WO2017142040A1 - Cyclic depsipeptide compound - Google Patents

Cyclic depsipeptide compound Download PDF

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WO2017142040A1
WO2017142040A1 PCT/JP2017/005777 JP2017005777W WO2017142040A1 WO 2017142040 A1 WO2017142040 A1 WO 2017142040A1 JP 2017005777 W JP2017005777 W JP 2017005777W WO 2017142040 A1 WO2017142040 A1 WO 2017142040A1
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ddd
group
hydrocarbon group
atom
salt
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PCT/JP2017/005777
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French (fr)
Japanese (ja)
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土井　隆行
将人 吉田
増田　裕一
勇一 恩田
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国立大学法人東北大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof

Definitions

  • the present invention relates to a cyclic depsipeptide compound, and more particularly to a cyclic depsipeptide compound that can be used as a pharmaceutical composition.
  • Alplatoxin A is a 25-membered ring depsipeptide obtained from marine cyanobacteria, and has been reported to exhibit strong cytotoxicity against cancer cells and the like (see Non-Patent Document 1).
  • This compound whose structure was determined by Moore et al. In 2001, has a unique structure in which a thiazoline ring is directly linked to a polyketide moiety.
  • amino acids such as proline, ⁇ , ⁇ -unsaturated cysteine derivatives, It contains a structure derived from hydroxycarboxylic acid.
  • Patent Document 1 a cyclic depsipeptide containing aplatoxin A has an effect of efficiently differentiating and proliferating cardiomyocytes and myocardial progenitor cells.
  • Patent Document 2 and Non-Patent Document 2 report derivatives of aplatoxin A.
  • Apratoxin A has a strong antitumor activity, but is chemically unstable and strongly toxic to normal cells, and has a problem that it is difficult to use as a pharmaceutical product.
  • An object of this invention is to provide the novel compound which can be utilized as a pharmaceutical.
  • a 1 , A 2 and A 3 are each independently an amino acid structure represented by any one of the following formulas (A-1) to (A-3),
  • An aromatic hydrocarbon group having 4 to 20 carbon atoms which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a halogen atom, R 1 is a hydrogen atom or a carbon atom having 1 to 6 represents a hydrocarbon group.
  • R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms
  • R 2 is a single bond or a divalent hydrocarbon group having 1 to 20 carbon atoms.
  • R 3 represents a divalent hydrocarbon group having 1 to 20 carbon atoms.
  • the A 1 is represented by the following formulas (A-1-1), (A-2-13), (A-2-14), (A-2-15), (A-2-16), The cyclic depsipeptide compound or a salt thereof according to ⁇ 1>, which is an amino acid structure represented by (A-2-19) or (A-2-20).
  • the A 2 is represented by the following formulas (A-2-1), (A-2-2), (A-2-3), (A-2-4), (A-2-5), (A-2-6), (A-2-11), (A-2-12), (A-2-17), (A-2-18), (A-2-19), or ( A cyclic depsipeptide compound or a salt thereof according to ⁇ 1> or ⁇ 2>, which is an amino acid structure represented by A-2-20).
  • a pharmaceutical composition comprising the cyclic depsipeptide compound or a salt thereof according to any one of ⁇ 1> to ⁇ 4>.
  • ⁇ 6> The pharmaceutical composition according to claim 5, which is an anticancer agent.
  • the cyclic depsipeptide compound which is one embodiment of the present invention or a salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention”) is a compound represented by the following general formula (I) or (II) or a salt thereof. is there.
  • a 1 , A 2 and A 3 are each independently an amino acid structure represented by any one of the following formulas (A-1) to (A-3), An aromatic hydrocarbon group having 4 to 20 carbon atoms which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a halogen atom, R 1 is a hydrogen atom or a carbon atom having 1 to 6 represents a hydrocarbon group.)
  • R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms
  • R 2 is a single bond or a divalent hydrocarbon group having 1 to 20 carbon atoms.
  • R 3 represents a divalent hydrocarbon group having 1 to 20 carbon atoms.
  • the cyclic depsipeptide compound represented by the general formula (I) or (II) is a cyclic depsipeptide compound in which the chemical structure is stabilized with respect to aplatoxin A while maintaining antitumor activity.
  • the “salt” means a salt formed by the cyclic depsipeptide compound represented by the general formula (I) or (II) and an ion, and the kind of ion for forming the salt is particularly It is not limited.
  • the compound of the present invention will be described in detail.
  • R 1 represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms. "" Is not limited to a straight-chain saturated hydrocarbon group, but may have a carbon-carbon unsaturated bond, a branched structure, or a cyclic structure.
  • the carbon number when R 1 is a hydrocarbon group is preferably 4 or less, more preferably 3 or less, and even more preferably 2 or less.
  • Examples of the hydrocarbon group for R 1 include a methyl group (—CH 3 ), an ethyl group (—C 2 H 5 ), an n-propyl group ( —n C 3 H 7 ), an i-propyl group ( —i C 3 H 7 ), an n-butyl group ( —n C 4 H 9 ), a t-butyl group ( —t C 4 H 9 ), a phenyl group (—C 6 H 5 ) and the like.
  • R 1 is preferably a hydrogen atom (—H) or a methyl group (—CH 3 ), particularly preferably a hydrogen atom (—H).
  • R 2 represents a single bond or a divalent hydrocarbon group having 1 to 20 carbon atoms.
  • Single bond means a piperidine structure or a pyrrolidine structure. Is directly bonded to a carbonyl group, and the “divalent hydrocarbon group” means a hydrocarbon group having two bonding sites.
  • the bonding position of the piperidine structure or pyrrolidine structure and R 2 is not particularly limited.
  • the carbon number when R 2 is a hydrocarbon group is preferably 12 or less, more preferably 8 or less, and even more preferably 6 or less.
  • the hydrocarbon group for R 2 includes a methylene group (—CH 2 —), an ethylene group (—C 2 H 4 —), an n-propylene group (—C 3 H 6 —), an i-propylene group (—CH ( CH 3 ) CH 2 —), n-butylene group (—C 4 H 8 —), n-pentylene group (—C 5 H 10 —), n-hexylene group (—C 6 H 12 —), etc. It is done.
  • R 2 is preferably a single bond, a methylene group (—CH 2 —) or an ethylene group (—C 2 H 4 —), particularly preferably a single bond.
  • R 3 represents a divalent hydrocarbon group having 1 to 20 carbon atoms, and the “divalent hydrocarbon group” is the same as in the case of R 2 . It is synonymous.
  • the carbon number of the hydrocarbon group for R 3 is preferably 12 or less, more preferably 8 or less, and even more preferably 6 or less.
  • hydrocarbon group for R 3 examples include a methylene group (—CH 2 —), a methylmethine group (—CH (CH 3 ) —), an ethylene group (—C 2 H 4 —), an n-propylene group (—C 3 H 6- ), i-propylene group (—CH (CH 3 ) CH 2 —), n-butylene group (—C 4 H 8 —), n-pentylene group (—C 5 H 10 —), n-hexylene A group (—C 6 H 12 —), a cyclohexylene group (—C 6 H 10 —), a phenylene group (—C 6 H 4 —) and the like.
  • R 3 includes a methylene group (—CH 2 —), a methylmethine group (—CH (CH 3 ) —), a cyclohexylene group (—C 6 H 10 —), and a phenylene group (—C 6 H 4 —).
  • a methylene group (—CH 2 —) and a methylmethine group (—CH (CH 3 ) —) are particularly preferable.
  • a 1 , A 2 and A 3 each independently represent an amino acid structure represented by any one of formulas (A-1) to (A-3), These amino acid structures are linked by amide bonds. Therefore, the wavy lines in formulas (A-1) to (A-3) indicate that the tip of the amino group is bonded to the carbonyl group and that the tip of the carbonyl group is bonded to the amino group. It shall be.
  • the amino acid structure may be either D-form or L-form.
  • Examples of the amino acid structure represented by the formula (A-1) include those represented by any of the following formulas (A-1-1) to (A-1-6).
  • the amino acid structure represented by the formula (A-1-4) is a nipecotic acid structure
  • the structure represented by the formula (A-1-1) is an isonipecotic acid structure.
  • Examples of the amino acid structure represented by the formula (A-2) include those represented by any of the following formulas (A-2-1) to (A-2-20).
  • the amino acid structure represented by the formula (A-2-1) is a glycine (Gly) structure
  • the amino acid structure represented by the formula (A-2-3) is an alanine (Ala) structure
  • the amino acid structure represented by A-2-5) is a valine (Val) structure
  • the amino acid structure represented by formula (A-2-7) is a leucine (Leu) structure
  • the amino acid structure represented by 9) is an isoleucine (Ile) structure
  • the amino acid structure represented by formula (A-2-11) is a phenylalanine (Phe) structure.
  • Examples of the amino acid structure represented by the formula (A-3) include those represented by any of the following formulas (A-3-1) to (A-3-6). Note that the amino acid structure represented by the formula (A-3-1) is a proline (Pro) structure.
  • Ar is an aromatic hydrocarbon group having 4 to 20 carbon atoms which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a halogen atom.
  • Represents “which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a halogen atom” means an amino group (—NH 2 ), a hydroxyl group (— OH), a fluoro group (—F), a chloro group (—Cl) and the like, which means that it may contain a functional group containing a nitrogen atom, an oxygen atom, or a halogen atom, and an imino group (—NH—)
  • a linking group containing a nitrogen atom, an oxygen atom, or a halogen atom such as an ether group (—O—) may be contained inside or at the end of the carbon skeleton.
  • aromatic hydrocarbon group is not limited to a monocyclic aromatic hydrocarbon group such as a phenyl group, but a polycyclic aromatic hydrocarbon group such as a naphthyl group or a heterocyclic ring such as a pyridyl group.
  • the number of carbon atoms of the hydrocarbon group of Ar is preferably 6 or more, preferably 14 or less, more preferably 12 or less.
  • the functional group contained in Ar include an amino group (—NH 2 ), a hydroxyl group (—OH), a methoxy group (—OCH 3 ), a fluoro group (—F), and a chloro group (—Cl).
  • aromatic hydrocarbon group for Ar include those represented by the following formula.
  • Examples of the compound of the present invention include those represented by the following formula.
  • the production method of the compound of the present invention is not particularly limited, and can be produced by appropriately combining known peptide solid phase synthesis methods, organic synthesis methods, etc., but utilizing a synthesis route represented by the following formula Is preferred.
  • the synthesis route represented by the following formula is described in Doi, T. et al. Chem. Asian J. 6, 180, 2011. For details, reference can be made to this document.
  • the synthetic route represented by the above formula is a method for producing the compound represented by the general formula (I), and uses a solid phase organic synthetic carrier having a trityl alcohol structure as a linker.
  • the trityl alcohol structure is chlorinated with acetyl chloride or the like, and an amino acid to be A 2 is first immobilized on a carrier.
  • Amino acids are successively introduced into the C-terminus using a condensing agent, and finally 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid (Dtena) having a proline structure is condensed to form a carrier And is macrolactonized (cyclized) to obtain a compound represented by the general formula (I).
  • the solid-phase organic synthesis carrier is not limited to those having a trityl alcohol structure as a linker, and any solid-phase organic synthesis as long as an amino acid structure such as A 1 , A 2 , A 3 or the like can be introduced. It may be a carrier.
  • the condensing agent used for peptide synthesis may be any of carbodiimide, imidazole, triazine, phosphonium, uronium, etc., and the amino protecting group is a 9-fluorenylmethyloxycarbonyl group. (Fmoc), tert-butoxycarbonyl group (Boc) and the like may be used.
  • the type of ion for forming the salt of the compound of the present invention is not particularly limited, but is preferably a pharmacologically acceptable salt, specifically an inorganic acid addition salt (for example, hydrochloric acid).
  • an inorganic acid addition salt for example, hydrochloric acid.
  • organic carboxylic acid / sulfonic acid addition salts eg
  • the compounds of the present invention include isomers such as optical isomers, rotational isomers, stereoisomers and tautomers, and mixtures of the isomers, which can be generated from the structure represented by formula (I) or (II). Is included.
  • the compound of the present invention may have a crystal polymorph, but may be any crystal form or crystal form mixture.
  • the compound of the present invention may be an anhydride, hydrate, solvate or the like.
  • the compound of the present invention can be used as a pharmaceutical.
  • a pharmaceutical composition containing the compound of the present invention that is, a compound represented by the general formula (I) or (II) or a salt thereof is also an aspect of the present invention.
  • the pharmaceutical composition of the present invention hereinafter sometimes abbreviated as “the pharmaceutical composition of the present invention”.
  • the pharmaceutical composition of the present invention will be described in detail.
  • the pharmaceutical composition of the present invention is not particularly limited as long as it contains the compound represented by the general formula (I) or (II) or a salt thereof, but is usually a pharmacologically acceptable carrier. Etc. to be formulated.
  • the content of the compound represented by the general formula (I) or (II) or a salt thereof (total content in the case of two or more types) in the pharmaceutical composition of the present invention is usually 0.001% by mass or more, preferably It is 0.01 mass% or more, and is 10 mass% or less normally, Preferably it is 1 mass% or less.
  • Examples of the pharmacologically acceptable carrier contained in the pharmaceutical composition of the present invention include carriers, solvents, solubilizers, suspensions used for solid preparations such as excipients, lubricants, binders, and disintegrants. Additives such as carriers, preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like used in liquid preparations such as turbidity agents, tonicity agents, buffers, soothing agents, etc. .
  • Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate (polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose) , Hydrophilic polymers such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.).
  • Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Antioxidants include sulfites, ascorbic acid, ⁇ -tocopherol and the like.
  • Examples of the dosage form of the pharmaceutical composition of the present invention include tablets, powders, granules, capsules, solutions, injections, suppositories, sustained release agents, and the like, and can be formulated based on known methods.
  • the administration target is preferably a mammal, and more preferably a human.
  • the dose of the compound represented by the general formula (I) or (II) or a salt thereof varies depending on the administration subject, target organ, symptom, administration method, etc., and is not particularly limited, but is generally a patient (with a weight of 60 kg). Is about 0.1 to 100 mg, preferably about 1.0 to 50 mg, more preferably about 1.0 to 20 mg per day. The number of administration and the administration interval can be appropriately set according to the symptom of the administration subject.
  • Examples of the disease targeted by the pharmaceutical composition of the present invention include malignant tumor (cancer). That is, the pharmaceutical composition of the present invention can be used as an anticancer agent or the like.
  • the type of cancer to be applied is not particularly limited, but lung cancer, malignant lymphoma (eg, reticulosarcoma, lymphosarcoma, Hodgkin's disease, etc.), digestive organ cancer (eg, stomach cancer, gallbladder / bile duct cancer, pancreas) Cancer, liver cancer, colon cancer, rectal cancer, etc.), breast cancer, ovarian cancer, bone and soft tissue sarcoma (eg osteosarcoma, etc.), bladder cancer, leukemia (eg, acute transformation of chronic myelogenous leukemia) Acute leukemia and the like), kidney cancer, prostate cancer and the like.
  • Examples 1 to 9, 17 Production of cyclic depsipeptide compound represented by general formula (I)> (1) A 10% acetyl chloride solution in dichloromethane (1 mL / lanthanum) was allowed to act at room temperature for 4 hours on SynPhase PS Trityl Alcohol linker (35 mol / lanthanum) manufactured by Mimotops. (2) lanthanum was washed 5 times with dry dichloromethane (1 mL / lantern), diisopropylethylamine (0.035 mL / lantern) and amino acid derivatives described in the column of A 2 in Tables 1-3 (0.10 mmol / lantern) It was allowed to act at room temperature.
  • SynPhase PS Trityl Alcohol linker 35 mol / lanthanum
  • lanthanum was washed 5 times with dry dichloromethane (1 mL / lantern), diisopropylethylamine (0.035 mL / lantern) and amino acid derivatives described in the column
  • the Fmoc group was deprotected by allowing 20% piperidine in dimethylformamide (DMF) (1 mL / lanthanum) to act at room temperature for 30 minutes. (12) The lanthanum was washed with DMF (1 mL / lanthanum) for 3 minutes 5 times.
  • DMF dimethylformamide
  • cyclic depsipeptide compound represented by general formula (II) Production of cyclic depsipeptide compound represented by general formula (II)> Tables 1 to amino acid derivative described in the column of A 3 of 3, an amino acid derivative according to the column of A 2, an amino acid derivative according to the column of FmocNR 1 CH (CH 2 Ar) COOH, amino acids listed in the column of A 1
  • a crude product was obtained by the same method as in the above Example, except that the derivative and FmocPro-Dtena were condensed in this order.
  • separation and purification were conducted by reversed-phase high-performance liquid chromatography to obtain a cyclic depsipeptide compound represented by the general formula (II) in a total yield of 16 to 44%.
  • the results of 1 HNMR, mass spectrometry, etc. of the cyclic depsipeptide compounds represented by the general formula (I) or (II) obtained in Examples 1 to 27 are shown below.
  • ⁇ Growth inhibitory effect of cyclic depsipeptide compound represented by general formula (I) or (II)> Human colon adenocarcinoma cell line HCT-116 was seeded in a 96-well dish at 5000 cells / well, and RPMI medium (10 FBS was added to each compound (Examples 1 to 27 and aplatoxin A) dissolved in DMSO). After 48 hours in DMSO (final concentration of DMSO 1%), cell proliferation assay was performed with WST-8. IC50 value was computed from the obtained result. The results are shown in Table 4. As a result, it was found that the compounds of the present invention show growth inhibitory effects on cancer cells.
  • the compounds of the present invention can be used as pharmaceuticals such as anticancer agents.

Abstract

A cyclic depsipeptide compound represented by general formula (I) or (II), or a salt thereof. (In formulas (I) and (II), A1, A2, and A3 each independently represent an amino acid structure represented by any of formulas (A-1) to (A-3), Ar represents a C4-20 aromatic hydrocarbon group optionally including at least one atom selected from the group consisting of a nitrogen atom, oxygen atom, and halogen atom, and R1 represents a hydrogen atom or a C1-6 hydrocarbon group.) (In formulas (A-1) to (A-3), R1 represents a hydrogen atom or a C1-6 hydrocarbon group, R2 represents a single bond or a C1-20 divalent hydrocarbon group, and R3 represents a C1-20 divalent hydrocarbon group.)

Description

環状デプシペプチド化合物Cyclic depsipeptide compound
　本発明は、環状デプシペプチド化合物に関し、より詳しくは医薬組成物として利用することができる環状デプシペプチド化合物に関する。 The present invention relates to a cyclic depsipeptide compound, and more particularly to a cyclic depsipeptide compound that can be used as a pharmaceutical composition.
　「アプラトキシンＡ（ａｐｒａｔｏｘｉｎ　Ａ）」は、海洋シアノバクテリアから得られる２５員環デプシペプチドであり、癌細胞等に対して強力な細胞毒性を示すことが報告されている（非特許文献１参照）。２００１年Ｍｏｏｒｅらによって構造決定がなされたこの化合物は、ポリケチド部位に対して直接チアゾリン環が連結した特異な構造を有しており、その他、プロリン等のアミノ酸、α，β-不飽和システイン誘導体、ヒドロキシカルボン酸に由来する構造を含んでいる。
　また、最近ではアプラトキシンＡを含む環状デプシペプチドが心筋細胞や心筋前駆細胞を効率よく分化増殖させる作用があることも報告されている（特許文献１参照）。
　さらに、特許文献２および非特許文献２ではアプラトキシンＡの誘導体が報告されている。 “Aplatoxin A” is a 25-membered ring depsipeptide obtained from marine cyanobacteria, and has been reported to exhibit strong cytotoxicity against cancer cells and the like (see Non-Patent Document 1). This compound, whose structure was determined by Moore et al. In 2001, has a unique structure in which a thiazoline ring is directly linked to a polyketide moiety. In addition, amino acids such as proline, α, β-unsaturated cysteine derivatives, It contains a structure derived from hydroxycarboxylic acid.
Recently, it has also been reported that a cyclic depsipeptide containing aplatoxin A has an effect of efficiently differentiating and proliferating cardiomyocytes and myocardial progenitor cells (see Patent Document 1).
Furthermore, Patent Document 2 and Non-Patent Document 2 report derivatives of aplatoxin A.
特開２０１４－０４７１９３号公報JP 2014-047193 A 国際公開第２０１０／０６５５６３号International Publication No. 2010/066553
　アプラトキシンＡは、強力な抗腫瘍活性を有するものの、化学的に不安定で正常細胞に対する毒性も強く、医薬品として利用し難い問題がある。
　本発明は、医薬品として利用することができる新規な化合物を提供することを目的とする。 Apratoxin A has a strong antitumor activity, but is chemically unstable and strongly toxic to normal cells, and has a problem that it is difficult to use as a pharmaceutical product.
An object of this invention is to provide the novel compound which can be utilized as a pharmaceutical.
　本発明者らは、上記の課題を解決すべく鋭意検討を重ねた結果、特定の構造を有する新規な環状デプシペプチド化合物が抗腫瘍活性等を示して、医薬品として活用できることを見出し、本発明を完成させた。 As a result of intensive investigations to solve the above problems, the present inventors have found that a novel cyclic depsipeptide compound having a specific structure exhibits antitumor activity and the like and can be used as a pharmaceutical, thereby completing the present invention. I let you.
