JP2000229998A - New compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new polypeptide compound (salt) having antifungal activity, useful for preventing and treating a Pneumocystis carinii infection, etc. SOLUTION: This compound is shown by the formula I [R1 is H, an alkyl, a lower alkoxyalkyl, carboxyl or the like; R2 is a (substituted) carboxyl, a (substituted) heterocyclic carbonyl or the like; A is a lower alkylene; R11 is hydroxyl or a (substituted) lower alkoxy; R12 is a H or a halogen; R13 is H, nitro, amino or an acylamino; R11 and R13 are bonded to form a bifunctional group of formula II or formula III; R14 is cyano, a (substituted) carbamoyl, an amino (lower)alkyl or the like; Z is O or an N-R15 (R15 is H or an alkyl); and (p) is (CH2)n ((n) is 0 or 1)] such as a compound (salt) of formula IV. The compound of formula I is obtained, for example, by reacting a compound (salt) of formula V with a compound of the formula R4a-Y1 [R4a is a (substituted) lower alkyl; and Y1 is an eliminable group].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel polypeptide compound and a salt thereof. More specifically, the present invention has an antibacterial activity (especially an antifungal activity), an inhibitory activity against β-1,3-glucan synthesis, and a Pneumocystis carinii ( Pneumocystis californica) of human or animal body.
rinii ) Novel polypeptide compounds and salts thereof which are expected to be useful for treatment and prevention of infectious diseases (for example, Carini pneumonia), and methods for producing the same. Accordingly, an object of the present invention is to provide a novel antimicrobial agent which has high activity against various pathogenic bacteria and is expected to be useful for treating or preventing Pneumocystis carinii infections (eg, Carinii pneumonia) in humans and animals. It is to provide a polypeptide compound and a salt thereof.

[0002] Another object of the present invention is to provide a method for producing the above-mentioned polypeptide compound and a salt thereof. Still another object of the present invention is to provide an antibacterial agent containing the above-mentioned polypeptide compound and a salt thereof as an active ingredient.

[0003]

The polypeptide compound which is the object of the present invention is novel and is represented by the following general formula (I). [Wherein, R ¹ represents hydrogen, an alkyl group, a lower alkoxyalkyl group, a carboxy group, a carbamoyl group optionally having a substituent, an aryl group optionally having a suitable substituent, An ar (lower) alkyl group which may have a substituent, or a heterocyclic carbonyl group which may have a suitable substituent, R ² is a carboxy group, a protected carboxy group, or a suitable substituent A heterocyclic carbonyl group optionally having the following formula: (Wherein R ³ and R ⁴ may be the same or different and are hydrogen; or a lower alkyl group, a sulfamoyl group, a carbamoyl group, a lower alkanoyl group, each of which may have a suitable substituent, A lower alkoxycarbonyl group, an ar (lower) alkoxycarbonyl group, a heterocyclic carbonyl group, an aroyl group or a cyclo (lower) alkylcarbonyl group), or the following formula: (Wherein, R ⁵ may be the same or different and a lower alkyl group or a lower alkenyl group optionally having a suitable substituent, X represents an acid residue), A is a lower alkylene group, R ¹¹ is a hydroxy group or a lower alkoxy group optionally having a substituent, R ¹² is hydrogen or halogen, R ¹³ is hydrogen, a nitro group, an amino group, an acylamino group, or a bond between R ¹¹ and R ¹³ And the following equation R ¹⁴ is a cyano group, a carbamoyl group optionally having a substituent, an amino (lower) alkyl group or a protected amino (lower) alkyl group,
Z represents O or N—R ¹⁵ (where R ¹⁵ is hydrogen or an alkyl group), and P represents (CH ₂ ) _n (where n is 0 or 1). And a salt thereof.

When the compound (I) has stereoisomers due to asymmetric carbon atoms, each stereoisomer and a mixture thereof are also included in the present invention. Compound (I) can form solvates with water, ethanol, glycerol and the like, and such solvates are also included in the present invention.

[0005] The polypeptide compound (I) of the present invention can be produced according to the following reaction formula.

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[0018]

[Wherein R ¹ , R ² , R ³ , R ⁵ , A, R ¹¹ ,
^{R 12, R 13, R 14} , Z, and P are each as defined, R ³ _b: each suitable substituent a lower alkyl group optionally having a lower alkenyl group, a sulfonyl group, a carbamoyl group , A lower alkanoyl group, an ar (lower) alkoxycarbonyl group, a heterocyclic carbonyl group, an aroyl group,
Or cyclo (lower) alkylcarbonyl group, R ⁴ _a: Suitable optionally substituted lower alkyl group, R ⁴ _b: each suitable optionally substituted lower alkanoyl group, a sulfonyl Group, carbamoyl group, ar (lower) alkoxycarbonyl group, heterocyclic carbonyl group, aroyl group, cyclo (lower) alkylcarbonyl group R ⁶ : hydrogen or C _1- which may have a suitable substituent
C ₅ alkyl group, R ^7: an appropriate optionally substituted lower alkyl group, R ⁸ _a: lower alkanoyl group having an appropriate substituent having a protected carboxy group, R ⁸ _b: a carboxy group R ⁸ _c : a lower alkyl group having a suitable substituent having a protected carboxy group, R ⁸ _d : a suitable substituent having a carboxy group a lower alkyl group optionally having, R ^9: protected appropriate optionally substituted lower alkanoyl group having an amino group, R ^10: have a suitable substituent having an amino group X represents an acid residue, Y ^{1 represents a} leaving group, and Y ^{2 represents a} leaving group. ]

The abbreviations used in the present invention are shown below. Boc: t-butoxycarbonyl Me: methyl Et: ethyl Bu ^t: t-butyl Ph: phenyl Z: benzyloxycarbonyl Bzl: Benzyl TFA: trifluoroacetic acid AcOH: acetic acid

Suitable salts of compound (I) are conventional non-toxic mono- or di-salts, such as metal salts, such as alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt). Salts, magnesium salts, etc.), ammonium salts, organic bases and their salts (for example,
Trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N '
Organic acid addition salts (eg, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); Inorganic acid addition salts (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), amino acids (eg, arginine,
Aspartic acid, glutamic acid, etc.).

In the preceding and following description of this specification, preferred examples and explanations of various definitions included within the scope of the present invention are described in detail below. "Lower", unless otherwise indicated, shall mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. "Higher" shall mean 7 to 20 carbon atoms, preferably 7 to 15 carbon atoms, unless otherwise indicated.

Preferred "lower alkyl" is a straight-chain or branched-chain C 1 -C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, hexyl and the like. It means a residue of 6 alkanes, and preferred examples thereof include a C ₁ -C ₅ alkyl group. Suitable “C ₁ -C ₅ alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
Neopentyl and the like.

The preferred "heterocyclic" portion of the "heterocyclic carbonyl" is a saturated or unsaturated monocyclic or polycyclic heterocyclic group having at least one hetero atom such as an oxygen atom, a sulfur atom and a nitrogen atom. Examples of the ring group include a 3- to 8-membered (preferably 5- or 6-membered, unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl,
Pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,
2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc., tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc .; having 1 to 4 nitrogen atoms A 3- to 8-membered (preferably 5- or 6-membered) saturated heteromonocyclic group such as pyrrolidinyl, imidazolidinyl, piperidyl,
Piperazinyl and the like; unsaturated fused heterocyclic groups having 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl and the like; 1 to 2 oxygen atoms and nitrogen A 3- to 8-membered (preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 to 3 atoms, such as oxazolyl,
Isoxazolyl, oxadiazolyl (for example, 1,
2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl) and the like; 3 to 8 members (preferably 5 or 6 members) having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms A) saturated heteromonocyclic groups such as morpholinyl and sydnonyl; unsaturated fused heterocyclic groups having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as benzoxazolyl and benzoxdiazolyl; To 8 membered (preferably 5 or 6 membered) unsaturated heteromonocyclic group having 1 to 3 nitrogen atoms and 1 to 3 nitrogen atoms, such as thiazolyl,
Isothiazolyl, thiadiazolyl (for example, 1,2,3
Thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like), dihydrothiazinyl and the like; sulfur atom 1 to 2
3- to 8-membered (preferably 5- or 6-membered) saturated heteromonocyclic group having 1 to 3 nitrogen atoms, such as thiazolidinyl; 3- to 8-membered having 1 to 2 sulfur atoms (preferably 5 or 6 6-membered) unsaturated heterocyclic groups such as thienyl, dihydrodithiynyl, dihydrodithionyl and the like; unsaturated condensed heterocyclic groups having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example benzothiazolyl, benzo Thiadiazolyl, 4,5
6,7-tetrahydrobenzothiazolyl or the like; 3 to 8 members having one oxygen atom (preferably 5 or 6 members)
An unsaturated heteromonocyclic group, for example, furyl and the like; oxygen atom 1
3- to 8-membered (preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 2 sulfur atoms, such as dihydrooxathiynyl;
Unsaturated fused heterocyclic groups having one oxygen atom and one or two sulfur atoms, such as benzothienyl, benzodithiynyl and the like.

Suitable "protected amino groups" include:
Acylamino and the like can be mentioned. Preferred “acyl” moieties of the aforementioned “acylamino” include carbamoyl, thiocarbamoyl, aliphatic acyl groups, acyl groups having an aromatic ring (referred to as aromatic acyl), and acyl groups having a heterocyclic ring (heterocyclic Acyl)). Suitable examples of such acyl groups include: carbamoyl; thiocarbamoyl; aliphatic acyl, such as lower or higher alkanoyl (eg, formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2 -Dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc. lower or higher alkoxycarbonyl For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, heptyloxycarbonyl, etc.); Is higher alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.); and the like; mono or di (lower) alkylaminocarbonyl (eg, methylaminocarbonyl, dimethylaminocarbonyl, Ethylaminocarbonyl, diethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl,
Propylaminocarbonyl, butylaminocarbonyl,
N-ethyl-N-propylaminocarbonyl, etc.); aromatic acyl, such as aroyl (eg, benzoyl,
Al (lower) alkanoyl (eg, phenyl (lower) alkanoyl (eg, phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) Alkanoyl (eg, naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.); al (lower) alkenoyl [eg, phenyl (lower) alkenoyl (eg, phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylpentenoyl) Xenoyl, etc.), naphthyl (lower) alkenoyl (eg, naphthyl propenoyl, naphthyl butenoyl, etc.); al (lower) alkoxycarbonyl [e.g. Phenyl (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, etc.); aryloxycarbonyl (eg, phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy (lower) alkanoyl (eg, phenoxyacetyl, phenoxypropionyl, etc.); arylcarbamoyl (eg, Arylthiocarbamoyl (eg, phenylthiocarbamoyl); arylglyoxyloyl (eg, phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (eg, phenylsulfonyl, p-tolylsulfonyl, etc.); Heterocyclic acyl, for example, heterocyclic carbonyl; heterocyclic (lower) alkanoyl (for example, heterocyclic acetyl, heterocyclic Heterocyclic (lower) alkenoyl (eg, heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, heterocyclic hexenoyl, etc.); heterocyclic glyoxyloyl; heterocyclic (Lower) alkyl carbamoyl (for example, heterocyclic methylcarbamoyl, heterocyclic ethylcarbamoyl, heterocyclic propylcarbamoyl, heterocyclic hexylcarbamoyl, etc.); and the like; among which, “heterocyclic carbonyl”, “heterocyclic (lower) Suitable examples of the "heterocycle" moiety of ") alkanoyl", "heterocycle (lower) alkenoyl" and "heterocycle glyoxyloyl" include the aforementioned "heterocycle" moiety.

Suitable "protected carboxy groups" include carboxy groups protected with conventional protecting groups such as esterified carboxy groups, and specific examples include substituted or substituted carboxy groups. Unsubstituted lower alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 2- (dimethylamino) ethoxycarbonyl, 2-iodoethoxycarbonyl, 2, 2,2-trichloroethoxycarbonyl,
Substituted or unsubstituted aryloxycarbonyl (eg, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl), and optionally substituted with unsubstituted or unsubstituted aryl (lower) alkoxycarbonyl, eg, nitro Mono- or di- or triphenyl (lower) alkoxycarbonyl (eg benzyloxycarbonyl,
Phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl), acyloxy (lower) alkoxycarbonyl (for example, tertiary butylcarbonyloxymethyloxycarbonyl,
Examples thereof include 1-tert-butylcarbonyloxy-1-methylmethyloxycarbonyl, 1-isopropylcarbonyloxy-1-methylmethyloxycarbonyl, and 1-isobutylcarbonyloxy-1-methylmethyloxycarbonyl.

Suitable "lower alkanoyl" include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, pivaloyl and the like.

Preferred "ar (lower) alkoxycarbonyl" include benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl and the like.

Preferred examples of "heterocyclic carbonyl" include azetidinylcarbonyl, pyrrolidylcarbonyl,
Examples include piperidylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, furylcarbonyl, tetrazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl and the like.

Preferred "aroyl" include benzoyl, naphthoyl, anthrylcarbonyl and the like.

Suitable "acid residues" include halogen (eg, fluoro, chloro, bromo, iodo) and acyloxy.

Suitable "leaving groups" include lower alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluoro, chloro, bromo, iodo), acyloxy,
For example, lower alkanoyloxy (eg, acetoxy,
Propionyloxy), an optionally substituted heterocyclic group (e.g., pyrazolyl and benzotriazolyl substituted with 1 to 2 methyl groups, etc.), O-succinimidate, and the like. More preferred "leaving groups" include the halogens described above.

Preferred "cyclo (lower) alkylcarbonyl" is cyclo (C ₃ -C ₆ ) alkylcarbonyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc. C ₅ -C ₆ alkylcarbonyl, more preferably cyclopentylcarbonyl, cyclohexylcarbonyl and the like.

Suitable "lower alkylene groups" include straight or branched chains having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, dimethylmethylene and the like. Alkylene groups, preferably those having 1 to 4 carbon atoms, are mentioned.

Suitable "alkyl groups" for R ¹ include, for example, lower alkyl groups and higher alkyl groups. Suitable "lower alkyl groups" include those exemplified above. Preferred "higher alkyl groups" include straight-chain or branched alkane residues having 7 to 20 carbon atoms such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and the like. And a preferred example is a C ₇ -C ₁₅ alkyl group.

Preferred "lower alkenyl groups" include vinyl, allyl, isopropenyl, 1 or 2 or 3-
Butenyl, 1 or 2 or 3 or 4-pentenyl,
A linear or branched alkenyl group having 2 to 6 carbon atoms such as 1 or 2 or 3 or 4 or 5-hexenyl is exemplified.

Preferred "lower alkoxy groups" are those exemplified above for the lower alkyl moiety, and preferred examples thereof include methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, 4-methyl Pentyloxy, hexyloxy and the like can be mentioned, and particularly preferred is methoxy.

Preferred "higher alkoxy groups" are those exemplified above for the higher alkyl moiety, and preferable examples thereof include heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy and dodecyloxy. Can be Suitable `` lower alkoxyalkyl groups '' are those wherein the lower alkoxy moiety is as exemplified above and the alkyl moiety is lower alkyl and higher alkyl as exemplified above, methoxypropyl,
Methoxyoctyl, methoxydecanyl, methoxypentadecanyl, ethoxybutyl and the like can be mentioned.

Suitable "aryl groups" include phenyl, naphthyl, dihydronaphthyl (eg, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, etc.), tetrahydronaphthyl (eg, 1,2,3,4-tetrahydronaphthyl) ), Indenyl, anthryl and the like, and among them, (C _6-
C ₁₀ ) aryl, more preferably phenyl and naphthyl.

The preferred "ar (lower) alkyl group" is a group in which an aryl group is bonded to an arbitrary carbon atom of the lower alkyl exemplified above.
Examples thereof include benzyl, phenethyl, 3-phenylpropyl, benzhydryl, and trityl, and particularly preferably benzyl and trityl.

Suitable "lower alkoxycarbonyl groups" are those exemplified above for the lower alkoxy moiety, and include methoxycarbonyl, t-butoxycarbonyl and the like.

Suitable "halogen groups" include fluoro, chloro, bromo and iodo, more preferably chloro or iodo.

Preferred “lower alkanoylamino” are those wherein the lower alkanoyl moiety is exemplified above;
Formylamino, acetylamino, propionylamino, butyrylamino, valerylamino and the like.

Preferred "lower alkylsulfonylamino"
The lower alkyl moiety is as exemplified above, and examples thereof include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, and pentylsulfonylamino.

As preferred "heterocyclic carbonylamino", the heterocyclic carbonyl moiety is as exemplified above, and examples thereof include pyrrolidinylcarbonylamino, piperidylcarbonylamino, piperazinylcarbonylamino and the like.

Suitable "amino (lower) alkyl" includes those exemplified above for the lower alkyl moiety, and includes aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl and the like.

Preferred "protected amino (lower) alkyl" are those exemplified above for the protected amino group and lower alkyl moiety, such as acetylaminomethyl, acetylaminoethyl, acetylaminopropyl, butadiene. Noylaminomethyl, butanoylaminoethyl and the like can be mentioned.

A lower alkyl group, a carbamoyl group, a lower alkanoyl group, an ar (lower) alkoxycarbonyl group, a heterocyclic carbonyl group, an aroyl group, a cyclo (lower) alkylcarbonyl, each of which may have a suitable substituent. Suitable substituents on a group, aryl group, ar (lower) alkyl group, sulfamoyl group, or lower alkoxycarbonyl group include imino group, amino group, protected amino group as exemplified above, mono (or di) A lower alkylamino group (lower alkyl includes those exemplified above), N-lower alkyl-
A protected amino group (lower alkyl and protected amino group moieties may include those exemplified above),
Lower alkyl, hydroxy group, acyloxy group (acyl group portion may be the same as those exemplified above) and lower alkoxy group (lower alkyl portion may be the same as those exemplified above for the above examples. ), Higher alkoxy groups (the higher alkyl moieties include those exemplified above), acyl groups as exemplified above, and amino (lower) alkyl groups (the lower alkyl moieties are those exemplified above). A protected amino (lower) alkyl group (the protected amino group and the lower alkyl moiety may be the same as those exemplified above), and a heterocyclic ring optionally having a substituent. Group (heterocyclic moieties include those exemplified above, and preferable substituents include acyl groups exemplified above. ), An aryl group having a hydroxy group, a mono (or di) lower alkyl heteronio group (the lower alkyl portion and the heteronio group portion can be the same as those exemplified above), two lower alkyl groups and an acyl group (Lower alkyl moieties and acyl moieties include those exemplified above), carboxy and the like.

More preferred substituents in the “lower alkyl group optionally having a substituent” and the “lower alkenyl group optionally having a suitable substituent” include:
Imino; carbamoyl; lower alkoxy (for example, methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, 4-methylpentyloxy, hexyloxy and the like, preferably methoxy); The heterocyclic group [preferable “heterocyclic group” includes the “heterocyclic” portion exemplified above, and is more preferably an unsaturated 3 to 8 membered (containing 1 to 4 nitrogen atoms) (Preferably 5 to 7 membered) heteromonocyclic group (more preferably pyrazolyl); saturated 3 to 8 membered (more preferably 5 to 7 membered) heteromonocyclic group containing 1 to 4 nitrogen atoms (further preferred) Is azetidinyl); unsaturated 3 containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
And an 8-membered (more preferably 5- or 6-membered) heteromonocyclic group (more preferably thiazolyl).

Suitable substituents of the "optionally substituted heterocyclic group" include lower alkanoylamino (for example, those exemplified above, preferably acetylamino), Al (lower) alkoxycarbonyl (for example, those exemplified above, preferably benzyloxycarbonyl); lower alkenyloxycarbonylamino (vinyloxycarbonylamino, allyloxycarbonylamino, isopropenyloxycarbonyl Amino, 1 or 2 or 3-butenyloxycarbonylamino, 1 or 2 or 3 or 4-pentenyloxycarbonylamino, 1 or 2 or 3 or 4 or 5-hexenyloxycarbonylamino, etc. Straight or branched An alkenyloxycarbonylamino group, preferably an allyloxycarbonylamino group); diaryloxycarbonyl (eg, diphenyloxycarbonyl, ditolyloxycarbonyl, dixyloxycarbonyl, dicumenyloxycarbonyl, dinaphthyloxycarbonyl) Etc.,
Preferably diphenyloxycarbonyl); hydroxy; lower alkoxycarbonyl (lower alkoxy includes those exemplified above, and preferably butoxycarbonyl);
An ammonio group having two lower alkyl groups and one carbamoyl (lower) alkyl group (the lower alkyl group portion can be the same as those exemplified above); carboxyl; You may have one.

More preferable substituents in the “sulfonyl group optionally having substituent (s)” include pyridyl; mono- or di-lower alkylamino (eg, methylamino, dimethylamino, diethylamino, di-n −
Propylamino, diisopropylamino, dibutylamino and the like, preferably dimethylamino)
Is mentioned.

As more preferred substituents in the “carbamoyl group optionally having substituent (s)” for R ³ and R ⁴ , lower alkyl (for example, those exemplified above, and the like can be mentioned. Can be propyl).

More preferable substituents in the "lower alkanoyl group optionally having substituent (s)" include carboxyl; amino; hydroxy; lower alkoxycarbonylamino (lower alkoxy is exemplified above. An amino which may have a lower alkyl (such as those exemplified above, preferably a methyl); lower Alkoxycarbonyl (lower alkoxy includes those exemplified above, preferably t-butoxy); hydroxyaryl; lower alkoxycarbonyl (lower alkoxy includes those exemplified above) And preferably t-butoxy). Imidazolyl; lower alkoxycarbonyl (preferably t- butoxycarbonyl mentioned are the) may have a piperazyl; ar (lower)
Alkoxycarbonyl (al (lower) alkoxy includes those described above, preferably benzyloxy); al (lower) alkoxycarbonylamino (al (lower) alkoxy is exemplified above. And preferably benzyloxy).

More preferred substituents in the “heterocyclic carbonyl group optionally having substituent (s)” for R ³ and R ⁴ include lower alkoxycarbonyl (lower alkoxy is the same as those exemplified above). And the like, preferably t-butoxy), and hydroxy.

As more preferred substituents in the “aroyl group optionally having substituent (s)”, higher alkoxy (for example, heptyloxy, octyloxy, nonyloxy and the like, preferably octyloxy); Lower alkoxycarbonylamino lower alkyl (lower alkoxy and lower alkyl include those exemplified above, preferably lower alkoxy includes t-butoxy, and lower alkyl includes methyl); amino lower alkyl (lower alkyl For lower alkoxycarbonylamino lower alkanoylamino (lower alkoxy and lower alkanoyl include the same as those exemplified above, and are preferred.) Is low Alkoxy is ethoxy, lower alkanoyl is acetyl); amino lower alkanoylamino lower alkyl (lower alkanoyl and lower alkyl include those exemplified above), preferably lower alkanoyl is acetyl and lower alkyl is methyl Are mentioned).

More preferred substituents in the “cyclo (lower) alkylcarbonyl group optionally having substituent (s)” include amino and lower alkoxycarbonylamino (lower alkoxy includes those exemplified above. And preferably t-butoxy).

As a more preferred substituent in the “carbamoyl group optionally having substituent (s)” for R ¹ , a higher alkyl group (as exemplified above) and the like, preferably undecanyl is used. And aryl groups which may have a higher alkoxyaryl heterocyclic group (preferably higher alkoxyphenylpiperazinyl group) (such as those exemplified above, and preferably phenyl). A heterocyclic group which may have a lower alkoxy (lower) alkoxyarylaryl group (preferably a lower alkoxy (lower) alkoxyphenylphenyl group) (such as those exemplified above; Preferably, piperidyl can be mentioned).

As more preferred substituents in the “aryl group optionally having substituent (s)”, higher alkoxy (the higher alkyl moieties exemplified above can be mentioned, preferably heptyloxy or Octyloxy can be mentioned), an aryl group optionally having a lower alkyl group (the above-mentioned examples can be mentioned, preferably phenyl or naphthyl can be mentioned), lower alkoxy (higher-grade) A) an aryl group optionally having an alkyl group (e.g., those exemplified above, preferably phenyl or naphthyl), and an aryl group optionally having a higher alkoxy group ( Examples thereof include those exemplified above, preferably phenyl or naphthyl), and Lower alkoxy (lower) alkoxy which may aryl group optionally having an aryl group (can be exemplified such as those exemplified above, preferably a phenyl or naphthyl) and the like.

More preferred substituents in the “ar (lower) alkyl group optionally having substituent (s)” include higher alkoxy (as exemplified above), preferably nonyloxy. Can be mentioned).

More preferred substituents in the “heterocyclic carbonyl group optionally having substituent (s)” for R ¹ include a lower alkoxyaryl group (preferably a lower alkoxyphenyl group). And an aryl group (e.g., those exemplified above, and preferably phenyl).

As a more preferred substituent in the "heterocyclic carbonyl group optionally having substituent (s)" for R ² , a lower alkoxycarbonyl group (as exemplified above, and the like can be mentioned. Preferably, t-butoxy can be mentioned).

As a more preferred substituent in the “lower alkoxycarbonyl optionally having a suitable substituent”, an aryl group (for example, those exemplified above, and preferably phenyl can be mentioned. Can be).

More preferred substituents in the “lower alkoxy optionally having a substituent” include a carboxy group and a lower alkoxycarbonyl group (the same as those exemplified above, and preferably t -Butoxy), having a carbamoyl group optionally having a lower alkyl group, a carbamoyl group optionally having an amino (lower) alkyl group, and a lower alkoxycarbonylamino (lower) alkyl group. And a carbamoyl group which may have a heterocyclic (lower) alkyl group.

More preferred substituents in “carbamoyl optionally having substituent (s)” for R ¹⁴ include a hydroxy group, a protected hydroxy group (a hydroxy group protected by a conventional protecting group). Carboxy, protected carboxy (such as those exemplified above, and preferably t-butoxycarbonyl). It is.

Preferable "acylamino" for R ¹³ includes lower alkanoylamino, lower alkylsulfonylamino which may have a substituent, and heterocyclic carbonylamino which may have a substituent.

Examples of suitable substituents in the “optionally substituted lower alkanoylamino” include an amino group and a protected amino group (as exemplified above, and preferably an acylamino group A heterocyclic group which may have a lower alkoxycarbonylamino group (e.g., those exemplified above, preferably an imidazolyl group), lower alkoxycarbonylamino A heterocyclic carbonyl group (which may have a heterocyclic moiety as described above, preferably a piperazinylcarbonyl group) which may have a group, a carboxy group,
Protected carboxy group (such as those exemplified above, preferably t-butoxycarbonyl can be exemplified), hydroxy group, protected hydroxy group (such as those exemplified above) And preferably acetyloxy), and a lower alkoxy (lower) alkoxy group (the lower alkoxy moieties include those exemplified above, and preferably methoxyethoxy). .

Suitable substituents in the "optionally substituted heterocyclic carbonylamino" include a hydroxy group and a protected hydroxy group (as exemplified above, preferably a hydroxy group). Acetyloxy) and a lower alkoxycarbonyl group (the above-mentioned examples can be mentioned, preferably a t-butoxycarbonyl group can be mentioned).

