WO1995030682A1 - Antitumor indolopyprolocarbazole derivative - Google Patents

Antitumor indolopyprolocarbazole derivative Download PDF

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Publication number
WO1995030682A1
WO1995030682A1 PCT/JP1995/000868 JP9500868W WO9530682A1 WO 1995030682 A1 WO1995030682 A1 WO 1995030682A1 JP 9500868 W JP9500868 W JP 9500868W WO 9530682 A1 WO9530682 A1 WO 9530682A1
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Prior art keywords
general formula
compound
meaning
compound represented
group
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PCT/JP1995/000868
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French (fr)
Japanese (ja)
Inventor
Katsuhisa Kojiri
Hisao Kondo
Hiroharu Arakawa
Mitsuru Ohkubo
Hiroyuki Suda
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Banyu Pharmaceutical Co., Ltd.
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Priority claimed from US08/255,980 external-priority patent/US5591842A/en
Priority to DE69532198T priority Critical patent/DE69532198T2/en
Priority to AT95917506T priority patent/ATE255121T1/en
Priority to US08/737,382 priority patent/US5804564A/en
Priority to EP95917506A priority patent/EP0760375B1/en
Priority to JP7528838A priority patent/JP3038921B2/en
Application filed by Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to DK95917506T priority patent/DK0760375T3/en
Priority to DK02018235T priority patent/DK1264836T3/en
Priority to CA002190007A priority patent/CA2190007C/en
Priority to KR1019960706296A priority patent/KR100312473B1/en
Priority to AU23535/95A priority patent/AU683749B2/en
Publication of WO1995030682A1 publication Critical patent/WO1995030682A1/en
Priority to HK97102485A priority patent/HK1000890A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
    • C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/044—Pyrrole radicals