　即ち、本発明は以下の通りである。
＜１＞ 下記一般式（Ｉ）又は（ＩＩ）で表される環状デプシペプチド化合物又はその塩。
Figure JPOXMLDOC01-appb-C000006
 （式（Ｉ）及び（ＩＩ）中、Ａ１、Ａ２及びＡ３はそれぞれ独立して下記式（Ａ－１）～（Ａ－３）の何れかで表されるアミノ酸構造を、Ａｒは窒素原子、酸素原子、及びハロゲン原子からなる群より選択される少なくとも１種の原子を含んでいてもよい炭素数４～２０の芳香族炭化水素基を、Ｒ１は水素原子又は炭素数１～６の炭化水素基を表す。）
Figure JPOXMLDOC01-appb-C000007
 （式（Ａ－１）～（Ａ－３）中、Ｒ１は水素原子又は炭素数１～６の炭化水素基を、Ｒ２は単結合又は炭素数１～２０の２価の炭化水素基を、Ｒ３は炭素数１～２０の２価の炭化水素基を表す。）
＜２＞ 前記Ａ１が、下記式（Ａ－１－１）、（Ａ－２－１３）、（Ａ－２－１４）、（Ａ－２－１５）、（Ａ－２－１６）、（Ａ－２－１９）、又は（Ａ－２－２０）で表されるアミノ酸構造である、＜１＞に記載の環状デプシペプチド化合物又はその塩。
Figure JPOXMLDOC01-appb-C000008
 ＜３＞ 前記Ａ２が、下記式（Ａ－２－１）、（Ａ－２－２）、（Ａ－２－３）、（Ａ－２－４）、（Ａ－２－５）、（Ａ－２－６）、（Ａ－２－１１）、（Ａ－２－１２）、（Ａ－２－１７）、（Ａ－２－１８）、（Ａ－２－１９）、又は（Ａ－２－２０）で表されるアミノ酸構造である、＜１＞又は＜２＞に記載の環状デプシペプチド化合物又はその塩。
Figure JPOXMLDOC01-appb-C000009
 ＜４＞ 下記式で表される環状デプシペプチド化合物又はその塩。
Figure JPOXMLDOC01-appb-C000010
 ＜５＞ ＜１＞～＜４＞の何れかに記載の環状デプシペプチド化合物又はその塩を含む医薬組成物。
＜６＞ 抗がん剤である、請求項５に記載の医薬組成物。 That is, the present invention is as follows.
<1> A cyclic depsipeptide compound represented by the following general formula (I) or (II) or a salt thereof.
Figure JPOXMLDOC01-appb-C000006
 (In the formulas (I) and (II), A 1 , A 2 and A 3 are each independently an amino acid structure represented by any one of the following formulas (A-1) to (A-3), An aromatic hydrocarbon group having 4 to 20 carbon atoms which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a halogen atom, R 1 is a hydrogen atom or a carbon atom having 1 to 6 represents a hydrocarbon group.)
Figure JPOXMLDOC01-appb-C000007
 (In the formulas (A-1) to (A-3), R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms, and R 2 is a single bond or a divalent hydrocarbon group having 1 to 20 carbon atoms. R 3 represents a divalent hydrocarbon group having 1 to 20 carbon atoms.)
<2> The A 1 is represented by the following formulas (A-1-1), (A-2-13), (A-2-14), (A-2-15), (A-2-16), The cyclic depsipeptide compound or a salt thereof according to <1>, which is an amino acid structure represented by (A-2-19) or (A-2-20).
Figure JPOXMLDOC01-appb-C000008
 <3> The A 2 is represented by the following formulas (A-2-1), (A-2-2), (A-2-3), (A-2-4), (A-2-5), (A-2-6), (A-2-11), (A-2-12), (A-2-17), (A-2-18), (A-2-19), or ( A cyclic depsipeptide compound or a salt thereof according to <1> or <2>, which is an amino acid structure represented by A-2-20).
Figure JPOXMLDOC01-appb-C000009
 <4> A cyclic depsipeptide compound represented by the following formula or a salt thereof.
Figure JPOXMLDOC01-appb-C000010
 <5> A pharmaceutical composition comprising the cyclic depsipeptide compound or a salt thereof according to any one of <1> to <4>.
<6> The pharmaceutical composition according to claim 5, which is an anticancer agent.
　本発明によれば、安定で副作用の少ない抗がん剤等の医薬として有用な化合物が提供される。 According to the present invention, there are provided compounds useful as pharmaceuticals such as anticancer agents which are stable and have few side effects.
　本発明の詳細を説明するに当たり、具体例を挙げて説明するが、本発明の趣旨を逸脱しない限り以下の内容に限定されるものではなく、適宜変更して実施することができる。 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Details of the present invention will be described with specific examples. However, the present invention is not limited to the following contents without departing from the gist of the present invention, and can be implemented with appropriate modifications.
＜環状デプシペプチド化合物又はその塩＞
　本発明の一態様である環状デプシペプチド化合物又はその塩（以下、「本発明の化合物等」と略す場合がある）は、下記一般式（Ｉ）又は（ＩＩ）で表される化合物又はその塩である。
Figure JPOXMLDOC01-appb-C000011
 （式（Ｉ）及び（ＩＩ）中、Ａ１、Ａ２及びＡ３はそれぞれ独立して下記式（Ａ－１）～（Ａ－３）の何れかで表されるアミノ酸構造を、Ａｒは窒素原子、酸素原子、及びハロゲン原子からなる群より選択される少なくとも１種の原子を含んでいてもよい炭素数４～２０の芳香族炭化水素基を、Ｒ１は水素原子又は炭素数１～６の炭化水素基を表す。）
Figure JPOXMLDOC01-appb-C000012
 （式（Ａ－１）～（Ａ－３）中、Ｒ１は水素原子又は炭素数１～６の炭化水素基を、Ｒ２は単結合又は炭素数１～２０の２価の炭化水素基を、Ｒ３は炭素数１～２０の２価の炭化水素基を表す。）
　本発明者らは、医薬品として利用することができる新規な化合物を求めて鋭意検討を重ねた結果、一般式（Ｉ）又は（ＩＩ）で表される環状デプシペプチド化合物が抗腫瘍活性を示して、医薬品として活用できることを見出したのである。
　アプラトキシンＡは、強力な抗腫瘍活性を有するものの、例えば構造内に含まれるチアゾリン環が分解し易く、不安定かつ正常細胞に対する毒性も強いという難点がある。一般式（Ｉ）又は（ＩＩ）で表される環状デプシペプチド化合物は、抗腫瘍活性を維持しつつ、アプラトキシンＡに対して化学構造の安定化を図った環状デプシペプチド化合物なのである。
　なお、本発明において「その塩」とは、一般式（Ｉ）又は（ＩＩ）で表される環状デプシペプチド化合物とイオンによって形成される塩を意味し、塩を形成するためのイオンの種類は特に限定されないものとする。
　以下、本発明の化合物等について詳細に説明する。 <Cyclic depsipeptide compound or salt thereof>
The cyclic depsipeptide compound which is one embodiment of the present invention or a salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention”) is a compound represented by the following general formula (I) or (II) or a salt thereof. is there.
Figure JPOXMLDOC01-appb-C000011
 (In the formulas (I) and (II), A 1 , A 2 and A 3 are each independently an amino acid structure represented by any one of the following formulas (A-1) to (A-3), An aromatic hydrocarbon group having 4 to 20 carbon atoms which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a halogen atom, R 1 is a hydrogen atom or a carbon atom having 1 to 6 represents a hydrocarbon group.)
Figure JPOXMLDOC01-appb-C000012
 (In the formulas (A-1) to (A-3), R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms, and R 2 is a single bond or a divalent hydrocarbon group having 1 to 20 carbon atoms. R 3 represents a divalent hydrocarbon group having 1 to 20 carbon atoms.)
As a result of intensive investigations for new compounds that can be used as pharmaceuticals, the present inventors have shown that the cyclic depsipeptide compound represented by the general formula (I) or (II) exhibits antitumor activity, They found it could be used as a medicine.
Apratoxin A has a strong antitumor activity, but has a drawback that, for example, the thiazoline ring contained in the structure is easily decomposed, is unstable, and is highly toxic to normal cells. The cyclic depsipeptide compound represented by the general formula (I) or (II) is a cyclic depsipeptide compound in which the chemical structure is stabilized with respect to aplatoxin A while maintaining antitumor activity.
In the present invention, the “salt” means a salt formed by the cyclic depsipeptide compound represented by the general formula (I) or (II) and an ion, and the kind of ion for forming the salt is particularly It is not limited.
Hereinafter, the compound of the present invention will be described in detail.
　式（Ｉ）及び（ＩＩ）中、及び式（Ａ－１）～（Ａ－３）中、Ｒ１は水素原子又は炭素数１～６の炭化水素基を表しているが、「炭化水素基」とは、直鎖状の飽和炭化水素基に限られず、炭素－炭素不飽和結合、分岐構造、環状構造のそれぞれを有していてもよいことを意味する。
　Ｒ１が炭化水素基である場合の炭素数は、好ましくは４以下、より好ましくは３以下、さらに好ましくは２以下である。
　Ｒ１の炭化水素基としては、メチル基（－ＣＨ３）、エチル基（－Ｃ２Ｈ５）、ｎ－プロピル基（－ｎＣ３Ｈ７）、ｉ－プロピル基（－ｉＣ３Ｈ７）、ｎ－ブチル基（－ｎＣ４Ｈ９）、ｔ－ブチル基（－ｔＣ４Ｈ９）、フェニル基（－Ｃ６Ｈ５）等が挙げられる。
　Ｒ１としては、水素原子（－Ｈ）、メチル基（－ＣＨ３）が好ましく、水素原子（－Ｈ）が特に好ましい。 In formulas (I) and (II) and in formulas (A-1) to (A-3), R 1 represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms. "" Is not limited to a straight-chain saturated hydrocarbon group, but may have a carbon-carbon unsaturated bond, a branched structure, or a cyclic structure.
The carbon number when R 1 is a hydrocarbon group is preferably 4 or less, more preferably 3 or less, and even more preferably 2 or less.
Examples of the hydrocarbon group for R 1 include a methyl group (—CH 3 ), an ethyl group (—C 2 H 5 ), an n-propyl group ( —n C 3 H 7 ), an i-propyl group ( —i C 3 H 7 ), an n-butyl group ( —n C 4 H 9 ), a t-butyl group ( —t C 4 H 9 ), a phenyl group (—C 6 H 5 ) and the like.
R 1 is preferably a hydrogen atom (—H) or a methyl group (—CH 3 ), particularly preferably a hydrogen atom (—H).
　式（Ａ－１）～（Ａ－３）中、Ｒ２は単結合又は炭素数１～２０の２価の炭化水素基を表しているが、「単結合」とは、ピペリジン構造やピロリジン構造がカルボニル基に直接結合していることを意味し、「２価の炭化水素基」とは、２つの結合部位を有する炭化水素基であることを意味する。また、ピペリジン構造やピロリジン構造とＲ２の結合位置は、特に限定されないことを意味する。
　Ｒ２が炭化水素基である場合の炭素数は、好ましくは１２以下、より好ましくは８以下、さらに好ましくは６以下である。
　Ｒ２の炭化水素基としては、メチレン基（－ＣＨ２－）、エチレン基（－Ｃ２Ｈ４－）、ｎ－プロピレン基（－Ｃ３Ｈ６－）、ｉ－プロピレン基（－ＣＨ（ＣＨ３）ＣＨ２－）、ｎ－ブチレン基（－Ｃ４Ｈ８－）、ｎ－ペンチレン基（－Ｃ５Ｈ１０－）、ｎ－へキシレン基（－Ｃ６Ｈ１２－）等が挙げられる。
　Ｒ２としては、単結合、メチレン基（－ＣＨ２－）、エチレン基（－Ｃ２Ｈ４－）が好ましく、単結合が特に好ましい。 In the formulas (A-1) to (A-3), R 2 represents a single bond or a divalent hydrocarbon group having 1 to 20 carbon atoms. “Single bond” means a piperidine structure or a pyrrolidine structure. Is directly bonded to a carbonyl group, and the “divalent hydrocarbon group” means a hydrocarbon group having two bonding sites. In addition, the bonding position of the piperidine structure or pyrrolidine structure and R 2 is not particularly limited.
The carbon number when R 2 is a hydrocarbon group is preferably 12 or less, more preferably 8 or less, and even more preferably 6 or less.
The hydrocarbon group for R 2 includes a methylene group (—CH 2 —), an ethylene group (—C 2 H 4 —), an n-propylene group (—C 3 H 6 —), an i-propylene group (—CH ( CH 3 ) CH 2 —), n-butylene group (—C 4 H 8 —), n-pentylene group (—C 5 H 10 —), n-hexylene group (—C 6 H 12 —), etc. It is done.
R 2 is preferably a single bond, a methylene group (—CH 2 —) or an ethylene group (—C 2 H 4 —), particularly preferably a single bond.
　式（Ａ－１）～（Ａ－３）中、Ｒ３は炭素数１～２０の２価の炭化水素基を表しているが、「２価の炭化水素基」は、Ｒ２の場合と同義である。
　Ｒ３の炭化水素基の炭素数は、好ましくは１２以下、より好ましくは８以下、さらに好ましくは６以下である。
　Ｒ３の炭化水素基としては、メチレン基（－ＣＨ２－）、メチルメチン基（－ＣＨ（ＣＨ３）－）、エチレン基（－Ｃ２Ｈ４－）、ｎ－プロピレン基（－Ｃ３Ｈ６－）、ｉ－プロピレン基（－ＣＨ（ＣＨ３）ＣＨ２－）、ｎ－ブチレン基（－Ｃ４Ｈ８－）、ｎ－ペンチレン基（－Ｃ５Ｈ１０－）、ｎ－へキシレン基（－Ｃ６Ｈ１２－）、シクロへキシレン基（－Ｃ６Ｈ１０－）、フェニレン基（－Ｃ６Ｈ４－）等が挙げられる。
　Ｒ３としては、メチレン基（－ＣＨ２－）、メチルメチン基（－ＣＨ（ＣＨ３）－）、シクロへキシレン基（－Ｃ６Ｈ１０－）、フェニレン基（－Ｃ６Ｈ４－）が好ましく、メチレン基（－ＣＨ２－）、メチルメチン基（－ＣＨ（ＣＨ３）－）が特に好ましい。 In the formulas (A-1) to (A-3), R 3 represents a divalent hydrocarbon group having 1 to 20 carbon atoms, and the “divalent hydrocarbon group” is the same as in the case of R 2 . It is synonymous.
The carbon number of the hydrocarbon group for R 3 is preferably 12 or less, more preferably 8 or less, and even more preferably 6 or less.
Examples of the hydrocarbon group for R 3 include a methylene group (—CH 2 —), a methylmethine group (—CH (CH 3 ) —), an ethylene group (—C 2 H 4 —), an n-propylene group (—C 3 H 6- ), i-propylene group (—CH (CH 3 ) CH 2 —), n-butylene group (—C 4 H 8 —), n-pentylene group (—C 5 H 10 —), n-hexylene A group (—C 6 H 12 —), a cyclohexylene group (—C 6 H 10 —), a phenylene group (—C 6 H 4 —) and the like.
R 3 includes a methylene group (—CH 2 —), a methylmethine group (—CH (CH 3 ) —), a cyclohexylene group (—C 6 H 10 —), and a phenylene group (—C 6 H 4 —). A methylene group (—CH 2 —) and a methylmethine group (—CH (CH 3 ) —) are particularly preferable.
　式（Ｉ）及び（ＩＩ）中、Ａ１、Ａ２及びＡ３はそれぞれ独立して式（Ａ－１）～（Ａ－３）の何れかで表されるアミノ酸構造を表しているが、これらのアミノ酸構造はアミド結合によって連結しているものとする。従って、式（Ａ－１）～（Ａ－３）中の波線は、アミノ基の先がカルボニル基と結合していることを、カルボニル基の先がアミノ基と結合していることを表しているものとする。また、アミノ酸構造はそれぞれＤ体、Ｌ体の何れであってもよいものとする。
　式（Ａ－１）で表されるアミノ酸構造としては、下記式（Ａ－１－１）～（Ａ－１－６）の何れかで表されるものが挙げられる。なお、式（Ａ－１－４）で表されるアミノ酸構造はニペコチン酸構造であり、式（Ａ－１－１）で表される構造はイソニペコチン酸構造である。
Figure JPOXMLDOC01-appb-C000013
 In formulas (I) and (II), A 1 , A 2 and A 3 each independently represent an amino acid structure represented by any one of formulas (A-1) to (A-3), These amino acid structures are linked by amide bonds. Therefore, the wavy lines in formulas (A-1) to (A-3) indicate that the tip of the amino group is bonded to the carbonyl group and that the tip of the carbonyl group is bonded to the amino group. It shall be. The amino acid structure may be either D-form or L-form.
Examples of the amino acid structure represented by the formula (A-1) include those represented by any of the following formulas (A-1-1) to (A-1-6). The amino acid structure represented by the formula (A-1-4) is a nipecotic acid structure, and the structure represented by the formula (A-1-1) is an isonipecotic acid structure.
Figure JPOXMLDOC01-appb-C000013
　式（Ａ－２）で表されるアミノ酸構造としては、下記式（Ａ－２－１）～（Ａ－２－２０）の何れかで表されるものが挙げられる。なお、式（Ａ－２－１）で表されるアミノ酸構造はグリシン（Ｇｌｙ）構造であり、式（Ａ－２－３）で表されるアミノ酸構造はアラニン（Ａｌａ）構造であり、式（Ａ－２－５）で表されるアミノ酸構造はバリン（Ｖａｌ）構造であり、式（Ａ－２－７）で表されるアミノ酸構造はロイシン（Ｌｅｕ）構造であり、式（Ａ－２－９）で表されるアミノ酸構造はイソロイシン（Ｉｌｅ）構造であり、式（Ａ－２－１１）で表されるアミノ酸構造はフェニルアラニン（Ｐｈｅ）構造である。
Figure JPOXMLDOC01-appb-C000014
 Examples of the amino acid structure represented by the formula (A-2) include those represented by any of the following formulas (A-2-1) to (A-2-20). The amino acid structure represented by the formula (A-2-1) is a glycine (Gly) structure, the amino acid structure represented by the formula (A-2-3) is an alanine (Ala) structure, The amino acid structure represented by A-2-5) is a valine (Val) structure, the amino acid structure represented by formula (A-2-7) is a leucine (Leu) structure, and the formula (A-2- The amino acid structure represented by 9) is an isoleucine (Ile) structure, and the amino acid structure represented by formula (A-2-11) is a phenylalanine (Phe) structure.
Figure JPOXMLDOC01-appb-C000014
　式（Ａ－３）で表されるアミノ酸構造としては、下記式（Ａ－３－１）～（Ａ－３－６）の何れかで表されるものが挙げられる。なお、式（Ａ－３－１）で表されるアミノ酸構造はプロリン（Ｐｒｏ）構造である。
Figure JPOXMLDOC01-appb-C000015
 Examples of the amino acid structure represented by the formula (A-3) include those represented by any of the following formulas (A-3-1) to (A-3-6). Note that the amino acid structure represented by the formula (A-3-1) is a proline (Pro) structure.
Figure JPOXMLDOC01-appb-C000015
　式（Ｉ）及び（ＩＩ）中、Ａｒは窒素原子、酸素原子、及びハロゲン原子からなる群より選択される少なくとも１種の原子を含んでいてもよい炭素数４～２０の芳香族炭化水素基を表しているが、「窒素原子、酸素原子、及びハロゲン原子からなる群より選択される少なくとも１種の原子を含んでいてもよい」とは、アミノ基（－ＮＨ２）、ヒドロキシル基（－ＯＨ）、フルオロ基（－Ｆ）、クロロ基（－Ｃｌ）等の窒素原子、酸素原子、又はハロゲン原子を含む官能基を含んでいてもよいことを意味するほか、イミノ基（－ＮＨ－）、エーテル基（－Ｏ－）等の窒素原子、酸素原子、又はハロゲン原子を含む連結基を炭素骨格の内部又は末端に含んでいてもよいことを意味する。また、「芳香族炭化水素基」とは、フェニル基のような単環の芳香族炭化水素基に限られず、ナフチル基のような多環の芳香族炭化水素基、ピリジル基のような複素環の芳香族炭化水素基が含まれることを意味する。
　Ａｒの炭化水素基の炭素数は、好ましくは６以上であり、好ましくは１４以下、さらに好ましくは１２以下である。
　Ａｒに含まれる官能基としては、アミノ基（－ＮＨ２）、ヒドロキシル基（－ＯＨ）、メトキシ基（－ＯＣＨ３）、フルオロ基（－Ｆ）、クロロ基（－Ｃｌ）等が挙げられる。
　Ａｒの芳香族炭化水素基としては、下記式で表されるものが挙げられる。
Figure JPOXMLDOC01-appb-C000016
 In the formulas (I) and (II), Ar is an aromatic hydrocarbon group having 4 to 20 carbon atoms which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a halogen atom. Represents “which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a halogen atom” means an amino group (—NH 2 ), a hydroxyl group (— OH), a fluoro group (—F), a chloro group (—Cl) and the like, which means that it may contain a functional group containing a nitrogen atom, an oxygen atom, or a halogen atom, and an imino group (—NH—) This means that a linking group containing a nitrogen atom, an oxygen atom, or a halogen atom such as an ether group (—O—) may be contained inside or at the end of the carbon skeleton. The “aromatic hydrocarbon group” is not limited to a monocyclic aromatic hydrocarbon group such as a phenyl group, but a polycyclic aromatic hydrocarbon group such as a naphthyl group or a heterocyclic ring such as a pyridyl group. Of the aromatic hydrocarbon group.
The number of carbon atoms of the hydrocarbon group of Ar is preferably 6 or more, preferably 14 or less, more preferably 12 or less.
Examples of the functional group contained in Ar include an amino group (—NH 2 ), a hydroxyl group (—OH), a methoxy group (—OCH 3 ), a fluoro group (—F), and a chloro group (—Cl).
Examples of the aromatic hydrocarbon group for Ar include those represented by the following formula.
Figure JPOXMLDOC01-appb-C000016
　本発明の化合物等としては、下記式で表されるものが挙げられる。
Figure JPOXMLDOC01-appb-C000017
 Examples of the compound of the present invention include those represented by the following formula.