The embodiment of the compound (I) will be described below. Preferred examples of the compound (I) include those wherein R ¹ is hydrogen, a higher alkyl group (more preferably, tridecyl); a lower alkoxyalkyl group (more preferably, a lower alkoxy (higher) alkyl group); a carboxy group; (More preferably higher alkoxyaryl heterocyclic group, more preferably higher alkoxyphenylpiperazinyl group) optionally having aryl group (more preferably phenyl group) and substituent (more preferably lower alkoxy (lower)) One or two (more preferably, a heterocyclic group (more preferably, a piperidyl group)) which may have an alkoxyarylaryl group, more preferably a lower alkoxy (lower) alkoxyphenylphenyl group) Is one) carbamoyl group optionally having a suitable substituent It may have a higher alkoxy and a substituent (more preferably a substituent selected from the group consisting of a lower alkyl group, a lower alkoxy (higher) alkyl group, a higher alkoxy group and a lower alkoxy (lower) alkoxyaryl group). One to three (more preferably one) aryl group optionally having one to three suitable substituents (more preferably phenyl group or naphthyl group) selected from the group consisting of aryl groups (more preferably phenyl group or naphthyl group) Group or naphthyl group); an ar (lower) alkyl group which may have a higher alkoxy group (more preferably a phenyl (lower) alkyl group); or 1 to 3 (more preferably 1) substituents ( An aryl group which may have a lower alkoxyaryl group (preferably a lower alkoxyphenyl group) is more preferable. A heterocyclic carbonyl group (preferably a phenyl group) (preferably a piperidylcarbonyl group), R ²
Is a carboxy group, a protected carboxy group, a heterocyclic carbonyl group which may have a lower alkoxycarbonyl group (more preferably a piperazinylcarbonyl group), Wherein R ³ and R ⁴ may be the same or different, and represent hydrogen; or imino, carbamoyl, lower alkoxy, amino, lower alkanoylamino, 1 to 3 (more preferably 1 or 2 And more preferably one) substituent (more preferably a lower alkyl group, an acyl group or an acylamino group; still more preferably a lower alkyl group, a phenyl (lower) alkoxycarbonyl group or a lower alkanoylamino group). Heterocyclic group (more preferably azetidinyl group, thiazolyl group or pyrazolyl group), lower alkenyloxycarbonylamino, diaryl (lower) alkoxycarbonyl [more preferably mono (or di) phenyl (lower) alkoxycarbonyl group] , Hydroxy, three substituents [more preferably, A substituent selected from the group consisting of bamoyl (lower) alkyl and lower alkyl], one or more (more preferably one to three) selected from the group consisting of ammonio, lower alkoxycarbonyl and carboxyl which may have A lower alkyl group optionally having substituent (s); a lower alkenyl group; a heterocyclic group (more preferably an unsaturated monocyclic heterocyclic group containing one nitrogen atom, more preferably a pyridyl group) or A sulfonyl group optionally having di-lower alkylamino; a carbamoyl group optionally having one or more (more preferably one) lower alkyl; carboxyl, hydroxy, and one or two substituents ( More preferably, a substituent selected from the group consisting of lower alkyl and acyl, even more preferably lower alkyl, lower alkoxy carbonyl And optionally substituted amino, lower alkoxycarbonyl, and hydroxyaryl (more preferably hydroxyphenyl), which may have a substituent selected from the group consisting of alk (lower) alkoxycarbonyl, (more preferably, phenyl (lower) alkoxycarbonyl). ) A heterocyclic group which may have 1 to 3 (more preferably 1 or 2; more preferably 1) substituents (more preferably lower alkoxycarbonyl) (more preferably a nitrogen atom A 3- to 8-membered unsaturated heteromonocyclic group having 1 to 4 groups, more preferably an imidazolyl group) and 1 to 3 (more preferably 1 or 2; still more preferably 1) substituents An optionally substituted heterocyclic carbonyl (more preferably a 3- to 8-membered saturated heteromonocyclic having 1 to 4 nitrogen atoms) Carbonyl, more preferably piperazinylcarbonyl), ar (lower) alkoxycarbonyl [more preferably phenyl (lower) alkoxycarbonyl], and one or more (more preferably one or more) selected from the group consisting of lower alkoxycarbonyl 2) a lower alkanoyl group which may have a substituent; an alk (lower) alkoxycarbonyl group [more preferably phenyl (lower) alkoxycarbonyl]; and 1 selected from the group consisting of lower alkoxycarbonyl and hydroxy
Heterocyclic carbonyl group optionally having at least one (more preferably one or two) substituents (more preferably a saturated 3-8 membered heteromonocyclic carbonyl group containing 1 to 4 nitrogen atoms) Group, more preferably azetidinylcarbonyl, pyrrolidinylcarbonyl or piperidylcarbonyl); consisting of higher alkoxy, lower alkoxycarbonylamino lower alkyl, amino lower alkyl, lower alkoxycarbonylamino lower alkanoylamino and amino lower alkanoylamino lower alkyl An aroyl group optionally having one or more (more preferably one) substituents selected from the group (more preferably benzoyl); or one selected from the group consisting of amino and lower alkoxycarbonylamino Having the above (more preferably one) substituent Optionally have cyclo (lower) alkylcarbonyl group; or R ² is the formula Wherein R ⁵ may be the same or different and a lower alkyl group or a lower alkenyl group which may have a heterocyclic group (more preferably pyrazolyl), X is a halogen,
A is a lower alkylene group, R ¹¹ is a hydroxy group; or a carboxy group, a lower alkoxycarbonyl group, an amino group,
A protected amino group (more preferably an acylamino group;
More preferably, a lower alkoxycarbonyl group amino group) and one or two substituents (more preferably, a lower alkyl group, an amino (lower) alkyl group, a lower alkoxycarbonylamino (lower) alkyl group, and a heterocycle (lower) A substituent selected from the group consisting of an alkyl group (more preferably an imidazolyl (lower) alkyl group)
3 from 1, also selected from the group consisting of a carbamoyl group optionally having (more preferably 1) suitable optionally substituted lower alkoxy group, R ¹² is hydrogen or halogen , R ¹³ is hydrogen; a nitro group; an amino group; an amino group, a protected amino group (more preferably an acylamino group, still more preferably a lower alkoxy (lower) alkoxycarbonylamino group), an acyl group (more preferably a lower alkoxycarbonyl A heterocyclic group (more preferably an imidazolyl group) which may have a heterocyclic carbonyl group (more preferably a piperazinylcarbonyl) which may have an acyl group (preferably a lower alkoxycarbonyl group). Group), a carboxy group, a protected carboxy group (more preferably an esterified carboxy group,
More preferably, 1 to 3 (more preferably 1 to 3) selected from the group consisting of a lower alkoxycarbonyl group), a hydroxy group, a protected hydroxy group (more preferably an acyloxy group), and a lower alkoxy (lower) alkoxy group. Or two) optionally substituted lower alkanoylamino groups; lower alkylsulfonylamino groups; hydroxy groups, protected hydroxy groups (more preferably acyloxy groups) and acyl groups (preferably lower 1 to 3 (more preferably 1 or 2) selected from the group consisting of
A heterocyclic carbonylamino group (more preferably a pyrrolidinylcarbonylamino group) optionally having a suitable substituent, or the following formula formed by bonding of R ¹¹ and R ¹³ R ¹⁴ is a cyano group; a hydroxy group, a protected hydroxy group (more preferably an acyloxy group), a carboxy group and a protected carboxy group (more preferably an esterified carboxy group) 1 to 3 (more preferably 1 to 3) selected from the group consisting of
A carbamoyl group optionally having a substituent; an amino (lower) alkyl group; or a protected amino (lower) alkyl group, wherein Z is O or NR ^15
15 is hydrogen or a higher alkyl group); and compounds wherein P is (CH ₂ ) _n (where n is 0 or 1) and salts thereof.

As more preferred examples of the compound (I), the following (1) a compound wherein Z is O, or (2) a compound wherein Z is N
Compounds of -R ¹⁵ and the like.

(1) Compound wherein Z is O R ¹ is a higher alkyl group, R ² is a carboxy group, a protected carboxy group (more preferably an esterified carboxy group, more preferably a lower alkoxycarbonyl group), an acyl group A piperazinylcarbonyl group optionally having a group (more preferably, a lower alkoxycarbonyl group); Wherein R ³ and R ⁴ may be the same or different, and represent hydrogen; or imino, carbamoyl, lower alkoxy, amino, lower alkanoylamino, 1 to 3 (more preferably 1 or 2 And more preferably one) substituent (more preferably a lower alkyl group, an acyl group or an acylamino group; still more preferably a lower alkyl group, a phenyl (lower) alkoxycarbonyl group or a lower alkanoylamino group). Heterocyclic group (more preferably azetidinyl group, thiazolyl group or pyrazolyl group), lower alkenyloxycarbonylamino, diaryl (lower) alkoxycarbonyl [more preferably mono (or di) phenyl (lower) alkoxycarbonyl group] , Hydroxy, three substituents [more preferably, A substituent selected from the group consisting of bamoyl (lower) alkyl and lower alkyl], one or more (more preferably one to three) selected from the group consisting of ammonio, lower alkoxycarbonyl and carboxyl which may have A lower alkyl group optionally having substituent (s); a lower alkenyl group; a heterocyclic group (more preferably an unsaturated monocyclic heterocyclic group containing one nitrogen atom, more preferably a pyridyl group) or A sulfonyl group optionally having di-lower alkylamino; a carbamoyl group optionally having one or more (more preferably one) lower alkyl; carboxyl, hydroxy, and one or two substituents ( More preferably, a substituent selected from the group consisting of lower alkyl and acyl, even more preferably lower alkyl, lower alkoxy carbonyl And optionally substituted amino, lower alkoxycarbonyl, and hydroxyaryl (more preferably hydroxyphenyl), which may have a substituent selected from the group consisting of alk (lower) alkoxycarbonyl, (more preferably, phenyl (lower) alkoxycarbonyl). ) A heterocyclic group which may have 1 to 3 (more preferably 1 or 2; more preferably 1) substituents (more preferably lower alkoxycarbonyl) (more preferably a nitrogen atom A 3- to 8-membered unsaturated heteromonocyclic group having 1 to 4 groups, more preferably an imidazolyl group) and 1 to 3 (more preferably 1 or 2; still more preferably 1) substituents An optionally substituted heterocyclic carbonyl (more preferably a 3- to 8-membered saturated heteromonocyclic having 1 to 4 nitrogen atoms) Carbonyl, more preferably piperazinylcarbonyl), ar (lower) alkoxycarbonyl [more preferably phenyl (lower) alkoxycarbonyl], and one or more (more preferably one or more) selected from the group consisting of lower alkoxycarbonyl 2) a lower alkanoyl group which may have a substituent; an alk (lower) alkoxycarbonyl group [more preferably phenyl (lower) alkoxycarbonyl]; and 1 selected from the group consisting of lower alkoxycarbonyl and hydroxy
Heterocyclic carbonyl group optionally having at least one (more preferably one or two) substituents (more preferably a saturated 3-8 membered heteromonocyclic carbonyl group containing 1 to 4 nitrogen atoms) Group, more preferably azetidinylcarbonyl, pyrrolidinylcarbonyl or piperidylcarbonyl); consisting of higher alkoxy, lower alkoxycarbonylamino lower alkyl, amino lower alkyl, lower alkoxycarbonylamino lower alkanoylamino and amino lower alkanoylamino lower alkyl An aroyl group optionally having one or more (more preferably one) substituents selected from the group (more preferably benzoyl); or one selected from the group consisting of amino and lower alkoxycarbonylamino Having the above (more preferably one) substituent Optionally have cyclo (lower) alkylcarbonyl group; or R ² is the formula Wherein R ⁵ may be the same or different and a lower alkyl group or a lower alkenyl group which may have a heterocyclic group (more preferably pyrazolyl), X is a halogen,
A is a lower alkylene group, R ¹¹ is a hydroxy group; or a carboxy group, a lower alkoxycarbonyl group, an amino group,
A protected amino group (more preferably an acylamino group,
More preferably, a lower alkoxycarbonylamino group)
And one or two substituents (more preferably a lower alkyl group, an amino (lower) alkyl group, a lower alkoxycarbonylamino (lower) alkyl group and a heterocyclic (lower) alkyl group (more preferably imidazolyl (lower)
Alkyl group) has one to three (more preferably one) suitable substituent (s) selected from the group consisting of carbamoyl groups which may have one or more carbamoyl groups. A lower alkoxy group, R ¹² is hydrogen or halogen, R ¹³ is hydrogen; a nitro group; an amino group; an amino group, a protected amino group (more preferably an acylamino group, even more preferably a lower alkoxy (lower) alkoxycarbonyl An amino group), a heterocyclic group (more preferably an imidazolyl group) that may have an acyl group (more preferably a lower alkoxycarbonyl group), or an acyl group (more preferably a lower alkoxycarbonyl group) that may have an acyl group (more preferably a lower alkoxycarbonyl group). Good heterocyclic carbonyl group (more preferably piperazinylcarbonyl group), carboxy group, protected carboxy group (more preferably From one selected from the group consisting of a stelated carboxy group, more preferably a lower alkoxycarbonyl group), a hydroxy group, a protected hydroxy group (more preferably an acyloxy group), and a lower alkoxy (lower) alkoxy group Three (more preferably one or two) lower alkanoylamino groups optionally having a suitable substituent; lower alkylsulfonylamino groups; hydroxy groups, protected hydroxy groups (more preferably acyloxy groups) And 1 to 3 (more preferably 1 or 2) selected from the group consisting of and an acyl group (more preferably a lower alkoxycarbonyl group)
Suitable substituents optionally heterocyclic carbonylamino group which may have a (more preferably pyrrolidinylcarbonyl amino group), or the following formula in which the R ¹¹ and R ¹³ is formed by bonding R ¹⁴ is a cyano group; a hydroxy group, a protected hydroxy group (more preferably an acyloxy group), a carboxy group and a protected carboxy group (more preferably an esterified carboxy group) 1 to 3 (more preferably 1 to 3) selected from the group consisting of
Carbamoyl group optionally having substituent (s); amino (lower) alkyl group; or protected amino (lower) alkyl group, wherein P is (CH ₂ ) _n , wherein n is 1 And a salt thereof.

(2) Compound wherein Z is NR ¹⁵ R ¹ is a higher alkyl group (more preferably tridecyl group); a lower alkoxy (higher) alkyl group; a higher alkyl group, a substituent (more preferably a higher alkoxyaryl heterocycle) Group, more preferably an aryl group (more preferably, a phenyl group) which may have a higher alkoxyphenylpiperazinyl group) and a substituent (more preferably, a lower alkoxy (lower) alkoxyarylaryl group, more preferably, a lower alkoxyalkylpiperazinyl group). One or two (more preferably one) suitable substituent (s) selected from the group consisting of a heterocyclic group (more preferably piperidyl group) which may have an alkoxy (lower) alkoxyphenylphenyl group) A carbamoyl group optionally having a higher alkoxy and a substituent (more preferably a lower alkyl An aryl group which may have a substituent selected from the group consisting of a lower alkoxy (higher) alkyl group, a higher alkoxy group and a lower alkoxy (lower) alkoxyaryl group (more preferably a phenyl group or a naphthyl group) 1 to 3 (more preferably 1) aryl group optionally having one or more suitable substituents (more preferably phenyl group or naphthyl group) selected from the group consisting of: Alk (lower) alkyl group (more preferably phenyl (lower) alkyl group); or 1 to 3 (more preferably 1) substituent (s) (preferably lower alkoxyaryl group, more preferably lower alkoxy group) Heterocyclic carbonyl optionally having an aryl group (preferably a phenyl group) Group (more preferably a piperidyl group), R ²
Is Wherein R ³ and R ⁴ may be the same or different, and are hydrogen or a lower alkoxycarbonyl group, A is a lower alkylene group, R ¹¹ is a hydroxy group, R ¹² is hydrogen, R ¹³
Is hydrogen, R ¹⁴ is a carbamoyl group, R ¹⁵ is hydrogen or a higher alkyl group, and P is (CH ₂ ) _n (where n is 0 or 1)
And a salt thereof.

The method for producing the target compound (I) or a salt thereof is described in detail below.

Production Method 1 The target compound (Ia) or a salt thereof can be produced by reacting the compound (A) or a salt thereof with the compound (II) or a salt thereof.

This reaction was carried out using water, a phosphate buffer, acetone,
Chloroform, acetonitrile, nitrobenzene, toluene, methylene chloride, ethylene chloride, formamide,
Solvents such as N, N-dimethylformamide, methanol, ethanol, secondary butanol, amyl alcohol, diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran, dimethyl sulfoxide, and any other organic solvents that do not adversely affect the reaction, preferably strong It can be carried out in a polar solvent. Among these solvents, hydrophilic solvents may be used as a mixture with water. When the compound (II) is in a liquid state, it can be used as a solvent.

The reaction is carried out using a base, for example, an inorganic base such as an alkali metal hydroxide, an alkali metal alkoxide, or an alkali metal carbonate such as potassium carbonate, an alkali metal bicarbonate, or an alkali metal hydride; benzyltrimethylammonium hydroxide; It is preferable to carry out the reaction in the presence of an organic base such as ethylamine and trialkylamine.

The reaction temperature is not particularly limited, but the reaction is usually carried out at ambient temperature, room temperature or under heating.

Production Method 2a The desired compound (Ib) or a salt thereof is reacted with the compound (A) or a salt thereof with the compound (III) [Step (1)], and then subjected to a reduction reaction [Step (2)]. It can be manufactured by the following.

In the reaction in step (1), preferably, a base, for example, an organic base such as triethylamine, pyridine, piperazine, piperidine and the like, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide,
For example, it may be carried out in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like. .

As the solvent, a conventional solvent which does not adversely influence the reaction, for example, water, alcohol (eg, methano-
Acetic acid, diethyl ether, dioxane, tetrahydrofuran, methylene chloride, or a mixture thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at ambient temperature, room temperature or under heating.

The reaction in step (2) is carried out in a conventional manner, that is, by 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.), aluminum hydride compounds (eg, lithium aluminum hydride, lithium hydride tri-t-butoxyaluminate, etc.), borohydride compounds (eg, Hydride transfer reagents such as sodium borohydride and sodium cyanoborohydride.

Suitable catalysts for use in the catalytic reduction include platinum catalysts (eg, platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.) and palladium catalysts (eg, palladium sponge, palladium black, oxidized platinum, etc.). palladium,
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 (eg, reduced iron, Raney-iron, etc.) ), Copper catalysts (eg, reduced copper, Raney-copper, Ullman copper, etc.) and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, for example, water, alcohol (eg, methanol,
Ethanol, propanol, etc.), acetic acid, diethyl ether, dioxane, tetrahydrofuran, methylene chloride,
Alternatively, the reaction is performed in a solvent such as a mixture thereof.

The reaction temperature for the reduction is not particularly limited, but the reaction is usually carried out under cooling or heating.

Production Method 2b The target compound (Ic) or a salt thereof is reacted with the compound (A) or a salt thereof with the compound (III) [Step (1)], and then subjected to a reduction reaction [Step (2)]. It can be manufactured by the following. This reaction is carried out according to Production Method 2a
Since the reaction can be carried out in substantially the same manner as described above, the description of the production method 2a can be referred to for the reaction method and reaction conditions (eg, solvent, reaction temperature, etc.).

Production Method 3 The target compound (Id) or a salt thereof can be produced by reacting the compound (A) or a salt thereof with the compound (IV) or a salt thereof. This reaction can be carried out in substantially the same manner as that described in Process 1, the reaction method and reaction conditions (e.g. solvent, reaction temperature, etc.) can incorporate the description of the production method 1.

Production Method 4 The desired compound (Ie) or a salt thereof can be produced by reacting the compound (A) or a salt thereof with the compound (V) or a salt thereof. Since this reaction can be carried out in substantially the same manner as described in Production Method 1 ,
The reaction method and reaction conditions (eg, solvent, reaction temperature, etc.)
The description of Manufacturing Method 1 can be referred to.

Production Method 5a The target compound (If) or a salt thereof can be produced by subjecting the compound (A) or a salt thereof to an acylation reaction. Suitable acylating agents used in the acylation reaction include a compound represented by the formula: R ⁴ _b —OH (VI) wherein R ⁴ _b is a lower alkanoyl group optionally having a suitable substituent, a sulfonyl group Carbamoyl group, ar (lower) alkoxycarbonyl group, heterocyclic carbonyl group, aroyl group, cyclo (lower) alkylcarbonyl group], or a reactive derivative thereof, or a salt thereof.

Suitable reactive derivatives at the carboxy group of compound (VI) include acid halides, acid anhydrides,
Activated amides, activated esters and the like can be mentioned. Preferred examples thereof include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid , Thiosulfuric acid, sulfuric acid,
Sulfonic acid (eg, methanesulfonic acid, etc.), alkyl carbonic acid, aliphatic carboxylic acid (eg, acetic acid, propionic acid,
Mixed anhydrides with acids such as butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid) or aromatic carboxylic acids (such as benzoic acid); symmetrical anhydrides ( Activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; 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-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8
-Quinolylthioester, etc.) or N-hydroxy compound (for example, N, N-dimethylhydroxylamine,
1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,
-Hydroxy-6-chloro-1H-benzotriazole etc.). These reactive derivatives can be appropriately selected from these depending on the type of compound (VI) to be used.

Suitable salts of the compound (VI) and its reaction derivative include the same as those exemplified for the salt of the compound (I).

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

When compound (VI) is used in this reaction in the form of a free acid or a salt thereof, the reaction is carried out using 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;
Ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; Lower alkyl haloformate such as isopropyl acid; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
-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 the reaction in the presence of a conventional condensing agent such as a so-called Vilsmeier reagent prepared by reaction with phosgene, phosphorus oxychloride or the like.

The reaction can also be carried out by alkali metal carbonate, alkali metal bicarbonate, tri (lower) alkylamine (eg, triethylamine), pyridine, di (lower) alkylaminopyridine (eg, 4-dimethylaminopyridine), N It is desirable to carry out the reaction in the presence of an inorganic or organic base such as-(lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Production Method 5b The desired compound (Ih) or a salt thereof can be produced by subjecting the compound (Ig) or a salt thereof to an acylation reaction. This reaction can be carried out in ones substantially the same method described in Process 5a, the reaction method and reaction conditions (e.g. solvent, reaction temperature, etc.) can incorporate the description of the manufacturing method 5a.

Production Method 6 The desired compound (Ii) or a salt thereof can be produced by reacting the compound (A) or a salt thereof with (VII). This method is performed by a method according to Example 23 described later.

Production Method 7 The desired compound (Ij) or a salt thereof can be produced by reacting the compound (A) or a salt thereof with the compound (VIII). This method is performed by a method according to Example 24 described later.

Production Method 8a Compound (Il) or a salt thereof can be produced by subjecting compound (Ik) or a salt thereof to a carboxy protecting group elimination reaction. Suitable salts of the compounds (Ik) and (Il) include those exemplified for the compound (I). This reaction is performed according to a conventional method such as hydrolysis and reduction.

The hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include, for example, alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, magnesium, calcium, etc.), hydroxides or carbonates or bicarbonates of those metals, alkali metal alkoxides (eg, sodium Methoxide, sodium ethoxide, potassium t-butoxide, etc.), alkali metal acetate, alkaline earth metal phosphate, alkali metal hydrogen phosphate (eg, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), tri (lower) alkyl Amines (eg, trimethylamine, triethylamine, etc.), pyridine or derivatives thereof (eg, picoline, lutidine, 4-dimethylaminopyridine, etc.), N- (lower) alkylmorpholines (eg, N-methylmorpholine), 1,5-diazabicyclo [4 .
3.0] Non-5-ene, 1,4-diazabicyclo [2.
2.2. ] Octane, 1,8-diazabicyclo [5.
[4.0] undec-7-ene, quinoline and the like.

Suitable acids include organic acids (for example, formic acid,
Examples thereof include acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like and inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid and the like). The elimination reaction using trihalogenated acetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.) is accelerated by the addition of a cation scavenger (eg, phenol, anisole, etc.).

This hydrolysis is usually effected by using water, alcohol (eg, methanol, ethanol, etc.), diethyl ether,
It is carried out in a conventional solvent such as dioxane, tetrahydrofuran, dichloromethane, ethyl acetate or a mixture thereof, or in any other organic solvent which does not adversely influence the reaction. When the above base or acid is liquid,
They can also be used as solvents.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling, at room temperature or under heating.

The reduction methods applicable to this 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) , Trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts for use in the catalytic reduction include conventional catalysts such as platinum catalysts (for example, platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.).
Palladium catalyst (for example, palladium sponge, palladium black, colloidal palladium, palladium oxide, palladium-carbon, palladium-barium sulfate, palladium-barium carbonate, etc.), nickel catalyst (for example, reduced nickel, nickel oxide, Raney-nickel, etc.), cobalt catalyst (Eg, reduced cobalt, Raney-cobalt, etc.), iron catalyst (eg, reduced iron, Raney-iron, etc.), copper catalyst (eg, reduced copper, Raney-cobalt, etc.)
Copper, Ullman copper, etc.).

The reduction is usually carried out in a solvent such as water, alcohol (for example, methanol, ethanol, propanol, etc.), N, N-dimethylformamide, etc. which does not adversely affect the reaction, or a mixture thereof. Done in When the above-mentioned acid used for the chemical reduction is liquid, it can also be used as a solvent. Further, as a suitable solvent used for the catalytic reduction, in addition to the above-mentioned solvents, a conventional solvent such as diethyl ether, dioxane, tetrahydrofuran or a mixture thereof can be exemplified.

The reaction temperature of this reduction is not particularly limited, but the reaction is usually carried out under cooling, at room temperature or under heating.

Production Method 8b The compound (In) or a salt thereof can be produced by subjecting the compound (Im) or a salt thereof to an elimination reaction of a carboxy protecting group. This reaction can be carried out in ones substantially the same method described in Process 8a, the reaction method and reaction conditions (e.g. solvent, reaction temperature, etc.) can incorporate the description of the manufacturing method 8a.

Production Method 9 Compound (Ip) or a salt thereof can be produced by subjecting compound (Io) or a salt thereof to an amino-protecting group elimination reaction. This reaction can be carried out in ones substantially the same method described in Process 8a, the reaction method and reaction conditions (e.g. solvent, reaction temperature, etc.) can incorporate the description of the manufacturing method 8a.

Production Method 10 Compound (Iq) or a salt thereof can be produced by subjecting compound (B) or a salt thereof to a cyclization reaction. This method is performed by a method according to Example 82 described later. The reaction is usually carried out using a conventional solvent such as water, alcohol (eg, methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or the like. The reaction is performed in any other organic solvent that does not adversely affect the reaction. These conventional solvents may be used by mixing with water. The reaction can be performed in the presence of 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide, 1-hydroxybenzotriazole, a conventional condensing agent such as those described in Preparation Method 5a . The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under heating.

The target compound (I) thus obtained can be converted into a salt thereof by a conventional method. The target compound (I) and a pharmaceutically acceptable salt thereof include solvates [eg, clathrates (eg, hydrates)]. The starting compound (A) can be produced by the fermentation and synthesis methods disclosed in WO 92/19648 and the production methods described in this specification.

In order to show the usefulness of the polypeptide compound (I) of the present invention, the biological data of representative compounds are shown below. Test A (Antibacterial Activity) The in vitro antibacterial activity of the target compound of Example 1 described later was measured by the following agar plate multiple dilution method. Test Method Each test strain was cultured overnight in Sabouraud broth containing 2% glucose, and one platinum loop (10 ⁵ cells / ml) of compound (I) at each concentration stage was obtained. After inoculating yeast nitrogen-containing dextrose agar (YNBD agar) and incubating at 30 ° C. for 24 hours, the minimum inhibitory concentration (MIC) was expressed in μg / ml. Test Results As is clear from the above test results, the polypeptide compound (I) of the present invention has an antibacterial activity (particularly an antifungal activity).

The antibacterial agent of the present invention can be administered rectally, pulmonary inhalation (inhalation through the nasal cavity or mouth), nasal administration, eye administration, topical administration (topical administration), oral administration, parenteral administration (subcutaneous, intravenous) Conventional pharmaceutical preparations containing the polypeptide compound (I) and its salts as active substances, eg in solid, semi-solid or liquid form, mixed with organic or inorganic carriers or excipients suitable for intramuscular injection). Can be used with The active ingredient may be mixed with conventional non-toxic and pharmaceutically acceptable carriers in any suitable dosage form, such as tablets, pellets, troches, capsules, suppositories, ointments, aerosols, powders for inhalation, or solutions, emulsions, It may be used as a form such as a suspension. If necessary, auxiliary agents, stabilizers, thickening agents, coloring agents and flavors may be used in the above preparations.

