R^TenIs hydrogen or lower
(Meaning a kill group) may be formed.
Yes. (However, R⁶And R⁷When both are hydroxy groups
Is R³Is not a palmitoyl group)]
And a salt thereof, which is represented by the formula (1):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶, And R⁸Is
Each has the same meaning as before, R⁷ _dIs hydroxysulfonyl
(Which means a xy group) or a salt thereof is added.
Following the water splitting reaction, the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶, And R⁸Is
The same meanings as before) or salts thereof
Or the expression (2):(In the formula, R², R³, R^Four, R^Five, R⁶, R⁷, And R⁸Is
Each has the same meaning as before) or
The salt has the formula: R¹ _a-H (In the formula, R¹ _aMeans a lower alkoxy group)
The compound of formula:(In the formula, R², R³, R^Four, R^Five, R⁶, R⁷, And R⁸Is
Each has the same meaning as before, R¹ _aMeans a lower alkoxy group
Or a salt thereof, or
Formula (3):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷ _d, And R⁸Is
Each has the same meaning as before) or
The salt is subjected to an acylation reaction to give the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷ _d, And R⁸Is
Each has the same meaning as before, and R⁶ _dIs a lower alkanoyloo
A compound represented by xy) or a salt thereof.
Or equation (4):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶ _d, R⁷ _d, And
And R⁸Each have the same meaning as before)
The compound or salt thereof is subjected to a hydrolysis reaction to obtain the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶ _d, And R⁸Is
Each has the same meaning as before) or
Obtaining the salt or formula (5):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁷ Is it
The same meaning as before) or a compound thereof
The salt is subjected to an alkylation reaction to give the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶, And R⁷ Is
Each has the same meaning as before, and R⁸ _aIs an appropriate substituent
The above means a lower alkyl group which may have)
Or a salt thereof, or a compound of formula (6):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶ And R⁸ _aIs it
Same meaning as before, R⁷ _aIs hydroxysulfonyloxy
(Meaning a group) or a salt thereof is hydrolyzed.
The equation for the reaction:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ _aIs it
The same meaning as before) or a compound thereof
Obtain salt or formula (7):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷ And R⁸Haso
The same meaning as before) or a salt thereof
Formula: R¹¹-X [wherein R¹¹Is a carboxy (lower) alkyl group or
Protected carboxy (lower) alkyl group, X is a leaving group
A compound represented by the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷And R⁸ Is it
Same meaning as before, R⁶ _aIs carboxy (lower) alkoxy
Si group or protected carboxy (lower) alkoxy group
Or a salt thereof, or
Or formula (8):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ Is it
The same meaning as before) or a compound thereof
Salt and formula: R¹¹-X (R in the formula¹¹, X is the same meaning as before)
React with the thing, the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ Haso
The same meaning as before, R⁷ _aIs carboxy (lower) Arco
Xy or protected carboxy (lower) alkoxy
Group), or a salt thereof.
Or, equation (9):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷And R⁸ Haso
The same meaning as before, R⁶ _bProtected carboxy (low
Class) meaning an alkoxy group) or
The salt is subjected to a carboxy protecting group elimination reaction to give the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁷And R⁸ Haso
The same meaning as before, R⁶ _cIs carboxy (lower) Arco
A compound represented by xy) or a salt thereof.
Or equation (10):(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ Haso
The same meaning as before, R⁷ _bProtected carboxy (low
Class) meaning an alkoxy group) or
The salt is subjected to a carboxy protecting group elimination reaction to give the formula:(In the formula, R¹ , R², R³, R^Four, R^Five, R⁶And R⁸ Haso
The same meaning as before, R⁷ _cIs carboxy (lower) Arco
A compound represented by xy) or a salt thereof.
Or equation (11):(In the formula, R³, R⁶, R⁷And R⁸ Each has the same meaning as before
Ketalize the compound represented by (Taste) or its salt
Add the reaction to the formula:[In the formula, R³, R⁶, R⁷ , R⁸Each has the same meaning as before,
R¹ _aAnd R² _aAre hydroxy groups or both
Combined, the formula:(In the formula, R⁹And R^TenIs hydrogen or lower
Forming a group represented by (meaning a kill group)
To obtain the compound or salt thereof.
A method for producing the above-mentioned polypeptide compound. 3. An antibacterial agent comprising the compound according to claim 1 or a salt thereof as an active ingredient.