Figure JPOXMLDOC01-appb-C000017
　本発明の化合物等の製造方法は、特に限定されず、公知のペプチド固相合成法、有機合成法等を適宜組み合わせて製造することができるが、下記式で表される合成経路を利用することが好ましい。なお、下記式で表される合成経路は、Doi, T. et al. Chem. Asian J. 6, 180, 2011.に記載されており、詳細については当該文献を参照することができる。
Figure JPOXMLDOC01-appb-C000018
 The production method of the compound of the present invention is not particularly limited, and can be produced by appropriately combining known peptide solid phase synthesis methods, organic synthesis methods, etc., but utilizing a synthesis route represented by the following formula Is preferred. The synthesis route represented by the following formula is described in Doi, T. et al. Chem. Asian J. 6, 180, 2011. For details, reference can be made to this document.
Figure JPOXMLDOC01-appb-C000018
　上記式で表される合成経路は、一般式（Ｉ）で表される化合物を製造する方法であり、リンカーとしてトリチルアルコール構造を有する固相有機合成担体を利用している。トリチルアルコール構造を塩化アセチル等により塩素化し、まずＡ２となるアミノ酸を担体に固定化する。縮合剤等を用いてＣ末端にアミノ酸を次々導入していき、最後にプロリン構造を有する３，７－ジヒドロキシ－２，５，８，８－テトラメチルノナン酸（Ｄｔｅｎａ）を縮合して、担体から切り離し、マクロラクトン化（環化）して、一般式（Ｉ）で表される化合物を得るのである。
　また、下記式で表される合成経路のように、まずＡ３となるアミノ酸を担体に固定化することによって、一般式（ＩＩ）で表される化合物を得ることもできる。
Figure JPOXMLDOC01-appb-C000019
 　なお、固相有機合成担体は、リンカーとしてトリチルアルコール構造を有するものに限られず、Ａ１、Ａ２、Ａ３等のアミノ酸構造を導入することができるものであれば、何れの固相有機合成担体であってもよい。
　また、ペプチド合成に用いる縮合剤は、カルボジイミド系、イミダゾール系、トリアジン系、ホスホニウム系、ウロニウム系等の何れであってもよく、さらにアミノ基の保護基は、９－フルオレニルメチルオキシカルボニル基（Ｆｍｏｃ）、ｔｅｒｔ－ブトキシカルボニル基（Ｂｏｃ）等の何れであってもよい。 The synthetic route represented by the above formula is a method for producing the compound represented by the general formula (I), and uses a solid phase organic synthetic carrier having a trityl alcohol structure as a linker. The trityl alcohol structure is chlorinated with acetyl chloride or the like, and an amino acid to be A 2 is first immobilized on a carrier. Amino acids are successively introduced into the C-terminus using a condensing agent, and finally 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid (Dtena) having a proline structure is condensed to form a carrier And is macrolactonized (cyclized) to obtain a compound represented by the general formula (I).
Also, as the synthesis route represented by the following formula, firstly by the amino acid to be A 3 immobilized on a carrier, it is also possible to obtain a compound represented by the general formula (II).
Figure JPOXMLDOC01-appb-C000019
 The solid-phase organic synthesis carrier is not limited to those having a trityl alcohol structure as a linker, and any solid-phase organic synthesis as long as an amino acid structure such as A 1 , A 2 , A 3 or the like can be introduced. It may be a carrier.
The condensing agent used for peptide synthesis may be any of carbodiimide, imidazole, triazine, phosphonium, uronium, etc., and the amino protecting group is a 9-fluorenylmethyloxycarbonyl group. (Fmoc), tert-butoxycarbonyl group (Boc) and the like may be used.
　前述のように、本発明の化合物の塩を形成するためのイオンの種類は特に限定されないが、薬理学的に許容される塩であることが好ましく、具体的には無機酸付加塩（例えば塩酸塩、硫酸塩、リン酸塩等）、有機カルボン酸・スルホン酸付加塩（例えば酢酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、クエン酸塩、乳酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩等）、アルカリ金属塩（ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（マグネシウム塩、カルシウム塩等）等が挙げられる。 As described above, the type of ion for forming the salt of the compound of the present invention is not particularly limited, but is preferably a pharmacologically acceptable salt, specifically an inorganic acid addition salt (for example, hydrochloric acid). Salts, sulfates, phosphates, etc.), organic carboxylic acid / sulfonic acid addition salts (eg acetate, trifluoroacetate, maleate, tartrate, fumarate, citrate, lactate, methanesulfonic acid) Salt, benzene sulfonate, toluene sulfonate, etc.), alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (magnesium salt, calcium salt, etc.) and the like.
　本発明の化合物等には、式（Ｉ）または（ＩＩ）で表される構造から生じうる、光学異性体、回転異性体、立体異性体、互変異性体等の異性体や該異性体混合物が含まれる。また、本発明の化合物等には結晶多形が存在することもありうるが、いずれの結晶形または結晶形混合物であってもよい。更に、本発明の化合物等は、無水物、水和物、溶媒和物等であってもよい。 The compounds of the present invention include isomers such as optical isomers, rotational isomers, stereoisomers and tautomers, and mixtures of the isomers, which can be generated from the structure represented by formula (I) or (II). Is included. In addition, the compound of the present invention may have a crystal polymorph, but may be any crystal form or crystal form mixture. Further, the compound of the present invention may be an anhydride, hydrate, solvate or the like.
＜医薬組成物＞
　本発明の化合物等が医薬品として活用できることを前述したが、本発明の化合物等、即ち一般式（Ｉ）又は（ＩＩ）で表される化合物又はその塩を含む医薬組成物も本発明の一態様（以下、「本発明の医薬組成物」と略す場合がある）である。
　以下、本発明の医薬組成物について詳細に説明する。 <Pharmaceutical composition>
As described above, the compound of the present invention can be used as a pharmaceutical. However, a pharmaceutical composition containing the compound of the present invention, that is, a compound represented by the general formula (I) or (II) or a salt thereof is also an aspect of the present invention. (Hereinafter sometimes abbreviated as “the pharmaceutical composition of the present invention”).
Hereinafter, the pharmaceutical composition of the present invention will be described in detail.
　本発明の医薬組成物は、一般式（Ｉ）又は（ＩＩ）で表される化合物又はその塩を含むものであれば、その他については特に限定されないが、通常、薬理学的に許容される担体等と混合して製剤化される。
　本発明の医薬組成物における一般式（Ｉ）又は（ＩＩ）で表される化合物又はその塩の含有量（２種類以上の場合は総含有量）は、通常０．００１質量％以上、好ましくは０．０１質量％以上であり、通常１０質量％以下、好ましくは１質量％以下である。 The pharmaceutical composition of the present invention is not particularly limited as long as it contains the compound represented by the general formula (I) or (II) or a salt thereof, but is usually a pharmacologically acceptable carrier. Etc. to be formulated.
The content of the compound represented by the general formula (I) or (II) or a salt thereof (total content in the case of two or more types) in the pharmaceutical composition of the present invention is usually 0.001% by mass or more, preferably It is 0.01 mass% or more, and is 10 mass% or less normally, Preferably it is 1 mass% or less.
　本発明の医薬組成物に含まれる薬理学的に許容される担体としては、賦形剤、滑沢剤、結合剤、崩壊剤等の固形製剤に利用される担体、溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等の液状製剤に利用される担体、防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加物が挙げられる。
　賦形剤としては、乳糖、白糖、Ｄ－マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸等が挙げられる。
　滑沢剤としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられる。
　結合剤としては、結晶セルロース、白糖、Ｄ－マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム等が挙げられる。
　崩壊剤としては、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルスターチナトリウム、Ｌ－ヒドロキシプロピルセルロース等が挙げられる。
　溶剤としては、注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、オリーブ油等が挙げられる。
　溶解補助剤としては、例えばポリエチレングリコール、プロピレングリコール、Ｄ－マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。
　懸濁化剤としては、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤（ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等）が挙げられる。
　等張化剤としては、ブドウ糖、Ｄ－ソルビトール、塩化ナトリウム、グリセリン、Ｄ－マンニトール等が挙げられる。
　緩衝剤としては、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液等が挙げられる。
　無痛化剤としては、ベンジルアルコール等が挙げられる。
　防腐剤としては、パラヒドロキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。
　抗酸化剤としては、亜硫酸塩、アスコルビン酸、α－トコフェロール等が挙げられる。 Examples of the pharmacologically acceptable carrier contained in the pharmaceutical composition of the present invention include carriers, solvents, solubilizers, suspensions used for solid preparations such as excipients, lubricants, binders, and disintegrants. Additives such as carriers, preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like used in liquid preparations such as turbidity agents, tonicity agents, buffers, soothing agents, etc. .
Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
As suspending agents, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate (polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose) , Hydrophilic polymers such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.).
Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
Examples of soothing agents include benzyl alcohol.
Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Antioxidants include sulfites, ascorbic acid, α-tocopherol and the like.
　本発明の医薬組成物の剤形としては、錠剤、散剤、顆粒剤、カプセル剤、液剤、注射剤、坐剤、徐放剤等が挙げられ、公知の方法に基づいて製剤化できる。 Examples of the dosage form of the pharmaceutical composition of the present invention include tablets, powders, granules, capsules, solutions, injections, suppositories, sustained release agents, and the like, and can be formulated based on known methods.
　投与対象は、哺乳動物であることが好ましく、ヒトであることがさらに好ましい。一般式（Ｉ）又は（ＩＩ）で表される化合物又はその塩の投与量は、投与対象、対象臓器、症状、投与方法などにより異なり特に制限されないが、一般的に、患者（体重６０ｋｇとして）に対して、一日につき約０.１～１００ｍｇ、好ましくは約１．０～５０ｍｇ、より好ましくは約１．０～２０ｍｇである。投与回数や投与間隔も投与対象の症状等に応じて適宜設定できる。 The administration target is preferably a mammal, and more preferably a human. The dose of the compound represented by the general formula (I) or (II) or a salt thereof varies depending on the administration subject, target organ, symptom, administration method, etc., and is not particularly limited, but is generally a patient (with a weight of 60 kg). Is about 0.1 to 100 mg, preferably about 1.0 to 50 mg, more preferably about 1.0 to 20 mg per day. The number of administration and the administration interval can be appropriately set according to the symptom of the administration subject.
　本発明の医薬組成物が対象とする疾病としては、悪性腫瘍（がん）等が挙げられる。即ち、本発明の医薬組成物は、抗がん剤等として利用することが挙げられる。
　適用対象となるがんの種類は特に制限されないが、肺がん、悪性リンパ腫(例えば、細網肉腫、リンパ肉腫、ホジキン病等)、消化器がん（例えば、胃がん、胆のう・胆管がん、膵臓がん、肝がん、結腸がん、直腸がん等）、乳がん、卵巣がん、骨軟部肉腫(例えば、骨肉腫等)、膀胱がん、白血病（例えば、慢性骨髄性白血病の急性転化を含む急性白血病等）、腎臓がん、および前立腺がん等が例示される。 Examples of the disease targeted by the pharmaceutical composition of the present invention include malignant tumor (cancer). That is, the pharmaceutical composition of the present invention can be used as an anticancer agent or the like.
The type of cancer to be applied is not particularly limited, but lung cancer, malignant lymphoma (eg, reticulosarcoma, lymphosarcoma, Hodgkin's disease, etc.), digestive organ cancer (eg, stomach cancer, gallbladder / bile duct cancer, pancreas) Cancer, liver cancer, colon cancer, rectal cancer, etc.), breast cancer, ovarian cancer, bone and soft tissue sarcoma (eg osteosarcoma, etc.), bladder cancer, leukemia (eg, acute transformation of chronic myelogenous leukemia) Acute leukemia and the like), kidney cancer, prostate cancer and the like.
　以下に実施例を挙げて本発明をさらに具体的に説明するが、本発明の趣旨を逸脱しない限り適宜変更することができる。従って、本発明の範囲は以下に示す具体例により限定的に解釈されるべきものではない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention can be modified as appropriate without departing from the spirit of the present invention. Accordingly, the scope of the present invention should not be construed as being limited by the specific examples shown below.
＜実施例１～９、１７：一般式（Ｉ）で表される環状デプシペプチド化合物の製造＞
（１）ミモトープス社製のＳｙｎＰｈａｓｅ　ＰＳ　Ｔｒｉｔｙｌ　Ａｌｃｏｈｏｌ　ｌｉｎｋｅｒ（３５ｍｏｌ／ランタン）に対し１０％塩化アセチルのジクロロメタン溶液（１ｍＬ／ランタン）を室温で４時間作用させた。
（２）ランタンを乾燥ジクロロメタン（１ｍＬ／ランタン）で５回洗浄し、ジイソプロピルエチルアミン（０．０３５ｍＬ／ランタン）と表１～３のＡ２の欄に記載のアミノ酸誘導体（０．１０ｍｍｏｌ／ランタン）を室温で作用させた。
（３）１２時間後ランタンをジクロロメタン（１ｍＬ／ランタン）で３分間振盪しながら洗浄を５回行った。続いて２０％ピペリジンのジメチルホルムアミド（ＤＭＦ）溶液（１ｍＬ／ランタン）を室温で３０分作用させることでＦｍｏｃ基を脱保護した。
（４）ランタンを（ＤＭＦ）溶液（１ｍＬ／ランタン）で３分間の洗浄を５回行った。
（５）得られた固相担持アミンに対して、表１～３のＦｍｏｃＮＲ１ＣＨ（ＣＨ２Ａｒ）ＣＯＯＨの欄に記載のアミノ酸誘導体（０．１０ｍｍｏｌ／ランタン）、ジイソプロピルアルボジイミド（０．０１６ｍＬ／ランタン）、１－ヒドロキシベンズトリアゾール（２０ｍｇ／ランタン）をＤＭＦ（１ｍＬ／ランタン）溶媒中室温で１２時間作用させた。
（６）ランタンをＤＭＦ（３分間×５回）、ジクロロメタン（３分間×３回）、ＴＨＦ－Ｈ２Ｏ（３：１）（３分間×３回）、メタノール（３分間×３回）、およびジクロロメタン（３分間×３回）で洗浄し、真空乾燥した。
（７）２０％ピペリジンのジメチルホルムアミド（ＤＭＦ）溶液（１ｍＬ／ランタン）を室温で３０分作用させることでＦｍｏｃ基を脱保護した。
（８）ランタンをＤＭＦ（１ｍＬ／ランタン）で３分間の洗浄を５回行った。
（９）固相担持の遊離アミノ基に対して、表１～３のＡ１の欄に記載のアミノ酸誘導体（０．１０ｍｍｏｌ／ランタン）、ジイソプロピルアルボジイミド（０．０１６ｍＬ／ランタン）、１－ヒドロキシベンズトリアゾール（２０ｍｇ／ランタン）をＤＭＦ（１ｍＬ／ランタン）溶媒中室温で１２時間作用させた。
（１０）ランタンをＤＭＦ（３分間×５回）、ジクロロメタン（３分間×３回）、ＴＨＦ－Ｈ２Ｏ（３：１）（３分間×３回）、メタノール（３分間×３回）、およびジクロロメタン（３分間×３回）で洗浄し、真空乾燥した。
（１１）２０％ピペリジンのジメチルホルムアミド（ＤＭＦ）溶液（１ｍＬ／ランタン）を室温で３０分作用させることでＦｍｏｃ基を脱保護した。
（１２）ランタンをＤＭＦ（１ｍＬ／ランタン）で３分間の洗浄を５回行った。
（１３）固相担持の遊離アミノ基に対して、ＦｍｏｃＰｒｏ－Ｄｔｅｎａ（０．０７０ｍｍｏｌ／ランタン）、ジイソプロピルエチルアミン（０．０４４ｍＬ／ランタン）、（１－シアノ－２－エトキシ－２－オキソエチリデンアミノオキシ）ジメチルアミノ－モルホリノ－カルベニウムヘキサフルオロリン酸塩（ＣＯＭＵ）（４３ｍｇ／ランタン）をＤＭＦ（１ｍＬ／ランタン）溶媒中室温で２４時間作用させた。
（１４）ランタンをＤＭＦ（３分間×５回）、ジクロロメタン（３分間×３回）、ＴＨＦ－Ｈ２Ｏ（３：１）（３分間×３回）、メタノール（３分間×３回）、およびジクロロメタン（３分間×３回）で洗浄し、真空乾燥した。
（１５）２０％ピペリジンのジメチルホルムアミド（ＤＭＦ）溶液（１ｍＬ／ランタン）を室温で３０分作用させることでＦｍｏｃ基を脱保護した。
（１６）ランタンをＤＭＦ（１ｍＬ／ランタン）で３分間の洗浄を５回行った。
（１７）ランタンを３０％ヘキサフルオロイソプロピルアルコールのジクロロメタン溶液で３０分間処理し、得られた溶液を濃縮し、環化前駆体の粗生成物を得た。
（１８）環化前駆体の粗生成物を精製することなく、ジクロロメタンで希釈して１ｍＭとした後、ジイソプロピルエチルアミン（９等量）およびＨＡＴＵ（３等量）を０℃で加え、室温で１８時間撹拌した。
（１９）反応溶液に０℃で水を加えた後、ジクロロメタン溶媒で抽出した。
（２０）抽出液を飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥してろ過し、ろ液を減圧下濃縮して粗生成物を得た。
（２１）逆相高速液体クロマトグラフで分離、精製して一般式（Ｉ）で表される環状デプシペプチド化合物を総収率８～３３％で得た。 <Examples 1 to 9, 17: Production of cyclic depsipeptide compound represented by general formula (I)>
(1) A 10% acetyl chloride solution in dichloromethane (1 mL / lanthanum) was allowed to act at room temperature for 4 hours on SynPhase PS Trityl Alcohol linker (35 mol / lanthanum) manufactured by Mimotops.
(2) lanthanum was washed 5 times with dry dichloromethane (1 mL / lantern), diisopropylethylamine (0.035 mL / lantern) and amino acid derivatives described in the column of A 2 in Tables 1-3 (0.10 mmol / lantern) It was allowed to act at room temperature.
(3) After 12 hours, the lanthanum was washed 5 times with dichloromethane (1 mL / lanthanum) while shaking for 3 minutes. Subsequently, the Fmoc group was deprotected by allowing 20% piperidine in dimethylformamide (DMF) (1 mL / lanthanum) to act at room temperature for 30 minutes.
(4) The lanthanum was washed with a (DMF) solution (1 mL / lanthanum) for 3 minutes 5 times.
(5) The amino acid derivative (0.10 mmol / lanthanum) described in the column of FmocNR 1 CH (CH 2 Ar) COOH in Tables 1 to 3 and diisopropylalbodiimide (0.016 mL) with respect to the obtained solid phase-supported amine / Lanthanum), 1-hydroxybenztriazole (20 mg / lanthanum) was allowed to act in a DMF (1 mL / lanthanum) solvent at room temperature for 12 hours.
(6) Lanthanum in DMF (3 minutes × 5 times), dichloromethane (3 minutes × 3 times), THF-H 2 O (3: 1) (3 minutes × 3 times), methanol (3 minutes × 3 times), And washed with dichloromethane (3 min x 3) and vacuum dried.
(7) The Fmoc group was deprotected by allowing 20% piperidine in dimethylformamide (DMF) (1 mL / lanthanum) to act at room temperature for 30 minutes.
(8) The lanthanum was washed with DMF (1 mL / lanthanum) for 3 minutes 5 times.
(9) relative to the free amino groups of the solid phase carrier, an amino acid derivative according to the column of A 1 in Table 1 ~ 3 (0.10 mmol / lantern), diisopropyl arbovirus diimide (0.016 mL / lantern), 1-hydroxy Benztriazole (20 mg / lanthanum) was allowed to act in DMF (1 mL / lanthanum) solvent at room temperature for 12 hours.
(10) Lanthanum in DMF (3 minutes × 5 times), dichloromethane (3 minutes × 3 times), THF-H 2 O (3: 1) (3 minutes × 3 times), methanol (3 minutes × 3 times), And washed with dichloromethane (3 min x 3) and vacuum dried.
(11) The Fmoc group was deprotected by allowing 20% piperidine in dimethylformamide (DMF) (1 mL / lanthanum) to act at room temperature for 30 minutes.
(12) The lanthanum was washed with DMF (1 mL / lanthanum) for 3 minutes 5 times.
(13) FmocPro-Dtena (0.070 mmol / lanthanum), diisopropylethylamine (0.044 mL / lanthanum), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) with respect to the solid-supported free amino group ) Dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) (43 mg / lanthanum) was allowed to act in DMF (1 mL / lanthanum) solvent at room temperature for 24 hours.
(14) Lanthanum with DMF (3 minutes × 5 times), dichloromethane (3 minutes × 3 times), THF-H 2 O (3: 1) (3 minutes × 3 times), methanol (3 minutes × 3 times), And washed with dichloromethane (3 min x 3) and vacuum dried.
(15) The Fmoc group was deprotected by allowing 20% piperidine in dimethylformamide (DMF) (1 mL / lanthanum) to act at room temperature for 30 minutes.
(16) The lanthanum was washed with DMF (1 mL / lanthanum) for 3 minutes 5 times.
(17) The lanthanum was treated with 30% hexafluoroisopropyl alcohol in dichloromethane for 30 minutes, and the resulting solution was concentrated to obtain a crude product of the cyclization precursor.
(18) Without purifying the crude product of the cyclization precursor without purification, dilute with dichloromethane to 1 mM, then add diisopropylethylamine (9 equivalents) and HATU (3 equivalents) at 0 ° C. Stir for hours.
(19) Water was added to the reaction solution at 0 ° C., followed by extraction with a dichloromethane solvent.
(20) The extract was washed with saturated brine, dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
(21) Separation and purification by reverse phase high performance liquid chromatography yielded a cyclic depsipeptide compound represented by general formula (I) in a total yield of 8 to 33%.