The amount of the polypeptide compound (I) and its salt contained in the antibacterial agent is sufficient to exert the desired antibacterial effect on the disease process and condition. When applied to, it is preferably carried out by a method of 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 the disease. In general, the daily dose of the polypeptide compound is about 0.01 to 20 mg / kg for intravenous injection, the daily dose is about 0.1 to 20 mg / kg for the intramuscular injection, Peptide compound daily dose about 0.5-5
0 mg / kg may be used for treating or preventing infectious diseases.

In particular, in the case of treatment or prevention of Pneumocystis carinii infection, the following should be noted. For administration by inhalation, the compounds of the invention are conveniently used in the form of an aerosol spray from a compressed container, or a nebulizer. The compound may be formed and used as a powder. The powdered antimicrobial agent may be inhaled with the aid of an inhaler for inhalable powders. A preferred inhalation method is by means of a graduated inhalation aerosol or the like, which may be formed as a suspension or solution of the compound in a suitable propellant such as a fluorocarbon or hydrocarbon.

[0115] Aerosol administration is the preferred method of administration because it is desirable to treat the lungs and bronchi directly. Inhalation is also a desirable method, especially if the infection has spread to the ears and other body cavities. Intravenous administration by drip is also used as parenteral administration.

Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples. Production Example 1 A mixed solution of (1R, 2S) -2-aminocyclopentane-1-carboxylic acid (5.0 g) in acetone and water (acetone / water = 1: 1) (50 ml) was prepared at 0 to 5 ° C. Treated with triethylamine (5.88 g), then di-t-butyl dicarbonate (9.34 g) in acetone (20 m
l) Treat with solution. After 3 hours, the organic solvent is distilled off from the mixture, the remaining aqueous solution is extracted three times with methylene chloride, and the organic layer is discarded. Adjust the aqueous layer to pH 2 and add 3
Extract twice. The extracts were combined, washed twice with brine, dried over magnesium sulfate, the solvent was distilled off, and the residue was crystallized from a mixed solution of acetone-hexane to give (1R, 2
S) -2-t-Butoxycarbonylaminocyclopentane-1-carboxylic acid is obtained as a white powder (4.7 g). _{^{1 HNMR (DMSO-d 6)}} : 1.36 (9H, s),
1.36-1.90 (6H, m), 2.72-2.83
(1H, m), 3.95-4.20 (1H, m), 6.
61 (1H, d, J = 8.2), 11.93 (1H, b
rs) IR (KBr) = 1706.7,1660.4 cm ^-1

Production Example 2 A solution of 1-t-butoxycarbonylazetidine-3-nitrile (12 g) in methylene chloride (100 ml) was treated in 4N hydrogen chloride-ethyl acetate (25 ml) at room temperature for 3 hours, and the solvent was distilled off. Leave. The residue was dissolved in a mixed solvent of tetrahydrofuran-water (1: 1), adjusted to pH 7 to 8, and benzyloxycarbonyl chloride (13.5 g) was added dropwise while maintaining the pH at 7 to 8 with a 5N sodium hydroxide solution. Add. After 30 minutes, the solution was extracted twice with ethyl acetate, the extracted organic layers were combined, washed with water, dried over magnesium sulfate, the solvent was distilled off, and silica gel chromatography (eluent: ethyl acetate / hexane = 1: 1) to give 1-benzyloxycarbonylazetidine-3-nitrile as an oil (6.30 g). ¹ H NMR (CDCl ₃ ): 3.34-3.51 (1H,
m), 4.14-4.34 (m, 4H), 5.10
(S, 2H), 7.35 (s, 5H)

Production Example 3 Acetyl chloride (25 ml) was added dropwise to ice-cooled ethanol (50 ml), and 30 minutes later, 1-benzyloxycarbonylazetidine-3-nitrile (6.3) was added.
g) is added and the solution is stirred overnight at 0-5 ° C. The resulting precipitate is filtered and dried to give 1-benzyloxycarbonyl-3- (1-ethoxy-1-iminomethyl) azetidine hydrochloride (6.9 g). _{^{1 HNMR (DMSO-d 6)}} : 1.37 (3H, t, J
= 7), 3.89-4.17 (5H, m), 4.47.
(2H, q, J = 7), 5.06 (2H, s), 7.3
6 (5H, s), 11.89 (2H, brs)

Production Example 4 Succinic anhydride (940.8 mg), 1-t-butoxycarbonylpiperazine (1.751 g) and 4-dimethylaminopyridine (one crystal) in methylene chloride (12 m
l) The solution is stirred for 3 days at room temperature, evaporated to dryness. The residue was crystallized from a mixed solution of acetone-hexane to give 1-t-butoxycarbonyl-4- (3-carboxypropionyl) piperazine as white crystals (2.275).
g). _{^{1 HNMR (DMSO-d 6)}} : 1.41 (9H, s),
2.36-2.56 (4H, m), 3.20-3.41
(8H, m), 12.01 (1H, br) IR (KB
r): 1689.3, 1643.1 cm ^-1

The starting compounds used in the following Production Examples and Examples and the obtained target compounds are shown in the following tables, and the structural formulas of the starting compounds are shown in the upper row, and the structural formulas of the target compounds are shown in the lower row. Is shown.

[0121] Example 1 Starting compound (500 mg) in dimethylformamide (5
ml) solution with diisopropylethylamine (0.555).
ml) and ethylformimidate hydrochloride (209m
g) and the solution is stirred at room temperature for 4 days. Ethyl acetate (〜100 ml) is added to the mixture and the resulting solid is collected and dried. The crude product is dissolved in water, subjected to ODS column chromatography, and eluted with a mixed solution of acetonitrile-water. The fractions containing the product were collected, the organic solvent was distilled off, the pH was adjusted to 2.8 and Amberlyst A-26
Pass through a column of (Cl ^- type) ion exchange resin and freeze-dry to obtain the target compound as a white solid. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.
55-3.40 (4H, m), 3.50-4.63 (2
4H, m), 4.63-5.40 (8H, m), 6.6.
1 (2H, d, J = 8.4 Hz), 6.86-7.02
(3H, m), 7.15 (1H, brs), 7.42
(1H, d, J = 8 Hz), 7.70-9.65 (14
H, m) FAB-MS: M / Z 1560 (MH ⁺ , free) IR (KBr): 3307.3, 1714.4, 165
4.6cm ^-1

Example 2 A buffer solution (10 ml) of the starting compound (717 mg) at pH 6.86 was added to ethyl acetimidate hydrochloride (56
4.3 mg) over 4 hours, divided into 8
Add while maintaining 7-8. The solution is diluted with water (90 ml), adjusted to pH 2.8, subjected to ODS column chromatography, and eluted with a mixed solution of acetonitrile-water. The fractions containing the product are collected, the solvent is distilled off and the pH
The mixture was adjusted to 2.8, passed through a short column of Amberlyst A-26 (Cl ^- type) ion exchange resin, and lyophilized to obtain the target compound as a white powder (440 mg). ¹ H NMR (CD ₃ OD): 0.75-1.00 (9H,
m), 1.14 (3H, d, J = 6.2 Hz), 1.2
0-1.50 (34H, m), 1.50-3.32 (1
9H, m), 2.15 (3H, s), 3.60-5.0.
0 (23H, m), 5.00-5.25 (2H, m),
6.91 (2H, d, J = 8.5 Hz), 7.09 (2
H, d, J = 8.5 Hz) FAB-MS: M / Z 1574 (MH ⁺ , free) IR (KBr): 3299.6, 1733.7, 165
2.7 cm ^-1

Example 3 Dimethylformamide (5.3 mg) of starting compound (525 mg) and t-butyl bromoacetate (7 to 8.3 mg)
ml) solution was treated with potassium carbonate (55.5 mg)
Stir for 15 hours at room temperature. Ethyl acetate (25m
1) is added and the resulting precipitate is collected and dried. The crude product is dissolved in water, adjusted to pH 3 and subjected to ODS column chromatography, eluting with a mixed solution of acetonitrile-water. The fractions containing the product were collected, the solvent was distilled off, and the residue was lyophilized to give the target compound as a white amorphous powder (175 m
g). FAB-MS: M / Z 1647 (MH ⁺ ) IR (KBr): 1735.6, 1654.6 cm ^-1

Example 4 In the same manner as in Example 1 , the starting compound and 1-amidino-
The target compound is obtained from 3,5-dimethylpyrazole. ¹ H NMR (CD ₃ OD): 0.70-1.20 (9H,
m), 1.13 (3H, d, J = 6.3 Hz), 1.2
0-1.45 (34H, m), 1.45-3.30 (1
9H, m), 3.50-4.90 (23H, m), 5.
00-5.15 (2H, m), 6.94 (2H, d, J
= 8.5 Hz), 7.08 (2H, d, J = 8.5H)
z) FAB-MS: M / Z 1575 (MH ⁺ , free) IR (KBr): 3276.5, 1731.8, 165
4.6cm ^-1

Example 5 The target compound was obtained in the same manner as in Example 1 . ¹ H NMR (CD ₃ OD): 0.70-1.00 (9H,
m), 1.13 (3H, d, J = 6.3 Hz), 1.2
0-1.50 (34H, m), 1.50-3.00 (1
9H, m), 3.50-4.90 (25H, m), 4.
15 (6H, s), 5.05-5.20 (2H, m),
6.93 (2H, d, J = 8.5 Hz), 7.07 (2
H, d, J = 8.5 Hz), 8.43 (2H, s) FAB-MS: M / Z 1669 (MH ⁺ , free) IR (KBr): 3307.3, 1729.8, 165
2.7 cm ^-1

Example 6 In the same manner as in Example 1 , the desired compound is obtained from the starting compound and ethyl 1-benzyloxycarbonyl-3- (1-imino-1-methoxymethyl) -azetidine hydrochloride. _{^{1 HNMR (DMSO-d 6)}} : 0.70-1.40 (4
6H, m), 1.40-2.50 (15H, m), 2.
50-4.80 (41H, m), 5.06 (2H,
s), 6.62 (2H, d, J = 8 Hz), 6.95.
(2H, d, J = 8 Hz), 6.97 (1H, br)
s), 7.17 (1H, brs), 7.36 (5H,
s), 7.25-8.40 (11H, m), 8.85
(1H, brs), 9.29 (1H, brs), 9.5
7 (1H, brs) FAB-MS: M / Z 1749 (MH ⁺ , free) IR (KBr): 3303.5, 1652.7 cm ⁻¹

Example 7 The target compound was obtained in the same manner as in Example 1 . ¹ H NMR (CD ₃ OD): 0.70-1.00 (9H,
m), 1.14 (3H, d, J = 6.2 Hz), 1.2
0-1.45 (34H, m), 1.45-3.35 (1
9H, m), 3.35-5.20 (35H, m), 6.
87-7.28 (4H, m) FAB-MS: M / Z 1675 (MH ⁺ , free) IR (KBr): 3313.1, 1724.0, 166
0.4cm ^-1

Example 8 The target compound was obtained in the same manner as in Example 2 . _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.
55-2.75 (1H, m), 2.75-5.40 (3
7H, m), 6.61 (2H, d, J = 8.3), 6.
86-7.02 (3H, m), 7.15 (1H, br
s), 7.32 (1H, brs), 7.42 (1H,
d, J = 8 Hz), 7.65-9.57 (14H, m) FAB-MS: M / Z 1617 (MH ⁺ , free) IR (KBr): 3322.7, 1654.6 cm ⁻¹

Example 9 The target compound was obtained in the same manner as in Example 2 . ¹ H NMR (CD ₃ OD): 0.88-0.95 (9H,
m), 1.14 (3H, d, J = 6.2 Hz), 1.2
0-1.40 (34H, m), 1.50-3.00 (1
9H, m), 2.75 (2H, t, J = 5.7 Hz),
3.37 (3H, s), 3.68 (2H, t, J = 5.
7 Hz), 3.60-4.90 (23H, m), 5.0
0-5.25 (2H, m), 6.90 (2H, d, J =
8.5 Hz), 7.09 (2H, d, J = 8.5 Hz) FAB-MS: M / Z 1618 (MH ⁺ , free) IR (KBr): 1733.7, 1654.6 cm ⁻¹

Example 10 In the same manner as in Example 2 , the desired compound is obtained from the starting compound and ethyl 2- (acetylamino) acetimidate hydrochloride. ¹ H NMR (CD ₃ OD): 0.70-1.00 (9H,
m), 1.13 (3H, d, J = 6.2 Hz), 1.2
0-1.43 (34H, m), 2.15 (3H, s),
1.50-3.30 (19H, m), 3.50-4.9
0 (25H, m), 5.00-5.15 (2H, m),
6.91 (2H, d, J = 8.5 Hz), 7.12 (2
H, d, J = 8.5 Hz) FAB-MS: M / Z 1631 (MH ⁺ , free) IR (KBr): 3303.5, 1658.5 cm ⁻¹

Example 11 The target compound was obtained in the same manner as in Example 2 . FAB-MS: M / Z 1814 (M ⁺ , free) IR (KBr): 3320.8, 3301.5, 165
4.6,155.1 cm ^-1

Example 12 In the same manner as in Example 13 , the desired compound is obtained from the starting compound and diphenylmethyl bromoacetate. ¹ H NMR (CD ₃ OD): 0.70-1.05 (9H,
m), 1.05-1.42 (37H, m), 1.05-
3.00 (19H, m), 3.40-5.20 (27
H, m), 6.86 (2H, d, J = 8.3 Hz),
6.92 (1H, s), 7.04 (2H, d, J = 8.
3 Hz), 7.29-7.35 (10H, m) FAB-MS: M / Z 1757 (MH ⁺ , free) IR (KBr): 3318.9, 1737.5, 165
8.5 cm ^-1

Examples 13 and 14 The starting compound (200 mg) in dimethylformamide (2
ml) solution was treated with allyl bromide (17 mg) and diisopropylethylamine (39.5 mg) and stirred for 7 hours, and then again treated with allyl bromide (17 mg) and diisopropylethylamine (39.5 mg), for a total of 9
Stir at room temperature for 6 hours. Ethyl acetate is added and the resulting precipitate is collected, dried, dissolved in water and subjected to ODS column chromatography. The two resulting fractions were each collected, concentrated, adjusted to pH 3, and Amberlyst A-26
(Cl ^- type) through a column of ion exchange resin and freeze-dried, the objective compound of Example 13 (77.8 mg) and the actual
The target compound of Example 14 (33.4 mg) is obtained as a white amorphous powder. Physical properties of the target compound of Example 13 FAB-MS: M / Z 1613 (M ⁺ , free) IR (KBr): 3309.2, 1733.7, 165
6.6 cm ^-1 Physical properties of the target compound of Example 14 FAB-MS: M / Z 1654 (MH ⁺ , free) IR (KBr): 3320.8, 1731.8, 165
6.6 cm ^-1

Example 15 The starting compound (300 mg) in dimethylformamide (3
ml) solution was treated with potassium carbonate (52.8 mg),
Then treat with methyl iodide (59.5 μl). The mixture was stirred for 2 hours and again methyl iodide (35.7μ)
Process in 1). After reacting for a total of 4 hours, ethyl acetate (25 ml) was added to the mixture and the resulting precipitate was collected,
dry. The solid obtained is dissolved in water, adjusted to pH 2.8 and subjected to ODS chromatography to give 30-35.
Elution with a mixed solution of% -acetonitrile-water. The obtained fraction was concentrated, adjusted to pH 2.8, passed through a short column of Amberlyst A-26 (Cl ^- type) ion exchange resin, and the obtained eluate was lyophilized to give the target compound (24).
3.3 mg). _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.40 (4
6H, m), 1.40-2.55 (15H, m), 2.
58-2.80 (1H, m), 2.80-3.10 (3
H, m), 3.02 (9H, s), 3.50-4.05.
(11H, m), 4.10-4.50 (11H, m),
4.50-4.65 (2H, m), 4.65-5.40
(8H, m), 6.62 (2H, d, J = 8.4),
6.90-7.03 (1H, br), 6.95 (2H,
d, J = 8.4), 7.14 (1H, s), 7.43
(1H, d, J = 8.5), 7.70-8.38 (9
H, m), 9.15 (1H, s) FAB-MS: 1575 (M ⁺ , free) IR (KBr): 3344, 1735.6, 1654.
6cm ^-1

Example 16 In the same manner as in Example 13 , the desired compound is obtained from the starting compound and 2-iodoethanol. FAB-MS: 1621 (MH ⁺ , free) IR (KBr): 3303.5, 1727.9, 165
8.5 cm ^-1

Example 17 In the same manner as in Example 13 , the desired compound is obtained from the starting compound and 4-chloromethylpyrazole hydrochloride. FAB-MS: M / Z 1774 (MH ⁺ , free) IR (KBr): 3270, 1731.8, 1654.
6cm ^-1

Example 18 In the same manner as in Example 13 , the desired compound is obtained from the starting compound and t-butyl bromoacetate. FAB-MS: M / Z 1761 (MH ⁺ ) IR (KBr): 3320.8, 1735.6, 164
8.8 cm ^-1

Example 19 Starting compound (300 mg) and 3-acetoamino-4-thiazolecarbaldehyde (39 mg) in methanol (6 mg)
ml) solution is treated with triethylamine (29.3 ml) and stirred for 19 hours at room temperature. The solution is treated with sodium borohydride (36mg) for 2 hours. Evaporate the solvent,
The residue is dissolved in water, adjusted to pH 2.8, subjected to ODS column chromatography, and eluted with a mixed solution of acetonitrile-water. The fractions containing the product were collected, the organic solvent was distilled off, the pH was adjusted to 2.8 and Amberlyst A-26
It is passed through a column of (Cl ^- type) ion exchange resin, washed with water, and the obtained eluate is freeze-dried to obtain the target compound as a white powder (264 mg). _{^{1 HNMR (DMSO-d 6)}} : 0.78-1.38 (4
6H, m), 1.38-3.30 (21H, m), 2.
16 (3H, s), 3.30-5.30 (32H,
m), 6.61 (2H, d, J = 8.3 Hz), 6.8
8-7.02 (3H, m), 7.17 (1H, br
s), 7.30 (1H, s), 7.40 (1H, d, J
= 8.0 Hz), 7.70-9.20 (12H, m),
12.10 (1H, s) FAB-MS: M / Z 1687 (MH ⁺ , free) IR (KBr): 3300, 1733.7, 1654.
6cm ^-1

Example 20 A methanol (4 ml) solution containing the starting compound (200 mg) and a 35% aqueous formaldehyde solution (66 μl) is treated with acetic acid (22 μl) and then with sodium cyanoborohydride (19.3 mg). 2 at room temperature
Stir for 4 hours and evaporate the solvent under reduced pressure. The residue was washed with water (2
00 ml) and subjected to ODS chromatography, eluting with a mixed solution of 35% -acetonitrile-water. The fractions containing the product are collected, the solvent is distilled off and the pH 2.
The resulting eluate was lyophilized by passing through a short column of Amberlyst A-26 (Cl ^- type) ion exchange resin to obtain the target compound (108.5 mg). _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.55-2.75 (1
H, m), 2.72 (6H, s), 2.76-3.12.
(3H, m), 3.55-4.05 (11H, m),
4.10-4.45 (11H, m), 4.45-4.6
5 (2H, m), 4.77-5.35 (8H, m),
6.61 (2H, d, J = 8.4), 6.95 (2H,
d, J = 8.4), 6.90-7.00 (1H, b
r), 7.14 (1H, brs), 7.43 (1H,
d, J = 8.3), 7.73-8.34 (9H, m),
9.14 (1H, s), 9.67 (1H, br) FAB-MS: M / Z 1561 (MH ⁺ , free) IR (KBr): 3371.0, 1735.6, 165
4.6cm ^-1

Example 21 In the same manner as in Example 19 , the starting compound and 1-methyl-4
-The desired compound is obtained from pyrazole carbaldehyde. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.38 (4
6H, m), 1.38-3.10 (21H, m), 3.
10-5.30 (32H, m), 3.84 (3H,
s), 6.61 (2H, d, J = 8.4 Hz), 6.8
8-7.03 (3H, m), 7.16 (1H, br
s), 7.43 (1H, d, J = 8.3 Hz), 7.5
2 (1H, s), 7.79 (1H, s), 7.74-
9.35 (12H, m) FAB-MS: M / Z 1627 (MH ⁺ , free) IR (KBr): 3299.6, 1729.8, 165
8.5 cm ^-1

Example 22 The starting compound (200 mg) in dimethylformamide (2
ml) solution with diisopropylethylamine (49 μl)
And after 5 minutes, with 3-pyridinesulfonyl chloride hydrochloride (30 mg). The solution is stirred for 1 hour at room temperature and treated with diisopropylethylamine (50 μl) and sulfonyl chloride (15 mg). After 1 hour, ethyl acetate (10 ml) is added and the resulting precipitate is collected and dried. The crude product is dissolved in water (60 ml) and p
The mixture was adjusted to H3.5 and subjected to ODS column chromatography, eluting with a mixed solution of 50% -acetonitrile-water. The fractions containing the product are collected, concentrated to remove the solvent and p
H4.0, Amber List A-26 (Cl
^- type) through a short column of ion exchange resin, the resulting eluate was lyophilized to give the desired compound as a white amorphous solid (148.2mg). _{^{1 HNMR (DMSO-d 6)}} : 0.70-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.
55-3.10 (4H, m), 3.10-5.15 (3
5. 2H, m), 6.60 (2H, d, J = 8.3),
90 (1H, brs), 6.94 (2H, d, J = 8.
3), 7.12 (1H, brs), 7.43 (1H,
d, J = 8.0), 7.63 (1H, dd, J = 8.
1,4.9), 7.70-8.33 (12H, m),
8.76-8.84 (1H, m), 8.92 (1H,
s), 9.10 (1H, brs) FAB-MS: M / Z 1674 (MH ⁺ , free) IR (KBr): 3340, 1733.7, 1658.
5cm ^-1

Example 23 The starting compound (200 mg) in dimethylformamide (2
ml) solution with 4-dimethylaminopyridine (17 mg)
And n-propyl isocyanate (13.1 μl). The solution was stirred for 1 hour at room temperature and ethyl acetate (8m
Process in 1). The resulting solid was treated as in Example 25 (ODS column chromatography, 45-50%
-Elution with a mixed solution of acetonitrile-water) and freeze-drying the fraction containing the product to obtain the target compound as a white amorphous solid. _{^{1 HNMR (DMSO-d 6)}} : 0.72-1.72 (5
7H, m), 1.72-2.55 (9H, m), 2.5
5-2.75 (1H, m), 2.80-3.02 (5
H, m), 3.55-4.05 (9H, m), 4.05.
-4.48 (13H, m), 4.48-4.65 (2
H, m), 4.70-4.85 (3H, m), 4.98
−5.22 (5H, m), 5.68-5.80 (2H,
m), 6.60 (2H, d, J = 8.3), 6.89
(1H, brs), 6.94 (2H, d, J = 8.
3), 7.13 (1H, brs), 7.46 (1H,
d, J = 8.0), 7.70-8.33 (9H, m),
9.10 (1H, s) FAB-MS: M / Z 1618 (MH ⁺ ) IR (KBr): 3345.9, 1729.8, 165
8.5 cm ^-1

Example 24 Starting compound (1.00 g), succinic anhydride (76.6 m
g) and 4-dimethylaminopyridine (101.25 m
A solution of g) in dimethylformamide (10 ml) is stirred for 18 hours at room temperature and treated with ethyl acetate (〜200 ml). The precipitate formed is filtered off and dried. The crude solid is dissolved in water (〜200 ml) and subjected to ODS column chromatography, eluting with a mixed solution of 40-50% -acetonitrile-water. The fractions containing the product are collected, the solvent is distilled off, and lyophilized to obtain the target compound as a white amorphous solid (980 mg). FAB-MS: M / Z 1633 (MH ⁺ ) IR (KBr): 3307.3, 1724.0, 165
2.7 cm ^-1

Example 25 N-ethyl-N'- was added to a solution of the starting compound (300 mg), 1-hydroxybenzotriazole (28.4 mg), acetic acid (12 μl) and diisopropylethylamine (36.6 μl) in dimethylformamide (3 ml). 3-dimethylaminopropylcarbodiimide hydrochloride (54.9
mg) is added and the solution is stirred at room temperature for 4 hours. Ethyl acetate (25 ml) is added to the solution and the resulting precipitate is collected, washed with ethyl acetate and dried. The crude white powder is subjected to ODS column chromatography and eluted with a mixed solution of water-acetonitrile (9: 1 to 1: 1). The fractions containing the product are collected, concentrated to remove the organic solvent, and lyophilized to give the desired compound as an amorphous powder (288.3 mg). _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.32 (4
6H, m), 1.32-2.55 (15H, m), 1.
77 (3H, s), 2.55-2.75 (1H, m),
2.90-3.10 (3H, m), 3.55-4.05
(11H, m), 4.05-4.50 (11H, m),
4.50-4.65 (2H, m), 4.70-4.85
(3H, m), 4.97-5.20 (5H, m), 6.
60 (2H, d, J = 8.4), 6.89 (1H, br)
s), 6.94 (2H, d, J = 8.4), 7.12.
(1H, brs), 7.4 (1H, d, J = 8.0),
7.70-8.35 (10H, m), 9.10 (1H,
s) FAB-MS: M / Z 1575 (MH ⁺ ) IR (KBr): 3317.0, 1735.6, 165
2.7 cm ^-1

Example 26 In the same manner as in Example 25 , the target compound is obtained by acylating the starting compound with N, N-dimethylglycine hydrochloride. Regarding purification, a treatment step with an ion exchange resin is inserted before freeze-drying in the same manner as in Example 56 . _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.
55-2.75 (1H, m), 2.79 (6H, s),
2.88-3.20 (3H, m), 3.55-4.05
(11H, m), 4.10-4.50 (13H, m),
4.50-4.63 (2H, m), 4.78-4.95
(3H, m), 4.95-5.40 (5H, m), 6.
61 (2H, d, J = 8.4), 6.87-7.02
(1H, br), 6.95 (2H, d, J = 8.4),
7.16 (1H, brs), 7.48 (1H, d, J =
7.5), 7.77 (1H, d, J = 8.4), 7.8
8 (1H, d, J = 6.9), 7.97 (1H, d, J
= 8.3), 8.05-8.40 (6H, m), 8.4.
5-8.60 (1H, m), 9.17 (1H, s),
9.71 (1H, br) FAB-MS: M / Z 1618 (MH ⁺ , free) IR (KBr): 3318.9, 1733.7, 165
4.6cm ^-1

Example 27 The target compound is obtained from the starting compound and dimethylsulfamoyl chloride in the same manner as in Example 22 except for the step of treating with Amberlyst A-26 at the final stage. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.
55-2.75 (1H, m), 2.64 (6H, s),
2.75-3.07 (3H, m), 3.55-4.05
(11H, m), 4.10-4.50 (11H, m),
4.50-4.65 (2H, m), 4.70-4.95
(3H, m), 4.95-5.20 (5H, m), 6.
60 (2H, d, J = 8.4), 6.89 (1H, br)
s), 6.94 (2H, d, J = 8.4), 7.00-
7.18 (2H, m), 7.45 (1H, d, J = 8.
4), 7.70-8.34 (9H, m), 9.09 (1
H, s) FAB-MS: M / Z 1640 (MH ^<+> ) IR (KBr): 3317.0, 1735.6, 165
6.6 cm ^-1