＜実施例１０～１６、１８～２７：一般式（ＩＩ）で表される環状デプシペプチド化合物の製造＞
　表１～３のＡ３の欄に記載のアミノ酸誘導体、Ａ２の欄に記載のアミノ酸誘導体、ＦｍｏｃＮＲ１ＣＨ（ＣＨ２Ａｒ）ＣＯＯＨの欄に記載のアミノ酸誘導体、Ａ１の欄に記載のアミノ酸誘導体、ＦｍｏｃＰｒｏ－Ｄｔｅｎａの順で縮合した以外、上記実施例の同様の方法により粗生成物を得た。同様に逆相高速液体クロマトグラフで分離、精製して一般式（ＩＩ）で表される環状デプシペプチド化合物を総収率１６～４４％で得た。
　なお、実施例１～２７で得られた一般式（Ｉ）又は（ＩＩ）で表される環状デプシペプチド化合物の１ＨＮＭＲ、質量分析等の結果を以下に示す。 <Examples 10 to 16, 18 to 27: Production of cyclic depsipeptide compound represented by general formula (II)>
Tables 1 to amino acid derivative described in the column of A 3 of 3, an amino acid derivative according to the column of A 2, an amino acid derivative according to the column of FmocNR 1 CH (CH 2 Ar) COOH, amino acids listed in the column of A 1 A crude product was obtained by the same method as in the above Example, except that the derivative and FmocPro-Dtena were condensed in this order. Similarly, separation and purification were conducted by reversed-phase high-performance liquid chromatography to obtain a cyclic depsipeptide compound represented by the general formula (II) in a total yield of 16 to 44%.
The results of 1 HNMR, mass spectrometry, etc. of the cyclic depsipeptide compounds represented by the general formula (I) or (II) obtained in Examples 1 to 27 are shown below.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
（実施例１(#56)）
Figure JPOXMLDOC01-appb-C000023
  
A1: A-2-19, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-19
1H NMR (600 MHz, CD3CN) δ7.41 (m, 1 H), 7.41 (m, 1 H), 7.60-7.30 (m, 8 H), 7.36 (m, 1 H), 7.21 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.9 Hz, 2 H), 4.88 (dd, J = 10.5, 2.2 Hz, 1 H), 4.71 (br, 1 H), 4.42 (dd, J = 15.1, 6.4 Hz, 1 H), 4.41 (dd, J = 15.1, 6.4 Hz, 1 H), 4.37 (dd, J = 8.3, 6.2 Hz, 1 H), 4.34 (dd, J = 15.2, 6.0 Hz, 1 H), 4.28 (dd, J = 15.4, 5.7 Hz, 1 H), 3.73 (s, 3 H), 3.67 (br, 1 H), 3.59 (ddd, J = 10.6, 5.6, 2.8 Hz, 1H), 3.45 (m, 1 H), 3.30 (m, 1 H), 3.21 (dd, J = 13.9, 5.5 Hz, 1 H), 3.00 (dd, J = 14.2, 9.4 Hz, 1 H), 2.30 (dq, J = 7.1, 5.6 Hz, 1 H), 2.28 (m, 1 H), 1.98 (m, 1 H), 1.94 (ddqdd, J = 11.1, 8.3, 6.6, 3.2, 3.0 Hz, 1 H), 1.80 (m, 2 H), 1.61 (ddd, J = 13.9, 10.3, 3.2 Hz, 1 H), 1.56 (ddd, J = 14.7, 8.3, 2.3 Hz, 1 H), 1.49 (ddd, J = 13.5, 10.6, 3.0 Hz, 1 H), 1.16 (ddd, J = 13.4, 11.1, 2.8 Hz, 1 H), 1.07 (d, J = 7.1 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.88 (s, 9 H); HRESIMS calcd for C44H56N4O8[M+H]+ 769.4171, found 769.4144. (Example 1 (# 56))
Figure JPOXMLDOC01-appb-C000023
A 1 : A-2-19, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-19
1 H NMR (600 MHz, CD 3 CN) δ7.41 (m, 1 H), 7.41 (m, 1 H), 7.60-7.30 (m, 8 H), 7.36 (m, 1 H), 7.21 (d , J = 8.8 Hz, 2 H), 6.87 (d, J = 8.9 Hz, 2 H), 4.88 (dd, J = 10.5, 2.2 Hz, 1 H), 4.71 (br, 1 H), 4.42 (dd, J = 15.1, 6.4 Hz, 1 H), 4.41 (dd, J = 15.1, 6.4 Hz, 1 H), 4.37 (dd, J = 8.3, 6.2 Hz, 1 H), 4.34 (dd, J = 15.2, 6.0 Hz, 1 H), 4.28 (dd, J = 15.4, 5.7 Hz, 1 H), 3.73 (s, 3 H), 3.67 (br, 1 H), 3.59 (ddd, J = 10.6, 5.6, 2.8 Hz, 1H), 3.45 (m, 1 H), 3.30 (m, 1 H), 3.21 (dd, J = 13.9, 5.5 Hz, 1 H), 3.00 (dd, J = 14.2, 9.4 Hz, 1 H), 2.30 (dq, J = 7.1, 5.6 Hz, 1 H), 2.28 (m, 1 H), 1.98 (m, 1 H), 1.94 (ddqdd, J = 11.1, 8.3, 6.6, 3.2, 3.0 Hz, 1 H) , 1.80 (m, 2 H), 1.61 (ddd, J = 13.9, 10.3, 3.2 Hz, 1 H), 1.56 (ddd, J = 14.7, 8.3, 2.3 Hz, 1 H), 1.49 (ddd, J = 13.5 , 10.6, 3.0 Hz, 1 H), 1.16 (ddd, J = 13.4, 11.1, 2.8 Hz, 1 H), 1.07 (d, J = 7.1 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.88 (s, 9 H); HRESIMS calcd for C 44 H 56 N 4 O 8 [M + H] + 769.4171, found 769.4144.
（実施例２(#57)）
Figure JPOXMLDOC01-appb-C000024
 A1: A-2-19, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-17(trans)
1H NMR (600 MHz, CD3CN) δ7.80 (m, 1 H), 7.77 (m, 1 H), 7.60 (dd, J = 6.1, 3.5 Hz, 1 H), 7.54 (m, 1 H), 7.40 (m, 1 H), 7.34 (m, 1 H), 7.23 (d, J = 9.0 Hz, 2 H), 6.83 (d, J = 8.9 Hz, 2 H), 6.70 (d, J = 8.1 Hz, 1 H), 4.73 (dd, J = 8.9, 1.9 Hz, 1 H), 4.72 (dd, J = 14.3, 8.1 Hz, 1 H), 4.64 (ddd, J = 10.0, 8.3, 5.7 Hz, 1 H), 4.49 (dd, J = 8.8 Hz, 2.4, 1 H), 3.99 (dd, J = 14.9, 4.1 Hz, 1 H), 3.73 (s, 3 H), 3.66 (dddd, J = 9.1, 6.2, 4.6, 3.1 Hz, 1 H), 3.42 (m, 1 H), 3.41 (br, 1 H), 3.40 (m, 1 H), 3.35 (m, 1 H), 3.21 (dd, J = 14.5, 5.9 Hz, 1 H), 3.02 (dd, J = 14.1, 9.5 Hz, 1 H), 2.46 (dq, J = 7.0, 4.6 Hz, 1 H), 2.31 (m, 1 H), 2.26 (m, 1 H), 2.17 (m, 1 H), 1.85 (m, 1 H), 1.80 (m, 1 H), 1.70 (m, 1 H), 1.69 (m, 1 H), 1.67 (m, 1 H), 1.61 (ddd, J = 10.2, 8.4, 2.4 Hz, 1 H), 1.54 (m, 1 H), 1.46 (ddqdd, J = 8.8, 8.4, 6.8, 5.6, 4.7 Hz, 1 H), 1.38 (ddd, J = 13.8, 9.1, 4.7 Hz, 1 H), 1.29 (ddd, J = 14.0, 9.1, 5.6 Hz, 1 H), 1.23 (m, 1 H), 1.21 (ddd, J = 12.0, 8.8, 3.1 Hz, 1 H), 1.20 (m, 1 H), 1.08 (d, J = 7.1 Hz, 3 H), 1.05 (m, 1 H), 0.95 (m, 1 H), 0.88 (s, 9 H), 0.73 (d, J = 6.8 Hz, 3 H); HRESIMS calcd for C43H60N4O8 [M+Na]+783.4303, found 783.4281. (Example 2 (# 57))
Figure JPOXMLDOC01-appb-C000024
 A 1 : A-2-19, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-17 (trans)
1 H NMR (600 MHz, CD 3 CN) δ 7.80 (m, 1 H), 7.77 (m, 1 H), 7.60 (dd, J = 6.1, 3.5 Hz, 1 H), 7.54 (m, 1 H ), 7.40 (m, 1 H), 7.34 (m, 1 H), 7.23 (d, J = 9.0 Hz, 2 H), 6.83 (d, J = 8.9 Hz, 2 H), 6.70 (d, J = 8.1 Hz, 1 H), 4.73 (dd, J = 8.9, 1.9 Hz, 1 H), 4.72 (dd, J = 14.3, 8.1 Hz, 1 H), 4.64 (ddd, J = 10.0, 8.3, 5.7 Hz, 1 H), 4.49 (dd, J = 8.8 Hz, 2.4, 1 H), 3.99 (dd, J = 14.9, 4.1 Hz, 1 H), 3.73 (s, 3 H), 3.66 (dddd, J = 9.1, 6.2, 4.6, 3.1 Hz, 1 H), 3.42 (m, 1 H), 3.41 (br, 1 H), 3.40 (m, 1 H), 3.35 (m, 1 H), 3.21 (dd, J = 14.5 , 5.9 Hz, 1 H), 3.02 (dd, J = 14.1, 9.5 Hz, 1 H), 2.46 (dq, J = 7.0, 4.6 Hz, 1 H), 2.31 (m, 1 H), 2.26 (m, 1 H), 2.17 (m, 1 H), 1.85 (m, 1 H), 1.80 (m, 1 H), 1.70 (m, 1 H), 1.69 (m, 1 H), 1.67 (m, 1 H ), 1.61 (ddd, J = 10.2, 8.4, 2.4 Hz, 1 H), 1.54 (m, 1 H), 1.46 (ddqdd, J = 8.8, 8.4, 6.8, 5.6, 4.7 Hz, 1 H), 1.38 ( ddd, J = 13.8, 9.1, 4.7 Hz, 1 H), 1.29 (ddd, J = 14.0, 9.1, 5.6 Hz, 1 H), 1.23 (m, 1 H), 1.21 (ddd, J = 12.0, 8.8, 3.1 Hz, 1 H), 1.20 (m, 1 H), 1.08 (d, J = 7.1 Hz, 3 H), 1.05 (m, 1 H), 0.95 (m, 1 H), 0.88 (s, 9 H), 0.73 (d, J = 6.8 Hz, 3 H); HRESIMS calcd for C 43 H 60 N 4 O 8 [M + Na] + 783.4303, found 783.4281.
（実施例３(#58)）
Figure JPOXMLDOC01-appb-C000025
 A1: A-2-19, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-17(cis)
1H NMR (600 MHz, CD3CN) δ 7.77 (m, 1 H), 7.55 (m, 1 H), 7.48 (m, 1 H), 7.48 (m, 1 H), 7.39 (m, 1 H), 7.34 (m, 1 H), 7.21 (d, J = 8.9 Hz, 2 H), 6.96 (m, 1 H), 6.83 (d, J = 8.9 Hz, 2 H), 4.82 (dd, J = 10.8, 1.8 Hz, 1 H), 4.65 (ddd, J = 9.6, 8.1, 5.3 Hz, 1 H), 4.41 (dd, J = 15.5, 5.9 Hz, 1 H), 4.39 (dd, J = 8.6, 3.8 Hz, 1 H), 4.34 (dd, J = 15.4, 4.1 Hz, 1 H), 3.97 (m, 1 H), 3.73 (s, 3 H), 3.67 (dddd, J = 10.2, 3.7, 6.9, 7.3 Hz, 1 H), 3.61 (m, 1 H), 3.57 (m, 1 H), 3.41 (br, 1 H), 3.19 (dd, J = 14.2, 5.3 Hz, 1 H), 2.99 (dd, J = 14.2, 9.7 Hz, 1 H), 2.52 (dddd, J = 10.6, 10.6, 5.2, 5.2 Hz, 1 H), 2.28 (dq, J = 6.9, 6.9 Hz, 1 H), 2.20 (m, 1 H), 1.99 (m, 1 H), 1.94 (m, 1 H), 1.86 (m, 1 H), 1.83 (ddqdd, 10.5, 9.5, 6.8, 4.1, 2.6 Hz, 1 H), 1.74 (m, 1 H), 1.68 (m, 1 H), 1.62 (m, 1 H), 1.62 (m, 1 H), 1.59 (m, 1 H), 1.59 (m, 1 H), 1.59 (ddd, J = 14.4, 10.9, 2.6 Hz, 1 H), 1.57 (m, 1 H), 1.47 (ddd, J = 14.6, 9.5, 2.2 Hz, 1 H), 1.46 (m, 1 H), 1.45 (ddd, J = 13.9, 10.2, 4.1 Hz, 1 H), 1.13 (ddd, J = 13.9, 10.5, 3.7 Hz, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.87 (s, 9 H); HRESIMS calcd for C43H60N4O8[M+Na]+ 783.4303, found 783.4274. (Example 3 (# 58))
Figure JPOXMLDOC01-appb-C000025
 A 1 : A-2-19, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-17 (cis)
1 H NMR (600 MHz, CD 3 CN) δ 7.77 (m, 1 H), 7.55 (m, 1 H), 7.48 (m, 1 H), 7.48 (m, 1 H), 7.39 (m, 1 H ), 7.34 (m, 1 H), 7.21 (d, J = 8.9 Hz, 2 H), 6.96 (m, 1 H), 6.83 (d, J = 8.9 Hz, 2 H), 4.82 (dd, J = 10.8, 1.8 Hz, 1 H), 4.65 (ddd, J = 9.6, 8.1, 5.3 Hz, 1 H), 4.41 (dd, J = 15.5, 5.9 Hz, 1 H), 4.39 (dd, J = 8.6, 3.8 Hz, 1 H), 4.34 (dd, J = 15.4, 4.1 Hz, 1 H), 3.97 (m, 1 H), 3.73 (s, 3 H), 3.67 (dddd, J = 10.2, 3.7, 6.9, 7.3 Hz, 1 H), 3.61 (m, 1 H), 3.57 (m, 1 H), 3.41 (br, 1 H), 3.19 (dd, J = 14.2, 5.3 Hz, 1 H), 2.99 (dd, J = 14.2, 9.7 Hz, 1 H), 2.52 (dddd, J = 10.6, 10.6, 5.2, 5.2 Hz, 1 H), 2.28 (dq, J = 6.9, 6.9 Hz, 1 H), 2.20 (m, 1 H ), 1.99 (m, 1 H), 1.94 (m, 1 H), 1.86 (m, 1 H), 1.83 (ddqdd, 10.5, 9.5, 6.8, 4.1, 2.6 Hz, 1 H), 1.74 (m, 1 H), 1.68 (m, 1 H), 1.62 (m, 1 H), 1.62 (m, 1 H), 1.59 (m, 1 H), 1.59 (m, 1 H), 1.59 (ddd, J = 14.4 , 10.9, 2.6 Hz, 1 H), 1.57 (m, 1 H), 1.47 (ddd, J = 14.6, 9.5, 2.2 Hz, 1 H), 1.46 (m, 1 H), 1.45 (ddd, J = 13.9 , 10.2, 4.1 Hz, 1 H), 1.13 (ddd, J = 13 .9, 10.5, 3.7 Hz, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.87 (s, 9 H); HRESIMS calcd for C 43 H 60 N 4 O 8 [M + Na] + 783.4303, found 783.4274.
（実施例４(#60)）
Figure JPOXMLDOC01-appb-C000026
 A1: A-2-15, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-19
1H NMR (600 MHz, CD3CN) δ7.71 (br, 1 H), 7.46 (br, 1 H), 7.42 (m, 1 H), 7.41 (m, 1 H), 7.39 (m, 1 H), 7.15 (d, J = 8.9 Hz, 2 H), 6.86 (br, 1 H), 6.82 (d, J = 8.9 Hz, 2 H), 6.81 (br, 1 H), 4.91 (m, 1 H), 4.53 (m, 1 H), 4.52 (m, 1 H), 4.46 (m, 1 H), 4.20 (dd, J = 15.0, 5.6 Hz, 1 H), 3.95 (br, 1 H), 3.74 (s, 3 H), 3.57 (m, 1 H), 3.50 (m, 1 H), 3.48 (br, 1 H), 3.12 (dd, J = 13.4, 4.5 Hz, 2 H), 3.05 (m, 1 H), 2.82 (dd, J = 14.2, 9.6 Hz, 2 H), 2.78 (ddd, J = 12.4, 6.5, 5.1 Hz, 1 H), 2.37 (m, 1 H), 2.10 (dq, J = 6.8, 6.8 Hz, 1 H), 2.05 (m, 1 H), 2.01 (ddd, J = 14.6, 6.9, 5.6 Hz, 1 H), 1.98 (m, 1 H), 1.97 (m, 1 H), 1.92 (m, 1 H), 1.92 (m, 1 H), 1.69 (m, 1 H), 1.60 (m, 1 H), 1.52 (br, 1 H), 1.49 (m, 1 H), 1.43 (m, 1 H), 1.13 (m, 1 H), 1.00 (d, J = 7.1 Hz, 3 H), 0.93 (br, 3 H), 0.91 (s, 9 H); HRESIMS calcd for C40H56N4O8[M+Na]+ 743.3990, found 743.3974. (Example 4 (# 60))
Figure JPOXMLDOC01-appb-C000026
 A 1 : A-2-15, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-19
1 H NMR (600 MHz, CD 3 CN) δ7.71 (br, 1 H), 7.46 (br, 1 H), 7.42 (m, 1 H), 7.41 (m, 1 H), 7.39 (m, 1 H), 7.15 (d, J = 8.9 Hz, 2 H), 6.86 (br, 1 H), 6.82 (d, J = 8.9 Hz, 2 H), 6.81 (br, 1 H), 4.91 (m, 1 H), 4.53 (m, 1 H), 4.52 (m, 1 H), 4.46 (m, 1 H), 4.20 (dd, J = 15.0, 5.6 Hz, 1 H), 3.95 (br, 1 H), 3.74 (s, 3 H), 3.57 (m, 1 H), 3.50 (m, 1 H), 3.48 (br, 1 H), 3.12 (dd, J = 13.4, 4.5 Hz, 2 H), 3.05 (m , 1 H), 2.82 (dd, J = 14.2, 9.6 Hz, 2 H), 2.78 (ddd, J = 12.4, 6.5, 5.1 Hz, 1 H), 2.37 (m, 1 H), 2.10 (dq, J = 6.8, 6.8 Hz, 1 H), 2.05 (m, 1 H), 2.01 (ddd, J = 14.6, 6.9, 5.6 Hz, 1 H), 1.98 (m, 1 H), 1.97 (m, 1 H) , 1.92 (m, 1 H), 1.92 (m, 1 H), 1.69 (m, 1 H), 1.60 (m, 1 H), 1.52 (br, 1 H), 1.49 (m, 1 H), 1.43 (m, 1 H), 1.13 (m, 1 H), 1.00 (d, J = 7.1 Hz, 3 H), 0.93 (br, 3 H), 0.91 (s, 9 H); HRESIMS calcd for C 40 H 56 N 4 O 8 [M + Na] + 743.3990, found 743.3974.
（実施例５(#61)）
Figure JPOXMLDOC01-appb-C000027
 A1: A-2-15, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-17(trans)
1H NMR (600 MHz, CD3CN) δ7.28 (br.d, J = 8.9 Hz, 1 H), 7.12 (d, J = 8.9 Hz, 2 H), 6.84 (m, 1 H), 6.82 (d, J = 8.9 Hz, 2 H), 6.80 (br, 1 H), 4.81 (dd, J = 10.3, 2.8 Hz, 1 H), 4.54 (dd, J = 8.5, 2.2 Hz, 1 H), 4.43 (ddd, J = 9.2, 9.2, 4.7 Hz, 1 H), 4.15 (br, 1 H), 3.74 (s, 3 H), 3.65 (m, 1 H), 3.63 (m, 1 H), 3.39 (m, 1 H), 3.34 (m, 1 H), 3.31 (m, 1 H), 3.12 (dd, J = 14.2, 5.1 Hz, 1 H), 2.92 (m, 1 H), 2.79 (dd, J = 14.2, 9.2 Hz, 1 H), 2.34 (m, 1 H), 2.25 (m, 1 H), 2.21 (m, 1 H), 2.14 (m, 1 H), 2.10 (ddd, J = 15.0, 9.8, 5.1 Hz, 1 H), 1.99 (ddd, J = 13.5, 6.5, 5.2 Hz, 1 H), 1.88 (m, 1 H), 1.75 (m, 1 H), 1.72 (m, 1 H), 1.72 (m, 1 H), 1.65 (ddqdd, J = 9.3, 7.8, 6.7, 5.1, 3.9 Hz, 1 H), 1.64 (m, 1 H), 1.60 (ddd, J = 14.0, 7.8, 2.7 Hz, 1 H), 1.59 (m, 1 H), 1.59 (m, 1 H), 1.51 (m, 1 H), 1.49 (ddd, J = 14.2, 10.1, 5.1 Hz, 1 H), 1.42 (m, 1 H), 1.36 (ddd, J = 14.0, 8.8, 3.9 Hz, 1 H), 1.35 (m, 1 H), 1.26 (m, 1 H), 1.19 (m, 1 H), 1.19 (ddd, J = 13.8, 9.3, 3.7 Hz, 1 H), 1.08 (d, J = 6.9 Hz, 3 H), 0.93 (d, J = 6.7 Hz, 3 H), 0.89 (s, 9 H)
; HRESIMS calcd for C39H60N4O8[M+Na]+ 735.4303, found 735.4298. (Example 5 (# 61))
Figure JPOXMLDOC01-appb-C000027
 A 1 : A-2-15, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-17 (trans)
1 H NMR (600 MHz, CD 3 CN) δ7.28 (br.d, J = 8.9 Hz, 1 H), 7.12 (d, J = 8.9 Hz, 2 H), 6.84 (m, 1 H), 6.82 (d, J = 8.9 Hz, 2 H), 6.80 (br, 1 H), 4.81 (dd, J = 10.3, 2.8 Hz, 1 H), 4.54 (dd, J = 8.5, 2.2 Hz, 1 H), 4.43 (ddd, J = 9.2, 9.2, 4.7 Hz, 1 H), 4.15 (br, 1 H), 3.74 (s, 3 H), 3.65 (m, 1 H), 3.63 (m, 1 H), 3.39 (m, 1 H), 3.34 (m, 1 H), 3.31 (m, 1 H), 3.12 (dd, J = 14.2, 5.1 Hz, 1 H), 2.92 (m, 1 H), 2.79 (dd, J = 14.2, 9.2 Hz, 1 H), 2.34 (m, 1 H), 2.25 (m, 1 H), 2.21 (m, 1 H), 2.14 (m, 1 H), 2.10 (ddd, J = 15.0 , 9.8, 5.1 Hz, 1 H), 1.99 (ddd, J = 13.5, 6.5, 5.2 Hz, 1 H), 1.88 (m, 1 H), 1.75 (m, 1 H), 1.72 (m, 1 H) , 1.72 (m, 1 H), 1.65 (ddqdd, J = 9.3, 7.8, 6.7, 5.1, 3.9 Hz, 1 H), 1.64 (m, 1 H), 1.60 (ddd, J = 14.0, 7.8, 2.7 Hz , 1 H), 1.59 (m, 1 H), 1.59 (m, 1 H), 1.51 (m, 1 H), 1.49 (ddd, J = 14.2, 10.1, 5.1 Hz, 1 H), 1.42 (m, 1 H), 1.36 (ddd, J = 14.0, 8.8, 3.9 Hz, 1 H), 1.35 (m, 1 H), 1.26 (m, 1 H), 1.19 (m, 1 H), 1.19 (ddd, J = 13.8, 9.3, 3.7 Hz, 1 H), 1.08 (d, J = 6.9 Hz, 3 H), 0. 93 (d, J = 6.7 Hz, 3 H), 0.89 (s, 9 H)
; HRESIMS calcd for C 39 H 60 N 4 O 8 [M + Na] + 735.4303, found 735.4298.
（実施例６(#62)）
Figure JPOXMLDOC01-appb-C000028
 A1: A-2-15, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-17(cis)
1H NMR (600 MHz, CD3CN) δ7.49 (d, J = 8.7 Hz, 1 H), 7.25 (br.d, J = 8.3 Hz, 1 H), 7.14 (d, J = 9.0 Hz, 1 H), 6.98 (dd, J = 6.3, 6.3 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 4.84 (dd, J = 12.2, 2.8 Hz, 1 H), 4.50 (ddd, J = 9.8, 8.4, 5.0 Hz, 1 H), 4.35 (dd, J = 8.9, 4.6 Hz, 1 H), 4.17 (d, J = 10.5 Hz,1 H), 4.03 (m, 1 H), 3.75 (s, 3 H), 3.60 (m, 1 H), 3.59 (m, 1 H), 3.49 (m, 1 H), 3.13 (dd, J = 14.2, 4.8 Hz, 1 H), 3.12 (m, 1 H), 3.05 (m, 1 H), 2.83 (dd, J = 14.2, 9.5 Hz, 1 H), 2.53 (m, 1 H), 2.23 (m, 1 H), 2.16 (m ,1 H), 2.15 (m, 1 H), 2.04 (ddd, J = 14.7, 9.3, 4.5 Hz, 1 H), 1.96 (m, 1 H), 1.95 (m, 1 H), 1.89 (m, 1 H), 1.87 (ddddd J = 11.0, 10.1, 6.6, 4.4, 3.3 Hz, 1 H), 1.73 (m, 1 H), 1.73 (m, 1 H), 1.69 (m, 1 H), 1.68 (ddd, J = 13.9, 12.4, 3.3 Hz, 1 H), 1.63 (m, 1 H), 1.63 (m, 1 H), 1.60 (m, 1 H), 1.60 (m, 1 H), 1.53 (m, 1 H), 1.46 (m, 1 H), 1.46 (m, 1 H), 1.39 (ddd, J = 14.0, 9.7, 4.4 Hz, 1 H), 1.38 (ddd, J = 13.4 Hz, 11.0, 2.6, 1 H), 1.14 (ddd, J = 13.3, 10.1, 4.3 Hz, 1 H), 1.04 (d, J = 7.0 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H), 0.88 (s, 9 H); HRESIMS calcd for C39H60N4O8[M+Na]+ 735.4303, found 735.4297. (Example 6 (# 62))
Figure JPOXMLDOC01-appb-C000028
 A 1 : A-2-15, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-17 (cis)
1 H NMR (600 MHz, CD 3 CN) δ7.49 (d, J = 8.7 Hz, 1 H), 7.25 (br.d, J = 8.3 Hz, 1 H), 7.14 (d, J = 9.0 Hz, 1 H), 6.98 (dd, J = 6.3, 6.3 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 4.84 (dd, J = 12.2, 2.8 Hz, 1 H), 4.50 (ddd , J = 9.8, 8.4, 5.0 Hz, 1 H), 4.35 (dd, J = 8.9, 4.6 Hz, 1 H), 4.17 (d, J = 10.5 Hz, 1 H), 4.03 (m, 1 H), 3.75 (s, 3 H), 3.60 (m, 1 H), 3.59 (m, 1 H), 3.49 (m, 1 H), 3.13 (dd, J = 14.2, 4.8 Hz, 1 H), 3.12 (m , 1 H), 3.05 (m, 1 H), 2.83 (dd, J = 14.2, 9.5 Hz, 1 H), 2.53 (m, 1 H), 2.23 (m, 1 H), 2.16 (m, 1 H ), 2.15 (m, 1 H), 2.04 (ddd, J = 14.7, 9.3, 4.5 Hz, 1 H), 1.96 (m, 1 H), 1.95 (m, 1 H), 1.89 (m, 1 H) , 1.87 (ddddd J = 11.0, 10.1, 6.6, 4.4, 3.3 Hz, 1 H), 1.73 (m, 1 H), 1.73 (m, 1 H), 1.69 (m, 1 H), 1.68 (ddd, J = 13.9, 12.4, 3.3 Hz, 1 H), 1.63 (m, 1 H), 1.63 (m, 1 H), 1.60 (m, 1 H), 1.60 (m, 1 H), 1.53 (m, 1 H ), 1.46 (m, 1 H), 1.46 (m, 1 H), 1.39 (ddd, J = 14.0, 9.7, 4.4 Hz, 1 H), 1.38 (ddd, J = 13.4 Hz, 11.0, 2.6, 1 H ), 1.14 (ddd, J = 13.3, 10.1, 4.3 Hz, 1 H), 1.04 (d, J = 7.0 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H), 0.88 (s, 9 H); HRESIMS calcd for C 39 H 60 N 4 O 8 [M + Na] + 735.4303, found 735.4297 .
（実施例７(#63)）
Figure JPOXMLDOC01-appb-C000029
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-19
1H NMR (600 MHz, CD3CN) δ7.43 (d, J = 8.0 Hz, 1 H), 7.39 (dd, J = 8.0, 7.5 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.22 (s, 1 H), 7.17 (d, J = 8.9 Hz, 2 H), 6.91 (br. dd, J = 7.7, 4.6 Hz, 1 H), 6.85 (d, J = 8.9 Hz, 2 H), 6.75 (d, J = 8.4 Hz, 1 H), 4.94 (dd, J = 12.2, 2.8 Hz, 1 H), 4.50 (m, 1 H), 4.48 (dd, J = 14.1, 7.3 Hz, 1 H), 4.41 (ddd, J = 8.8, 8.4, 6.6 Hz, 1 H), 4.36 (ddd, J = 13.1, 6.4, 3.5 Hz, 1 H), 4.09 (dd, J = 14.1, 5.1 Hz, 1 H), 3.75 (s, 3 H), 3.68 (d, J = 10.7 Hz, 1 H), 3.65 (ddd, J = 14.2, 7.5, 4.2 Hz, 1 H), 3.59 (dddd, J = 11.6, 10.7, 8.8, 2.8 Hz, 1 H), 3.33 (m, 1 H), 3.28 (m, 1 H), 3.07 (dd, J = 14.2, 6.3 Hz, 1 H), 2.77 (dd, J = 14.2, 8.8 Hz, 1 H), 2.74 (ddd, J = 14.7, 10.7, 2.7 Hz, 1 H), 2.65 (dq, J = 8.8, 6.8 Hz, 1 H), 2.49 (ddd, J = 14.1, 11.5, 3.3 Hz, 1 H), 2.37 (m, 1 H), 2.11 (m, 1 H), 2.00 (m, 1 H), 2.00 (ddqdd, J = 12.0, 11.0, 6.8, 3.2, 3.1 Hz, 1 H), 1.84 (m, 1 H), 1.84 (m, 1 H), 1.76 (ddd, J = 13.9, 12.2, 3.2 Hz, 1 H), 1.48 (ddd, J = 14.0, 11.6, 3.1 Hz, 1 H), 1.42 (ddd, J = 13.9, 11.0, 2.7 Hz, 1 H), 1.41 (m, 1 H), 1.31 (m, 1 H), 1.15 (ddd, J = 14.0, 12.0, 2.8 Hz, 1 H), 0.99 (m, 1 H), 0.93 (d, J = 6.3 Hz, 3 H), 0.91 (s, 9 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.74 (m, 1 H); HRESIMS calcd for C42H58N4O8[M+Na]+ 769.4147, found 769.4144. (Example 7 (# 63))
Figure JPOXMLDOC01-appb-C000029
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-19
1 H NMR (600 MHz, CD 3 CN) δ7.43 (d, J = 8.0 Hz, 1 H), 7.39 (dd, J = 8.0, 7.5 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.22 (s, 1 H), 7.17 (d, J = 8.9 Hz, 2 H), 6.91 (br.dd, J = 7.7, 4.6 Hz, 1 H), 6.85 (d, J = 8.9 Hz , 2 H), 6.75 (d, J = 8.4 Hz, 1 H), 4.94 (dd, J = 12.2, 2.8 Hz, 1 H), 4.50 (m, 1 H), 4.48 (dd, J = 14.1, 7.3 Hz, 1 H), 4.41 (ddd, J = 8.8, 8.4, 6.6 Hz, 1 H), 4.36 (ddd, J = 13.1, 6.4, 3.5 Hz, 1 H), 4.09 (dd, J = 14.1, 5.1 Hz , 1 H), 3.75 (s, 3 H), 3.68 (d, J = 10.7 Hz, 1 H), 3.65 (ddd, J = 14.2, 7.5, 4.2 Hz, 1 H), 3.59 (dddd, J = 11.6 , 10.7, 8.8, 2.8 Hz, 1 H), 3.33 (m, 1 H), 3.28 (m, 1 H), 3.07 (dd, J = 14.2, 6.3 Hz, 1 H), 2.77 (dd, J = 14.2 , 8.8 Hz, 1 H), 2.74 (ddd, J = 14.7, 10.7, 2.7 Hz, 1 H), 2.65 (dq, J = 8.8, 6.8 Hz, 1 H), 2.49 (ddd, J = 14.1, 11.5, 3.3 Hz, 1 H), 2.37 (m, 1 H), 2.11 (m, 1 H), 2.00 (m, 1 H), 2.00 (ddqdd, J = 12.0, 11.0, 6.8, 3.2, 3.1 Hz, 1 H ), 1.84 (m, 1 H), 1.84 (m, 1 H), 1.76 (ddd, J = 13.9, 12.2, 3.2 Hz, 1 H), 1.48 (ddd, J = 14.0, 11.6, 3.1 Hz, 1 H ), 1. 42 (ddd, J = 13.9, 11.0, 2.7 Hz, 1 H), 1.41 (m, 1 H), 1.31 (m, 1 H), 1.15 (ddd, J = 14.0, 12.0, 2.8 Hz, 1 H), 0.99 (m, 1 H), 0.93 (d, J = 6.3 Hz, 3 H), 0.91 (s, 9 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.74 (m, 1 H); HRESIMS calcd for C 42 H 58 N 4 O 8 [M + Na] + 769.4147, found 769.4144.
（実施例８(#64)）
Figure JPOXMLDOC01-appb-C000030
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-17(trans)
1H NMR (600 MHz, CD3CN) δ7.17 (d, J = 9.0 Hz, 2 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.45 (d, J = 8.5 Hz, 1 H), 4.71 (dd, J = 7.9, 2.4 Hz, 1 H), 4.55 (dd, J = 8.6, 2.1 Hz, 1 H), 4.48 (m, 1 H), 4.41 (ddd, J = 9.0, 8.2, 6.3 Hz, 1 H), 4.00 (m, 1 H), 3.86 (m, 1 H), 3.74 (s, 3 H), 3.55 (m, 1 H), 3.53 (m, 1 H), 3.40 (m, 1 H), 3.37 (m, 1 H), 3.10 (dd, J = 14.4, 6.2 Hz, 1 H), 3.07 (m, 1 H), 2.93 (dq, J = 6.9, 6.9 Hz, 1 H), 2.75 (dd, J = 14.4, 9.0 Hz, 1 H), 2.55 (m, 1 H), 2.41 (m, 1 H), 2.29 (m, 1 H), 2.23 (m, 1 H), 2.05 (m, 1 H), 1.88 (m, 1 H), 1.88 (ddqdd, J = 8.5, 7.9, 6.8. 6.4, 3.4 Hz, 1 H), 1.86 (m, 1 H), 1.86 (m, 1 H), 1.79 (m, 1 H), 1.75 (m, 1 H), 1.74 (m, 1 H), 1.74 (m, 1 H), 1.74 (ddd, J = 14.9, 6.4, 2.7 Hz, 1 H), 1.56 (m, 1 H), 1.55 (m, 1 H), 1.46 (m, 1 H), 1.46 (m, 1 H), 1.37 (m, 1 H), 1.37 (ddd, J = 14.3, 8.5, 4.4 Hz, 1 H), 1.25 (ddd, J = 14.9, 7.9, 7.9 Hz, 1 H), 1.21 (m, 1 H), 1.14 (ddd, J = 14.1, 8.7, 3.4 Hz, 1 H), 1.08 (m, 1 H), 1.07 (d, J = 7.0 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.91 (s, 9 H); HRESIMS calcd for C41H62N4O8[M+Na]+ 761.4460, found 761.4456. (Example 8 (# 64))
Figure JPOXMLDOC01-appb-C000030
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-17 (trans)
1 H NMR (600 MHz, CD 3 CN) δ7.17 (d, J = 9.0 Hz, 2 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.83 (d, J = 9.0 Hz, 2 H ), 6.45 (d, J = 8.5 Hz, 1 H), 4.71 (dd, J = 7.9, 2.4 Hz, 1 H), 4.55 (dd, J = 8.6, 2.1 Hz, 1 H), 4.48 (m, 1 H), 4.41 (ddd, J = 9.0, 8.2, 6.3 Hz, 1 H), 4.00 (m, 1 H), 3.86 (m, 1 H), 3.74 (s, 3 H), 3.55 (m, 1 H ), 3.53 (m, 1 H), 3.40 (m, 1 H), 3.37 (m, 1 H), 3.10 (dd, J = 14.4, 6.2 Hz, 1 H), 3.07 (m, 1 H), 2.93 (dq, J = 6.9, 6.9 Hz, 1 H), 2.75 (dd, J = 14.4, 9.0 Hz, 1 H), 2.55 (m, 1 H), 2.41 (m, 1 H), 2.29 (m, 1 H), 2.23 (m, 1 H), 2.05 (m, 1 H), 1.88 (m, 1 H), 1.88 (ddqdd, J = 8.5, 7.9, 6.8. 6.4, 3.4 Hz, 1 H), 1.86 ( m, 1 H), 1.86 (m, 1 H), 1.79 (m, 1 H), 1.75 (m, 1 H), 1.74 (m, 1 H), 1.74 (m, 1 H), 1.74 (ddd, J = 14.9, 6.4, 2.7 Hz, 1 H), 1.56 (m, 1 H), 1.55 (m, 1 H), 1.46 (m, 1 H), 1.46 (m, 1 H), 1.37 (m, 1 H), 1.37 (ddd, J = 14.3, 8.5, 4.4 Hz, 1 H), 1.25 (ddd, J = 14.9, 7.9, 7.9 Hz, 1 H), 1.21 (m, 1 H), 1.14 (ddd, J = 14.1, 8.7, 3.4 Hz, 1 H), 1.08 (m, 1 H), 1.07 (d, J = 7.0 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.91 (s, 9 H); HRESIMS calcd for C 41 H 62 N 4 O 8 [M + Na] + 761.4460, found 761.4456.
（実施例９(#65)）
Figure JPOXMLDOC01-appb-C000031
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-17(cis)
1H NMR (600 MHz, CD3CN) δ7.17 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.83 (m, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), 4.79 (dd, J = 11.8, 2.9 Hz, 1 H), 4.55 (dd, J = 8.6, 2.1 Hz, 1 H), 4.45 (ddd, J = 9.2, 8.3, 5.6 Hz, 1 H), 4.38 (m, 1 H), 3.96 (m, 1 H), 3.96 (m, 1 H), 3.74 (s, 3 H), 3.72 (m, 1 H), 3.60 (m, 1 H), 3.54 (m, 1 H), 3.29 (m, 1 H), 3.13 (dd, J = 14.3, 5.5 Hz, 1 H), 3.11 (m, 1 H), 2.77 (dd, J = 14.3, 9.2 Hz, 1 H), 2.70 (dq, J = 6.8, 6.8 Hz, 1 H), 2.68 (m, 1 H), 2.46 (m, 1 H), 2.40 (m, 1 H), 2.18 (m, 1 H), 2.07 (m, 1 H), 1.93 (m, 1 H), 1.81 (m, 1 H), 1.80 (ddqdd, J = 10.8, 10.4, 6.8, 3.5, 3.3 Hz, 1 H), 1.76 (m, 1 H), 1.75 (m, 1 H), 1.75 (m, 1 H), 1.68 (m, 1 H), 1.68 (m, 1 H), 1.65 (ddd, J = 14.2, 11.9, 3.5 Hz, 1 H), 1.60 (m, 1 H), 1.58 (m, 1 H), 1.54 (m, 1 H), 1.50 (m, 1 H), 1.49 (m, 1 H), 1.44 (m, 1 H), 1.41 (ddd, J = 14.2, 10.8, 2.9 Hz, 1 H), 1.35 (m, 1 H), 1.28 (ddd, J = 13.9, 10.4, 3.3 Hz, 1 H), 1.19 (ddd, J = 13.8, 10.4, 2.7 Hz, 1 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.88 (s, 9 H); HRESIMS calcd for C41H62N4O8[M+Na]+ 761.4460, found 761.4445. (Example 9 (# 65))
Figure JPOXMLDOC01-appb-C000031
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-17 (cis)
1 H NMR (600 MHz, CD 3 CN) δ7.17 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.83 (m, 1 H), 6.77 (d , J = 8.3 Hz, 1 H), 4.79 (dd, J = 11.8, 2.9 Hz, 1 H), 4.55 (dd, J = 8.6, 2.1 Hz, 1 H), 4.45 (ddd, J = 9.2, 8.3, 5.6 Hz, 1 H), 4.38 (m, 1 H), 3.96 (m, 1 H), 3.96 (m, 1 H), 3.74 (s, 3 H), 3.72 (m, 1 H), 3.60 (m , 1 H), 3.54 (m, 1 H), 3.29 (m, 1 H), 3.13 (dd, J = 14.3, 5.5 Hz, 1 H), 3.11 (m, 1 H), 2.77 (dd, J = 14.3, 9.2 Hz, 1 H), 2.70 (dq, J = 6.8, 6.8 Hz, 1 H), 2.68 (m, 1 H), 2.46 (m, 1 H), 2.40 (m, 1 H), 2.18 ( m, 1 H), 2.07 (m, 1 H), 1.93 (m, 1 H), 1.81 (m, 1 H), 1.80 (ddqdd, J = 10.8, 10.4, 6.8, 3.5, 3.3 Hz, 1 H) , 1.76 (m, 1 H), 1.75 (m, 1 H), 1.75 (m, 1 H), 1.68 (m, 1 H), 1.68 (m, 1 H), 1.65 (ddd, J = 14.2, 11.9 , 3.5 Hz, 1 H), 1.60 (m, 1 H), 1.58 (m, 1 H), 1.54 (m, 1 H), 1.50 (m, 1 H), 1.49 (m, 1 H), 1.44 ( m, 1 H), 1.41 (ddd, J = 14.2, 10.8, 2.9 Hz, 1 H), 1.35 (m, 1 H), 1.28 (ddd, J = 13.9, 10.4, 3.3 Hz, 1 H), 1.19 ( ddd, J = 13.8, 10.4, 2.7 Hz, 1 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.88 (s, 9 H); HRESIMS calcd for C 41 H 62 N 4 O 8 [M + Na] + 761.4460, found 761.4445.