Example 28 The target compound is obtained from the starting compound and benzyloxycarbonyl chloride in the same manner as in Example 22 except for the step of treating with Amberlyst A-26 at the final stage. FAB-MS: M / Z 1690 (M + Na) ⁺ , 16
68 (MH) ⁺ IR (KBr): 3318.9, 1731.8, 165
4.6cm ^-1

Example 29 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and glycolic acid. _{^{1 HNMR (DMSO-d 6)}} :
0.75-1.35 (46H, m), 1.35-2.5
5 (15H, m), 2.55-2.75 (1H, m),
2.90-3.15 (3H, m), 3.55-4.05
(11H, m), 4.05-4.50 (13H, m),
4.50-4.65 (2H, m), 4.70-4.85
(3H, m), 4.97-5.20 (5H, m), 5.
41 (1H, t, J = 5.8), 6.60 (2H, d,
J = 8.4), 6.90 (1H, brs), 6.94.
(2H, d, J = 8.4), 7.12 (1H, br
s), 7.45 (1H, d, J = 8.6), 7.60-
8.33 (10H, m), 9.10 (1H, s) FAB
-MS: M / Z 1591 (MH ^<+> ) IR (KBr):
3313.1, 1733.7, 1654.6 cm ^-1

Example 30 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and Nt-butoxycarbonylglycine. FAB-MS: M / Z 1590 (MH + -Bu t O
₂ C) IR (KBr): 3324.7, 1658.5 cm ^-1

Example 31 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and Nt-butoxycarbonyl-β-alanine. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
2H, m), 1.37 (9H, s), 1.73-2.5
5 (11H, m), 2.55-2.75 (1H, m),
2.85-3.20 (5H, m), 3.55-4.50
(22H, m), 4.50-4.65 (2H, m),
4.75-4.90 (3H, m), 4.90-5.28
(5H, m), 6.60 (2H, d, J = 8.3),
6.67-6.78 (1H, m), 6.94 (2H,
d, J = 8.3), 6.87-7.00 (1H, b
r), 7.15 (1H, brs), 7.48 (1H,
d, J = 7.9), 7.70-8.35 (10H,
m), 9.14 (1H, s ) FAB-MS: M / Z 1604 (M + -Bu t OCO +
2H ⁺ ) IR (KBr): 3324.7, 1730, 1654.
6cm ^-1

Example 32 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and 4-Nt-butoxycarbonylaminobutyric acid. FAB-MS: M / Z 1619 (M + -Bu t O 2 C +
2H) IR (KBr): 3313.1, 1733.7, 165
2.7 cm ^-1

Example 33 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and 5-t-butoxyloxyaminovaleric acid. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
6H, m), 1.37 (9H, s), 1.73-2.5.
5 (11H, m), 2.55-2.75 (1H, m),
2.80-3.10 (5H, m), 3.55-4.50
(22H, m), 4.50-4.65 (2H, m),
4.73-4.90 (3H, m), 4.90-5.25
(5H, m), 6.60 (2H, d, J = 8.4),
6.75 (1H, t, J = 5.5), 6.94 (2H,
d, J = 8.4), 6.87-7.00 (1H, b
r), 7.14 (1H, brs), 7.47 (1H,
d, J = 8.2), 7.65-8.35 (10H,
m), 9.12 (1H, s ) FAB-MS: M / Z 1632 (M + -Bu t O 2 C +
2H ⁺ ) IR (KBr): 3315.0, 1729.8, 165
4.6cm ^-1

Example 34 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and 6-t-butoxycarbonylaminohexanoic acid. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
8H, m), 1.36 (9H, s), 1.73-2.5
5 (11H, m), 2.55-2.75 (1H, m),
2.80-3.10 (5H, m), 3.55-4.50
(22H, m), 4.50-4.65 (2H, m),
4.73-4.90 (3H, m), 4.90-5.25
(5H, m), 6.60 (2H, d, J = 8.4),
6.74 (1H, t, J = 5.5), 6.94 (2H,
d, J = 8.4), 6.87-6.98 (1H, b
r), 7.14 (1H, brs), 7.48 (1H,
d, J = 8.3), 7.65-8.35 (10H,
m), 9.13 (1H, s ) FAB-MS: M / Z 1646 (M + -Bu t O 2 C +
2H) IR (KBr): 3311.2, 1729.8, 165
4.6cm ^-1

Example 35 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and Nt-butoxycarbonylsarcosine. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
2H, m), 1.39 and 1.48 (9H, s),
1.75-2.55 (9H, m), 2.55-2.75
(1H, m), 2.78 (3H, brs), 2.85-
3.15 (3H, m), 3.55-4.10 (11H,
m), 4.10-4.50 (13H, m), 4.50-
4.67 (2H, m), 4.70-4.87 (3H,
m), 4.98-5.25 (5H, m), 6.60 (2
H, d, J = 8.4), 6.90 (1H, brs),
6.94 (2H, d, J = 8.4), 7.12 (1H,
brs), 7.45 (1H, d, J = 7.1), 7.7
0-8.35 (10H, m), 9.10 (1H, s) FAB-MS: M / Z 1604 (M + -Bu t O 2 C +
2H ⁺ ) IR (KBr): 3330.5, 1735.6, 165
6.6 cm ^-1

Example 36 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and t-butoxycarbonyl-L-serine. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
2H, m), 1.38 (9H, s), 1.75-2.5
5 (9H, m), 2.55-2.75 (1H, m),
2.85-3.12 (3H, m), 3.40-4.50
(25H, m), 4.50-4.65 (2H, m),
4.73-4.90 (4H, m), 4.96-5.26
(5H, m), 6.51 (1H, d, J = 8.2),
6.60 (2H, d, J = 8.4), 6.94 (2H,
d, J = 8.4), 6.85-7.00 (1H, b
r), 7.14 (1H, brs), 7.48 (1H,
d, J = 7.4), 7.70-8.40 (10H,
m), 9.13 (1H, s ) FAB-MS: M / Z 1620 (M + -Bu t O 2 C +
2H ⁺ ) IR (KBr): 3324.7, 1730, 1656.
6cm ^-1

Example 37 In the same manner as in Example 25 , the starting compound and (S) -1-
The target compound is obtained from (t-butoxycarbonyl) -2-azetidinecarboxylic acid. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
2H, m), 1.34 (9H, s), 1.73-2.5
5 (11H, m), 2.55-2.75 (1H, m),
2.80-3.18 (3H, m), 3.55-4.50
(25H, m), 4.50-4.65 (2H, m),
4.70-4.92 (3H, m), 4.97-5.25
(5H, m), 6.60 (2H, d, J = 8.4),
6.90 (1H, brs), 6.94 (2H, d, J =
8.4), 7.12 (1H, brs), 7.46 (1
H, d, J = 7.5), 7.70-8.35 (10H,
m), 9.10 (1H, s ) FAB-MS: M / Z 1616 (M + -Bu t O 2 C +
2H ⁺ ) IR (KBr): 3313.1, 1733.7, 165
8.5 cm ^-1

Example 38 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and 1-tert-butoxycarbonyl-3-azetidinecarboxylic acid. _{^{1 HNMR (DMSO-d 6)}} : 0.72-1.72 (5
2H, m), 1.37 (9H, s), 1.72-2.5
5 (9H, m), 2.55-2.75 (1H, m),
2.80-3.30 (4H, m), 3.50-4.05
(13H, m), 4.05-4.48 (13H, m),
4.48-4.65 (2H, m), 4.70-4.85
(3H, m), 4.98-5.22 (5H, m), 6.
60 (2H, d, J = 8.4), 6.90 (1H, br)
s), 6.94 (2H, d, J = 8.4), 7.12.
(1H, brs), 7.46 (1H, d, J = 8.
0), 7.70-8.33 (10H, m), 9.10
(1H, s) FAB-MS : M / Z 1616 (M + -Bu t O 2 C +
2H ⁺ ) IR (KBr): 3327, 1733.7, 1654.
6cm ^-1

Example 39 In the same manner as in Example 25 , the starting compound and (R) -1-t
-The desired compound is obtained from -butoxycarbonyl-3-piperidinecarboxylic acid. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
5H, m), 1.40 (9H, s), 1.75-2.5
5 (11H, m), 2.55-3.13 (6H, m),
3.55-4.50 (24H, m), 4.50-4.6
5 (2H, m), 4.73-4.93 (3H, m),
4.98-5.25 (5H, m), 6.61 (2H,
d, J = 8.3), 6.95 (2H, d, J = 8.3).
3), 6.88-7.00 (1H, brs), 7.16
(1H, brs), 7.48 (1H, d, J = 8.
0), 7.73-8.40 (10H, m), 9.14
(1H, s) FAB-MS: M / Z 1644 (M ⁺ -BOC + 2
H ⁺ ) IR (KBr): 3317.0, 1735.6, 165
8.5 cm ^-1

Example 40 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and 1-t-butoxycarbonyl-4-piperidinecarboxylic acid. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
6H, m), 1.39 (9H, s), 1.75-2.5
5 (10H, m), 2.55-3.10 (6H, m),
3.55-4.50 (24H, m), 4.50-4.6
5 (2H, m), 4.73-4.95 (3H, m),
4.95-5.28 (5H, m), 6.60 (2H,
d, J = 8.4), 6.94 (2H, d, J = 8.
4), 6.90-7.00 (1H, br), 7.15
(1H, brs), 7.48 (1H, d, J = 9.
0), 7.70-8.40 (10H, m), 9.14
(1H, s) FAB-MS : M / Z 1644 (M + -Bu t O 2 C +
2H ⁺ ) IR (KBr): 3330.5, 1733.7, 165
6.6 cm ^-1

Example 41 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and t-butoxycarbonyl-L-alanine. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
2H, m), 1.14 (3H, d, J = 7.3), 1.
37 (9H, s), 1.75-2.55 (9H, m),
2.55-2.75 (1H, m), 2.80-3.20
(3H, m), 3.55-4.05 (12H, m),
4.05-4.50 (11H, m), 4.50-4.6
7 (2H, m), 4.70-4.95 (3H, m),
4.95-5.28 (5H, m), 6.60 (2H,
d, J = 8.3), 6.79 (1H, d, J = 7.
8), 6.94 (2H, d, J = 8.3), 6.90 −
7.00 (1H, br), 7.15 (1H, brs),
7.49 (1H, d, J = 7.4), 7.70-8.4
0 (10H, m), 9.14 (1H, s) FAB-MS: M / Z 1604 (M + -Bu t O 2 C +
2H ⁺ ) IR (KBr): 3317.0, 1732.1654.
6cm ^-1

Example 42 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and t-butoxycarbonyl-L-hydroxyproline. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
2H, m), 1.31 and 1.38 (9H, s),
1.75-2.55 (11H, m), 2.55-2.7
5 (1H, m), 2.85-3.45 (5H, m),
3.55-4.02 (11H, m), 4.02-4.5
0 (13H, m), 4.50-4.67 (2H, m),
4.70-4.90 (3H, m), 4.95 (1H,
d, J = 3.4), 4.98-5.25 (5H, m)
6.60 (2H, d, J = 8.4), 6.90 (1H,
brs), 6.94 (2H, d, J = 8.4), 7.1.
2 (1H, brs), 7.46 (1H, d, J = 8.
4), 7.70-8.35 (10H, m), 9.10
(1H, s) FAB-MS : M / Z 1646 (M-Bu t O 2 C + 2
H ⁺ ) IR (KBr): 3311.2, 1735.6, 165
6.6 cm ^-1

Example 43 In the same manner as in Example 25 , the starting compound and N ² , N ⁵ -di-
The target compound is obtained from t-butoxycarbonyl-L-ornithine. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
6H, m), 1.37 (18H, m), 1.75-2.
75 (m), 2.75-3.15 (5H, m), 3.5
5-4.05 (12H, m), 4.05-4.50 (1
1H, m), 4.50-4.67 (2H, m), 4.7
0-4.95 (3H, m), 4.95-5.30 (5
H, m), 6.60 (2H, d, J = 8.3), 6.6
3-7.00 (5H, m), 7.13 (1H, br
s), 7.46 (1H, d, J = 8.0), 7.70-
8.40 (10H, m), 9.11 (1H, s) FAB-MS: M / Z 1869 (M + + Na +) IR (KBr): 3329,1733,1656.6c
m ^-1

Example 44 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and 4-octyloxybenzoic acid benzotriazol-1-yl-ester. FAB-MS: M / Z 1765 (MH + -Bu t O
_{2 C) IR (KBr):} 3282.3,1733.7,165
2.7 cm ^-1

Example 45 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and N-succinimide-tert-butoxycarbonyl-L-tyrosine ester. FAB-MS: M / Z 1696 (M + -Bu t O 2 C) IR (KBr): 3344.0,1658.5cm -1

Example 46 In the same manner as in Example 25 , the starting compound _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
2H, m), 1.33 (9H, s), 1.55 (9H,
s), 1.73-3.20 (15H, m), 3.57-
4.50 (23H, m), 4.50-4.65 (2H,
m), 4.72-4.90 (3H, m), 4.98-
5.23 (5H, m), 6.60 (2H, d, J = 8.
4Hz), 6.79 (1H, d, J = 8.7Hz),
6.83-6.98 (3H, m), 6.96 (1H,
s), 7.14 (1H, s), 7.46 (1H, d, J
= 8.1 Hz), 7.70-8.40 (10H, m),
8.09 (1H, s), 9.12 (1H, s) FAB-MS: M / Z 1771 (M + -Bu t O 2 C) IR (KBr): 3309.2,1756.8,173
7.5,1654.6cm ^-1

Example 47 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and Nt-butoxycarbonyl-L-glutamic acid-α-t-butyl ester. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
4H, m), 1.38 (9H, s), 1.39 (9H,
s), 1.73-3.10 (15H, m), 3.50-
4.47 (23H, m), 4.47-4.64 (2H,
m), 4.73-4.90 (3H, m), 4.90-
5.28 (5H, m), 6.60 (2H, d, J = 8.
4Hz), 6.87-7.02 (3H, m), 7.05
−7.23 (2H, m), 7.50 (1H, d, J = 8)
Hz), 7.70-8.40 (10H, m), 9.12
(1H, s) FAB-MS : M / Z 1719 (M + -Bu t O 2 C) IR (KBr): 3305.4,1729.8,165
2.7 cm ^-1

Example 48 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and Nt-butoxycarbonyl-L-aspartic acid-α-benzyl ester. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
2H, m), 1.73-3.10 (15H, m), 3.
55-4.50 (23H, m), 4.50-4.63
(2H, m), 4.70-4.88 (3H, m), 4.
93-5.22 (5H, m), 5.09 (2H, s),
6.60 (2H, d, J = 8.4), 6.83-7.0
0 (3H, m), 7.08-7.20 (2H, m),
7.30-7.40 (5H, m), 7.40-7.55
(1H, m), 7.70-8.38 (10H, m),
9.12 (1H, s) FAB- MS: M / Z 1739 (M + -Bu t O 2 C) IR (KBr): 3311.2,1735.6,165
4.6cm ^-1

Example 49 In the same manner as in Example 25 , the starting compound and (1R, 2S)
-2-t-butoxycarbonylaminocyclopentane-
The target compound is obtained from 1-carboxylic acid. FAB-MS: M / Z 1645 (M + -Bu t O 2 C) IR (KBr): 3309.2,1733,1652.
7cm ^-1

Example 50 In the same manner as in Example 25 , the starting compound and 3-[(4-t
-Butoxycarbonylpiperazin-1-yl) carbonyl] propionic acid to give the desired compound. FAB-MS: M / Z 1701 (M + -Bu t O 2 C) IR (KBr): 3336.2,1731.8,165
4.6cm ^-1

Example 51 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and 3- (t-butoxycarbonylaminomethyl) benzoic acid. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
2H, m), 1.39 (9H, s), 1.73-3.5.
0 (13H, m), 3.50-4.52 (24H,
m), 4.52-4.65 (2H, m), 4.70-
4.95 (3H, m), 4.95-5.30 (5H,
m), 6.60 (2H, d, J = 8.4 Hz), 6.8
5-7.00 (3H, m), 7.13 (1H, s),
7.30-8.47 (16H, m), 9.11 (1H,
s) FAB-MS: M / Z 1789 (M + Na) ⁺ IR (KBr): 3322.7, 1735, 1652.
7cm ^-1

Example 52 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and Nt-butoxycarbonylglycine. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
2H, m) 1.38 (9H, s), 1.73-4.50
(39H, m), 4.50-4.65 (2H, m),
4.73-4.95 (3H, m), 4.95-5.27
(5H, m), 6.60 (2H, d, J = 8.3H
z), 6.84-8.50 (21H, m) 9.11 (1
H, s) FAB-MS: M / Z 1724 (M + -Bu t O 2 C) IR (KBr): 3322.7,1733,1652.
7cm ^-1

Example 53 In the same manner as in Example 25 , the desired compound is obtained from the starting compound and N-benzyloxycarbonyl-L-aspartic acid-α-benzyl ester. FAB-MS: M / Z 1872 (MH ⁺ ) IR (KBr): 3320.8, 1727.9, 165
8.5 cm ^-1

Example 54 A solution of the starting compound (845 mg) in methanol (10 ml) is treated with wet 10% palladium-carbon (50 mg) and the solution is placed under an atmosphere of hydrogen gas at atmospheric pressure for 5 hours. The catalyst was removed by filtration, the solvent was distilled off from the filtrate, and water (10 m
Dissolved in 1) and lyophilized to give the desired compound as a white amorphous solid (780 mg). FAB-MS: M / Z 1771 (M + Na) ⁺ IR (KBr): 3322.7, 1724.0, 165
8.5 cm ^-1

Example 55 A solution of the starting compound (220 mg) in methanol (15 ml) is treated with wet 10% -palladium on carbon (50 mg) and the solution is reacted for 6 hours at atmospheric pressure in a hydrogen gas atmosphere. The catalyst was filtered off, the solvent was removed to dryness and water (15 m
1), adjusted to pH 2.5, and freeze-dried to obtain the target compound as a white powder (196 mg). _{^{1 HNMR (DMSO-d 6)}} : 0.70-1.35 (4
6H, m), 1.40-2.50 (15H, m), 2.
50-3.40 (4H, m), 3.50-4.60 (2
9H, m), 4.70-5.45 (8H, m), 6.6
2 (2H, d, J = 8.4 Hz), 6.93-6.98
(3H, m), 7.18 (1H, brs), 7.49-
9.80 (16H, m) FAB-MS: M / Z 1615 (MH ⁺ , free) IR (KBr): 3290.0, 1729.8, 165
8.5 cm ^-1

Example 56 Starting compound (420 mg) of trifluoroacetic acid (8 m
l) The solution is left at room temperature for 2.5 hours and evaporated to dryness under reduced pressure. Ethyl acetate (10 ml) is added to the residue, the solution is repeatedly dried to an additional 5 times and the resulting white powder (trifluoroacetate) is dried under vacuum for 1 hour. The salt was dissolved in water, treated with 0.1N hydrochloric acid (~ 5 mL), Amberlyst A-26 ^- through a short column of (Cl type) ion exchange resin, eluted with water, the eluate was lyophilized To obtain a white amorphous solid (400 m
g). Alternatively, the target compound is obtained by performing ODS column chromatography (eluting with a mixed solution of acetonitrile-water) before the treatment step with the ion exchange resin (high-performance liquid chromatography). FAB-MS: M / Z 1590 (MH ⁺ , free) IR (KBr): 3297.7, 1735.6, 165
4.6cm ^-1

Example 57 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. FAB-MS: M / Z 1591 (MH ⁺ , free) IR (KBr): 3291.9, 1737.5, 165
4.6cm ^-1

Example 58 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.36 (4
6H, m), 1.36-2.55 (17H, m), 2.
55-2.78 (1H, m), 2.90-3.16 (5
H, m), 3.55-4.50 (22H, m), 4.5
0-4.65 (2H, m), 4.80-5.30 (8
H, m), 6.61 (2H, d, J = 8.4), 6.9
5 (2H, d, J = 8.4), 6.90-7.00 (1
H, br), 7.16 (1H, brs), 7.48 (1
H, d, J = 9.7), 7.70-8.40 (13H,
m), 9.16 (1H, s) FAB-MS: M / Z 1604 (MH ⁺ ) IR (KBr): 3301.5, 1733.7, 165
4.6cm ^-1

Example 59 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. FAB-MS: M / Z 1618 (MH ⁺ , free) IR (KBr): 3288.0, 1735.6, 165
6.6 cm ^-1

Example 60 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
6H, m), 1.73-2.55 (11H, m), 2.
55-3.10 (6H, m), 3.55-4.50 (2
2H, m), 4.50-4.65 (2H, m), 4.8
0-5.30 (8H, m), 6.61 (2H, d, J =
8.3), 6.95 (2H, d, J = 8.3), 6.9
0-7.00 (1H, br), 7.16 (brs),
7.47 (1H, d, J = 9.3), 7.65-8.4
5 (13H, m) 9.16 (1H, s) FAB-MS: M / Z 1632 (MH ⁺ , free) IR (KBr): 3307.3, 1733.7, 165
2.7 cm ^-1

Example 61 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
8H, m), 1.73-2.55 (11H, m), 2.
55-3.10 (6H, m), 3.55-4.50 (2
2H, m), 4.50-4.65 (2H, m), 4.7
8-5.30 (8H, m), 6.61 (2H, d, J =
8.3), 6.95 (2H, d, J = 8.3), 6.9
0-7.00 (1H, br), 7.15 (1H, br)
s), 7.48 (1H, d, J = 7.5), 7.65-
8.50 (13H, m) 9.16 (1H, s) FAB-MS: M / Z 1646 (MH ⁺ , free) IR (KBr): 3297.7, 1733.7, 165
2.7 cm ^-1

Example 62 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.75 (5
2H, m), 1.34 (3H, d, J = 6.9), 1.
75-2.55 (9H, m), 2.55-2.75 (1
H, m), 2.89-3.25 (3H, m), 3.55
-4.50 (23H, m), 4.50-4.62 (2
H, m), 4.62-5.40 (8H, m), 6.61.
(2H, d, J = 8.3), 6.95 (2H, d, J =
8.3), 6.85-7.00 (1H, br), 7.1
3 (1H, brs), 7.44 (1H, d, J = 8.
5), 7.75 (1H, d, J = 9.4), 7.82
(1H, d, J = 7.1), 7.93 (1H, d, J =
6.9), 8.00-8.40 (10H, m), 9.3
1 (1H, brs) FAB-MS: M / Z 1604 (MH ⁺ , free) IR (KBr): 3320.8, 1731.8, 166
0.4cm ^-1

Example 63 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-2.55 (15H, s), 2.
55 (3H, s), 2.55-2.75 (1H, m),
2.90-3.20 (3H, m), 3.55-4.05
(11H, m), 4.10-4.50 (13H, m),
4.50-4.65 (2H, m), 4.70-4.90
(3H, m), 4.90-5.30 (5H, m), 6.
61 (2H, d, J = 8.4), 6.90-6.95
(1H, br), 6.95 (2H, d, J = 8.4),
7.14 (1H, brs), 7.44 (1H, d, J =
8.4), 7.75 (1H, d, J = 8.6), 7.8
4 (1H, d, J = 7.3), 7.94 (1H, d, J
= 8.1), 8.00-8.45 (7H, m), 8.6.
5-8.80 (2H, m), 9.29 (1H, s) FAB-MS: M / Z 1604 (MH ⁺ , free) IR (KBr): 3303.5, 1731.8, 165
6.6 cm ^-1

Example 64 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.70-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.
58-2.78 (1H, m), 2.80-3.20 (4
H, m), 3.20-5.15 (36H, m), 6.6.
1 (2H, d, J = 8.4), 6.85-7.00 (1
H, br), 6.95 (2H, d, J = 8.4), 7.
14 (1H, brs), 7.46 (1H, d, J = 8.
0), 7.76 (1H, d, J = 8.5), 7.85
(1H, d, J = 6.9), 7.94 (1H, d, J =
7.2), 8.00-8.35 (7H, m), 8.70
(1H, br), 8.90 (1H, br), 9.13
(1H, br) FAB-MS: M / Z 1616 (MH ⁺ , free) IR (KBr): 3305.4, 1731.8, 165
6.6 cm ^-1

Example 65 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.36 (4
6H, m), 1.36-2.78 (18H, m), 2.
80-3.20 (3H, m), 3.55-4.50 (2
5H, m), 4.50-4.65 (2H, m), 4.7
5-4.90 (3H, m), 4.92-5.27 (5
H, m), 6.61 (2H, d, J = 8.3), 6.9
0-7.00 (1H, br), 6.95 (2H, d, J
= 8.3), 7.14 (1H, brs), 7.46 (1
H, d, J = 8.3), 7.75 (1H, d, J = 7.
9), 7.84 (1H, d, J = 7.4), 7.93
(1H, d, J = 6.5), 8.00-8.43 (8
H, m), 8.88 (1H, br), 9.22 (1H,
s) FAB-MS: M / Z 1616 (MH ⁺ , free) IR (KBr): 3304,1733.7,1656.
6cm ^-1

Example 66 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-2.55 (15H, m), 2.
55-2.75 (1H, m), 2.90-3.18 (3
H, m), 3.50-4.50 (25H, m), 4.5
0-4.65 (2H, m), 4.78-4.90 (3
H, m), 4.90-5.27 (5H, m), 5.46.
(1H, t, J = 4.8), 6.61 (2H, d, J =
8.4), 6.95 (2H, d, J = 8.4), 6.9
0-7.00 (1H, brs), 7.16 (1H, br)
s), 7.45 (1H, d, J = 8.0), 7.78
(1H, d, J = 8.8), 7.87 (1H, d, J =
8.2), 7.96 (1H, d, J = 8.5), 8.0
0-8.45 (10H, m), 9.16 (1H, s) FAB-MS: M / Z 1620 (MH ⁺ , free) IR (KBr): 3307.3, 1729.8, 166
0.4cm ^-1

Example 67 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.36 (4
6H, m), 1.36-3.20 (21H, m), 3.
50-5.40 (33H, m), 6.62 (2H, d,
J = 8.3 Hz), 6.88-7.07 (3H, m),
7.15 (1H, brs), 7.49 (1H, d, J =
9.0Hz), 7.76 (1H, d, J = 7.4H)
z), 7.86 (1H, d, J = 7.2 Hz), 7.9
9 (1H, d, J = 8.1 Hz), 8.05-8.65
(12H, m) FAB-MS: M / Z 1650 (MH ⁺ , free) IR (KBr): 3297.7, 1737.5, 165
8.5 cm ^-1

Example 68 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
4H, m), 1.73-3.20 (15H, m), 3.
50-5.30 (33H, m), 6.61 (2H, d,
J = 8.4 Hz), 6.86-7.02 (3H, m),
7.10-8.60 (17H, m) FAB-MS: M / Z 1662 (MH ⁺ , free) IR (KBr): 3305.4, 1737.5, 165
4.6cm ^-1

Example 69 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. FAB-MS: M / Z 1645 (M ⁺ , free) IR (KBr): 3297.7, 1733.7, 165
2.7 cm ^-1

Example 70 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. FAB-MS: M / Z 1701 (MH ⁺ , free) IR (KBr): 3286.1, 1729.8, 165
0.8cm ^-1

Example 71 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.37 (4
6H, m), 1.37-3.50 (19H, m), 3.
50-4.50 (24H, m), 4.50-4.63
(2H, m), 4.77-4.90 (3H, m), 4.
90-5.30 (5H, m), 6.60 (2H, d, J
= 8.5 Hz), 6.88-7.02 (3H, m),
7.16 (1H, s), 7.40-8.58 (18H,
m), 9.15 (1H, s) FAB-MS: M / Z 1666 (MH ⁺ , free) IR (KBr): 3315.0, 1733.7, 165
2.7 cm ^-1