（実施例１０(#55)）
Figure JPOXMLDOC01-appb-C000032
 A1: A-2-19, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.64 (m, 1 H), 7.61 (m, 1 H), 7.41 (m, 1 H), 7.34 (m, 1 H), 7.28 (br, 1 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.59 (br, 1 H), 5.06 (br, 1 H), 4.98 (d, J = 11.4 Hz, 1 H), 4.92 (dd, J = 12.6, 2.2 Hz, 1 H), 4.85 (dd, J = 14.6, 8.6 Hz, 1 H), 4.27 (br, 1 H), 3.90 (dd, J = 14.6, 4.0 Hz, 1 H), 3.78 (m, 1 H), 3.75 (s, 3 H), 3.39 (br, 1 H), 3.10 (br, 1 H), 2.98 (br, 1 H), 2.94 (br, 3 H), 2.73 (br, 3 H), 2.06 (ddqdd, J = 11.7, 10.8, 6.9, 4.0, 2.2 Hz, 1 H), 1.84 (dq, J = 10.0, 7.4 Hz, 1 H), 1.76 (m, 1 H), 1.74 (ddd, J = 14.4, 12.2, 2.2 Hz, 1 H), 1.52 (ddd, J = 14.0, 11.8, 4.0 Hz, 1 H), 1.31 (ddd, J = 14.0, 11.7, 2.5 Hz, 1 H), 1.07 (ddd, J = 14.4, 10.8, 2.6 Hz, 1 H), 1.07 (d, J = 6.8 Hz, 3 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3 H), 0.86 (s, 9 H), 0.74 (br, 3 H), 0.59 (br, 1 H), 0.53 (br, 1 H), 0.15 (m, 3 H); HRESIMS calcd for C47H69N5O9 [M+Na]+870.4987, found 870.4952. (Example 10 (# 55))
Figure JPOXMLDOC01-appb-C000032
 A 1 : A-2-19, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.64 (m, 1 H), 7.61 (m, 1 H), 7.41 (m, 1 H), 7.34 (m, 1 H), 7.28 (br, 1 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.59 (br, 1 H), 5.06 (br, 1 H), 4.98 (d, J = 11.4 Hz, 1 H), 4.92 (dd, J = 12.6, 2.2 Hz, 1 H), 4.85 (dd, J = 14.6, 8.6 Hz, 1 H), 4.27 (br, 1 H), 3.90 (dd, J = 14.6, 4.0 Hz, 1 H), 3.78 (m, 1 H), 3.75 (s, 3 H), 3.39 (br, 1 H), 3.10 (br, 1 H), 2.98 (br, 1 H) , 2.94 (br, 3 H), 2.73 (br, 3 H), 2.06 (ddqdd, J = 11.7, 10.8, 6.9, 4.0, 2.2 Hz, 1 H), 1.84 (dq, J = 10.0, 7.4 Hz, 1 H), 1.76 (m, 1 H), 1.74 (ddd, J = 14.4, 12.2, 2.2 Hz, 1 H), 1.52 (ddd, J = 14.0, 11.8, 4.0 Hz, 1 H), 1.31 (ddd, J = 14.0, 11.7, 2.5 Hz, 1 H), 1.07 (ddd, J = 14.4, 10.8, 2.6 Hz, 1 H), 1.07 (d, J = 6.8 Hz, 3 H), 0.99 (d, J = 6.9 Hz , 3 H), 0.97 (d, J = 6.9 Hz, 3 H), 0.86 (s, 9 H), 0.74 (br, 3 H), 0.59 (br, 1 H), 0.53 (br, 1 H), 0.15 (m, 3 H); HRESIMS calcd for C 47 H 69 N 5 O 9 [M + Na] + 870.4987, found 870.4952.
（実施例１１(#66)）
Figure JPOXMLDOC01-appb-C000033
 A1: A-2-15, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.14 (d, J = 8.9 Hz, 2 H), 6.83 (m, 1 H), 6.83 (d, J = 8.9 Hz, 2 H), 6.39 (m, 1 H), 5.24 (d, J = 11.5 Hz, 1 H), 5.01 (m, 1 H), 4.89 (dd, J = 12.5, 2.1 Hz, 1 H), 4.43 (d, J = 8.2 Hz, 1 H), 4.11 (dd, J = 7.8, 7.8 Hz, 1 H), 3.99 (m, 1 H), 3.74 (s, 3 H), 3.62 (m, 1 H), 3.58 (dddd, J = 11.2, 8.2, 6.8, 3.1 Hz, 1 H), 3.36 (m, 1 H), 3.36 (m, 1 H), 2.94 (m, 1 H), 2.89 (s, 3 H), 2.81 (m, 1 H), 2.78 (m, 1 H), 2.65 (s, 3 H), 2.30 (m, 1 H), 2.10 (m, 1 H), 2.09 (ddqdd, J = 12.1, 11.4, 7.1, 3.6, 3.2 Hz, 1 H), 2.04 (m, 1 H), 2.00 (m, 1 H), 1.88 (dq, J = 10.1, 7.1 Hz, 1 H), 1.87 (m, 1 H), 1.80 (m, 1 H), 1.78 (m, 1 H), 1.72 (ddd, J = 14.3, 12.1, 3.2 Hz, 1 H), 1.71 (m, 1 H), 1.54 (m, 1 H), 1.45 (ddd, J = 14.1, 11.2, 3.6 Hz, 1 H), 1.41 (m, 1 H), 1.33 (ddd, J = 14.1, 12.1, 2.1 Hz, 1 H), 1.21 (m, 1 H), 1.13 (ddd, J = 14.4, 11.4, 3.1 Hz, 1 H), 1.05 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 7.1 Hz, 3 H), 0.92 (d, J = 7.1 Hz, 3 H), 0.87 (m, 3 H), 0.86 (s, 9 H) HRESIMS calcd for C43H69N5O9[M+Na]+ 822.4987, found 822.4987. (Example 11 (# 66))
Figure JPOXMLDOC01-appb-C000033
 A 1 : A-2-15, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.14 (d, J = 8.9 Hz, 2 H), 6.83 (m, 1 H), 6.83 (d, J = 8.9 Hz, 2 H), 6.39 (m , 1 H), 5.24 (d, J = 11.5 Hz, 1 H), 5.01 (m, 1 H), 4.89 (dd, J = 12.5, 2.1 Hz, 1 H), 4.43 (d, J = 8.2 Hz, 1 H), 4.11 (dd, J = 7.8, 7.8 Hz, 1 H), 3.99 (m, 1 H), 3.74 (s, 3 H), 3.62 (m, 1 H), 3.58 (dddd, J = 11.2 , 8.2, 6.8, 3.1 Hz, 1 H), 3.36 (m, 1 H), 3.36 (m, 1 H), 2.94 (m, 1 H), 2.89 (s, 3 H), 2.81 (m, 1 H ), 2.78 (m, 1 H), 2.65 (s, 3 H), 2.30 (m, 1 H), 2.10 (m, 1 H), 2.09 (ddqdd, J = 12.1, 11.4, 7.1, 3.6, 3.2 Hz , 1 H), 2.04 (m, 1 H), 2.00 (m, 1 H), 1.88 (dq, J = 10.1, 7.1 Hz, 1 H), 1.87 (m, 1 H), 1.80 (m, 1 H ), 1.78 (m, 1 H), 1.72 (ddd, J = 14.3, 12.1, 3.2 Hz, 1 H), 1.71 (m, 1 H), 1.54 (m, 1 H), 1.45 (ddd, J = 14.1 , 11.2, 3.6 Hz, 1 H), 1.41 (m, 1 H), 1.33 (ddd, J = 14.1, 12.1, 2.1 Hz, 1 H), 1.21 (m, 1 H), 1.13 (ddd, J = 14.4 , 11.4, 3.1 Hz, 1 H), 1.05 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 7.1 Hz, 3 H), 0.92 (d, J = 7.1 Hz, 3 H), 0.87 (m, 3 H), 0.86 (s, 9 H) H RESIMS calcd for C 43 H 69 N 5 O 9 [M + Na] + 822.4987, found 822.4987.
（実施例１２(#67)）
Figure JPOXMLDOC01-appb-C000034
 #67 (II) A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.10 (d, J = 8.9 Hz, 2 H), 6.97 (m, 1 H), 6.82 (d, J = 8.9 Hz, 2 H), 5.15 (ddd, J = 10.2, 9.0, 5.6 Hz, 1 H), 4.96 (d, J = 11.7 Hz, 1 H), 4.82 (q, J = 6.6 Hz, 1 H), 4.76 (dd, J = 8.9, 4.2 Hz, 1 H), 4.39 (m, 1 H), 4.16 (dd, J = 7.7, 7.7 Hz, 1 H), 3.93 (m, 1 H), 3.91 (m, 1 H), 3.73 (s, 3 H), 3.59 (m, 1 H), 3.56 (m, 1 H), 3.08 (m, 1 H), 2.99 (m, 1 H), 2.82 (m, 1 H), 2.80 (s, 3 H), 2.80 (m, 1 H), 2.67 (m, 1 H), 2.53 (s, 3 H), 2.49 (m, 1 H), 2.26 (m, 1 H), 1.95 (m, 1 H), 1.95 (m, 1 H), 1.87 (m, 1 H), 1.83 (m, 1 H), 1.80 (ddqdd, J = 10.2, 6.8, 6.6, 5.7, 3.1 Hz, 1 H), 1.62 (m, 1 H), 1.62 (m, 1 H), 1.61 (ddd, J = 14.5, 8.8, 5.7 Hz, 1 H), 1.54 (m, 1 H), 1.53 (ddd, J = 14.4, 6.8, 4.2 Hz, 1 H), 1.37 (m, 1 H), 1.35 (ddd, J =14.2, 9.1, 3.1 Hz, 1 H), 1.31 (m, 1 H), 1.23 (ddd, J = 14.2, 10.2, 2.7 Hz, 1 H), 1.02 (d, J = 7.0 Hz, 3 H), 1.02 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 6.6, Hz 3 H), 0.88 (s, 9 H), 0.88 (m, 1 H), 0.84 (dd, J = 7.5, 7.5 Hz, 3 H), 0.67 (d, J = 6.6 Hz, 3 H); HRESIMS calcd for C45H71N5O9[M+Na]+ 848.5144, found 848.5144. (Example 12 (# 67))
Figure JPOXMLDOC01-appb-C000034
 # 67 (II) A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.10 (d, J = 8.9 Hz, 2 H), 6.97 (m, 1 H), 6.82 (d, J = 8.9 Hz, 2 H), 5.15 (ddd , J = 10.2, 9.0, 5.6 Hz, 1 H), 4.96 (d, J = 11.7 Hz, 1 H), 4.82 (q, J = 6.6 Hz, 1 H), 4.76 (dd, J = 8.9, 4.2 Hz , 1 H), 4.39 (m, 1 H), 4.16 (dd, J = 7.7, 7.7 Hz, 1 H), 3.93 (m, 1 H), 3.91 (m, 1 H), 3.73 (s, 3 H ), 3.59 (m, 1 H), 3.56 (m, 1 H), 3.08 (m, 1 H), 2.99 (m, 1 H), 2.82 (m, 1 H), 2.80 (s, 3 H), 2.80 (m, 1 H), 2.67 (m, 1 H), 2.53 (s, 3 H), 2.49 (m, 1 H), 2.26 (m, 1 H), 1.95 (m, 1 H), 1.95 ( m, 1 H), 1.87 (m, 1 H), 1.83 (m, 1 H), 1.80 (ddqdd, J = 10.2, 6.8, 6.6, 5.7, 3.1 Hz, 1 H), 1.62 (m, 1 H) , 1.62 (m, 1 H), 1.61 (ddd, J = 14.5, 8.8, 5.7 Hz, 1 H), 1.54 (m, 1 H), 1.53 (ddd, J = 14.4, 6.8, 4.2 Hz, 1 H) , 1.37 (m, 1 H), 1.35 (ddd, J = 14.2, 9.1, 3.1 Hz, 1 H), 1.31 (m, 1 H), 1.23 (ddd, J = 14.2, 10.2, 2.7 Hz, 1 H) , 1.02 (d, J = 7.0 Hz, 3 H), 1.02 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 6.6, Hz 3 H), 0.88 (s, 9 H), 0.88 ( m, 1 H), 0.84 (dd, J = 7.5, 7.5 Hz, 3 H), 0.67 (d, J = 6.6 Hz, 3 H) ; HRESIMS calcd for C 45 H 71 N 5 O 9 [M + Na] + 848.5144, found 848.5144.
（実施例１３(#68)）
Figure JPOXMLDOC01-appb-C000035
 A1: A-2-20, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.32 (m, 1 H), 7.27 (d, J = 9.1 Hz, 2 H), 6.86 (d, J = 9.1 Hz, 2 H), 5.74 (d, J = 14.3 Hz, 1 H), 5.04 (m, 1 H), 4.97 (d, J = 11.4 Hz, 1 H), 4.89 (dd, J =12.4, 2.1 Hz, 1 H), 4.13 (d, J = 7.4 Hz, 1 H), 4.12 (m, 1 H), 4.06 (dd, J = 8.0, 8.0 Hz, 1 H), 3.90 (dddd, J = 11.3, 10.3, 7.4, 3.3 Hz, 1 H), 3.75 (s, 3 H), 3.53 (m, 1 H), 3.39 (m, 1 H), 3.38 (d, J = 14.3 Hz, 1 H), 3.08 (m, 1 H), 2.98 (m, 1 H), 2.93 (s, 3 H), 2.77 (s, 3 H), 2.74 (s, 3 H), 2.46 (dq, J = 10.3, 7.0 Hz, 1 H), 2.25 (m, 1 H), 2.13 (ddqdd, J = 12.1, 11.3, 6.8, 3.7, 2.7 Hz, 1 H), 1.99 (m, 1 H), 1.84 (m, 1 H), 1.74 (m, 1 H), 1.72 (m, 1 H), 1.72 (ddd, J = 14.7, 12.1, 2.7 Hz, 1 H), 1.57 (ddd, J = 14.7, 11.8, 3.7 Hz, 1 H), 1.33 (ddd, J = 14.0, 12.1, 2.3 Hz, 1 H), 1.14 (ddd, J = 14.3, 11.3, 3.3 Hz, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.86 (s, 9 H), 0.72 (m, 3 H), 0.62 (m, 1 H), 0.60 (m, 1 H), 0.13 (dd, J = 7.3, 7.3 Hz, 3 H); HRESIMS calcd for C48H71N5O9[M+Na]+ 884.5144, found 884.5119. (Example 13 (# 68))
Figure JPOXMLDOC01-appb-C000035
 A 1 : A-2-20, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.32 (m, 1 H), 7.27 (d, J = 9.1 Hz, 2 H), 6.86 (d, J = 9.1 Hz, 2 H), 5.74 (d , J = 14.3 Hz, 1 H), 5.04 (m, 1 H), 4.97 (d, J = 11.4 Hz, 1 H), 4.89 (dd, J = 12.4, 2.1 Hz, 1 H), 4.13 (d, J = 7.4 Hz, 1 H), 4.12 (m, 1 H), 4.06 (dd, J = 8.0, 8.0 Hz, 1 H), 3.90 (dddd, J = 11.3, 10.3, 7.4, 3.3 Hz, 1 H) , 3.75 (s, 3 H), 3.53 (m, 1 H), 3.39 (m, 1 H), 3.38 (d, J = 14.3 Hz, 1 H), 3.08 (m, 1 H), 2.98 (m, 1 H), 2.93 (s, 3 H), 2.77 (s, 3 H), 2.74 (s, 3 H), 2.46 (dq, J = 10.3, 7.0 Hz, 1 H), 2.25 (m, 1 H) , 2.13 (ddqdd, J = 12.1, 11.3, 6.8, 3.7, 2.7 Hz, 1 H), 1.99 (m, 1 H), 1.84 (m, 1 H), 1.74 (m, 1 H), 1.72 (m, 1 H), 1.72 (ddd, J = 14.7, 12.1, 2.7 Hz, 1 H), 1.57 (ddd, J = 14.7, 11.8, 3.7 Hz, 1 H), 1.33 (ddd, J = 14.0, 12.1, 2.3 Hz , 1 H), 1.14 (ddd, J = 14.3, 11.3, 3.3 Hz, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.95 ( d, J = 7.0 Hz, 3 H), 0.86 (s, 9 H), 0.72 (m, 3 H), 0.62 (m, 1 H), 0.60 (m, 1 H), 0.13 (dd, J = 7.3 , 7.3 Hz, 3 H); HRESIMS calcd for C 48 H 71 N 5 O 9 [M + Na] + 884.5144, found 884.5119.
（実施例１４(#69)）
Figure JPOXMLDOC01-appb-C000036
 A1: A-2-16, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.14 (d, J = 8.9 Hz, 2 H), 6.83 (d, J = 8.9 Hz, 2 H), 6.81 (m, 1 H), 5.27 (d, J = 11.0 Hz, 1 H), 4.99 (m, 1 H), 4.87 (dd, J = 12.5, 2.0 Hz, 1 H), 4.10 (dd, J = 9.3, 7.0 Hz, 1 H), 4.03 (m, 1 H), 3.90 (m, 1 H), 3.74 (s, 3 H), 3.66 (m, 1 H), 3.61 (m, 1 H), 3.36 (m, 1 H), 3.01 (s, 3 H), 2.94 (m, 1 H), 2.92 (s, 3 H), 2.78 (m, 1 H), 2.66 (s, 3 H), 2.58 (dq, J = 9.4, 6.8 Hz, 1 H), 2.43 (m, 1 H), 2.29 (m, 1 H), 2.25 (m, 1 H), 2.09 (m, 1 H), 2.04 (m, 1 H), 2.04 (ddqdd, J = 11.5, 11.0, 6.8, 2.9, 2.5 Hz, 1 H), 1.92 (m, 1 H), 1.87 (m, 1 H), 1.78 (m, 1 H), 1.74 (m, 1 H), 1.66 (ddd, J = 14.1, 12.3, 2.5 Hz, 1 H), 1.56 (m, 1 H), 1.48 (ddd, J = 13.8, 11.0, 2.9 Hz, 1 H), 1.35 (m, 1 H), 1.35 (ddd, J = 14.9, 11.5, 2.2 Hz, 1 H), 1.17 (ddd, J = 14.8, 11.0, 2.9 Hz, 1 H), 1.16 (m, 1 H), 1.03 (d, J = 6.4 Hz, 3 H), 0.93 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.88 (m, 3 H), 0.88 (d, J = 7.1 Hz, 3 H), 0.86 (s, 9 H); HRESIMS calcd for C44H71N5O9 [M+Na]+ 836.5144, found 836.5119. (Example 14 (# 69))
Figure JPOXMLDOC01-appb-C000036
 A 1 : A-2-16, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.14 (d, J = 8.9 Hz, 2 H), 6.83 (d, J = 8.9 Hz, 2 H), 6.81 (m, 1 H), 5.27 (d , J = 11.0 Hz, 1 H), 4.99 (m, 1 H), 4.87 (dd, J = 12.5, 2.0 Hz, 1 H), 4.10 (dd, J = 9.3, 7.0 Hz, 1 H), 4.03 ( m, 1 H), 3.90 (m, 1 H), 3.74 (s, 3 H), 3.66 (m, 1 H), 3.61 (m, 1 H), 3.36 (m, 1 H), 3.01 (s, 3 H), 2.94 (m, 1 H), 2.92 (s, 3 H), 2.78 (m, 1 H), 2.66 (s, 3 H), 2.58 (dq, J = 9.4, 6.8 Hz, 1 H) , 2.43 (m, 1 H), 2.29 (m, 1 H), 2.25 (m, 1 H), 2.09 (m, 1 H), 2.04 (m, 1 H), 2.04 (ddqdd, J = 11.5, 11.0 , 6.8, 2.9, 2.5 Hz, 1 H), 1.92 (m, 1 H), 1.87 (m, 1 H), 1.78 (m, 1 H), 1.74 (m, 1 H), 1.66 (ddd, J = 14.1, 12.3, 2.5 Hz, 1 H), 1.56 (m, 1 H), 1.48 (ddd, J = 13.8, 11.0, 2.9 Hz, 1 H), 1.35 (m, 1 H), 1.35 (ddd, J = 14.9, 11.5, 2.2 Hz, 1 H), 1.17 (ddd, J = 14.8, 11.0, 2.9 Hz, 1 H), 1.16 (m, 1 H), 1.03 (d, J = 6.4 Hz, 3 H), 0.93 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.88 (m, 3 H), 0.88 (d, J = 7.1 Hz, 3 H), 0.86 (s, 9 H); HRESIMS calcd for C 44 H 71 N 5 O 9 [M + Na] + 836.5144, foun d 836.5119.
（実施例１５(#70)）
Figure JPOXMLDOC01-appb-C000037
 A1: A-2-14, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.08 (d, J = 8.9 Hz, 2 H), 6.86 (m, 1 H), 6.80 (d, J = 8.9 Hz, 2 H), 5.25 (dd, J = 9.4, 7.3 Hz, 1 H), 4.85 (d, J = 11.3 Hz, 1 H), 4.79 (dd, J =11.9, 3.1 Hz, 1 H), 4.75 (q, J = 6.6 Hz, 1 H), 4.13 (dd, J = 7.7, 7.7 Hz, 1 H), 4.01 (m, 1 H), 3.90 (m, 1 H), 3.73 (m, 1 H), 3.72 (s, 3 H), 3.59 (m, 1 H), 2.88 (m, 2 H), 2.86 (s, 3 H), 2.84 (s, 3 H), 2.70 (m, 1 H), 2.63 (m, 1 H), 2.58 (dq, J = 9.1, 7.0 Hz, 1 H), 2.52 (s, 3 H), 2.31 (m, 1 H), 2.31 (m, 1 H), 2.26 (m, 1 H), 1.96 (ddqdd, J = 12.4, 10.6, 6.7, 3.3, 3.1 Hz, 1 H), 1.95 (m, 1 H), 1.94 (m, 1 H), 1.86 (m, 1 H), 1.80 (m, 1 H), 1.73 (ddd, J = 14.2, 12.4, 3.2 Hz, 1 H), 1.47 (ddd, J = 13.7, 10.6, 3.1 Hz, 1 H), 1.36 (ddd, J = 14.2, 11.5, 3.1 Hz, 1 H), 1.30 (m, 1 H), 1.13 (d, J = 6.8 Hz, 3 H), 1.07 (ddd, J = 14.3, 11.3, 3.3 Hz, 1 H), 1.01 (m, 1 H) 0.92 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.86 (s, 9 H), 0.85 (dd, J = 7.5, 7.5 Hz, 3 H), 0.39 (d, J = 6.7 Hz, 3 H); HRESIMS calcd for C43H69N5O9[M+Na]+ 822.4987, found 822.4964. (Example 15 (# 70))
Figure JPOXMLDOC01-appb-C000037
 A 1 : A-2-14, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.08 (d, J = 8.9 Hz, 2 H), 6.86 (m, 1 H), 6.80 (d, J = 8.9 Hz, 2 H), 5.25 (dd , J = 9.4, 7.3 Hz, 1 H), 4.85 (d, J = 11.3 Hz, 1 H), 4.79 (dd, J = 11.9, 3.1 Hz, 1 H), 4.75 (q, J = 6.6 Hz, 1 H), 4.13 (dd, J = 7.7, 7.7 Hz, 1 H), 4.01 (m, 1 H), 3.90 (m, 1 H), 3.73 (m, 1 H), 3.72 (s, 3 H), 3.59 (m, 1 H), 2.88 (m, 2 H), 2.86 (s, 3 H), 2.84 (s, 3 H), 2.70 (m, 1 H), 2.63 (m, 1 H), 2.58 ( dq, J = 9.1, 7.0 Hz, 1 H), 2.52 (s, 3 H), 2.31 (m, 1 H), 2.31 (m, 1 H), 2.26 (m, 1 H), 1.96 (ddqdd, J = 12.4, 10.6, 6.7, 3.3, 3.1 Hz, 1 H), 1.95 (m, 1 H), 1.94 (m, 1 H), 1.86 (m, 1 H), 1.80 (m, 1 H), 1.73 ( ddd, J = 14.2, 12.4, 3.2 Hz, 1 H), 1.47 (ddd, J = 13.7, 10.6, 3.1 Hz, 1 H), 1.36 (ddd, J = 14.2, 11.5, 3.1 Hz, 1 H), 1.30 (m, 1 H), 1.13 (d, J = 6.8 Hz, 3 H), 1.07 (ddd, J = 14.3, 11.3, 3.3 Hz, 1 H), 1.01 (m, 1 H) 0.92 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.86 (s, 9 H), 0.85 (dd, J = 7.5, 7.5 Hz, 3 H), 0.39 (d, J = 6.7 Hz, 3 H); HRESIMS calcd for C 43 H 69 N 5 O 9 [M + Na] + 822.4987, found 822.4964.
（実施例１６(#71)）
Figure JPOXMLDOC01-appb-C000038
 A1: A-2-13, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.79 (m, 1 H), 7.11 (d, J = 8.8 Hz, 2 H), 6.89 (br, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 5.27 (ddd, J = 9.5, 9.5, 5.8 Hz, 1 H), 4.89 (d, J = 11.4 Hz, 1 H), 4.84 (dd, J = 12.3, 3.1 Hz, 1 H), 4.82 (q, J = 6.7 Hz, 1 H), 4.31 (d, J = 11.2 Hz, 1 H), 4.22 (dd, J = 8.2, 8.2 Hz, 1 H), 4.04 (m, 1 H), 3.73 (s, 3 H), 3.60 (m, 1 H), 3.54 (m, 1 H), 3.53 (dddd, J = 11.6, 11.2, 9.3, 2.8 Hz, 1 H), 3.19 (m, 1 H), 2.97 (dd, J = 12.7, 9.5 Hz, 1 H), 2.84 (s, 3 H), 2.78 (dd, J = 12.7, 5.8 Hz, 1 H), 2.50 (s, 3 H), 2.30 (m, 1 H), 2.30 (m, 1 H), 2.21 (m, 1 H), 2.13 (dq, J = 9.3, 7.2 Hz, 1 H), 1.96 (ddqdd, J = 11.6, 11.1, 6.7, 3.6, 3.4 Hz, 1 H), 1.95 (m, 1 H), 1.90 (m, 1 H), 1.85 (m, 1 H), 1.83 (m, 1 H), 1.76 (ddd, J = 14.6, 12.4, 3.4 Hz, 1 H), 1.47 (ddd, J = 14.6, 11.6, 2.8 Hz, 1 H), 1.35 (ddd, J = 14.6, 11.1, 3.0 Hz, 1 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.06 (ddd, J = 14.6, 11.6, 3.6 Hz, 1 H), 0.94 (d, J = 7.2 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 1.10-0.90 (m, 2 H), 0.87 (s, 9 H), 0.81 (dd, J = 7.4, 7.4 Hz, 3 H), 0.59 (d, J = 6.7 Hz, 3 H); HRESIMS calcd for C42H67N5O9[M+Na]+ 808.4831, found 808.4814. (Example 16 (# 71))
Figure JPOXMLDOC01-appb-C000038
 A 1 : A-2-13, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ 7.79 (m, 1 H), 7.11 (d, J = 8.8 Hz, 2 H), 6.89 (br, 1 H), 6.82 (d, J = 8.8 Hz , 2 H), 5.27 (ddd, J = 9.5, 9.5, 5.8 Hz, 1 H), 4.89 (d, J = 11.4 Hz, 1 H), 4.84 (dd, J = 12.3, 3.1 Hz, 1 H), 4.82 (q, J = 6.7 Hz, 1 H), 4.31 (d, J = 11.2 Hz, 1 H), 4.22 (dd, J = 8.2, 8.2 Hz, 1 H), 4.04 (m, 1 H), 3.73 (s, 3 H), 3.60 (m, 1 H), 3.54 (m, 1 H), 3.53 (dddd, J = 11.6, 11.2, 9.3, 2.8 Hz, 1 H), 3.19 (m, 1 H), 2.97 (dd, J = 12.7, 9.5 Hz, 1 H), 2.84 (s, 3 H), 2.78 (dd, J = 12.7, 5.8 Hz, 1 H), 2.50 (s, 3 H), 2.30 (m, 1 H), 2.30 (m, 1 H), 2.21 (m, 1 H), 2.13 (dq, J = 9.3, 7.2 Hz, 1 H), 1.96 (ddqdd, J = 11.6, 11.1, 6.7, 3.6, 3.4 Hz, 1 H), 1.95 (m, 1 H), 1.90 (m, 1 H), 1.85 (m, 1 H), 1.83 (m, 1 H), 1.76 (ddd, J = 14.6, 12.4, 3.4 Hz , 1 H), 1.47 (ddd, J = 14.6, 11.6, 2.8 Hz, 1 H), 1.35 (ddd, J = 14.6, 11.1, 3.0 Hz, 1 H), 1.08 (d, J = 6.8 Hz, 3 H ), 1.06 (ddd, J = 14.6, 11.6, 3.6 Hz, 1 H), 0.94 (d, J = 7.2 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 1.10-0.90 (m , 2 H), 0.87 (s, 9 H), 0.81 ( dd, J = 7.4, 7.4 Hz, 3 H), 0.59 (d, J = 6.7 Hz, 3 H); HRESIMS calcd for C 42 H 67 N 5 O 9 [M + Na] + 808.4831, found 808.4814.
（実施例１７(#72)）
Figure JPOXMLDOC01-appb-C000039
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-20
1H NMR (600 MHz, CD3CN) δ7.38 (m, 1 H), 7.27 (m, 1 H), 7.10 (d, J = 8.7, 2 H), 7.07 (m, 1 H), 7.05 (m, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 6.58 (d, J = 10.7 Hz, 1 H), 5.00 (ddd, J = 10.7, 8.7, 5.7 Hz, 1 H), 4.97 (d, J = 17.9 Hz, 1 H), 4.94 (dd, J = 12.3, 2.2 Hz, 1 H), 4.43 (dd, J = 7.7, 7.7 Hz, 1 H), 4.25 (m, 1 H), 4.14 (d, J = 17.6 Hz, 1 H), 3.72 (s, 3 H), 3.49 (m, 1 H), 3.48 (dddd, J = 11.6, 10.6, 9.1 Hz, 1 H), 3.42 (d, J = 10.6 Hz, 1 H), 3.41 (m, 1 H), 3.26 (m, 1 H), 3.08 (dd, J = 14.1, 5.5 Hz, 1 H), 2.91 (s, 3 H), 2.73 (dd, J = 13.9, 9.3 Hz, 1 H), 2.52 (m, 1 H), 2.48 (dq, J = 9.1, 6.8 Hz, 1 H), 2.40 (m, 1 H), 2.37 (m, 1 H), 1.94 (ddqdd, J = 11.4, 10.7, 6.7, 3.9, 3.0 Hz, 1 H), 1.92 (m, 1 H), 1.91 (m, 1 H), 1.83 (m, 1 H), 1.82 (m, 1 H), 1.74 (ddd, J = 14.3, 12.3, 3.0 Hz, 1 H), 1.54 (ddd, J = 13.3, 11.6, 3.9 Hz, 1 H), 1.35 (ddd, J = 14.3, 11.4, 2.5 Hz, 1 H), 1.28 (m, 1 H), 1.10 (ddd, J = 13.3, 10.7, 3.0 Hz, 1 H), 1.08 (m, 1 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.90 (s, 9 H), 0.82 (d, J = 6.8 Hz, 3 H), 0.52 (m, 1 H), -0.28 (m, 1 H); HRESIMS calcd for C43H60N4O8[M+Na]+ 783.4303, found 783.4290. (Example 17 (# 72))
Figure JPOXMLDOC01-appb-C000039
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-20
1 H NMR (600 MHz, CD 3 CN) δ 7.38 (m, 1 H), 7.27 (m, 1 H), 7.10 (d, J = 8.7, 2 H), 7.07 (m, 1 H), 7.05 (m, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 6.58 (d, J = 10.7 Hz, 1 H), 5.00 (ddd, J = 10.7, 8.7, 5.7 Hz, 1 H), 4.97 (d, J = 17.9 Hz, 1 H), 4.94 (dd, J = 12.3, 2.2 Hz, 1 H), 4.43 (dd, J = 7.7, 7.7 Hz, 1 H), 4.25 (m, 1 H) , 4.14 (d, J = 17.6 Hz, 1 H), 3.72 (s, 3 H), 3.49 (m, 1 H), 3.48 (dddd, J = 11.6, 10.6, 9.1 Hz, 1 H), 3.42 (d , J = 10.6 Hz, 1 H), 3.41 (m, 1 H), 3.26 (m, 1 H), 3.08 (dd, J = 14.1, 5.5 Hz, 1 H), 2.91 (s, 3 H), 2.73 (dd, J = 13.9, 9.3 Hz, 1 H), 2.52 (m, 1 H), 2.48 (dq, J = 9.1, 6.8 Hz, 1 H), 2.40 (m, 1 H), 2.37 (m, 1 H), 1.94 (ddqdd, J = 11.4, 10.7, 6.7, 3.9, 3.0 Hz, 1 H), 1.92 (m, 1 H), 1.91 (m, 1 H), 1.83 (m, 1 H), 1.82 ( m, 1 H), 1.74 (ddd, J = 14.3, 12.3, 3.0 Hz, 1 H), 1.54 (ddd, J = 13.3, 11.6, 3.9 Hz, 1 H), 1.35 (ddd, J = 14.3, 11.4, 2.5 Hz, 1 H), 1.28 (m, 1 H), 1.10 (ddd, J = 13.3, 10.7, 3.0 Hz, 1 H), 1.08 (m, 1 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.90 (s, 9 H), 0.82 (d, J = 6 .8 Hz, 3 H), 0.52 (m, 1 H), -0.28 (m, 1 H); HRESIMS calcd for C 43 H 60 N 4 O 8 [M + Na] + 783.4303, found 783.4290.
（実施例１８(#73)）
Figure JPOXMLDOC01-appb-C000040
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-12
1H NMR (600 MHz, CD3CN) δ7.50-6.57 (m, 10 H), 5.80-3.36 (m, 13 H), 3.33-0.02 (m, 45 H); 13C NMR (150 MHz, CD3CN) δ176.1, 175.6, 175.0, 174.7, 172.8, 172.4, 171.8, 171.1, 170.9, 170.7, 169.4, 167.7, 165.6, 159.7, 159.6, 138.5, 131.6, 131.5, 131.4, 131.3, 130.4, 130.1, 129.8, 129.6, 129.6, 129.4, 129.2, 127.9, 127.4, 114.8, 114.7, 114.7, 80.3, 78.2, 72.9, 72.9, 61.1, 60.5, 60.3, 58.0, 56.5, 55.9, 55.9, 55.8, 55.5, 50.4, 48.1, 48.1, 46.4, 46.3, 44.1, 42.9, 42.3, 42.2, 41.9, 41.7, 41.6, 41.5, 39.9, 39.5, 39.0, 38.7, 38.4, 38.2, 37.3, 35.6, 35.5, 34.9, 34.0, 32.3, 32.3, 31.7, 30.2, 29.9, 29.7, 28.9, 27.9, 27.4, 27.2, 27.0, 26.5, 26.4, 26.3, 26.3, 25.9, 25.8, 25.3, 21.7, 20.6, 15.9, 15.7, 14.6, 14.3; HRESIMS calcd for C48H69N5O9[M+Na]+ 882.4987, found 882.4971. (Example 18 (# 73))
Figure JPOXMLDOC01-appb-C000040
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-12
1 H NMR (600 MHz, CD 3 CN) δ7.50-6.57 (m, 10 H), 5.80-3.36 (m, 13 H), 3.33-0.02 (m, 45 H); 13 C NMR (150 MHz, CD 3 CN) δ 176.1, 175.6, 175.0, 174.7, 172.8, 172.4, 171.8, 171.1, 170.9, 170.7, 169.4, 167.7, 165.6, 159.7, 159.6, 138.5, 131.6, 131.5, 131.4, 131.3, 130.4, 130.1, 129.8, 129.6, 129.6, 129.4, 129.2, 127.9, 127.4, 114.8, 114.7, 114.7, 80.3, 78.2, 72.9, 72.9, 61.1, 60.5, 60.3, 58.0, 56.5, 55.9, 55.9, 55.8, 55.5, 50.4, 48.1, 48.1, 46.4, 46.3, 44.1, 42.9, 42.3, 42.2, 41.9, 41.7, 41.6, 41.5, 39.9, 39.5, 39.0, 38.7, 38.4, 38.2, 37.3, 35.6, 35.5, 34.9, 34.0, 32.3, 32.3, 31.7, 30.2, 29.9, 29.7, 28.9, 27.9, 27.4, 27.2, 27.0, 26.5, 26.4, 26.3, 26.3, 25.9, 25.8, 25.3, 21.7, 20.6, 15.9, 15.7, 14.6, 14.3; HRESIMS calcd for C 48 H 69 N 5 O 9 [M + Na] + 882.4987, found 882.4971.
（実施例１９(#74)）
Figure JPOXMLDOC01-appb-C000041
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-6
1H NMR (600 MHz, CD3CN) δ7.23-7.03 (m, 2 H), 6.92-6.75 (m, 2 H), 5.50-3.42 (m, 13 H), 3.37-0.58 (m, 50 H); 13C NMR (150 MHz, CD3CN) δ174.8, 172.8, 172.2, 172.1, 171.6, 171.0, 164.9, 159.7, 159.6, 132.2, 131.6, 131.5, 131.5, 129.8, 129.7, 126.7, 114.8, 114.8, 114.7, 114.7, 114.6, 80.2, 79.7, 78.3, 73.1, 72.8, 66.6, 62.8, 60.8, 60.7, 60.4, 59.6, 55.9, 55.5, 53.1, 51.4, 51.1, 50.6, 48.7, 47.2, 46.4, 45.6, 44.4, 42.0, 41.9, 40.3, 39.3, 38.1, 35.7, 35.6, 35.5, 33.2, 32.5, 31.7, 31.4, 31.0, 30.7, 30.4, 30.2, 30.1, 29.3, 28.2, 26.8, 26.5, 26.3, 26.3, 26.2, 26.1, 25.2, 25.1, 23.3, 20.9, 20.4, 20.0, 20.0, 19.8, 19.3, 18.8, 15.8, 15.7, 15.3, 14.6, 14.4, 14.3, 14.1; HRESIMS calcd for C44H69N5O9[M+Na]+ 834.4987, found 834.4975. (Example 19 (# 74))
Figure JPOXMLDOC01-appb-C000041
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-6
1 H NMR (600 MHz, CD 3 CN) δ7.23-7.03 (m, 2 H), 6.92-6.75 (m, 2 H), 5.50-3.42 (m, 13 H), 3.37-0.58 (m, 50 H); 13 C NMR (150 MHz, CD 3 CN) δ174.8, 172.8, 172.2, 172.1, 171.6, 171.0, 164.9, 159.7, 159.6, 132.2, 131.6, 131.5, 131.5, 129.8, 129.7, 126.7, 114.8, 114.8, 114.7, 114.7, 114.6, 80.2, 79.7, 78.3, 73.1, 72.8, 66.6, 62.8, 60.8, 60.7, 60.4, 59.6, 55.9, 55.5, 53.1, 51.4, 51.1, 50.6, 48.7, 47.2, 46.4, 45.6, 44.4, 42.0, 41.9, 40.3, 39.3, 38.1, 35.7, 35.6, 35.5, 33.2, 32.5, 31.7, 31.4, 31.0, 30.7, 30.4, 30.2, 30.1, 29.3, 28.2, 26.8, 26.5, 26.3, 26.3, 26.2, 26.1, 25.2, 25.1, 23.3, 20.9, 20.4, 20.0, 20.0, 19.8, 19.3, 18.8, 15.8, 15.7, 15.3, 14.6, 14.4, 14.3, 14.1; HRESIMS calcd for C 44 H 69 N 5 O 9 [M + Na] + 834.4987, found 834.4975.
（実施例２０(#75)）
Figure JPOXMLDOC01-appb-C000042
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-4, A3: A-2-4
1H NMR (600 MHz, CD3CN) δ7.22-7.06 (m, 2 H), 6.90-6.74 (m, 2 H), 5.58-3.44 (m, 13 H), 3.36-1.87 (m, 16 H), 1.85-0.66 (m, 30 H); 13C NMR (150 MHz, CD3CN) δ165.0, 159.7, 159.6, 132.3, 131.6, 130.1, 129.7, 129.0, 114.8, 114.7, 79.9, 73.3, 60.3, 55.9, 51.6, 50.8, 49.9, 48.2, 47.9, 46.6, 42.4, 40.2, 38.3, 35.7, 35.5, 31.8, 31.4, 30.9, 30.4, 30.0, 29.6, 27.2, 26.4, 26.3, 26.2, 26.0, 23.7, 20.5, 17.2, 16.2, 15.7, 14.8, 14.5; HRESIMS calcd for C42H65N5O9[M+Na]+ 806.4674, found 806.4660. (Example 20 (# 75))
Figure JPOXMLDOC01-appb-C000042
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-4, A 3 : A-2-4
1 H NMR (600 MHz, CD 3 CN) δ7.22-7.06 (m, 2 H), 6.90-6.74 (m, 2 H), 5.58-3.44 (m, 13 H), 3.36-1.87 (m, 16 H), 1.85-0.66 (m, 30 H); 13 C NMR (150 MHz, CD 3 CN) δ165.0, 159.7, 159.6, 132.3, 131.6, 130.1, 129.7, 129.0, 114.8, 114.7, 79.9, 73.3, 60.3, 55.9, 51.6, 50.8, 49.9, 48.2, 47.9, 46.6, 42.4, 40.2, 38.3, 35.7, 35.5, 31.8, 31.4, 30.9, 30.4, 30.0, 29.6, 27.2, 26.4, 26.3, 26.2, 26.0, 23.7, 20.5, 17.2, 16.2, 15.7, 14.8, 14.5; HRESIMS calcd for C 42 H 65 N 5 O 9 [M + Na] + 806.4674, found 806.4660.
（実施例２１(#76)）
Figure JPOXMLDOC01-appb-C000043
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-12, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.51-6.53 (m, 10 H), 5.72-3.35 (m, 13 H), 3.32-0.16 (m, 51 H); 13C NMR (150 MHz, CD3CN) δ173.4, 172.2, 170.8, 170.4, 170.2, 159.4, 139.2, 131.8, 131.6, 131.0, 130.9, 130.7, 130.5, 130.0, 129.9, 129.3, 127.8, 115.0, 114.7, 114.3, 79.9, 72.8, 61.6, 61.1, 58.5, 56.0, 55.9, 50.0, 49.6, 48.4, 46.5, 42.5, 42.0, 38.7, 36.7, 35.8, 35.7, 34.9, 34.7, 31.9, 31.4, 31.0, 30.4, 30.3, 30.2, 28.1, 27.2, 26.6, 26.4, 26.3, 26.2, 15.8, 15.2, 14.7, 14.2, 13.8, 10.4; HRESIMS calcd for C51H75N5O9[M+Na]+ 924.5457, found 924.5454. (Example 21 (# 76))
Figure JPOXMLDOC01-appb-C000043
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-12, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.51-6.53 (m, 10 H), 5.72-3.35 (m, 13 H), 3.32-0.16 (m, 51 H); 13 C NMR (150 MHz, CD 3 CN) δ173.4, 172.2, 170.8, 170.4, 170.2, 159.4, 139.2, 131.8, 131.6, 131.0, 130.9, 130.7, 130.5, 130.0, 129.9, 129.3, 127.8, 115.0, 114.7, 114.3, 79.9, 72.8, 61.6, 61.1, 58.5, 56.0, 55.9, 50.0, 49.6, 48.4, 46.5, 42.5, 42.0, 38.7, 36.7, 35.8, 35.7, 34.9, 34.7, 31.9, 31.4, 31.0, 30.4, 30.3, 30.2, 28.1, 27.2, 26.6, 26.4, 26.3, 26.2, 15.8, 15.2, 14.7, 14.2, 13.8, 10.4; HRESIMS calcd for C 51 H 75 N 5 O 9 [M + Na] + 924.5457, found 924.5454.