Example 72 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.36 (4
6H, m), 1.36-5.15 (55H, m), 6.
60 (2H, d, J = 8.2 Hz), 6.83-6.9
9 (3H, m), 7.15 (1H, s), 7.30-
8.53 (18H, m), 8.91 (1H, t, J =
5.9 Hz) FAB-MS: M / Z 1724 (MH ⁺ , free) IR (KBr): 3311.2, 1727.9, 165
8.5 cm ^-1

Example 73 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.73 (5
2H, m), 1.73-5.50 (48H, m), 6.
61 (2H, d, J = 8.3 Hz), 6.87-7.1
0 (3H, m), 7.17 (1H, s), 7.37-
7.57 (2H, m), 7.78 (1H, d, J = 8.
5 Hz), 7.86 (1H, d, J = 7 Hz), 7.9
8 (1H, d, J = 7.9 Hz), 8.03-8.70
(10H, m), 9.00 (1H, s), 9.17 (1
H, s), 14.00-14.70 (2H, brm) FAB-MS: M / Z 1708 (MH ⁺ , free) IR (KBr): 3286.1, 1731.8, 166
0.4cm ^-1

Example 74 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.70-1.36 (4
6H, m), 1.36-2.55 (19H, m), 2.
55-3.20 (6H, m), 3.55-4.05 (1
2H, m), 4.10-4.65 (13H, m), 4.
76-4.95 (3H, m), 4.95-5.40 (5
H, m), 6.62 (2H, d, J = 8.2), 6.9
5 (2H, d, J = 8.2), 6.90-7.05 (1
H, br), 7.17 (1H, brs), 7.47 (1
H, d, J = 9.4), 7.70-8.70 (16H,
m), 9.18 (1H, brs) FAB-MS: M / Z 1647 (MH ⁺ , free) IR (KBr): 3318.9, 1731.8, 165
8.5 cm ^-1

Example 75 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.36 (4
6H, m), 1.36-2.55 (17H, m), 2.
55-2.75 (1H, m), 2.85-4.05 (1
6H, m), 4.05-4.50 (13H, m), 4.
50-4.65 (2H, m), 4.65-5.60 (9
H, m), 6.61 (2H, d, J = 8.4), 6.9
5 (2H, d, J = 8.4), 6.85-7.00 (1
H, br), 7.14 (1H, brs), 7.44 (1
H, d, J = 8.9), 7.75 (1H, d, J = 8.
0), 7.83 (1H, d, J = 7.5), 7.94
(1H, d, J = 7.1), 8.00-8.75 (8
H, m), 9.13 (1H, brs), 9.71 (1
H, br) FAB-MS: M / Z 1646 (M ⁺ , free) IR (KBr): 3304.11735.6, 1654.
6cm ^-1

Example 76 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-3.45 (28H, m), 3.
55-4.50 (22H, m), 4.50-4.63
(2H, m), 4.63-5.35 (8H, m), 6.
61 (2H, d, J = 8.4), 6.94 (2H, d,
J = 8.4), 6.88-6.98 (1H, br),
7.14 (1H, brs), 7.47 (1H, d, J =
9.2), 7.65-8.80 (12H, m), 9.1
4 (1H, s) FAB-MS: M / Z 1644 (MH ⁺ , free) IR (KBr): 3317.0, 1735.6, 165
2.7 cm ^-1

Example 77 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. _{^{1 HNMR (DMSO-d 6)}} : 0.75-1.35 (4
6H, m), 1.35-3.45 (28H, m), 3.
50-4.48 (22H, m), 4.48-4.62
(2H, m), 4.62-5.28 (8H, m), 6.
61 (2H, d, J = 8.3), 6.95 (2H, d,
J = 8.3), 6.87-7.00 (1H, brs),
7.26 (1H, brs), 7.47 (1H, d, J =
8.3), 7.77 (1H, d, J = 8.4), 7.8
7 (1H, d, J = 7.3), 7.95 (1H, d, J
= 7.6), 8.00-8.80 (9H, m), 9.1.
5 (1H, s) FAB-MS: M / Z 1644 (MH ⁺ , free) IR (KBr): 3297.7, 1733.7, 165
2.7 cm ^-1

Example 78 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. FAB-MS: M / Z 1649 (MH ⁺ ) IR (KBr): 1735.6, 1654.6 cm ^-1

Example 79 In the same manner as in Example 56 , the desired compound is obtained from the starting compound. FAB-MS: M / Z 1696 (MH ⁺ , free) IR (KBr): 3301.5, 1660.4 cm ⁻¹

Example 80 In the same manner as in Example 54 , the desired compound is obtained from the starting compound. FAB-MS: M / Z 1649 (MH ⁺ ) IR (KBr): 3367.1, 1729.8, 165
8.5 cm ^-1

Example 81 In the same manner as in Example 25 , the target compound is obtained from the starting compound and the target compound of Example 24 . IR (KBr): 3330.5, 1731.8, 165
4.6cm ^-1

Production Example 5 N-[(R) -2-phenylethyl] -N-benzylamine (3.43 g) in tetrahydrofuran (150 ml)
The solution in ice was cooled to 1.6 in hexane (10.66 ml) under ice cooling.
Add 2N n-butyllithium. After 15 minutes, the mixture is cooled to -78 ° C and to the cooled solution is added the starting compound (2.5 g) in tetrahydrofuran (35 ml). The mixture was stirred at the same temperature for 1 hour, and a saturated aqueous solution of ammonium chloride (25 ml) was added. The resulting mixture was extracted with ethyl acetate (100 ml), and the separated organic layer was washed twice with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (150 g). The obtained compound was eluted with a mixture of n-hexane-ethyl acetate (40-1),
The target compound (1.70 g) is obtained as a vitreous solid. NMR (CDCl ₃ , δ); 0.90 (3H, t, J =
_{6H Z), 1.1~1.5 (9H,} m), 1.61 (2
H, m), 2.6 to 2.8 (2H, m), 3.48 (3
H, s), 3.7-3.9 (2H, m), 3.95-
4.2 (1H, m), 4.47 (1H, dd, J = 9H)
_{Z, 6H Z), 7.1~7.7 (} 18H, m)

Production Example 6 Starting compound (1.70 g) and 20% palladium hydroxide-carbon (170 mg) in ethyl acetate (20 ml) were prepared.
A suspension in methanol (20 ml), acetic acid (0.2 ml)
Hydrogenate at room temperature for 6 hours (1 atm). After removing the catalyst, the resulting solution is concentrated under reduced pressure. The residue is dissolved in a mixture of dioxane (15ml) and water (10ml). The mixture was added to benzyloxycarbonyl chloride (0.22
(3 ml) is added dropwise in the pH range 8.5-9.0. The resulting mixture is extracted with ethyl acetate at pH 7.0. The separated organic layer is washed with water, dried over magnesium sulfate, distilled off in vacuo, and purified by column chromatography using silica gel to obtain the desired compound (680 mg). _{NMR (DMSO-d 6, δ} ); 0.86 (3H, t,
_{J = 6.7H Z), 1.1~1.5 (} 4H, m), 1.
5 to 1.7 (2H, m), 2.60 (2H, t, J =
_{7.8H Z), 2.8~3.0 (2H,} m), 3.57
(3H, s), 4.95-5,20 (3H, m), 7.
2 to 7.6 (13H, m), 8.01 (1H, d, J =
8.6H _Z )

Preparation 7 To a solution of the starting compound (650 mg) in ethanol (4.25 ml) was added 2N potassium hydroxide (2.1 ml). After stirring at room temperature for 2.5 hours, the mixture was washed with water (40 ml).
And acidify to pH 2.0 with 6N hydrochloric acid. The resulting precipitate is collected by filtration, washed with water, and dried over phosphorus pentoxide to give the desired compound (0.42g). _{NMR (DMSO-d 6, δ} ); 0.87 (3H, t,
_{J = 6.7H Z), 1.2~1.5 (} 4H, m) 1.
5 to 1.7 (2H, m), 2.5 to 2.8 (4H,
m), 4.9-5.1 (1H, m), 4.99 (2H,
s) 7.2-7.6 (13H, m), 8.02 (1
H, d, J = 8.6H _Z )

Production Example 8 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g) and 1-hydroxybenzoic acid were added to a suspension of the starting compound (0.35 g) in dichloromethane (10 ml). Add triazole (0.12 g). After stirring for 1 hour, the mixture is poured into water (50 ml) and extracted with dichloromethane. The separated organic layer is washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated with diisopropyl ether and the precipitate is collected by filtration to give the desired compound (384mg). _{NMR (DMSO-d 6, δ} ); 0.78 (3H, t,
_{J = 6.7H Z), 1.2~1.5 (} 4H, m), 1.
5 to 1,8 (2H, m), 2.55 to 2.8 (2H,
m), 3.4-3.7 (2H, m), 4.9-5.3
(3H, m), 7.2 to 8.4 (18H, m)

Production Example 9 N, N-dimethylformamide of starting compound A (0.40 g) and monotrimethylsilylacetamide (1.13 g)
(8 ml) is stirred at room temperature for 1 hour. Starting compound B (0.193 g) is added to the mixture. The reaction mixture is stirred under the same conditions for 3 hours. The mixture obtained is concentrated under reduced pressure. The residue was subjected to an ODS medium pressure column (YMC G
Purification by EL ODS-AM120-S50) affords the desired compound (400 mg). NMR (DMSO-d ₆ , δ); 0.87 (9H,
m), 0.95-1.2 (19H, m), 1.36 (9
H, s), 1.3-1.45 (2H, m), 1.8-
2.3 (7H, m), 2.60 (4H, m), 2.8-
3.0 (2H, m), 3.3 to 4.1 (21H, m),
4.1 to 4.9 (17H, m), 4.9 to 5.3 (3
H, m), 6.62 (2H , d, J = 8.3H Z),
6.7 (1H, m), 6.8 (1H, br, s), 6.
96 (2H, d, J = 8.3H Z). 7.1 (1H, b
r, s), 7.2-7.4 (14H, m), 7.7-
8.25 (11H, m)

Preparation 10 To a solution of the starting compound (0.37 g) in methanol (70 ml) is added 10% Pd-C (270 mg) and the mixture is hydrogenated at room temperature for 5.5 hours (1 atm). After removing the catalyst, the methanol solution is distilled off in vacuo to obtain the desired compound (340 mg). NMR (DMSO-d ₆ , δ); 0.8 to 1.2 (29
H, m), 1.35 (9H, s), 1.2-1.45.
(2H, m), 1.5 to 2.4 (7H, m), 2.60
(4H, m), 2.85 (2H, m), 3.2 to 5.2
(38H, m), 6.5-7.6 (17H, m), 7.
6 to 8.4 (10H, m)

Production Example 11 The target compound is obtained from the starting compound in the same manner as in Production Example 5. _{NMR (DMSO-d 6, δ} ); 0.86 (3H, t,
J = 6.7H _Z ), 1.06 (3H, d, J = 6.8)
_{H Z), 1.25~1.60 (8H,} m), 1.7~
1.9 (2H, m), 2.7 to 2.9 (2H, m),
3.40 (3H, s), 3.70 (2H, s), 4.0
-4.15 (3H, m), 4.35 (1H, m), 7.
1 to 7.8 (16H, m)

Production Example 12 The target compound is obtained from the starting compound in the same manner as in Production Example 6. IR (KBr, cm ^-1 ); 2952, 1726, 169
1,1606,1531,1182, NMR (DMSO
-D ₆ , δ); 8.75 (3H, t, J = 6.7 H _Z ),
1.1 to 1.5 (8H, m), 1.7 to 1.9 (2H,
m), 2.7-3.0 (2H, m), 3.55 (3H,
s), 4.06 (2H, t , J = 6.8H Z), 4.9
-5.2 (3H, m), 7.1-8.1 (12H, m)

Production Example 13 The target compound is obtained from the starting compound in the same manner as in Production Example 7. NMR (DMSO-d6, δ); 0.87 (3H, t,
_{J = 6.7H Z), 1.1~1.6 (} 8H, m), 1.
7 to 1.9 (2H, m), 2.7 to 2.9 (2H,
m), 4.06 (2H, t , J = 6.8H Z), 4.9
9 (2H, s), 4.95 to 5.15 (1H, m),
7.1 to 8.0 (12H, m), 12.27 (1H, b
r, s)

Production Example 14 The target compound is obtained from the starting compound in the same manner as in Production Example 8. _{NMR (DMSO-d 6, δ} ); 0.87 (3H, t,
_{J = 6.7H Z), 1.2~1.6 (} 8H, m), 1.
7 to 1.9 (2H, m), 2.6 to 2.9 (2H,
m), 4.0-4.1 (2H, m), 4.9-5.4
(3H, m), 7.0 to 8.4 (16H, m)

Production Example 15 The target compound is obtained from the starting compound in the same manner as in Production Example 9. NMR (DMSO-d ₆ , δ); 0.75 to 1.0 (1
2H, m), 1.0 to 1.2 (14H, m), 1.25
~ 1.5 (12H, m), 1.36 (9H, s), 1.
6-2.4 (7H, m), 2.6-3.0 (4H,
m), 3.4-5.2 (38H, m), 6.62 (2
_{H, d, J = 8.5H Z} ), 6.73 (1H, m),
6.81 (1H, br, s), 6,96 (2H, d, J
_{= 8.5H Z), 7.0~7.5 (8H} , m), 7.6
5-8.2 (16H, m)

Production Example 16 The target compound is obtained from the starting compound in the same manner as in Production Example 10. NMR (DMSO-d ₆ , δ); 0.8 to 1.0 (1
2H. m), 1.0-1.2 (14H, m), 1.2-
1.5 (12H, m), 1.36 (9H, s), 1.6
~ 2.2 (7H, m), 2.6 to 3.0 (4H, m),
3.5-5.2 (37H, m), 6.55-7.6 (1
0H, m). 7.7 to 8.4 (15H, m)

Preparation Example 17 In the same manner as in Preparation Example 5, the target compound is obtained from the starting compound. NMR (DMSO-d ₆ , δ); 1.05 (3H,
_{t, J = 6.7H Z),} 1.08 (3H, d, J = 6.
_{8H Z), 2.6~2.9 (2H,} m), 3.79 (2
H, s). 3.8 to 4.1 (3H, m), 4.20 (1
H, m), 7.1 to 7.7 (14H, m)

Production Example 18 Starting compound A (560 mg) and starting compound B (777 m
g), sodium carbonate (424 mg), tetrakis (triphenylphosphine) palladium (0) (96 m
g), water (2.1 ml), dimethoxyethane (11.2)
ml) is refluxed for 4.5 hours. After cooling,
The mixture is extracted with dichloromethane, washed with water and dried over magnesium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography to obtain the desired compound (0.93 g). NMR (DMSO-d ₆ , δ); 1.00 (3H,
_{t, J = 6.7H Z),} 1.08 (3H, d, J = 6.
_{8H Z), 1.2~1.6 (12H,} m), 1.72
(2H, m), 2.6 to 2.9 (2H, m), 3.2
(3H, s), 3.29 (2H, t, J = 6.4)
_{H Z), 3.68 (2H,} s), 3.9~4.1 (3
H, m), 4.24 (1H , dd, J = 9H Z, 6
_{H Z), 7.0~7.7 (18H,} m)

Preparation Example 19 The target compound is obtained from the starting compound in the same manner as in Preparation Example 6. NMR (DMSO-d ₆ , δ); 1.12 (3H,
_{t, J = 6.7H Z),} 1.2~1.6 (10H,
m), 1.6-1.8 (2H, m), 2.7-2.9
(2H, m), 3.20 (3H, s), 3.29 (2
_{H, t, J = 6.4H Z} ), 3.9~4.1 (4H,
m), 4.95~5.05 (2H, AB q, J = 12.
_{5H Z), 4.9~5.1 (1H,} m), 6.9~7.
6 (13H, m), 8.0 (1H, d, J = 8.9)
H _Z )

Production Example 20 The target compound is obtained from the starting compound in the same manner as in Production Example 7. NMR (DMSO-d ₆ , δ); 1.2 to 1.6 (1
0H, m), 1.6 to 1.8 (2H, m), 2.6 to
2.8 (2H, m), 3.20 (3H, s), 3.29
(2H, t, J = 6.4H Z), 4.00 (2H, t,
_{J = 6.5H Z), 4.9~5.1 (} 3H, m), 6.
9 to 7.6 (13H, m), 7.93 (1H, d, J =
_{8.9H Z), 12.25 (1H,} br, s)

Preparation Example 21 The target compound is obtained from the starting compound in the same manner as in Preparation Example 8. NMR (DMSO-d ₆ , δ); 1.2 to 1.6 (1
0H, m), 1.6-1.8 (2H, m), 3.21
(3H, s), 3.29 (2H, t, J = 6.5)
_{H Z), 3.3~3.7 (2H,} m), 4.00 (2
H, m), 4.9-5.3 (3H, m), 7.0-8.0.
4 (18H, m)

Production Example 22 The target compound is obtained from the starting compound in the same manner as in Production Example 9. NMR (DMSO-d ₆ , δ); 0.8 to 1.6 (3
7H, m), 1.36 (9H, s), 1, 6-2.4.
(7H, m), 2.6-3.0 (4H, m), 3.20
(3H, s), 3.3-5.3 (41H, m), 6.6
3 (2H, d, J = 8.5H Z), 6.75 (1H,
m), 6.8 to 7.6 (12H, m), 7.33 (5
H, m), 7.6-8.3 (11H, m)

Production Example 23 The target compound is obtained from the starting compound in the same manner as in Production Example 10. _{NMR (DMSO-d 6, δ} ); 0.85~1.6
(37H, m), 1.36 (9H, s), 1.6-2.
3 (7H, m), 2.5 to 3.0 (4H, m), 3.2
6 (3H, s), 3.1 to 5.3 (39H, m),
63 (2H, d, J = 8.5H Z), 6.7~7.6
(15H, m), 7.6-8.5 (10H, m)

Production Example 24 The target compound is obtained from the starting compound in the same manner as in Production Example 18. NMR (DMSO-d ₆ , δ); 1.01 (3H,
_{t, J = 6.7H Z),} 1.10 (3H, d, J = 6.
_{8H Z), 1.4~1.8 (6H,} m), 2.6~2.
9 (2H, m), 3.27 (3H, s), 3.33 (2
_{H, d, J = 6.4H Z} ), 3.70 (2H, s),
3.9-4.1 (3H, m), 4.28 (1H, dd,
_{J = 9H Z, 6H Z)} , 7.0~7.8 (22H, m)

Production Example 25 In the same manner as in Production Example 6, the target compound is obtained from the starting compound. NMR (DMSO-d ₆ , δ); 1.12 (3H,
_{t, J = 6.7H Z),} 1.3~1.7 (4H, m),
1.7 to 1.8 (2H, m), 2.6 to 2.9 (2H,
m), 3.23 (3H, s), 3.33 (2H, t, J
_{= 6.7H Z), 3.9~4.1 (4H} , m), 4.9
To 5.1 (3H, m), 7.0 to 7.8 (17H,
m), 8.01 (1H, d , J = 8.7H Z)

Production Example 26 The target compound is obtained from the starting compound in the same manner as in Production Example 7. NMR (DMSO-d ₆ , δ); 1.4 to 1.65
(4H, m), 1.65 to 1.8 (2H, m), 2.6
２2.9 (2H, m), 3.23 (3H, s), 3.3
4 (2H, t, J = 6,4H Z), 4.01 (2H,
_{t, J = 6.7H Z),} 4.9~5.1 (3H, m),
7.0 to 7.8 (17H, m), 7.96 (1H, d,
_{J = 8.6H Z), 12.2 (} 1H, br, s)

[0223]Production Example 27 The target compound was obtained from the starting compound in the same manner as in Production Example 8.
You. NMR (DMSO-d₆, Δ); 1.4 to 1.8 (6
H, m), 2.6 to 2.9 (2H, m), 3.22 (3
H, s), 3.37 (2H, t, J = 6.4H) _Z),
4.01 (2H, t, J = 4.8H_Z), 4.9-5.
4 (3H, m), 7.0 to 8.4 (22H, m)

Preparation 28 The target compound is obtained from the starting compound in the same manner as in Preparation 9. NMR (DMSO-d ₆ , δ); 0.8 to 1.2 (2
3H, m), 1.37 (9H, s), 1.4-2.3.
(15H, m), 2.6-3.0 (4H, m), 3.2
3 (3H, s), 3.3 to 3.95 (21H, m),
4.01 (2H, t, J = 6.7H Z), 4.1~4.
6. (15H, m), 4.9-5.2 (3H, m),
60 (2H, d, J = 8.5H Z), 6.7~6.9
(2H, m), 6.9 to 7.2 (5H, m), 7.3 to
7.5 (7H, m), 7.55-7.8 (8H, m),
7.8 to 8.2 (11H, m)

Production Example 29 The target compound is obtained from the starting compound in the same manner as in Production Example 10. NMR (CD ₃ OD ₆ , δ); 0.8 to 1.3 (23
H, m), 1.40 (9H, s), 1.5 to 2.5 (1
5H, m), 2.7-3.15 (4H, m), 3.20
(3H, s), 3.3-5.0 (31H, m), 6.7
0 (2H, d, J = 8.5H Z), 7.0 (4H,
m), 7.55 to 7.8 (10H, m)

Preparation 30 The target compound is obtained from the starting compound in the same manner as in Preparation 18. NMR (DMSO-d ₆ , δ); 0.87 (3H,
_{t, J = 6.4H Z),} 1.01 (3H, t, J = 6.
_{7H Z), 1.10 (3H,} d, J = 6.4H Z), 1.
2 to 1.5 (10H, m), 1.7 to 1.9 (2H,
m), 2.6-3.0 (2H, m), 3.70 (2H,
s), 4.0 to 4.2 (3H, m), 4.30 (1H,
_{dd, J = 9H Z, 6H} Z), 7.1~8.2 (20H,
m)

Production Example 31 The objective compound is obtained from the starting compound in the same manner as in Production Example 6. NMR (DMSO-d ₆ , δ); 0.88 (3H,
_{t, J = 6.7H Z),} 1.13 (3H, t, J = 7.
_{1H Z), 1.2~1.5 (8H,} m), 1.7~1.
9 (2H, m), 2.7 to 3.0 (2H, m), 3.9
~ 4.2 (4H, m), 4.9 ~ 5.1 (3H, m),
7.1 to 8.1 (16H, m)

Production Example 32 The target compound is obtained from the starting compound in the same manner as in Production Example 7. _{NMR (DMSO-d 6, δ} ); 0.88 (3H, t,
_{J = 6.7H Z), 1.1~1.6 (} 8H, m), 1.
7 to 1.9 (2H, m), 2.6 to 2.9 (2H,
m), 4.09 (2H, t , J = 6.8H Z), 4.9
7, 5.04 (2H, AB _q , J = 12.5H _Z );
95-5.1 (1H, m), 7.1-8.2 (16H,
m), 12.28 (1H, br, s)

Preparation Example 33 The target compound is obtained from the starting compound in the same manner as in Preparation Example 8. NMR (DMSO-d _6, δ); 0.88 (3H, t, J
_{= 6.7H Z) 1.2~1.6 (8H,} m), 1.7~
1.9 (2H, m), 2.6 to 2.9 (2H, m),
4.10 (2H, t, J = 6.8H Z), 5.0~5.
4 (3H, m), 7.1 to 8.4 (20H, m)

Production Example 34 In the same manner as in Production Example 9, the target compound is obtained from the starting compound. NMR (CD ₃ OD, δ); 0.9-1.65 (34
H, m), 1.40 (9H, s), 1.7 to 2.6 (1
1H, m), 2.7 to 3.2 (4H, m), 3.7 to
5.0 (28H, m), 5.04 (2H, m), 5.1
6 (1H, m), 6.64 (2H, d, J = 8.5)
_{H Z), 6.9~8.0 (17H,} m)

Preparation Example 35 The target compound is obtained from the starting compound in the same manner as in Preparation Example 10. NMR (CD ₃ OD, δ); 0.95 to 1.6 (34
H, m), 1.40 (9H, s), 1.7 to 2.6 (1
1H, m), 2.7 to 3.2 (4H, m), 3.6 to
5.0 (29H, m), 6.69 (2H, d, J = 8.
_{5H Z), 6.9~8.1 (12H,} m)

Production Example 36 3-oxohexadecanoic acid methyl ester (28.4
g), Ru ₂ Cl ₄ [(R) -BINAP] ₂ -NEt
₃ (179 mg), camphoroylsulfonic acid (184 m
g) in the tube of degassed methanol (55 m
The tube is sealed and filled with hydrogen gas at 20 atm. After 5 hours at 50 ° C., the reaction mixture is distilled off. The residue is dissolved in ethyl acetate, washed with sodium hydrogen carbonate solution, water and brine, dried over magnesium sulfate and evaporated. The crude residue was purified by silica gel column chromatography (elution with hexane-ethyl acetate), and 26.3 g of methyl (R) -3-hydroxy- was purified.
Hexadecanate is obtained as a solid. _{^{1 H NMR (CDCl 3, δ}} ); 0.88 (3H, t,
_{J = 6.7H Z), 1.20~1.60 (} 24H,
m), 2.40 (1H, dd, J = 16.4, 8.5H)
_Z ), 2.53 (1H, dd, J = 16.4, 3.6)
_{H Z), 2.82 (1H,} d, J = 4.1H Z), 3.7
1 (3H, s), 3.92 to 4.08 (1H, m)

Production Example 37 In the same manner as in Production Example 7, methyl (R) -3-hydroxy-
(R) -3-Hydroxy-hexadecanoic acid is obtained from hexadecanoate. _{^{1 H NMR (CDCl 3, δ}} ); 0.88 (3H, t,
J = 6.8 Hz), 1.20 to 1.62 (24H,
m), 2.46 (1H, dd, J = 16.6, 8.4H
_Z ), 2.59 (1H, dd, J = 16.6, 3.7)
_{H Z), 3.98~4.12 (1H,} m)

Production Example 38 (R) -3-Hydroxy-hexadecanoic acid (19.9)
g), 4-dimethylaminopyridine (89.4 mg),
A suspension of 2,2,2-trichloroethanol (7 ml) in dichloromethane (200 ml) was cooled to 0-5 ° C. and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (14. 7g).
After 1 hour, the cooling bath is removed and the solution is stirred at room temperature for 18 hours and evaporated to dryness. Ethyl acetate (25
0 ml), and the organic solution was washed with 0.5N hydrochloric acid, water, saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and the residue obtained by evaporation was distilled off using silica gel column chromatography (hexane-ethyl acetate). To give 26.11 g of 2'2'2'-trichloroethyl (R) -3-hydroxyhexadecanoate as a solid. _{^{1 H NMR (CDCl 3, δ}} ); 0.88 (3H, t,
_{J = 6.8H Z), 1.15~1.65 (} 24H,
m), 2.52 (1H, br), 2.58 (1H, d
_{d, J = 16.4,8.1H Z),} 2.69 (1H, d
_{d, J = 16.4,4.0H Z),} 4.02~4.18
(1H, m), 4.75 (1H, d, J = 12.0
_{H Z), 4.81 (1H,} d, J = 12.0H Z)

Production Example 39 Starting compound (1 g), N-benzyloxycarbonyl-
A solution of (L) -glutamic acid, 5-tert-butyl ester (920 mg) in dichloromethane (35 ml) was treated with benzotriazol-1-yl-oxy-tris-
Pyrrolidinophosphonium hexafluorophosphate (Py
(BOP) (1.42 g) followed by 4-dimethylaminopyridine (606 mg). After 12 hours, the solution was evaporated to dryness, diluted with ethyl acetate, washed with water, ice-cold 0.1N hydrochloric acid, water, sodium bicarbonate solution, water, brine, dried over magnesium sulfate, The residue is purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the desired compound (1.61 g) as an oil. _{^{1 H NMR (CDCl 3, δ}} ); 0.88 (3H, t,
_{J = 6.7H Z), 1.10~1.50 (} 22H,
m), 1.43 (9H, s), 1.50 to 1.78 (2
H, m), 1.80 to 2.02 (1H, m), 2.05
~ 2.42 (3H, m), 2.60-2.83 (2H,
m), 4.22 to 4.42 (1H, m), 4.74 (2
H, s), 5.10 (2H, s), 5.18 to 5.42.
(2H, m), 7.25 to 7.40 (5H, m)

Preparation 40 A solution of the starting compound (1.61 g) in 90% aqueous acetic acid (50 ml) at 0-5 ° C. is treated with zinc powder (7.29 g). After 30 minutes at 0-5 ° C and 30 minutes at room temperature,
The insoluble material is removed by filtration and the filtrate is evaporated to dryness. Ice-cooled 1N hydrochloric acid is added to the residue and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to give the desired compound (1.3
1 g) is obtained as a waxy oil. _{^{1 H NMR (CDCl 3);}} 0.88 (3H, t, J =
6.7H _Z ), 1.10 to 1.45 (22H, m),
1.43 (9H, S), 1.50 to 1.73 (2H,
m), 1.80-2.40 (4H, m), 2.48-
2.70 (2H, m), 4.25 to 4.45 (1H,
m), 5.10 (2H, s), 5.13 to 5.35 (1
H, m), 5.46 (1H , d, J = 8.2H Z),
7.27 to 7.38 (5H, m)

Preparation Example 41 The target compound is obtained from the starting compound in the same manner as in Preparation Example 8. IR (neat film); 2925.5, 2854.
1,1820.5,1729.8cm ^-1

Preparation Example 42 The target compound is obtained from the starting compound in the same manner as in Preparation Example 9. ¹ H NMR (CD ₃ OD, δ); 0.82-1.00
(9H, m), 1.1 to 1.4 (37H, m), 1.4
3 (9H, s), 1.5 to 1.7 (2H, m), 1.7
9 to 2.40 (9H, m), 2.4 to 2.6 (4H,
m), 2.7-3.1 (2H, m), 3.68-4.7
0 (24H, m), 5.10 (2H, s), 5.18-
5.33 (1H, m), 6.70 (2H, d, J = 8.
_{4H Z), 7.02 (2H,} d, J = 8.4H Z), 7.
27-7.42 (5H, m)

Production Example 43 The target compound is obtained from the starting compound in the same manner as in Production Example 10. ¹ H NMR (CD ₃ OD, δ); 0.83 to 1.05
(9H, m), 1.10 to 1.40 (37H, m),
1.46 (9H, s), 1.6-1.8 (2H, m),
1.9 to 2.7 (13H, m), 2.7 to 3.1 (2
H, m), 3.6-4.8 (24H, m), 5.27-
5.47 (1H, m), 6.72 (2H, d, J = 8.
_{5H Z), 7.02 (2H,} d, J = 8.5H Z)

Production Example 44 Tetradecanal (10.0 g, 47 mmol) and methyl (triphenylphosphoraneylidene) acetate (1
(5.7 g, 47 mmol) in toluene (100 mL) is stirred at 100 ° C. for 2 hours. The reaction mixture is distilled off in a vacuum. The resulting precipitate is removed by filtration and purified by silica gel column chromatography (hexane-ethyl acetate 200: 7) to obtain (E) -2-hexadecanoic acid methyl ester (6.54 g, 52%) as an oil. ¹ H NMR (CDCl ₃ ) δ 0.88 (3H, t, J =
_{6.4H Z), 1.15~1.55 (22H,} m),
2.12 to 2.27 (2H, m), 3.72 (3H,
s), 5.81 (1H, dt, J = 15.6, 1.6H)
_Z ), 6.97 (1H, dt, J = 15.6, 7.0).
H _z )

Production Example 45 The target compound is obtained from the starting compound in the same manner as in Production Example 5. ¹ H NMR (CDCl ₃ ) δ 0.88 (3H, t, J =
_{6.7H Z), 1.12~1.42 (22H,} m),
1.34 (3H, d, J = 7.0H Z), 1.42~
1.65 (2H, m), 1.95 to 2.15 (2H,
m), 3.20-3.40 (1H, m), 3.53 (3
H, s), 3.56 (1H , d, J = 14.3H Z),
3.78 (1H, d, J = 14.3H Z), 3.84
(1H, q, J = 7.0H Z), 7.15~7.48
(10H, m)

[0242]Production Example 46 Starting compound (5.27 g, 11.0 mmol), 20%
Palladium hydroxide-carbon (0.53 g), acetic acid (1.2
5ml) methanol solution (53ml) and ethyl acetate
(53 ml) is hydrogenated at room temperature for 7 hours.
The catalyst is filtered off and the mixture is distilled off in vacuo
You. Dissolve the residue in water and add saturated sodium bicarbonate solution
Add it there. The mixture is extracted with methylene chloride,
Wash with brine, dry over magnesium sulfate, and in vacuo
Distilled off, the target compound (3.13 g, 100%) was converted to an oil.
Get it.¹ H NMR (CDCl_Three) Δ 0.88 (3H, t, J =
6.7H_Z), 1.15 to 1.47 (24H, m),
2.25 (1H, dd, J = 15.6, 8.9H _Z),
2.48 (1H, dd, J = 15.6, 4.0H_Z),
3.08-3.26 (1H, m), 3.69 (3H,
s)

Production Example 47 To a mixture of the starting compound (2.00 g) and N ² -benzyloxycarbonyl-N ⁵ -tert-butoxycarbonylornithine (2.83 g) in methylene chloride (60 ml) was added 1-hydroxybenzotriazole. (1.04g)
And 1-ethyl-3- (3'-dimethylaminopropyl)
Add carbodiimide hydrochloride (2.02 g) at 5 ° C.
The mixture is stirred for 1 hour at the same temperature and for 1 hour at room temperature. The reaction mixture is washed with 0.1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, water, brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (hexane-ethyl acetate, eluted with 3: 2 to 1: 1) to obtain the desired compound (3.98 g) as crystals. _{^{1 H NMR (DMSO-d 6}} , δ); 0.85 (3
_{H, t, J = 6.6H Z} ), 1.08~1.60 (28
H, m), 1.36 (9H, s), 2.28 to 2.52
(2H, m), 2.80-2.97 (2H, m), 3.
54 (3H, s), 3.80-4.10 (2H, m),
5.01 (2H, s), 6.70 to 6.80 (1H,
m), 7.28 (1H, d , J = 8.5H Z), 7.2
8 to 7.40 (5H, m), 7.78 (1H, d, J =
11.5H _Z)

Production Example 48 The objective compound is obtained from the starting compound in the same manner as in Production Example 7. _{^{1 H NMR (DMSO-d 6}} , δ); 0.85 (3
_{H, t, J = 6.7H Z} ), 1.08~1.62 (28
H, m), 1.37 (9H, s), 2.20-2.45.
(2H, m), 2.75-3.00 (2H, m), 3.
80-4.08 (2H, m), 5.01 (2H, s),
6.70 to 6.80 (1H, m), 7.27 (1H,
_{d, J = 8.2H Z),} 7.28~7.40 (5H,
m), 7.71 (1H, d , J = 8.3H Z), 12.
16 (1H, br)

Production Example 49 The target compound is obtained from the starting compound in the same manner as in Production Example 8. _{^{1 H NMR (DMSO-d 6}} , δ); 0.85 (3
_{H, t, J = 6.3H Z} ), 1.08~1.70 (28
H, m), 1.36 (9H, s), 2.77-2.97.
(2H, m), 3.00 to 3.50 (2H, m), 3.
80 to 4.35 (2H, m), 4.83 to 5.05 (2
H, m), 6.68-6,80 (1H, m), 7.20
~ 8.18 (11H, m)

Production Example 50 (1) To a solution of the starting compound A (10.91 g) and diisopropylethylamine (2.41 ml) in N, N-dimethylformamide (160 ml) was added the desired compound of production example 49 (7.47 g). Is added at room temperature and the mixture is stirred for 3 hours. The reaction mixture is evaporated in vacuo to give crude starting compound B.

Production Example 50 (2) The above crude starting compound B in methanol (330 ml)
And 10% palladium on carbon (8.0 g) are hydrogenated at room temperature for 6 hours. The catalyst is filtered off and the mixture is distilled off in vacuo. The residue was dissolved in water (500 ml) and 1
PH 3 with N hydrochloric acid, ODS medium pressure column (YMC G
EL ODS-AM120-S50) to obtain the target compound (10.8 g). ¹ H NMR (CD ₃ OD, δ); 0.80 to 1.05
(9H, m), 1.10 to 1.70 (43H, m),
1.43 (9H, s), 1.70 to 2.65 (9H,
m), 2.65 to 3.18 (4H, m), 3.60 to
4.80 (25H, m), 6.74 (2H, J = 8.5)
_{H Z), 7.01 (2H,} J = 8.5H Z)

Preparation Example 51 The target compound is obtained from the starting compound in the same manner as in Preparation Example 47. _{^{1 H NMR (CDCl 3);}} 0.88 (3H, t, J
_{= 6.8H Z), 1.25 (18H} , brs), 1,4
3 (9H, s), 2.59 (1H, dd, J = 6.9,
_{17H Z), 2.91 (1H,} dd, J = 4.4,17
_{H Z), 3.21 (2H,} brq, J = 6.7H Z),
4.4 to 4.55 (1H, m), 5.12 (2H,
s), 5.9-6.1 (1H, m), 6.45-6.6.
(1H, m), 7.35 (5H, s)

Production Example 52 A methylene chloride solution of the starting compound (1.49 g) (15 m
l) and trifluoroacetic acid (10 ml)
Stir for 1.5 hours at C and 2 hours at room temperature. After distilling off,
The product is obtained by trituration with 10: 1 hexane-ethyl acetate to give the desired compound (1.03 g). _{^{1 H NMR (CDCl 3);}} 0.88 (3H, t, J
_{= 6.8H Z), 1.46 (16H} , brs), 1.4
To 1.6 (2H, m), 2.0 to 3.0 (1H, br)
s), 2.73 (1H, dd, J = 6.3, 17)
H _Z ), 3.05 (1H, dd, J = 4.3, 17)
_{H Z), 3.22 (2H,} brq, J = 7H Z), 4.5
(1H, brs), 5.14 (2H, s), 5.9-
6.0 (1H, m), 6.5 (1H, brs). 7.3
6 (5H, s)

Production Example 53 The objective compound is obtained from the starting compound in the same manner as in Production Example 8. _{^{1 H NMR (CDCl 3);}} 0.88 (3H, t, J =
_{6.8H Z), 1.2~2.0 (18H,} m), 3.1
To 3.3 (2H, m), 3.3 to 3.5 (1H, m),
3.8 to 3.9 (1H, m), 4.7 to 4.9 (1H,
m), 5.17 (2H, s), 5.8-6.0 (1H,
m), 6.3 to 6.5 (1H, m), 7.36 (5H,
s), 7.5-8.4 (4H, m)

Production Example 54 Production Examples 50 (1) and 50
The target compound is obtained from the starting compound in the same manner as in (2). IR (KBr); 3301, 3074, 2970, 2
927, 2856, 1660, 1535, 1522, 1
452cm ^-1

Preparation Example 55 The target compound is obtained from the starting compound in the same manner as in Preparation Example 5. _{^{1 H NMR (CDCl 3);}} 0.88 (3H, t, J
_{= 6.7H Z), 1.17~1.6 (13H} , m),
1.7 to 1.81 (2H, m), 2.51 (1H, d
_{d, J = 9.3,14.7H Z),} 2.67 (1H, d
_{d, J = 5.9,14.7H Z),} 3.46 (3H,
s), 3.68 (2H, ABq , J = 14.6H Z),
3.94 (2H, t, J = 6.6H Z), 3.95 (1
_{H, q, J = 6.9H Z} ), 4.37 (1H, dd, J
_{= 5.9,9.2H Z), 6.86 (2H} , d, J =
_{8.6H Z), 7.17~7.43 (12H,} m)

Production Example 56 The objective compound is obtained from the starting compound in the same manner as in Production Example 46. _{^{1 H NMR (CDCl 3);}} 0.88 (3H, t, J
_{= 6.7H Z), 1.2~1.5 (10H} , m), 1.
7 to 1.8 (2H, m), 2.01 (3H, s), 2.
69-2.95 (2H, m), 3.67 (3H, s),
3.92 (2H, t, J = 6.5H Z), 4.01 (3
H, brs), 4.44 (1H, dd, J = 5.4,
_{8.3H Z), 6.86 (2H,} d, J = 8.7H Z),
7.29 (2H, d, J = 8,7H Z)

Production Example 57 The target compound is obtained from the starting compound in the same manner as in Production Examples 6 and 7. _{^{1 H NMR (CDCl 3);}} 0.88 (3
_{H, t, J = 6.7H Z} ), 1.29 (10H, br
s), 1.69-1.79 (2H, m), 2.7-3.
05 (2H, m), 3.91 (2H, t, J = 6.5H
_Z ), 5.08 (2H, s), 5.0-5.2 (1H,
m), 5.5-5.7 (1H, m), 6.83 (2H,
_{d, J = 8.7H Z),} 7.17~7.32 (7H,
m)

Preparation Example 58 The target compound is obtained from the starting compound in the same manner as in Preparation Example 8. _{^{1 H NMR (CDCl 3);}} 0.88 (3H, d, J
_{= 6.7H Z), 1.2~1.5 (10H} , m), 1.
6 to 1.8 (2H, m), 3.55 to 3.75 (2H,
m), 3.91 (2H, t , J = 6.5H Z), 5.0
5 (2H, ABq, J = 12.3H Z), 5.37~
5.48 (2H, m), 6.85 (2H, d, J = 8.
_{6H Z), 7.27~7.31 (7H,} m), 7.55
(1H, t, J = 7.5H Z), 7.75 (1H, t,
_{J = 7.5H Z), 7.98 (} 1H, d, J = 8.3
_{H Z), 8.33 (1H,} d, J = 8.3H Z)

Production Example 59 The target compound is obtained from the starting compound in the same manner as in Production Example 9. IR (KBr) 3319, 2975, 2933, 16
52cm ^-1

Preparation Example 60 The target compound is obtained from the starting compound in the same manner as in Preparation Example 10. IR (KBr) 3332, 2974, 1657, 15
18, 1452, 1396, 1252, 1171, 11
01cm ^-1

Production Example 61 1- (16-Hydroxyhexadecanoyl) benzotriazole-3-oxide (5.5 g) in tetrahydrofuran (55 ml) and N, N-dimethylformamide (3
5 ml) is treated with N, O-dimethylhydroxylamine hydrochloride (2.76 g), followed by triethylamine (4.32 ml) and the mixture is treated at room temperature for 5 minutes.
Stir for hours. The reaction is diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, evaporated and the crude N-methyl-N-methoxy-16-
Obtain hydroxyhexadecaneamide (4.48 g). _{^{1 H NMR (CDCl 3);}} 1.26 (22H,
m), 1.5-1.7 (4H, m), 2.37-2.4
4 (2H, m), 3.12 (3H, s), 3.64 (2
_{H, t, J = 6,5H Z} ), 3,68 (3H, s)

Preparation Example 62 To a mixture of sodium hydride (0.86 g, 60% suspension in oil) in N, N-dimethylformamide (67.2 ml) was added N-methyl-N-methoxy-16-hydroxy. Hexadecanamide (4.48 g) was added and the mixture was added to 60
Stir at 30 ° C. for 30 minutes and treat with methyl iodide (2.65 ml). After 2 hours, the reaction is cooled and extracted with ethyl acetate. The dried organic layer is distilled off to obtain 4.48 g of crude N-methyl-N-methoxy-16-methoxyhexadecaneamide. _{^{1 H NMR (CDCl 3);}} 1.26 (22H, br
s), 1.5-1.7 (4H, m), 2.45-2.7.
3 (2H, m), 3.18 (3H, s), 3.33 (3
H, s), 3,40 (2H , t, J = 6.5H Z),
3.68 (3H, s)

Production Example 63 A suspension of lithium aluminum hydride (0.52 g) in ice-cooled tetrahydrofuran (90 ml) was added to N-methyl-N-methoxy-tetrahydrofuran (22.4 ml).
16-methoxyhexadecaneamide (4.48 g) was added to 1
Add dropwise over 0 minutes. After 6 hours at room temperature, the mixture was recooled to 0 ° C. and sodium fluoride (2.2
8 g) and water (1 ml). After 30 minutes, the insoluble material was removed by filtration, the filtrate was distilled off and the crude 16-
Obtain methoxyhexadecanal (4.3 g). IR (neat) 2916, 2848, 1726, 14
66cm ^-1

Production Example 64 In the same manner as in Production Example 44, methyl = 17-methoxy-2-heptadexenate is obtained from 16-methoxyhexadecanal. _{^{1 H NMR (CDCl 3);}} 1.26 (22H, br
s), 1.4-1.6 (4H, m), 2.14-2.2.
4 (2H, m), 3.36 (2H, t, J = 6.5)
_{H Z), 3.33 (3H,} s), 3.72 (3H,
s), 5.81 (1H, ddd, J = 15.6, 1.
_{5,1.5H Z), 6.97 (1H,} ddd, J = 1
5.6,6.9,6.9H _Z)

Preparation Example 65 The target compound is obtained from the starting compound in the same manner as in Preparation Example 5. IR (neat) 1736, 1601, 1456 cm ^-1

Preparation Example 66 The target compound is obtained from the starting compound in the same manner as in Preparation Example 46. IR (KBr) 2922, 2852, 1737, 16
18,1535,1398cm ^-1

Preparation Example 67 The target compound is obtained from the starting compound in the same manner as in Preparation Example 7. _{^{1 H NMR (CDCl 3);}} 1.25 (26H, br
s), 1.5-1.65 (3H, m), 2.5-2.6.
5 (2H, m), 3.33 (3H, s), 3.37 (2
_{H, t, J = 6.5H Z} ), 3.9~4.05 (1H,
m), 5.10 (2H, s), 5,. 1 to 5.25 (1
H, m), 7.35 (5H, s)

Production Example 68 The target compound is obtained from the starting compound in the same manner as in Production Examples 8 and 9. FAB-MS M / Z 1865 (M + Na ⁺ )

Production Example 69 In the same manner as in Production Example 10, the target compound is obtained from the starting compound. FAB-MS M / Z 1709 (MH ⁺ )

Preparation Example 70 The target compound is obtained from the starting compound in the same manner as in Preparation Example 5. _{^{1 H NMR (CDCl 3);}} 0.85~1.00 (3
H, m), 1.21 (3H , d, J = 6.8H Z),
1.19 to 1.50 (10H, m), 1.74 to 1.8
1 (2H, m), 2.51 (1H, dd, J = 14.
_{8,9.3H Z), 2.67 (1H,} dd, J = 14.
_{8,5.9H Z), 3.46 (3H,} s), 3.68
(2H, ABq, J = 14.7H _z , internal separation = 6.8
_{H Z), 3.94 (2H,} t, J = 6.5H Z), 3.9
9 (1H, q, J = 6.8H Z), 4.37 (1H, d
_{d, J = 9.2,5.9H Z),} 6.86 (2H, d,
_{J = 8.6H Z), 7.1~7.5 (} 12H, m)

Production Example 71 The target compound is obtained from the starting compound in the same manner as in Production Example 46. ^{1 H NMR (DMSO); 0.83~0.89} (3
H, m), 1.20 to 1.50 (10H, m), 1.6
1-1.71 (2H, m), 1.89 (3H, s),
2.56 to 2.64 (2H, m), 3.54 (3H,
s), 3.91 (2H, t , J = 6.4H Z), 4.0
9 (3H, brs), 4.13 to 4.21 (1H,
m), 6.84 (2H, d , J = 8.6H Z), 7.2
6 (2H, d, J = 8.6H Z)

Preparation Example 72 The target compound is obtained from the starting compound in the same manner as in Preparation Example 6. ¹ H NMR (CDCl ₃ ); 0.85 to 0.92 (3
H, m), 1.2 to 1.55 (10H, m), 1.72
~ 1.8 (2H, m), 2.74 to 2.96 (2H,
m), 3.60 (3H, s), 3.92 (2H, t, J
_{= 6.5H Z), 5.02~5.15 (3H} , m),
5.63 (1H, brs), 6.84 (2H, d, J =
_{8.6H Z), 7.17~7.38 (7H,} m)

Preparation Example 73 The target compound is obtained from the starting compound in the same manner as in Preparation Example 7. ¹ H NMR (CDCl ₃ ); 0.85 to 0.95 (3
H, m), 1.2-1.5 (10H, m), 1.69-
1.79 (2H, m), 2.75 to 3.05 (2H,
m), 3.92 (2H, t , J = 6.5H Z), 5.0
9 (2H, s), 5.0 to 5.2 (1H, m), 5.5
9 (1H, brs), 6,84 (2H, d, J = 8.6)
_{H Z), 7.19 (2H,} d, J = 8.6H Z), 7.3
2 (5H, s)

Preparation Example 74 The target compound is obtained from the starting compound in the same manner as in Preparation Examples 8 and 9. FAB-MS 1830 (M + Na ⁺ )

Production Example 75 The target compound is obtained from the starting compound in the same manner as in Production Example 10. IR (KBr); 2972, 2929, 1647, 1
514, 1456, 1252 cm ^-1 FAB-MS M / Z 1673 (MH ⁺ )

[0273]Production Example 76 In the same manner as in Production Example 6, L-aspartic acid-4-benzyl
Ester to N-benzyloxycarbonyl-LA
Spartic acid 4-benzyl ester is obtained. EI-MS 358 (MH⁺)¹ H NMR (CDCl_Three); 2.91 (1H, dd,
J = 17.3, 4.7H _Z), 3.11 (1H, dd,
J = 17.3, 4.3H_Z), 4.65 to 4.80 (1
H, m), 5.12 (4H, s), 5.6 to 6.0 (2
H, m), 7.33 (5H, s), 7.34 (5H,
s)

Production Example 77 N-benzyloxycarbonyl-L-aspartic acid 4
-Benzyl ester (68.13 g), concentrated sulfuric acid (5 m
l), a mixture of methylene chloride (300 ml)
Cool to 100 g and treat with 100 g of isobutene. -5 ° C
For 1 hour and at room temperature for 3 hours, then hold overnight. After evaporation, the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give N-benzyloxycarbonyl-L-aspartic acid 1-3. Obtain tert-butyl-4-benzyl ester (74.59 g) as an oil. ¹ H NMR (CDCl ₃ ); 1.40 (9H, s),
2.80-3.07 (2H, m), 4.45-4.58
(1H, s), 5.10 to 5.11 (4H, brs),
5.72 (1H, brd, J = 8.1H Z), 7.33
~ 7.37 (10H, m)

Production Example 78 (1) N-benzyloxycarbonyl-L-aspartic acid 1
Tertiary butyl-4-benzyl ester (67.56
A solution of g) in tetrahydrofuran (170 ml) is treated dropwise at room temperature over 5 minutes with 85 ml of a 2M aqueous sodium hydroxide solution. 9 hours later, 200 ml of 1,
4-Dioxane was added, followed by methanol (100 m
l) and a 1M aqueous sodium hydroxide solution (50 ml) for an additional 6 hours. After a further 30 minutes, the mixture is adjusted to pH 6-8 with concentrated hydrochloric acid and concentrated to 100 ml. The solution is ice-cooled, adjusted to pH 2, diluted with water and extracted with ethyl acetate. Wash the organic layer with saline,
Dry over magnesium sulfate and evaporate to give the crude product (69.
2 g) are obtained. The product was esterified by dissolving in N, N-dimethylformamide (160 ml),
Subsequently, it is treated with cesium carbonate (30 g) and methyl iodide (15 ml) at room temperature for 30 minutes. Extract with ethyl acetate, wash with water and brine, dry over magnesium sulfate and evaporate to give a crude oil, which is purified by silica gel chromatography (hexane-ethyl acetate elution), 39.3 g N-benzyloxycarbonyl-L-aspartic acid 1-tert-butyl-4-methyl ester of

Production Example 78 (2) N-benzyloxycarbonyl-L-aspartic acid 1-tert-butyl-4-methyl ester to L-aspartic acid 1-tert-butyl-4 in the same manner as in Production Example 10. −
Obtain the methyl ester. _{^{1 H NMR (CDCl 3);}} 1.46 (9H, s),
1.95 (2H, s), 2.59 to 2.83 (2H,
m), 3.70 (3H, s), 3.68-3.75 (1
H, m)

Preparation Example 79 The target compound is obtained from the starting compound in the same manner as in Preparation Example 47. _{^{1 H NMR (CDCl 3);}} 1.43 (9H, s),
1.44 (9H, s), 1.50 to 2.0 (4H,
m), 2.71 to 3.01 (2H, m), 3.01 to
3.30 (2H, m), 3.68 (3H, s), 4.2
0 to 4.40 (1H, m), 4.60 to 4.80 (2
H, m), 5.10 (2H, s), 5.40 to 5.55.
(1H, m), 6.92 (1H, brd, J = 8.1H
_Z ), 7.35 (5H, s)

Preparation Example 80 The target compound is obtained from the starting compound in the same manner as in Preparation Example 7. IR (KBr); 3323, 2978, 2935, 1
716, 1695, 1657, 1525 cm ^-1 EI-MS M / Z 438 (M ⁺ Bu ⁺ OCO)

Preparation Example 81 The target compound is obtained from the starting compound in the same manner as in Preparation Example 8. IR (KBr); 3325, 2978, 2935, 1
813, 1714, 1691, 1657, 1525, 1
498 cm ^-1

Production Example 82 The target compound is obtained from the starting compound in the same manner as in Production Example 50 (1). IR (KBr); 3411, 3373, 1734, 1
668, 1653, 1539, 1522 cm ^-1

Production Example 83 The target compound is obtained from the starting compound in the same manner as in Production Example 10. LD-MS M / Z 1591.59 (M ⁺ + Na)

Production Example 84 A solution of the starting compound (307 mg) and 4- (tert-butoxycarbonylamino) piperidine (220 mg) in toluene (15 ml) was treated with potassium tert-butoxide (120 mg) and 2,2′-bis ( The mixture is treated with diphenylphosphino) -1,1′-binaphthyl (31 mg) and tris (dibenzylideneacetone) dipalladium (0) -chloroform adduct (16 mg), and the mixture is refluxed under a nitrogen atmosphere for 6.5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, evaporated and the residue was purified by silica gel chromatography (eluting with hexane-ethyl acetate) to give 0.21 g of the desired product. Obtain the compound. _{^{1 H NMR (CDCl 3);}} 1.46 (9H, s),
1.6 to 2.0 (6H, m), 2.0 to 2.2 (2H,
m), 2.8-3.1 (2H, m), 3.35 (3H,
s), 3.45 (2H, t , J = 6H Z), 3.6~
3.75 (2H, m), 4.01 (2H, t, J = 6H)
_Z ), 4.4-4.6 (1H, m), 6.93 (4H,
_{d, J = 8.7H Z),} 7.0~7.15 (1H,
m), 7.46 (4H, d , J = 8.7H Z)

Production Example 85 Starting compound (191 mg) in tetrahydrofuran (2 m
The solution in 1) is cooled to 0-5 ° C. and treated with 4N hydrogen chloride in ethyl acetate (2 ml). After 4 hours, the volatiles were removed by evaporation and the residue was triturated with ethyl acetate-hexane to give the desired compound (18).
0 mg) as a solid. EI-MS M / Z 355 (MH ⁺ , free)