（実施例２２(#77)）
Figure JPOXMLDOC01-appb-C000044
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-8, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.22-6.62 (m, 5 H), 5.53-3.37 (m, 13 H), 3.34-0.05 (m, 58 H); 13C NMR (150 MHz, CD3CN) δ175.9, 174.9, 172.9, 172.2, 170.8, 169.9, 159.7, 131.6, 130.1, 114.8, 79.7, 79.6, 73.1, 60.8, 58.2, 58.1, 57.7, 55.9, 55.8, 50.7, 48.6, 46.4, 42.9, 42.1, 40.3, 39.9, 38.3, 35.7, 35.6, 35.1, 35.0, 32.4, 30.2, 30.1, 30.0, 29.9, 27.6, 27.2, 26.5, 26.3, 26.2, 26.1, 26.0, 25.5, 25.1, 23.8, 21.9, 20.7, 15.7, 15.5, 14.7, 14.6, 11.4, 10.3, 9.7; HRESIMS calcd for C48H77N5O9Na [M+Na]+ 890.5614, found 890.5597. (Example 22 (# 77))
Figure JPOXMLDOC01-appb-C000044
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-8, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.22-6.62 (m, 5 H), 5.53-3.37 (m, 13 H), 3.34-0.05 (m, 58 H); 13 C NMR (150 MHz, CD 3 CN) δ 175.9, 174.9, 172.9, 172.2, 170.8, 169.9, 159.7, 131.6, 130.1, 114.8, 79.7, 79.6, 73.1, 60.8, 58.2, 58.1, 57.7, 55.9, 55.8, 50.7, 48.6, 46.4, 42.9, 42.1, 40.3, 39.9, 38.3, 35.7, 35.6, 35.1, 35.0, 32.4, 30.2, 30.1, 30.0, 29.9, 27.6, 27.2, 26.5, 26.3, 26.2, 26.1, 26.0, 25.5, 25.1, 23.8, 21.9, 20.7, 15.7, 15.5, 14.7, 14.6, 11.4, 10.3, 9.7; HRESIMS calcd for C 48 H 77 N 5 O 9 Na [M + Na] + 890.5614, found 890.5597.
（実施例２３(#78)）
Figure JPOXMLDOC01-appb-C000045
 A1: A-1-1, R1: H, Ar: 4-(MeO)C6H4, A2: A-2-2, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.19-7.05 (m, 2 H), 6.89-6.60 (m, 2 H), 5.32-3.23 (m, 14 H), 3.21-0.67 (m, 49 H); 13C NMR (150 MHz, CD3CN) δ176.2, 174.3, 172.0, 171.4, 171.3, 169.9, 168.4, 159.6, 159.2, 131.6, 131.3, 114.7, 114.3, 78.7, 74.3, 61.0, 60.8, 55.8, 52.2, 51.2, 48.4, 45.8, 44.9, 42.9, 41.8, 40.5, 40.1, 38.2, 37.5, 37.4, 36.4, 36.0, 35.5, 33.5, 30.6, 30.0, 29.2, 28.3, 27.9, 27.5, 26.8, 26.5, 26.5, 26.2, 25.9, 25.5, 25.2, 24.9, 17.8, 16.3, 16.1, 14.4, 11.4; HRESIMS calcd for C44H69N5O9[M+Na]+ 834.4987, found 834.4975. (Example 23 (# 78))
Figure JPOXMLDOC01-appb-C000045
 A 1 : A-1-1, R 1 : H, Ar: 4- (MeO) C 6 H 4 , A 2 : A-2-2, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.19-7.05 (m, 2 H), 6.89-6.60 (m, 2 H), 5.32-3.23 (m, 14 H), 3.21-0.67 (m, 49 H); 13 C NMR (150 MHz, CD 3 CN) δ 176.2, 174.3, 172.0, 171.4, 171.3, 169.9, 168.4, 159.6, 159.2, 131.6, 131.3, 114.7, 114.3, 78.7, 74.3, 61.0, 60.8, 55.8, 52.2, 51.2, 48.4, 45.8, 44.9, 42.9, 41.8, 40.5, 40.1, 38.2, 37.5, 37.4, 36.4, 36.0, 35.5, 33.5, 30.6, 30.0, 29.2, 28.3, 27.9, 27.5, 26.8, 26.5, 26.5, 26.2, 25.9, 25.5, 25.2, 24.9, 17.8, 16.3, 16.1, 14.4, 11.4; HRESIMS calcd for C 44 H 69 N 5 O 9 [M + Na] + 834.4987, found 834.4975.
（実施例２４(#79)）
Figure JPOXMLDOC01-appb-C000046
 A1: A-1-1, R1: H, Ar: 4-Ph-C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.65-7.52 (m, 4 H), 7.47-7.42 (m, 2 H), 7.38-7.27 (m, 3 H), 6.99 (d, J = 9.6 Hz, 1 H), 5.24 (ddd, J = 9.6, 8.9, 6.1 Hz, 1 H), 4.96 (d, J = 11.3 Hz, 1 H), 4.84 (q, J = 6.7 Hz, 1 H), 4.77 (dd, J = 9.0, 4.2 Hz, 1 H), 4.38 (m, 1 H), 4.16 (dd, J = 7.9, 7.9 Hz, 1 H), 3.92 (m, 1 H), 3.90 (m, 1 H), 3.67 (m, 1 H), 3.60 (m, 1 H), 3.56 (m, 1 H), 3.10 (dd, J = 12.9, 8.9 Hz, 1 H), 3.08 (m, 1 H), 2.93 (dd, J = 12.9, 6.1 Hz, 1 H), 2.81 (s, 3 H), 2.81 (m, 1 H), 2.67 (m, 1 H), 2.55 (s, 3 H), 2.52 (m, 1 H), 2.26 (m, 1 H), 1.96 (m, 1 H), 1.93 (m, 1 H), 1.87 (m, 1 H), 1.83 (m, 1 H), 1.80 (ddqdd, J = 10.1, 7.1, 6.2, 5.7, 3.6 Hz, 1 H), 1.65 (m, 1 H), 1.64 (m, 1 H), 1.61 (ddd, J = 14.5, 8.9, 5.7 Hz, 1 H), 1.54 (m, 1 H), 1.53 (ddd, J = 14.5, 7.1, 4.0 Hz, 1 H), 1.37 (m, 1 H), 1.34 (ddd, J = 14.3, 9.1, 3.6 Hz, 1 H), 1.31 (m, 1 H), 1.23 (ddd, J = 13.6, 10.1, 2.6 Hz, 1 H), 1.02 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.2 Hz, 3 H), 0.91 (m, 1 H), 0.88 (s, 9 H), 0.83 (dd, J = 7.4, 7.4 Hz, 3 H), 0.67 (d, J = 6.7 Hz, 3 H); HRESIMS calcd for C50H73N5O8[M+Na]+ 894.5351, found 894.5341. (Example 24 (# 79))
Figure JPOXMLDOC01-appb-C000046
 A 1 : A-1-1, R 1 : H, Ar: 4-Ph-C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.65-7.52 (m, 4 H), 7.47-7.42 (m, 2 H), 7.38-7.27 (m, 3 H), 6.99 (d, J = 9.6 Hz, 1 H), 5.24 (ddd, J = 9.6, 8.9, 6.1 Hz, 1 H), 4.96 (d, J = 11.3 Hz, 1 H), 4.84 (q, J = 6.7 Hz, 1 H), 4.77 (dd, J = 9.0, 4.2 Hz, 1 H), 4.38 (m, 1 H), 4.16 (dd, J = 7.9, 7.9 Hz, 1 H), 3.92 (m, 1 H), 3.90 (m, 1 H), 3.67 (m, 1 H), 3.60 (m, 1 H), 3.56 (m, 1 H), 3.10 (dd, J = 12.9, 8.9 Hz, 1 H), 3.08 (m, 1 H), 2.93 (dd, J = 12.9, 6.1 Hz, 1 H), 2.81 (s, 3 H), 2.81 (m, 1 H), 2.67 (m, 1 H), 2.55 (s, 3 H), 2.52 (m , 1 H), 2.26 (m, 1 H), 1.96 (m, 1 H), 1.93 (m, 1 H), 1.87 (m, 1 H), 1.83 (m, 1 H), 1.80 (ddqdd, J = 10.1, 7.1, 6.2, 5.7, 3.6 Hz, 1 H), 1.65 (m, 1 H), 1.64 (m, 1 H), 1.61 (ddd, J = 14.5, 8.9, 5.7 Hz, 1 H), 1.54 (m, 1 H), 1.53 (ddd, J = 14.5, 7.1, 4.0 Hz, 1 H), 1.37 (m, 1 H), 1.34 (ddd, J = 14.3, 9.1, 3.6 Hz, 1 H), 1.31 (m, 1 H), 1.23 (ddd, J = 13.6, 10.1, 2.6 Hz, 1 H), 1.02 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.2 Hz, 3 H), 0.91 (m, 1 H), 0.88 (s, 9 H), 0. 83 (dd, J = 7.4, 7.4 Hz, 3 H), 0.67 (d, J = 6.7 Hz, 3 H); HRESIMS calcd for C 50 H 73 N 5 O 8 [M + Na] + 894.5351, found 894.5341.
（実施例２５(#80)）
A1: A-1-1, R1: H, Ar: 4-Cl-C6H4, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.44-6.57 (m, 5 H), 5.47-3.46 (m, 10 H), 3.42-0.54 (m, 52 H); 13C NMR (150 MHz, CD3CN) δ176.4, 175.8, 174.8, 172.9, 172.4, 172.2, 171.2, 171.0, 170.8, 137.1, 136.9, 133.1, 133.1, 132.2, 129.4, 129.3, 79.8, 78.4, 73.1, 72.8, 60.9, 60.7, 58.3, 55.6, 50.2, 48.7, 48.5, 46.5, 46.4, 44.3, 43.0, 42.3, 42.0, 41.8, 41.5, 40.3, 39.3, 38.3, 38.2, 35.7, 35.6, 35.0, 33.2, 32.4, 31.8, 31.5, 30.3, 30.1, 30.0, 29.3, 27.8, 27.2, 26.8, 26.5, 26.4, 26.3, 26.2, 26.2, 26.1, 25.4, 25.1, 20.9, 20.4, 16.1, 15.8, 14.7, 14.5, 14.4, 14.2, 10.2, 9.8; HRESIMS calcd for C44H68N5O8[M+Na]+ 852.4649, found 852.4636. (Example 25 (# 80))
A 1 : A-1-1, R 1 : H, Ar: 4-Cl-C 6 H 4 , A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.44-6.57 (m, 5 H), 5.47-3.46 (m, 10 H), 3.42-0.54 (m, 52 H); 13 C NMR (150 MHz, CD 3 CN) δ176.4, 175.8, 174.8, 172.9, 172.4, 172.2, 171.2, 171.0, 170.8, 137.1, 136.9, 133.1, 133.1, 132.2, 129.4, 129.3, 79.8, 78.4, 73.1, 72.8, 60.9, 60.7, 58.3, 55.6, 50.2, 48.7, 48.5, 46.5, 46.4, 44.3, 43.0, 42.3, 42.0, 41.8, 41.5, 40.3, 39.3, 38.3, 38.2, 35.7, 35.6, 35.0, 33.2, 32.4, 31.8, 31.5, 30.3, 30.1, 30.0, 29.3, 27.8, 27.2, 26.8, 26.5, 26.4, 26.3, 26.2, 26.2, 26.1, 25.4, 25.1, 20.9, 20.4, 16.1, 15.8, 14.7, 14.5, 14.4, 14.2, 10.2, 9.8; HRESIMS calcd for C 44 H 68 N 5 O 8 [M + Na] + 852.4649, found 852.4636.
（実施例２６(#81)）
Figure JPOXMLDOC01-appb-C000048
 A1: A-1-1, R1: H, Ar: Ph, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.38-6.66 (m, 6 H), 5.44-3.48 (m, 10 H), 3.39-0.46 (m, 52 H); 13C NMR (150 MHz, CD3CN) δ175.8, 174.8, 172.9, 172.7, 172.2, 171.4, 171.0, 170.8, 138.2, 138.0, 130.5, 130.5, 129.5, 129.5, 129.4, 129.4, 127.8, 127.7, 79.7, 78.3, 73.1, 72.8, 60.9, 60.7, 58.2, 55.7, 50.5, 48.7, 48.5, 46.5, 46.4, 44.3, 43.0, 42.3, 42.0, 42.0, 41.8, 41.5, 41.2, 39.3, 38.3, 38.2, 35.7, 35.6, 35.0, 33.2, 32.4, 31.8, 31.5, 30.2, 30.1, 30.0, 29.3, 27.8, 27.2, 26.8, 26.5, 26.3, 26.2, 26.2, 26.1, 25.4, 25.1, 20.9, 20.4, 15.8, 15.7, 14.7, 14.5, 14.4, 14.2, 10.2, 9.8; HRESIMS calcd for C44H69N5O8[M+Na]+ 818.5038, found 818.5026. (Example 26 (# 81))
Figure JPOXMLDOC01-appb-C000048
 A 1 : A-1-1, R 1 : H, Ar: Ph, A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ 7.38-6.66 (m, 6 H), 5.44-3.48 (m, 10 H), 3.39-0.46 (m, 52 H); 13 C NMR (150 MHz, CD 3 CN) δ175.8, 174.8, 172.9, 172.7, 172.2, 171.4, 171.0, 170.8, 138.2, 138.0, 130.5, 130.5, 129.5, 129.5, 129.4, 129.4, 127.8, 127.7, 79.7, 78.3, 73.1, 72.8, 60.9, 60.7, 58.2, 55.7, 50.5, 48.7, 48.5, 46.5, 46.4, 44.3, 43.0, 42.3, 42.0, 42.0, 41.8, 41.5, 41.2, 39.3, 38.3, 38.2, 35.7, 35.6, 35.0, 33.2, 32.4, 31.8, 31.5, 30.2, 30.1, 30.0, 29.3, 27.8, 27.2, 26.8, 26.5, 26.3, 26.2, 26.2, 26.1, 25.4, 25.1, 20.9, 20.4, 15.8, 15.7, 14.7, 14.5, 14.4, 14.2, 10.2, 9.8; HRESIMS calcd for C 44 H 69 N 5 O 8 [M + Na] + 818.5038, found 818.5026.
（実施例２７(#８３)）
Figure JPOXMLDOC01-appb-C000049
 A1: A-1-1, R1: H, Ar: 7-メトキシクマリン-4-イル, A2: A-2-4, A3: A-2-10
1H NMR (600 MHz, CD3CN) δ7.94-5.95 (m, 5 H), 5.59-3.42 (m, 13 H), 3.36-0.52 (m, 52 H); 13C NMR (150 MHz, CD3CN) δ176.9, 175.8, 175.3, 172.1, 171.3, 170.4, 164.0, 161.2, 129.7, 126.9, 113.8, 113.4, 102.2, 79.6, 73.1, 60.8, 58.3, 56.8, 55.6, 48.5, 48.2, 46.3, 42.8, 42.1, 41.7, 38.2, 37.1, 35.7, 35.6, 35.0, 32.5, 31.9, 30.1, 29.4, 27.6, 27.1, 26.5, 26.3, 26.0, 20.9, 16.3, 14.5, 14.5, 10.2; HRESIMS calcd for C48H71N5O11 [M+Na]+916.5042, found 916.5023. (Example 27 (# 83))
Figure JPOXMLDOC01-appb-C000049
 A 1 : A-1-1, R 1 : H, Ar: 7-methoxycoumarin-4-yl, A 2 : A-2-4, A 3 : A-2-10
1 H NMR (600 MHz, CD 3 CN) δ7.94-5.95 (m, 5 H), 5.59-3.42 (m, 13 H), 3.36-0.52 (m, 52 H); 13 C NMR (150 MHz, CD 3 CN) δ176.9, 175.8, 175.3, 172.1, 171.3, 170.4, 164.0, 161.2, 129.7, 126.9, 113.8, 113.4, 102.2, 79.6, 73.1, 60.8, 58.3, 56.8, 55.6, 48.5, 48.2, 46.3, 42.8, 42.1, 41.7, 38.2, 37.1, 35.7, 35.6, 35.0, 32.5, 31.9, 30.1, 29.4, 27.6, 27.1, 26.5, 26.3, 26.0, 20.9, 16.3, 14.5, 14.5, 10.2; HRESIMS calcd for C 48 H 71 N 5 O 11 [M + Na] + 916.5042, found 916.5023.
＜一般式（Ｉ）又は（ＩＩ）で表される環状デプシペプチド化合物の生育阻害効果＞
　ヒト結腸腺癌細胞株HCT-116を5000個/ウェルで96ウェルディッシュに播種し、DMSOに溶解した各化合物（実施例１～２７の化合物及びアプラトキシンＡ）を添加したRPMI培地（FBSを10%含む、DMSOの最終濃度1%）中で48時間培養した後、WST-8で細胞増殖アッセイを行った。得られた結果からIC50値を算出した。結果を表４に示す。
　その結果、本発明の化合物等は、がん細胞に対して生育阻害効果を示すことが分かった。 <Growth inhibitory effect of cyclic depsipeptide compound represented by general formula (I) or (II)>
Human colon adenocarcinoma cell line HCT-116 was seeded in a 96-well dish at 5000 cells / well, and RPMI medium (10 FBS was added to each compound (Examples 1 to 27 and aplatoxin A) dissolved in DMSO). After 48 hours in DMSO (final concentration of DMSO 1%), cell proliferation assay was performed with WST-8. IC50 value was computed from the obtained result. The results are shown in Table 4.
As a result, it was found that the compounds of the present invention show growth inhibitory effects on cancer cells.
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
　本発明の化合物等は、抗がん剤等の医薬として利用することができる。 The compounds of the present invention can be used as pharmaceuticals such as anticancer agents.

Claims (6)

  1. 　下記一般式（Ｉ）又は（ＩＩ）で表される環状デプシペプチド化合物又はその塩。
    Figure JPOXMLDOC01-appb-C000001
      
    （式（Ｉ）及び（ＩＩ）中、Ａ１、Ａ２及びＡ３はそれぞれ独立して下記式（Ａ－１）～（Ａ－３）の何れかで表されるアミノ酸構造を、Ａｒは窒素原子、酸素原子、及びハロゲン原子からなる群より選択される少なくとも１種の原子を含んでいてもよい炭素数４～２０の芳香族炭化水素基を、Ｒ１は水素原子又は炭素数１～６の炭化水素基を表す。）
    Figure JPOXMLDOC01-appb-C000002
      
    （式（Ａ－１）～（Ａ－３）中、Ｒ１は水素原子又は炭素数１～６の炭化水素基を、Ｒ２は単結合又は炭素数１～２０の２価の炭化水素基を、Ｒ３は炭素数１～２０の２価の炭化水素基を表す。）     The cyclic depsipeptide compound or its salt represented by the following general formula (I) or (II).
    Figure JPOXMLDOC01-appb-C000001
    (In the formulas (I) and (II), A 1 , A 2 and A 3 are each independently an amino acid structure represented by any one of the following formulas (A-1) to (A-3), An aromatic hydrocarbon group having 4 to 20 carbon atoms which may contain at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a halogen atom, R 1 is a hydrogen atom or a carbon atom having 1 to 6 represents a hydrocarbon group.)
    Figure JPOXMLDOC01-appb-C000002
    (In the formulas (A-1) to (A-3), R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms, and R 2 is a single bond or a divalent hydrocarbon group having 1 to 20 carbon atoms. R 3 represents a divalent hydrocarbon group having 1 to 20 carbon atoms.)
  2. 　前記Ａ１が、下記式（Ａ－１－１）、（Ａ－２－１３）、（Ａ－２－１４）、（Ａ－２－１５）、（Ａ－２－１６）、（Ａ－２－１９）、又は（Ａ－２－２０）で表されるアミノ酸構造である、請求項１に記載の環状デプシペプチド化合物又はその塩。
    Figure JPOXMLDOC01-appb-C000003
         A 1 is represented by the following formulas (A-1-1), (A-2-13), (A-2-14), (A-2-15), (A-2-16), (A- The cyclic depsipeptide compound or a salt thereof according to claim 1, which has an amino acid structure represented by 2-19) or (A-2-20).
    Figure JPOXMLDOC01-appb-C000003
  3. 　前記Ａ２が、下記式（Ａ－２－１）、（Ａ－２－２）、（Ａ－２－３）、（Ａ－２－４）、（Ａ－２－５）、（Ａ－２－６）、（Ａ－２－１１）、（Ａ－２－１２）、（Ａ－２－１７）、（Ａ－２－１８）、（Ａ－２－１９）、又は（Ａ－２－２０）で表されるアミノ酸構造である、請求項１又は２に記載の環状デプシペプチド化合物又はその塩。
    Figure JPOXMLDOC01-appb-C000004
         A 2 represents the following formulas (A-2-1), (A-2-2), (A-2-3), (A-2-4), (A-2-5), (A- 2-6), (A-2-11), (A-2-12), (A-2-17), (A-2-18), (A-2-19), or (A-2 The cyclic depsipeptide compound or a salt thereof according to claim 1 or 2, which has the amino acid structure represented by -20).
    Figure JPOXMLDOC01-appb-C000004
  4. 　下記式で表される環状デプシペプチド化合物又はその塩。
    Figure JPOXMLDOC01-appb-C000005
         The cyclic depsipeptide compound or its salt represented by a following formula.
    Figure JPOXMLDOC01-appb-C000005
  5. 　請求項１～４の何れか１項に記載の環状デプシペプチド化合物又はその塩を含む医薬組成物。 A pharmaceutical composition comprising the cyclic depsipeptide compound or a salt thereof according to any one of claims 1 to 4.
  6. 　抗がん剤である、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, which is an anticancer agent.
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