Production Example 86 The objective compound is obtained from the starting compound in the same manner as in Production Example 84. ¹ H NMR (CDCl ₃ ); 0.90 to 0.97 (3
H, m), 1.3 to 1.6 (4H, m), 1.49 (9
H, s), 1.70-1.90 (2H, m), 3.10
~ 3.3 (4H, m), 3.55-3.70 (4H,
m), 3.98 (2H, t , J = 6.5H Z), 6.9
4 (2H, d, J = 8.8H Z), 6.96~7.10
(2H, m), 7.44 to 7.50 (4H, m)

Preparation Example 87 The target compound is obtained from the starting compound in the same manner as in Preparation Example 85. _{^{1 H NMR (DMSO-d 6}} ); 0.87~0.94
(3H, m), 1.3 to 1.5 (4H, m), 1.65
~ 1.8 (2H, m), 3.15-3.30 (4H,
m), 3.38 to 3.41 (4H, m), 3.98 (2
_{H, t, J = 6.5H Z} ), 6.97 (2H, d, J =
_{8.7H Z), 7.04 (2H,} d, J = 8.7H Z),
7.5-7.54 (4H, m), 9.22 (2H, br
s)

Production Example 88 N, N of starting compound (2.1 g), 4-chloronitrobenzene (1.01 g) and potassium carbonate (2.88 g)
Mixture in dimethylformamide (45 ml)
Heat at 0 ° C. for 16 hours and cool. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated to give a residue, which was purified by silica gel chromatography (eluted with methylene chloride) to give the desired compound (1). .15 g). ¹ H NMR (CDCl ₃ ); 0.90 (3H, br)
s), 1.2-1.9 (8H, m), 3.24 (4H,
brs), 3.59 (4H, brs), 3.85-4.
00 (2H, m), 6.80 to 7.10 (6H, m),
8.10 to 8.20 (2H, m)

Production Example 89 The target compound is obtained from the starting compound in the same manner as in Production Example 10. _{^{1 H NMR (DMSO-d 6}} ); 0.8~0.9 (3
H, m), 1.2 to 1.5 (6H, m), 1.5 to 1.
8 (2H, m), 3.0 to 3.2 (8H, m), 3.8
8 (2H, t, J = 6.5H Z), 4.59 (2H, b
rs), 6.51 (2H, d , J = 8.7H Z), 6.
74 (2H, d, J = 8.7H Z), 6.81 (2H,
_{d, J = 9.2H Z),} 6.92 (2H, d, J = 9.
2H _Z )

Production Example 90 Thionyl chloride (8.10) was added to ice-cooled methanol (50 ml).
05 ml) are added dropwise. After 20 minutes, D-tyrosine (5
g) is added, the mixture is stirred at room temperature for 24 hours, evaporated to dryness and the residue is triturated with isopropyl ether to give 6.55 g of D-tyrosine methyl ester-hydrochloride. ¹ H NMR (DMSO-d ₆ ); 2.92 to 3.13
(2H, m), 3.65 (3H, s), 4.15 (1
_{H, t, J = 6.7H Z} ), 6.72 (2H, d, J =
_{8.45H Z), 7.01 (2H,} d, J = 8.45
_{H Z), 8.61 (3H,} brs), 9.47 (1H,
s)

Production Example 91 In the same manner as in Production Example 6, N-benzyloxycarbonyl-D-tyrosine methyl ester is obtained from D-tyrosine methyl ester-hydrochloride. _{^{1 H NMR (CDCl 3);}} 2.9~3.15 (2H,
m), 3.71 (3H, s), 4.5-4.7 (1H,
m), 5.03-5.16 (2H, m), 5.16-
5.26 (1H, m), 6.70 (2H, d, J = 8.
_{45H Z), 6.94 (2H,} d, J = 8.46H Z),
7.33 (5H, s)

Production Example 92 Starting compound (1 g) and n-hexyl bromide (0.57
A solution of 7 ml) in acetone (10 ml) is treated with potassium carbonate (839 mg) and heated to reflux for 26 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated to give a residue.
This is purified by silica gel chromatography (elution with hexane-ethyl acetate) to obtain the desired compound (512 mg) as an oil. _{^{1 H NMR (CDCl 3);}} 0.85~0.92 (3
H, m), 1.2-1.5 (10H, m), 1.69-
1.80 (2H, m), 2.9 to 3.1 (2H, m),
3.71 (3H, s), 3.91 (2H, t, J = 6.
_{5H Z), 4.5~4.7 (1H,} m), 5.10 (2
H, s), 5.1 to 5.3 (1H, m), 6.78 (2
_{H, d, J = 8.6H Z} ), 6.98 (2H, d, J =
_{8.6H Z), 7.33 (5H,} s)

Production Example 93 The target compound is obtained from the starting compound in the same manner as in Production Example 7. _{^{1 H NMR (CDCl 3);}} 0.85~1.0 (3H,
m), 1.2-1.5 (10H, m), 1.69-1.
79 (2H, m), 3.0 to 3.2 (2H, m), 3.
91 (3H, t, J = 6.5H Z), 4.6~4.7
(1H, m), 5.10 (2H, s), 5.0 to 5.2
(1H, m), 6.80 (2H, d, J = 8.6)
_{H Z), 7.04 (2H,} d, J = 8.6H Z), 7.3
3 (5H, s)

Production Example 94 The target compound is obtained from the starting compound in the same manner as in Production Example 8. IR (KBr) 3321, 2925, 2854, 18
17, 1734, 1693, 1612, 1535 cm ^-1

Production Example 95 The target compound is obtained from the starting compound in the same manner as in Production Example 9. IR (KBr) 3303, 2958, 1662, 16
39, 1514, 1446, 1252 cm ^-1

Production Example 96 The objective compound is obtained from the starting compound in the same manner as in Production Example 10. IR (KBr) 3315,2958,1664,15
16, 1448, 1252, 1171, 1101, 84
5cm ^-1

Production Example 97 N-benzyloxycarbonyl-β-alanine methyl ester is obtained from β-alanine methyl ester hydrochloride in the same manner as in Production Example 6. ¹ H NMR (CDCl ₃ ); 2.55 (2H, t, J =
_{6H Z), 3.47 (2H,} q, J = 6H Z), 3.69
(3H, s), 5.09 (2H, s), 5.28 (1
H, brs), 7.30-7.37 (5H, m)

Production Example 98 N-benzyloxycarbonyl β-alanine methyl ester (2) was added to an ice-cooled solution of sodium hydride (0.46 g, 60% suspension in oil) in N, N-dimethylformamide (7 ml). .19 g) in N, N-dimethylformamide (8 ml) is added dropwise. After 20 minutes, 1-bromododecane (2.3 ml) is added and the solution is stirred at room temperature for 3 hours. Cool the reaction with ethyl acetate-1N hydrochloric acid. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate elution) to give 2.42 g of N-dodecyl-N Obtaining benzyloxycarbonyl β-alanine methyl ester as an oil. IR (neat) 2925, 2854, 1739, 17
05cm ^-1

Preparation Example 99 In the same manner as in Preparation Example 7, N-dodecyl-N-benzyloxycarbonyl-β-alanine is obtained from N-dodecyl-N-benzyloxycarbonyl-β-alanine methyl ester. IR (neat) 2925.2854, 1734, 170
3cm ^-1

Preparation Example 100 The target compound is obtained from the starting compound in the same manner as in Preparation Example 8. IR (neat) 2925, 2854, 1818, 173
2,1701 cm ^-1

Production Example 101 The objective compound is obtained from the starting compound in the same manner as in Production Examples 50 (1) and 50 (2). IR (KBr) 1666, 1649 cm ^-1 LD-MS M / Z 1637.66 (MH ⁺ )

Example 82 To a solution of the starting compound (330 mg) in N, N-dimethylformamide (200 ml) was added 1-hydroxybenzotriazole (132 mg) and 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide hydrochloride. Salt (22
4 mg) and the mixture is stirred at ambient temperature for 6.5 hours.
After removing the solvent under reduced pressure, the residue is purified by ODS medium pressure column (YMC GEL ODS-AM120-S50) to obtain the desired compound (280 mg). NMR (DMSO-d ₆ , δ); 0.7 to 1.0 (1
2H, m), 1.0 to 1.2 (16H, m), 1.35
(9H, s), 1.2-1.4 (4H, m), 1,5-
2.4 (7H, m), 2.65 (4H, m), 2.9
(2H, m), 3.3-4.6 (29H, m), 4.6
~ 5.3 (8H, m), 6.60 (2H, d, J = 8.
_{5H Z), 6.7 (1H,} m), 6.92 (2H, d,
_{J = 8.5H Z), 6.9~7.6 (} 11H, m),
7.9 to 8.3 (10H, m)

Example 83 Starting compound (140 mg) of trifluoroacetic acid (3 m
1) The solution is stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, the residue is purified by HP-20 column chromatography to obtain the desired compound (110 mg). _{NMR (DMSO-d 6, δ} ); 0.75~1.4
(32H, m), 1.4 to 2.4 (7H, m), 2.5
２2.9 (6H, m), 3.3 to 5.3 (37H,
m), 6.60 (2H, d , J = 8.5H Z), 6.8
5 to 7.6 (14H, m), 8.0 to 8.3 (11H,
m)

Example 84 The target compound is obtained from the starting compound in the same manner as in Example 82. NMR (DMSO-d ₆ , δ); 0.6 to 1.5 (3
8H, m), 1.35 (9H, s), 1.7-2.3.
(7H, m), 2.6 to 2.9 (4H, m), 3.6 to
5.3 (37H, m), 6.60 (2H, d, J = 8.
_{5H Z), 6.65 (1H,} m), 6.9~7.4 (6
H, m), 7.5-7.8 (4H, m), 7.9-8.
3 (11H, m) 9.14 (1H, s)

Example 85 The target compound is obtained from the starting compound in the same manner as in Example 83. NMR (DMSO-d ₆ , δ); 0.8 to 1.6 (3
8H, m), 1.7 to 2.3 (7H, m), 2.6 to
3.0 (4H, m), 3.5-5.4 (37H, m),
6.60 (2H, d, J = 8.5 Hz), 6.9-8.
3 (23H, m), 9.15 (1H, s)

Example 86 The target compound is obtained from the starting compound in the same manner as in Example 82. NMR (CD ₃ OD, δ); 0.8 to 1.6 (37
H, m), 1.42 (9H, s), 1.6 to 2.3 (7
H, m), 2.7 to 3.1 (4H, m), 3.30 (3
H, s), 3.38 (2H , t, J = 6.3H Z),
3.8-5.0 (28H, m), 5.28 (1H,
m), 6.76 (2H, d , J = 8.5H Z), 6.9
5 (2H, d, J = 9.0H Z), 7.03 (2H,
_{d, J = 8.5H Z),} 7.3~7.5 (6H, m)

Example 87 The target compound is obtained from the starting compound in the same manner as in Example 83. NMR (CD ₃ OD, δ); 0.8 to 1.7 (37
H, m), 1.7-2.6 (7H, m), 2.65-
3.1 (4H, m), 3.30 (3H, s), 3.38
(2H, d, J = 6.3H Z), 3.6~5.1 (28
H, m), 5.24 (1H, m), 6.91 (2H,
_{d, J = 8.3H Z),} 6.95 (2H, d, J = 8.
_{9H Z), 7.06 (2H,} d, J = 8.3H Z), 7.
35 (2H, d, J = 8.3H Z), 7.49 (2H,
_{d, J = 8.9H Z),} 7.51 (2H, d, J = 8.
3H _Z )

Example 88 The target compound is obtained from the starting compound in the same manner as in Example 82. NMR (CD ₃ OD, δ); 0.85 to 1.3 (23
H, m), 1.42 (9H, s), 1.5 to 2.6 (1
5H, m), 2.7-3.2 (4H, m), 3.33
(3H, s), 3.43 (2H, t, J = 6.7)
_{H Z), 3.6~5.0 (30H,} m), 5.28 (1
_{H, t, J = 6.5H Z} ), 6.75 (2H, d, J =
_{8.5H Z), 7.0 (4H,} m), 7.40 (2H,
_{d, J = 8.1H Z),} 7.57 (4H, m), 7.6
3 (4H, s)

Example 89 In the same manner as in Example 83, the desired compound is obtained from the starting compound. NMR (CD ₃ OD, δ); 0.9 to 1.7 (31
H, m), 1.7 to 2.5 (7H, m), 2.6 to 3.
05 (4H, m), 3.30 (3H, s), 3.4-
5.1 (30H, m), 5.30 (1H, m), 6.7
~ 8.2 (16H, m)

Example 90 The target compound is obtained from the starting compound in the same manner as in Example 82. NMR (CD ₃ OD, δ); 0.9 to 1.7 (34
H, m), 1.42 (9H, s), 1.8 to 2.6 (1
1H, m), 2.7 to 3.2 (4H, m), 3.7 to
5.0 (28H, m), 5.30 (1H, m), 6.7
6 (2H, d, J = 8.5H Z), 7.02 (2H,
_{d, J = 8.5H Z),} 7.1~8.0 (10H, m)

Example 91 The target compound is obtained from the starting compound in the same manner as in Example 83. NMR (CD ₃ OD, δ); 0.8-1.0 (9H,
m), 1.15 to 1.60 (25H, m), 1.8 to
2.6 (11H, m), 2.7 to 3.0 (4H, m),
3.6 to 5.1 (28H, m), 5.30 (1H,
m), 6.90 (2H, d , J = 8.5H Z), 7.0
5 (2H, d, J = 8.5H Z). 7.1 to 8.0 (1
0H, m)

Example 92 The target compound is obtained from the starting compound in the same manner as in Example 82. ¹ H NMR (CD ₃ OD, δ); 0.75 to 1.05
(9H, m), 1.12 (3H, d, J = 6.3)
_{H Z), 1.12~1.40 (34H,} m), 1.46
(9H, s), 1.50 to 2.65 (15H, m),
2.75-3.00 (2H, m), 3.60-4.70
(23H, m), 4.98 (1H, d, J = 3.3)
_{H Z), 5.02~5.20 (1H,} m), 6.87
(2H, d, J = 8.5H Z), 7.10 (2H, d,
J = 8.5H _Z)

Example 93 Starting compound (440 mg) of trifluoroacetic acid (18 m
The solution in 1) is stirred at 0-5 ° C. for 1.5 hours and at room temperature for 1 hour. The trifluoroacetic acid is removed by evaporation under reduced pressure, ethyl acetate is added and the mixture is again evaporated to dryness. Water is added and the solution is lyophilized to give the crude product (0.45 g). The crude product was subjected to YMC ODS silica column chromatography (acetonitrile-pH 3).
(Eluted with a phosphate buffered mixture). The fractions containing the product are pooled and evaporated to remove acetonitrile.
The solution is desalted by applying to an ODS column, washed with water, eluted with 90% acetonitrile-water, the eluate is distilled off, and lyophilized to obtain the target compound as a white amorphous powder. (369.9 mg). NMR (CD ₃ OD, δ); 0.75 to 1.0 (9
H, m), 1.12 (3H , d, J = 6.3H Z),
1.15 to 1.43 (34H, m), 1.5 to 2.65
(15H, m), 2.75-3.00 (2H, m),
3.58 to 4.70 (23H, m), 5.00 (1H,
_{d, J = 3.6H Z),} 5.03~5.2 (1H,
m), 6.89 (2H, d , J = 8.5H Z), 7.1
1 (2H, d, J = 8.5H Z),

Example 94 A solution of the starting compound (248 mg) and 1-tert-butoxycarbonylpiperazine (32.8 mg) in N, N-dimethylformamide (2.5 ml) was treated with 1-hydroxybenzotriazole (23.8 mg). Followed by 1-ethyl-3- (3'-dimethylaminopropyl)
Treat with carbodiimide hydrochloride (46 mg). The solution is stirred at room temperature for 3 hours. Ethyl acetate is added, the solid is separated off and dried. The crude product is dissolved in water and OD
Purify by S column chromatography and elute with a mixture of acetonitrile-water. The fractions containing the product are pooled, evaporated, the organic solvent is removed and lyophilized to give the desired compound as a white solid (200mg). ¹ H NMR (CD ₃ OD, δ); 0.75-1.00
(9H, m), 1.12 (3H, d, J = 6.0)
_{H Z), 1.15~1.43 (34H,} m), 1.47
(9H, s), 1.50 to 2.66 (15H, m),
2.74 to 3.02 (2H, m), 3.30 to 4.75
(31H, m), 5.00 (1H, d, J = 3.0)
_{H Z), 5.05~5.25 (1H,} m), 6.89
(2H, d, J = 8.3H Z), 7.10 (2H, d,
J = 8.3H _Z)

Example 95 The starting compound (170 mg) in trifluoroacetic acid (10 m
The solution in 1) is kept at room temperature for 4 hours and distilled off under reduced pressure until dry. Ethyl acetate is added to the residue and the solution is again evaporated to dryness. 100 ml of crude product
And purified by ODS column chromatography. The fractions containing the product were pooled, evaporated and
The pH was adjusted to 2 with N hydrochloric acid, and Amberlyst A-26 (C
The elute was lyophilized by passing through a short column of l ^- type) ion exchange resin and extracted with water to obtain 122.6 mg of the target compound as a white amorphous solid. ¹ H NMR (CD ₃ OD, δ); 0.70-1.00
(9H, m), 1.11 (3H, d, J = 6.5)
_{H Z), 1.18~1.44 (34H,} m), 1,44
~ 2.65 (15H, m), 2.70 ~ 3.30 (6
H, m), 3.30-4.80 (27H, m), 5.0.
0 to 5.25 (2H, m), 6.95 (2H, d, J =
_{8.4H Z), 7.12 (2H,} d, J = 8.4H Z)

Reference Example 1 The target compound was obtained from the starting compound in the same manner as in Example 82. ¹ H NMR (CD ₃ OD, δ); 0.82-1.00
(9H, m), 1.10 to 1.65 (44H, m),
1.43 (9H, s), 1.82 to 2.60 (8H,
m), 2.85 to 3.12 (4H, m), 3.60 to
4.86 (25H, m), 6.78 (2H, d, J =
_{8.5H Z), 7.05 (2H,} d, J = 8.5H Z)

Example 96 The objective compound is obtained from the starting compound in the same manner as in Example 93. ¹ H NMR (CD ₃ OD, δ); 0.76-1.00
(9H, m), 1.15 (3H, d, J = 6.3)
_{H Z), 1.18~1.65 (40H,} m), 1.65
２2.60 (9H, m), 2.80 to 3.05 (4H,
m), 3.58-4.90 (24H, m), 5.04.
(1H, d, J = 3.0H Z), 6.90 (2H, d,
_{J = 8.5H Z), 7.06 (} 2H, d, J = 8.5
H _Z )

Example 97 The target compound is obtained from the starting compound in the same manner as in Example 82. IR (KBr) 3346,2972,2927,28
56,1657,1531,1522cm ^-1

Example 98 In the same manner as in Example 83, the desired compound is obtained from the starting compound. IR (KBr) 3396, 2925, 2854, 16
60, 1529, 1446 cm ^-1

Example 99 The target compound is obtained from the starting compound in the same manner as in Example 82. IR (KBr) 3336,1655,1516,14
48,1248cm ^-1

Example 100 The title compound is obtained from the starting compound in the same manner as in Example 83. IR (KBr) 3298, 2933, 2860, 16
68,1541,1516,1452,1246,12
03,1180,1138cm ^-1

Example 101 In the same manner as in Example 82, the desired compound is obtained from the starting compound. FAB-MS: M / Z 1691 (MH ⁺ )

Example 102 The target compound is obtained from the starting compound in the same manner as in Example 83. IR (KBr): 2929, 2856, 1786, 16
60cm ^-1 FAB-MS M / Z 1614 (M + Na)

Example 103 The target compound is obtained from the starting compound in the same manner as in Example 82. IR (KBr): 2935, 1678, 1452, 12
46, 1176, 1099 cm ^-1

Example 104 The target compound is obtained from the starting compound in the same manner as in Example 83. IR (KBr): 1662, 1647, 1539, 15
16,1248cm ^-1

Example 105 The target compound is obtained from the starting compound in the same manner as in Example 82. IR (KBr): 3404, 3373, 1732, 16
66,1655,1537,1523cm ^-1

Example 106 The objective compound is obtained from the starting compound in the same manner as in Example 95. LD-MS: M / Z 1394.03 (M ⁺ )

Example 107 Starting compound (1.2 g) in 1: 1 tetrahydrofuran
A solution in water (30 ml) was mixed with triethylamine (0.5 m
1), followed by di-tert-butyl dicarbonate (0.25 g). After 24 hours at room temperature, additional di-tert-butyl dicarbonate (1.
0 g) and triethylamine (1 ml) are added, the mixture is stirred for 1 hour and the organic solvent is distilled off. The residue is adjusted to pH 2 with 1N hydrochloric acid, purified by ODS column chromatography, and lyophilized to give a total of 358 mg of the desired compound as an amorphous white powder. IR (KBr): 3334, 1732, 1666, 16
53, 1537, 1522 cm ^-1

Example 108 The target compound is obtained from the starting compound in the same manner as in Example 94. IR (KBr): 3392, 1668, 1653, 15
39,1514cm ^-1

Example 109 The title compound is obtained from the starting compound in the same manner as in Example 94. IR (KBr): 3404, 1676, 1668, 16
51, 1554, 1541, 1523 cm ^-1

Example 110 The desired compound is obtained from the starting compound in the same manner as in Example 94. IR (KBr): 3411, 2946, 2931, 16
68, 1653, 1539, 1522 cm ^-1

Example 111 The desired compound is obtained from the starting compound in the same manner as in Example 95. IR (KBr): 3402,3251,1653,15
39,1516,1454,1400

Example 112 The target compound is obtained from the starting compound in the same manner as in Example 95. IR (KBr): 3392, 1653, 1539, 15
23, 1456, 1394, 1248 cm ^-1

Example 113 The target compound is obtained from the starting compound in the same manner as in Example 95. IR (KBr): 3398, 2962, 2935, 16
53, 1539, 1523, 1454, 1392, 12
46cm ^-1

Example 114 In the same manner as in Example 82, the desired compound is obtained from the starting compound. IR (KBr): 3311, 3076, 2931, 16
60, 1518, 1446, 1246, 1171, 10
97cm ^-1

Example 115 The target compound is obtained from the starting compound in the same manner as in Example 83. IR (KBr): 3338, 2933, 1664, 15
16, 1446, 1244, 1201, 1182, 11
38,1099 cm ^-1

Example 116 The title compound is obtained from the starting compound in the same manner as in Example 82. IR (KBr): 1666, 1649, 1554, 15
39,1523 cm ^-1

Example 117 The target compound is obtained from the starting compound in the same manner as in Example 95. IR (KBr): 3367, 2927, 1651, 15
37, 1523, 1454 cm ^-1

Example 118 A solution of the starting compound (500 mg) in acetic acid (5 ml) was prepared.
Treat with IM aqueous sodium nitrite solution (1.27 ml), stir the solution at room temperature for 8 days, dilute to 500 ml with water and purify by ODS column chromatography eluting with acetonitrile-water mixture. The fractions containing the product are pooled, evaporated to remove the organic solvent and lyophilized to give 370 mg of the desired compound as a yellow powder. FAB-MS: M / Z 1620 (MH ⁺ ) IR (KBr): 3309.2, 1733.7, 16
56.6, 1535.1, 1446.4 cm ^-1

Example 119 A solution of the starting compound (350 mg) in methanol (15 ml) was treated with 10% wet palladium on carbon (50 mg) at 1 atmosphere under a hydrogen atmosphere for 5 hours, filtered and evaporated.
The residue is dissolved in water (10 ml) and freeze-dried to obtain the desired compound (302 mg) as a white powder. FAB-MS: M / Z 1590 (MH) ⁺ IR (KBr): 3320.8, 1731.8, 16
54.6, 1529.3, 1448.3 cm ^-1

Example 120 Starting compound (248 mg), 1-hydroxybenzotriazole (25.3 mg), N-tert-butoxycarbonyl-β-alanine (35.4 mg), N-ethyl-N-
3-dimethylaminopropylcarbodiimide hydrochloride (4
8 mg) in N, N-dimethylformamide (3 ml) was stirred for 20 hours and ethyl acetate (about 50 m
1), collect and dry the precipitate. This solid is dissolved in water and purified by ODS column chromatography, eluting with an acetonitrile-water mixture. The fractions containing the product were separated and pooled, evaporated and lyophilized to give the desired compound A (133 mg) and the desired compound B (5
6 mg) as a white amorphous powder. Target compound A FAB-MS: M / Z 1784.4 (M + Na) ⁺ IR (KBr): 3315.0, 1733.7, 16
52.7, 1538.9, 1523.5 cm ^-1 Target compound B FAB-MS: M / Z 1933.3 (MH ⁺ ) IR (KBr): 3313.1, 1735.6, 16
54.6, 1538.9, 1525.4 cm ^-1

[0340]Example 121 Starting compound (130 mg) in trifluoroacetic acid (6 m
l) stir the solution in at room temperature for 2.5 hours and dry in vacuo
Evaporate until Add ethyl acetate and re-distill the mixture
Leave (repeat 5 times). Crude residue under high vacuum for 2 hours
Dry, dissolve in water and treat with 0.1N hydrochloric acid (5ml)
And Amberlyst A-26 (Cl ^―-Type) empty
And freeze-dry to obtain 116 mg of the target compound.
Obtained as a colored powder. FAB-MS: M / Z 1662 (MH⁺) IR (KBr): 3297.7,1835.6,16
54.6,1540.8,1444.4cm^-1

Example 122 Starting compound (100 mg) at 0 ° C. under a nitrogen atmosphere and 4Å
A solution of molecular sieves (250 mg) in N, N-dimethylformamide (2 ml) was treated with cyanuric chloride (1 ml).
2 mg) and stirred at the same temperature for 1 hour and at room temperature for 1 hour. After recooling to 0 ° C., 6 mg of cyanuric chloride are added. After 2 hours, an additional 6 mg of cyanuric chloride is added, followed by an additional 6 mg after 1 hour. After an additional 10 minutes, the reaction was quenched with pH 4 buffer, kept at 0 ° C. for 18 hours, diluted with water, purified by ODS chromatography eluting with acetonitrile-water mixture, and 53.4 mg of lyophilized The target compound is obtained as a white amorphous powder. _{^{1 H NMR (DMSO-d 6}} ) 0.75~1.35 (4
6H, m), 1.35 to 2.20 (11H, m), 1.
78 (3H, s), 2.30-3.10 (8H, m),
3.55-4.47 (22H, m), 4.47-4.6
7 (2H, m), 1.70 to 4.90 (3H, m),
4.95 to 5.28 (4H, m), 5.78 (1H,
d, J = 6H _Z ), 6.59 (2H, d, J = 8.3)
_{H Z), 6.94 (2H,} d, J = 8.3H Z), 7.4
8 (1H, d, J = 8.5H Z), 7.72~8.38
(10H, m), 9.12 (1H, s)

Example 123 The target compound is obtained from the starting compound in the same manner as in Example 118. FAB-MS: M / Z 1578.8 (M + H) ⁺ IR (KBr): 1731.8, 1656.6, 15
37.0, 1450.2 cm ^-1

Example 124 A solution of the starting compound (203 mg) in methanol (5 ml) is treated with 50% wet palladium on carbon, water (5 ml), sodium borohydride (24 mg). 5 minutes later, 5
ml of acetic acid are added and the reaction is stirred at room temperature for 1 hour. The reaction is diluted with water, filtered, purified by ODS column chromatography, and extracted with an acetonitrile-water mixture. The fractions containing the product are pooled, evaporated and lyophilized to give 78 mg of the desired compound as a white powder. FAB-MS: M / Z 1548 (MH ⁺ ) IR (KBr): 3305.4, 1731.8, 16
56.6,1533.1,1452.1 cm ^-1

Reference Example 2 A solution of the starting compound (1.0 g) in N, N-dimethylformamide (10 ml) is treated with diisopropylethylamine (123.5 mg) and di-tert-butyl dicarbonate (167 mg). After 18 hours, add water to a total volume of 500 ml and adjust to pH 6.0 with 0.1N hydrochloric acid. Purification by ODS chromatography, eluting with an acetonitrile-water mixture, followed by freeze-drying of the product-containing fractions gives the target compound (1.1 g) as a white powder. FAB-MS: M / Z 1533 IR (KBr): 3315.0, 1733.7, 164
5.0, 1517.7 cm ^-1

Example 125 The target compound is obtained from the starting compound in the same manner as in Reference Example 2. FAB-MS: M / Z 1578, 1701.8
(MH + Na) ⁺ IR (KBr): 1733.7, 1654.6, 15
37.0 cm ^-1

Example 126 The target compound is obtained from the starting compound in the same manner as in Example 118. FAB-MS: M / Z 1700 (M + Na) ⁺ IR (KBr): 2927.4, 1733.7, 16
54.6, 1537.0, 1452.1 cm ^-1

Example 127 The title compound is obtained from the starting compound in the same manner as in Example 119. FAB-MS: M / Z 1671.9 (MH + N
a) ⁺ IR (KBr): 3301.5, 1729.8, 16
52.7, 1523.5, 1450.2 cm ^-1

Example 128 A mixture of the starting compound (500 mg), an excess of 4-molecular sieves in N, N-dimethylformamide (15 ml) was treated with glyoxylic acid monohydrate (141 mg).
Treat at room temperature for 8 hours, dilute with water and filter through a membrane filter. The solution is adjusted to pH 6.86 and purified by ODS column chromatography, eluting with acetonitrile-water mixture. The fractions containing the product are pooled, evaporated to remove the organic solvent, adjusted to pH 3 with 0.1N hydrochloric acid, and lyophilized to give 350 mg of the desired compound as a white powder. FAB-MS: M / Z 1730 (MH + Na) ⁺ IR (KBr): 3318.9, 1737.5, 165
2.7, 1537.0, 1521.6, 1452.1c
m ^-1

Example 129 Starting compound (218 mg) of trifluoroacetic acid (2 m
l) The medium solution is kept at room temperature for 2 hours and evaporated to dryness in vacuo. Ethyl acetate (5 ml) is added and the mixture is again distilled off (repeated three times). 15 crude residues
For 15 minutes under high vacuum, dissolved in water, adjusted to pH 1.5 with 0.1 N hydrochloric acid, and added to Amberlist A-26 (C
l ^- - through the column of ion exchange resin type), and finally lyophilized to give the object compound (121 mg) as a white powder. FAB-MS: M / Z 1608 (M + H) ⁺ IR (KBr): 3297.7, 1733.7, 165
4.6, 1523.5, 1448.3 cm ^-1

Example 130 In the same manner as in Example 120, the starting compound was converted to the target compound A.
And B. Target compound A FAB-MS: M / Z 1842 (MH ⁺ + Na) IR (KBr): 3322.7, 2927.4, 17
32,1656.6,1535.1,1450.2cm
^-1 target compound B FAB-MS: M / Z 1991 (M + H) ⁺ IR (KBr): 3318.9, 2929.3, 16
60.4, 1654.6, 1535.1, 1525.4
cm ^-1

Example 131 The target compound is obtained from the starting compound in the same manner as in Example 120. FAB-MS: M / Z 1985 (MH ⁺ ) IR (KBr): 3317.0, 2975.6, 29
29.3, 2856.1, 1758.8, 1660.
4,1531.2,1446.4,1390.4,12
80.5, 1253.5, 1160.9 cm ^-1

Example 132 The target compound is obtained from the starting compound in the same manner as in Example 120. FAB-MS: M / Z 1938 (M + Na) ⁺ IR (KBr): 3401.8, 2973.7, 29
27.4, 2856.1, 1735.6, 1660.4

Example 133 The target compound is obtained from the starting compound in the same manner as in Example 120. IR (KBr): 3326.6,2973.7,29
27.4, 2856.1, 1654.6, 1596.
8,1533.1,1446.4 cm ^-1

Example 134 The target compound is obtained from the starting compound in the same manner as in Example 120. LD-MS: M / Z 1941 (M + Na) ⁺ IR (KBr): 3293.8, 2975.6, 29
31.3, 2856.1, 1726, 1658, 153
1,1446,1369,1249,1150,108
7cm ^-1

Example 135 The objective compound is obtained from the starting compound in the same manner as in Example 120. LD-MS: M / Z 1857 (M + Na) ⁺ IR (KBr): 1664.3, 1637.3, 15
31.2cm ^-1

Example 136 In the same manner as in Example 120, the desired compound is obtained from the starting compound. LD-MS: M / Z 1786 (M + Na) ⁺ IR (KBr): 3380.6, 1727.9, 16
60.4, 1548.6, 1533.1, 1446.4
cm ^-1

Example 137 A solution of the starting compound (200 mg) in N, N-dimethylformamide (2 ml) was treated with diisopropylethylamine (24 ml) followed by methanesulfonyl chloride (11 m) in 5 ml N, N-dimethylformamide.
Process in 1). After 5 hours, more methanesulfonyl chloride (11 ml) and diisopropylethylamine (24 ml) are added and the mixture is stirred at room temperature for 24 hours. The mixture is diluted with water and purified by ODS column chromatography eluting with a mixture of acetonitrile-water to give the desired compound (163 mg). LD-MS: M / Z 1750 (M + Na) ⁺ IR (KBr): 2927.4, 1727, 166
4.3, 1643.1, 1529.3 cm ^-1

Example 138 In the same manner as in Example 120, the desired compound is obtained from the starting compound. FAB-MS: M / Z 1957 (M + Na) ⁺

Example 139 In the same manner as in Example 121, the desired compound was obtained from the starting compound. FAB-MS: M / Z 1619 (MH ⁺ , free) IR (KBr): 3295.7, 1733.7, 16
54.6, 1537.0, 1450.2 cm ^-1

Example 140 The target compound is obtained from the starting compound in the same manner as in Example 121. FAB-MS: M / Z 1685 (M + H) ⁺ IR (KBr): 3290.0, 2927.4, 17
29.8, 1658.5, 1533.1, 1446.4
cm ^-1

Example 141 The objective compound is obtained from the starting compound in the same manner as in Example 121. FAB-MS: M / Z 1716 (M + H) ⁺ IR (KBr): 3322.7, 2927.4, 17
27.9, 1656.6, 1533.1, 1446.4
cm ^-1

Example 142 The objective compound is obtained from the starting compound in the same manner as in Example 121. IR (KBr): 3380.6, 2927.4, 17
08.6, 1658.5, 1533.1 cm ^-1

Example 143 In the same manner as in Example 121, the desired compound is obtained from the starting compound. LD-MS: M / Z 1663 (M + H) ⁺ IR (KBr): 1727.9, 1660.4, 16
37.3, 1552.4, 1637.3 cm ^-1

Example 144 The target compound is obtained from the starting compound in the same manner as in Example 121. LD-MS: M / Z 1657 (M + Na) ⁺ IR (KBr): 1722,1664.3,163
5.3 cm ^-1

Example 145 In the same manner as in Example 121, the desired compound is obtained from the starting compound. LD-MS: M / Z (MH ⁺ ) IR (KBr): 1664.3, 1635.3 cm ⁻¹

Example 146 Starting compound (200 mg) and succinic anhydride (12 m
A solution of g) in N, N-dimethylformamide (2 ml) is treated with 4-dimethylaminopyridine, stirred overnight, evaporated and precipitated with ethyl acetate. Dissolve the dried powder in excess trifluoroacetic acid, stir at room temperature for 1.5 hours, evaporate and purify by ODS chromatography to obtain the desired compound (40 mg). LD-MS: M / Z 1648 (M + H) ⁺ IR (KBr): 3309.2, 2927.4, 17
27.9, 1658.5, 1538.9, 1446.4
cm ^-1

Example 147 In the same manner as in Example 121, the desired compound is obtained from the starting compound. FAB-MS: M / Z 1699.25 (M + Na
⁺ ) IR (KBr): 3305.4, 2927.4, 17
33.7, 1656.6, 1535.1 cm ^-1

Example 148 The target compound is obtained from the starting compound in the same manner as in Example 121. LD-MS: M / Z 1626.39 (M + H) ⁺ IR (KBr): 1727.9, 1664.3, 15
31.2cm ^-1

Example 149 A solution of the starting compound (300 mg) in acetic acid (12 ml) was added at room temperature to a 6% aqueous sodium hypochlorite solution (237 ml).
Process in 1). After 3 hours, a further 6% aqueous sodium hypochlorite solution (118 ml) is added, and after another hour, a further 6% aqueous sodium hypochlorite solution (118 ml) is added, and the reaction is continued for another hour. The solution was distilled off, the residue was dissolved in water (100 ml) and the solution was adjusted to pH 2 with 0.1N hydrochloric acid.
Adjust to This solution was purified by ODS column chromatography, eluting with a mixture of acetonitrile-water,
Get one fraction. Each fraction was separated and distilled off to remove acetonitrile, adjusted to pH 2.8 with 0.1N hydrochloric acid, and extracted with Am
berlyst A-26 (Cl ^{- -} type) through a column of ion exchange resin and freeze-dried, the target compound A (14
2.2 mg) and the target compound B (25.1 mg) are obtained as a white amorphous powder. Target compound A NMR (DMSO-d ₆ , δ): 0.70 to 1.36
(46H, m), 1,36 to 2.55 (15H, m),
2.55-3.10 (4H, m), 3.50-4.10.
(11H, m), 4.10 to 4.63 (13H, m),
4.75-4.95 (3H, m), 4.95-5.40
(5H, m), 6.82 (1H, d, J = 8.3)
_{H Z), 6.93 (1H,} d, J = 8.3H Z), 6.9
5 (1H, brs), 7.13 (1H, s), 7.18
(1H, brs), 7.50 (1H, d, J = 8.4H)
_Z ), 7.62-8.40 (12H, m), 9.94.
(1H, br) Target compound B ¹ H NMR (DMSO-d ₆ ): 0.70 to 1.36
(46H, m), 1.36 to 2.55 (15H, m),
2.55-3.10 (4H, m), 3.50-4.05
(11H, m), 4.05 to 4.60 (13H, m),
4.60 to 5.40 (8H, m), 6.96 (1H, b
rs), 7.17 (2H, s), 7.12-7.20.
(1H, br), 7.51 (1H, d, J = 7.9)
_{H Z), 7.40~8.45 (12H,} m), 9.89
(1H, s)

Example 150 The starting compound (500 mg) in methanol (2
0 ml) was treated with sodium iodide (48 mg) followed by a 6% aqueous sodium hypochlorite solution (395%).
ml). After 6 hours at the same temperature, sodium iodide (48 mg) and a 6% sodium hypochlorite aqueous solution (395 ml) were added, and the aqueous solution was kept for another hour, cooled with a 10% sodium thiosulfate solution, and distilled. Leave. The residue was dissolved in water, adjusted to pH 3 and purified by ODS column chromatography eluting with acetonitrile-water mixture, the fractions containing the product were pooled and evaporated to remove the organic solvent, pH 2.8. Adjust to Amb
erlyst A-26 (Cl ^{- -} type) through a column of ion exchange resin and freeze-dried, the target compound (114.9
mg) as a white solid. FAB-MS: M / Z 1659 (M + H) ⁺ IR (KBr): 3303.5, 2927.4, 17
29.8, 1654.6, 1535.1, 1448.3
cm ^-1

Example 151 A solution of the starting compound (500 mg), tert-butyl bromoacetate (200 ml) and potassium carbonate (30 mg) in N, N-dimethylformamide (10 ml) was prepared.
Stir at room temperature for 24 hours, dilute with water, add acetonitrile-
Purify by ODS column chromatography eluting with a mixture of water. Product fractions are pooled, evaporated and lyophilized to give 450 mg of the desired compound. LD-MS: M / Z 1805.12 (M + Na) ⁺ IR (KBr): 2971.8, 2927.4, 28
54.1, 1733.7, 1654.6, 1533.
1,1517.7,1450.2cm ^-1

Example 152 The target compound is obtained from the starting compound in the same manner as in Example 151. _{^{1 H NMR (DMSO-d 6}} ): 0.75~1.40
(46H, m), 1.40 to 2.55 (15H, m),
2.55-3.10 (4H, m), 3.02 (9H,
s), 3.55-4.08 (11H, m), 3.70.
(3H, s), 4.10 to 4.50 (11H, m),
4.50 to 4.65 (2H, m), 4.78 to 5.30
(8H, m), 6.79 (2H, d, J = 8.6),
6.94 (1H, s), 7.08 (2H, d, J = 8.
6), 7.13 (1H, s), 7.45 (1H, d, J
= 8.5), 7.70 to 8.38 (9H, m)

Example 153 In the same manner as in Example 121, the desired compound is obtained from the starting compound. LD-MS: M / Z 1748.45 (M + Na)
⁺ IR (KBr): 3324.7, 2927.4, 17
31.8, 1658.5, 1531.2, 1517.
7,1448.3cm ^-1

Example 154 In the same manner as in Example 120, the desired compound is obtained from the starting compound. LD-MS: M / Z 1774.57 (M + Na)
⁺ IR (KBr): 2927.4, 1737.5, 16
54.6, 1531.2, 1517.7, 1448.
3,1240.0cm ^-1

Example 155 The target compound is obtained from the starting compound in the same manner as in Example 119. IR (KBr): 3367.1, 927.2, 28
54.1, 1733.7, 1654.6, 1533.
1,1450.2,1235.2 cm ^-1

Example 156 The desired compound is obtained from the starting compound in the same manner as in Example 120. LD-MS: M / Z 1855.09 (M + Na) IR (KBr): 1733.7, 1654.6, 15
38.9, 1515.8 cm ^-1

Example 157 In the same manner as in Example 119, the desired compound is obtained from the starting compound. LD-MS: 1698.97 (M + H) ⁺ IR (KBr): 2925.5, 1731.8, 16
58.5, 1537.0, 1448.3 cm ^-1

Example 158 The target compound is obtained from the starting compound in the same manner as in Example 151. LD-MS: M / Z 1769.38 (M + Na)
⁺ IR (KBr): 1727.9, 1664.3, 16
43.1cm ^-1

Example 159 The target compound is obtained from the starting compound in the same manner as in Example 121. LD-MS: M / Z 1614.88 (MH ⁺ + N
a) IR (KBr): 3328.5, 2927.4, 17
33.7, 1654.6, 1535.1 cm ^-1

[0380]Example 160 The target compound was obtained from the starting compound in the same manner as in Reference Example 2.
You. LD-MS: M / Z 1713.95 (M + Na)
⁺ IR (KBr): 3369,2927.4,173
3.7,1658.5cm ^-1

Example 161 The target compound is obtained from the starting compound in the same manner as in Example 120. LD-MS: M / Z 1855.72 (M + Na)
⁺ IR (KBr): 3365.2, 2927.4, 16
58.5, 1531.2, 1517.7, 1448.3
cm ^-1

Example 162 The target compound is obtained from the starting compound in the same manner as in Example 121. IR (KBr): 1731.8, 1658.5, 15
35.1, 1446.4 cm ^-1

Example 163 Starting compound (60 mg) in tetrahydrofuran (10 m
The solution in 1) is stirred for 7 days at room temperature in the presence of 1,1'-carbonyldiimidazole (5.9 mg). After evaporation, the residue is purified by ODS column chromatography to give 40 mg of the desired compound as a white amorphous powder. FAB-MS: M / Z 1696.6 (M + Na)
⁺ IR (KBr): 1764.5, 1741.4, 16
58.5cm ^-1

Example 164 The target compound is obtained from the starting compound in the same manner as in Example 121. FAB-MS: M / Z 1574 (M + H) ⁺ IR (KBr): 1764.5, 1654.6, 15
37.0 cm ^-1

Example 165 The target compound is obtained from the starting compound in the same manner as in Example 151. LD-MS: M / Z 1772.15 (M + Na) IR (KBr): 1654.6, 1533.1 cm ^-1

Example 166 In the same manner as in Example 119, the desired compound is obtained from the starting compound. LD-MS: M / Z 1711.03 (MH ⁺ ) IR (KBr): 1733.7, 1666.2, 16
54.6, 1523.5 cm ^-1

Example 167 In the same manner as in Example 121, the desired compound is obtained from the starting compound. LD-MS: M / Z 1588.45 (MH ⁺ ) IR (KBr): 1727.9, 1664.3, 15
31.2cm ^-1

Example 168 The target compound is obtained from the starting compound in the same manner as in Example 151. LD-MS: M / Z 1814.06 (M + N
a ⁺ ) IR (KBr): 2929.3,1727.9,16
64.3, 1643.1, 1546.6, 1531.
2,1446.4cm ^-1

Example 169 The target compound is obtained from the starting compound in the same manner as in Example 121. LD-MS: M / Z 1636.36 (MH ⁺ ) IR (KBr): 1727.9, 1664.3, 16
27.6,1531.2cm ^-1

Example 170 The title compound is obtained from the starting compound in the same manner as in Example 119. LD-MS: M / Z 1785.09 (M + Na)
⁺ IR (KBr): 3324.7, 2927.4, 17
37.5,1658.5,1525.4,1448.3
cm ^-1

Example 171 In the same manner as in Example 120, the desired compound is obtained from the starting compound. LD-MS: M / Z 195.29 (M + Na)
⁺ IR (KBr): 2929.3, 1731.8, 16
66.2,1535.1 cm ^-1

Example 172 In the same manner as in Example 121, the desired compound is obtained from the starting compound. LD-MS: M / Z 1677 (M ⁺ , free) IR (KBr): 3371.0, 2927.4, 17
33.7, 1658.5, 15389. cm ^-1

Continuation of the front page (72) Inventor Hidenori Oki 4-4-13-107 Nakasuji, Takarazuka-shi, Hyogo (72) Inventor Hideaki Yamanaka 2-77-10, Nakanoshiba Kusuba, Hirakata-shi, Osaka (72) Inventor Koji Kawabata 2-5-30 Maruyamadai, Kawanishi-shi, Hyogo

Claims (5)

[Claims] 1. The following general formula (I): [Wherein, R ¹ represents hydrogen, an alkyl group, a lower alkoxyalkyl group, a carboxy group, a carbamoyl group optionally having a substituent, an aryl group optionally having a suitable substituent, An ar (lower) alkyl group which may have a substituent, or a heterocyclic carbonyl group which may have a suitable substituent, R ² is a carboxy group, a protected carboxy group, or a suitable substituent A heterocyclic carbonyl group optionally having the following formula: (Wherein R ³ and R ⁴ may be the same or different and are hydrogen; or a lower alkyl group, a sulfonyl group, a carbamoyl group, a lower alkanoyl group, each of which may have a suitable substituent, A lower alkoxycarbonyl group, an ar (lower) alkoxycarbonyl group, a heterocyclic carbonyl group, an aroyl group or a cyclo (lower) alkylcarbonyl group), or the following formula: (Wherein, R ⁵ may be the same or different and a lower alkyl group or a lower alkenyl group optionally having a suitable substituent, X represents an acid residue), A is a lower alkylene group, ¹¹ is a hydroxy group or a lower alkoxy group optionally having a substituent, R ¹² is hydrogen or halogen, R ¹³ is hydrogen, a nitro group, an amino group, an acylamino group, or a bond between R ¹¹ and R ¹³ And the following equation R ¹⁴ is a cyano group, a carbamoyl group which may have a suitable substituent, an amino (lower) alkyl group or a protected amino (lower) alkyl group, and Z is O or N —R ¹⁵ (where R ¹⁵ is hydrogen or an alkyl group), and P represents (CH ₂ ) _n (where n is 0 or 1). And a salt thereof. 2. R ¹ is hydrogen; a higher alkyl group; a lower alkoxy (higher) alkyl group; a carboxy group; a higher alkyl, an aryl group which may have a substituent, and a hetero group which may have a substituent. 1 selected from the group consisting of cyclic groups
One or two suitable substituents selected from the group consisting of one or two carbamoyl groups optionally having substituents; higher alkoxy and aryl groups optionally having substituents An aryl group which may have a higher alkoxy; an ar (lower) alkyl group which may have a higher alkoxy group; or an aryl group which may have 1 to 3 substituents. A good heterocyclic carbonyl group, a heterocyclic carbonyl group in which R ² may have a carboxy group, a protected carboxy group, or a lower alkoxycarbonyl group; And R ³ and R ⁴ may be the same or different and may be hydrogen; or may have imino, carbamoyl, lower alkoxy, amino, lower alkanoylamino, 1 to 3 substituents At least one member selected from the group consisting of a heterocyclic group, a lower alkenyloxycarbonylamino, a diaryl (lower) alkoxycarbonyl, a hydroxy, an ammonio optionally having three substituents, a lower alkoxycarbonyl and a carboxyl; A lower alkyl group optionally having a substituent; a lower alkenyl group; a sulfonyl group optionally having a heterocyclic group or a di (lower) alkylamino group; Carbamoyl group; carboxyl, hydroxy, amino optionally having one or two substituents, lower alkoxy Cycarbonyl, hydroxy ant-
1, a heterocyclic group optionally having 1 to 3 substituents, a heterocyclic carbonyl optionally having 1 to 3 substituents, alk (lower) alkoxycarbonyl, and lower 1 selected from the group consisting of alkoxycarbonyl
A lower alkanoyl group optionally having at least one substituent; an alk (lower) alkoxycarbonyl group; a heterocyclic group optionally having at least one substituent selected from the group consisting of lower alkoxycarbonyl and hydroxy A cyclic carbonyl group having at least one substituent selected from the group consisting of higher alkoxy, lower alkoxycarbonylamino lower alkyl, amino lower alkyl, lower alkoxycarbonylamino lower alkanoylamino and amino lower alkanoylamino lower alkyl An aroyl group which may be optionally substituted; or a cyclo (lower) alkylcarbonyl group which may have one or more substituents selected from the group consisting of amino and lower alkoxycarbonylamino; or Wherein R ⁵ may be the same or different and may be a lower alkyl group or a lower alkenyl group which may have a heterocyclic group, X is a halogen, A is a lower alkylene group, R ¹¹ is a hydroxy group; Group, a lower alkoxycarbonyl group, and one to three lower substituents optionally having one or two suitable substituents selected from the group consisting of a carbamoyl group optionally having one or two substituents An alkoxy group, R ¹² is hydrogen or halogen, R ¹³ is hydrogen; a nitro group; an amino group; an amino group, a protected amino group, a heterocyclic group optionally having an acyl group, or an acyl group; Selected from the group consisting of a heterocyclic carbonyl group, a carboxy group, a protected carboxy group, a hydroxy group, a protected hydroxy group, and a lower alkoxy (lower) alkoxy group Three suitable optionally substituted lower alkanoylamino group from pieces; lower alkylsulfonylamino group; hydroxy group, from one selected from the group consisting of protected hydroxy groups and acyl groups 3
Number of which may have suitable substituent heterocyclic carbonylamino group, or the following formula and R ¹¹ and R ¹³ is formed by bonding Wherein R ¹⁴ is a cyano group; one to three selected from the group consisting of a hydroxy group, a protected hydroxy group, a carboxy group and a protected carboxy group
Carbamoyl groups optionally having one or more suitable substituents;
An amino (lower) alkyl group; or a protected amino (lower) alkyl group, wherein Z is O or NR ¹⁵ (wherein R ¹⁵
Is a hydrogen or a higher alkyl group); and P is (CH ₂ ) _n (where n is 0 or 1). 3. The following general formula (II): Wherein R ¹ is a higher alkyl group, R ² is a carboxy group,
A protected carboxy group, a piperazinylcarbonyl group optionally having an acyl group, And R ³ and R ⁴ may be the same or different and may be hydrogen; or may have imino, carbamoyl, lower alkoxy, amino, lower alkanoylamino, 1 to 3 substituents At least one member selected from the group consisting of a heterocyclic group, a lower alkenyloxycarbonylamino, a diaryl (lower) alkoxycarbonyl, a hydroxy, an ammonio optionally having three substituents, a lower alkoxycarbonyl and a carboxyl; A lower alkyl group optionally having a substituent; a lower alkenyl group; a sulfonyl group optionally having a heterocyclic group or a di (lower) alkylamino group; Carbamoyl group; carboxyl, hydroxy, amino optionally having one or two substituents, lower alkoxy Cycarbonyl, hydroxy ant-
1, a heterocyclic group optionally having 1 to 3 substituents, a heterocyclic carbonyl optionally having 1 to 3 substituents, alk (lower) alkoxycarbonyl, and lower 1 selected from the group consisting of alkoxycarbonyl
A lower alkanoyl group optionally having at least one substituent; an alk (lower) alkoxycarbonyl group; a heterocyclic group optionally having at least one substituent selected from the group consisting of lower alkoxycarbonyl and hydroxy A cyclic carbonyl group having at least one substituent selected from the group consisting of higher alkoxy, lower alkoxycarbonylamino lower alkyl, amino lower alkyl, lower alkoxycarbonylamino lower alkanoylamino and amino lower alkanoylamino lower alkyl An optionally substituted aroyl group; or a cyclo (lower) alkylcarbonyl group optionally having one or more substituents selected from the group consisting of amino and lower alkoxycarbonylamino; Wherein R ⁵ may be the same or different and may be a lower alkyl group or a lower alkenyl group which may have a heterocyclic group, X is a halogen, A is a lower alkylene group, R ¹¹ is a hydroxy group, or It may have one to three suitable substituents selected from the group consisting of a carboxy group, a lower alkoxycarbonyl group, and a carbamoyl group which may have one or two substituents. A lower alkoxy group, R ¹² is hydrogen or halogen, R ¹³ is hydrogen; a nitro group; an amino group; an amino group, a protected amino group, a heterocyclic group optionally having an acyl group, or an acyl group; Selected from the group consisting of a heterocyclic carbonyl group, a carboxy group, a protected carboxy group, a hydroxy group, a protected hydroxy group, and a lower alkoxy (lower) alkoxy group which may be One to three may have suitable substituent lower alkanoylamino group, lower alkylsulfonylamino group; or a hydroxy group, selected from the group consisting of protected hydroxy groups and acyl groups 1
A heterocyclic carbonylamino group optionally having 1 to 3 suitable substituents, or the following formula formed by combining R ¹¹ and R ¹³ Wherein R ¹⁴ is a cyano group; one to three selected from the group consisting of a hydroxy group, a protected hydroxy group, a carboxy group and a protected carboxy group
Carbamoyl groups optionally having one or more suitable substituents;
_2. The compound according to claim 1, wherein P is (CH ₂ ) _n , wherein n is 1; an amino (lower) alkyl group; or an acylamino (lower) alkyl group. 4. The following general formula (III) Wherein R ¹ is hydrogen; a higher alkyl group; a lower alkoxy (higher) alkyl group; a higher alkyl, an aryl group which may have a substituent, and a heterocyclic group which may have a substituent. A carbamoyl group optionally having one or two substituents selected from the group; one to three selected from the group consisting of higher alkoxy and an aryl group optionally having a substituent; Aryl groups optionally having a substituent; alk (lower) alkyl groups optionally having a higher alkoxy group; or aryl groups optionally having 1 to 3 substituents good heterocyclic carbonyl group which may have a, R ² is the formula Wherein R ³ and R ⁴ may be the same or different, and hydrogen, a lower alkoxycarbonyl group, A is a lower alkylene group, R ¹¹ is a hydroxy group, R ¹² is hydrogen, R ¹³ is hydrogen, and R ¹⁴ is _2. The compound according to claim 1, wherein R ¹⁵ is hydrogen or a higher alkyl group, P is (CH ₂ ) _n (where n is 0 or 1). 5. An antibacterial agent comprising, as an active ingredient, the compound according to any one of claims 1 to 4 or a salt thereof.