Definitions

  • the present invention is useful in the field of medicine, and more particularly, relates to a novel indolopyrrolocarbazole derivative which inhibits the growth of tumor cells and exhibits an antitumor effect, an intermediate thereof, a production method thereof, and a use thereof.
  • the present inventors have screened a wide range of microbial metabolites, and have found that a novel compound having antitumor activity, BE-13793C (12,13-dihydroxy-1,1 todihydroxy-5H- Indolo [2,3-a] pyro-mouth [3,4-c] carbazomono-5,7 (6H) -dione) was discovered and disclosed in “Japanese Patent Application Publication No. 3-20277 and the 'Journal'. J. Antibiotics, Vol. 44, pp. 723-728 (1991)].
  • BE-13793C was chemically modified to create and disclose a pyrrocarbazole compound having excellent antitumor activity (see International Publication W091-18003 and European Patent Publication EP0545195 A1).
  • the present invention is based on the creation of a compound having an antitumor activity that is even better than the indolopyrrolocarbazole-based antitumor substance disclosed in the earlier patent application (International Publication W091 / 18003 and European Patent Publication EP0545195 A1). Akira is the task to be solved.
  • the present inventors have synthesized a large number of indolopyrrolocarbazole derivatives with the aim of creating a compound having an antitumor activity that is even better than the previously disclosed indlopyrrolocarbazole-based antitumor compounds.
  • the present inventors have found that the compound represented by the following general formula [I] is a novel compound having extremely excellent antitumor activity, stability and safety.
  • the present invention provides a compound of the general formula [I]
  • R 1 and R 2 represent 0H, and the bonding position thereof is R 1 is 1 or 2 position, R 2 is 10 or 11 position, and when R 1 force, R 2 is 11-position, and when R 1 is 2-position, R 2 is 10-position], or a pharmaceutically acceptable salt thereof, an intermediate thereof, production methods and uses.
  • R 1 and R 2 in the general formula represent OH. However, R 1 is bonded to the 1-position or 2-position on the ring, R 2 is bonded to the 10-position or 11-position, respectively, when R 1 is 1-position, R 2 is 11-position, and when R 1 is 2-position , R 2 is in the 10th place.
  • R 3 represents a lower alkyl group, a benzyloxymethyl group or an aralkyl group
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a sec-propyl group, a butyl group, a pentyl group, and a hexyl group.
  • the aralkyl group means an aralkyl group having 7 to 12 carbon atoms such as a benzyl group, a phenyl group and a phenyl group.
  • R 4 represents a hydrogen atom, a lower alkyl group, a benzyloxymethyl group or an aralkyl group, and the meanings of the lower alkyl group and the aralkyl group are the same as those described for R 3 .
  • R 5 and R 6 show protected ⁇ H. Provided that R 5 is bonded to the 1- or 2-position on the ring, R 6 is bonded to the 10- or 11-position, and when R 5 is in the 1 position, R 6 is in the 11 position and is in the 2 position , R 6 is 10th.
  • Examples of the protecting group that can be used include a benzyl group, a tolyl group, a paramethoxybenzyl group, and a benzyloxymethyl group.
  • R 7 to R 1D are the same or different and means a protecting group of the OH, is a protecting group which can be used may include, for example, base Njiru group, a tolyl group, parameters Tokishibenjiru group, a Benjiruo Kishimechiru group.
  • R 11 represents a hydrogen atom or a protecting group for an amino group of an indole skeleton, and examples of the protecting group include lower alkoxycarbonyl groups such as tert-butynecarbonyl group and methyloxycarbonyl group, benzyl group and benzyloxy group. Examples thereof include a methyl group, a trisoprovirsilyl group, a 2-trimethylsilylethyloxymethyl group, a mesyl group, and a tosyl group.
  • R 12 represents a protecting group for the amino group of the indole skeleton, and examples of the protecting group are the same as those described above.
  • X is a leaving group, and examples thereof include a chlorine atom, a bromine atom, and an iodine atom.
  • X 1 is a leaving group, and examples thereof include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, and an organic sulfonyloxy group such as a mesyl group and a tosyl group.
  • halogen atom such as a chlorine atom, a bromine atom and an iodine atom
  • organic sulfonyloxy group such as a mesyl group and a tosyl group.
  • Organometallic compounds include, for example, alkyllithiums such as butyllithium, lithium diisopropylamide, and lithium hexamethyldisilazide.
  • Metal hexaalkyldisilazides such as sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.
  • Grignard such as ethylmagnesium bromide and methylmagnesium chloride
  • the Mitsunobu reaction is defined as triphosphinyl phosphine, tributyl phosphine, and other organic phosphines and azodicarboxylic acid dimethyl ester, azodicarboxylic acid ditert-butylester, azodicarboxylic acid diisopropyl ester, azodicarboxylic acid di-N, N-dimethylamide, Azodicarboxylic acid Refers to a reaction that forms a glycosidic bond using an azodicarboxylic acid derivative such as di-N-methylbiperazine amide [see Synthesis, 1, 1981, pl-28].
  • the reaction between the maleimide compound represented by the general formula [IX] and the indole compound represented by the general formula [X] is carried out using an alkali metal hexane such as lithium hexamethyldisilazide.
  • the reaction can be carried out using a Grignard reagent such as alkyldisilazide and ethylmagnesium bromide.
  • solvents that can be used include toluene, benzene, tetrahydrofuran (THF), dioxane, and dimethyl ether. Can be mentioned.
  • the reaction temperature is generally -78 ° C to 130 ° C, preferably -20 ° C to 110 ° C.
  • a protecting group into the amino group of the indole skeleton of the compound represented by the general formula [XI]
  • the general formula [ ⁇ ] can be produced.
  • a protecting reagent that can be used in this case a halide or an acid anhydride corresponding to the above-mentioned protecting group can be used.
  • di-tert-butyl dicarbonate, tert-butyloxyl alcohol and the like are preferably used.
  • Nyl chloride and the like can be used.
  • reaction temperature is usually -78 ° C to 100 ° C, Preferably it is ⁇ 25 ° C. to 25 ° C.
  • the compound represented by the general formula [XIV] is produced by reacting the compound represented by the general formula [XII] with the compound represented by the general formula [XIII]. And the compound represented by the general formula [XI].
  • the reaction between the compound represented by the general formula [XIV] and the compound represented by the general formula [XV] can be performed by a so-called Mitsunobu reaction.
  • the above-mentioned organic phosphines and azodicarboxylic acid derivatives are used.
  • organic phosphines such as tributylphosphine and triphenylphosphine
  • azodicarboxylic acid derivatives such as azodicarboxylic acid getyl ester and azodicarboxylic acid diisopropyl ester can be used.
  • reaction solvent THF, dioxane, ether and the like can be suitably used, and the reaction temperature is generally -78 ° C to 50 ° C, preferably -40 ° C to 20 ° C. is there.
  • the deprotection of the amino group of the indole skeleton of the compound represented by the general formula [XVI] is preferably performed under conditions that allow selective deprotection.
  • the protecting group of another moiety may be removed. It is preferable that the conditions are such that the tert-butoxycarbonyl group, 2-trimethylsilylethoxymethyl group and the like of the amino group can be selectively removed while maintaining the above.
  • acids such as trifluoroacetic acid and HF
  • bases such as methylamine, tert-butoxylium, and tetra-n-butylammonium fluoride can be suitably used.
  • the compound represented by the general formula [XVIII] can be produced by oxidatively cyclizing the compound represented by the general formula [XVII].
  • the oxidizing agent used in this case the above-mentioned DDQ, CuCl 2 , Cu ( ⁇ Ac) 2 , Cu (N0 2 ) 2 , PdCl 2 , Pd (OAc) 2 , Pd (CF 3 COO) 2 etc.
  • the reaction solvent is toluene, methylene chloride, dimethyl Formamide, dioxane, ether and the like can be used, and the reaction temperature is usually 0 ° C to 100 ° C.
  • the compound represented by the general formula [XX] can be produced by reacting the compound represented by the general formula [XIX] with a base.
  • the base used in this NaOH, K0H, K 2 C0 3, Na 2 C_ ⁇ 3, Ki is permitted to use NaHCO 3 and the like.
  • the solvent which can be used water methanol, ethanol, Jimechiruho Rumuami And the like.
  • the reaction temperature is usually in the range of o ° c to the boiling point of the solvent.
  • the compound represented by the general formula [I] By reacting the compound represented by the general formula [XX] with H 2 NNHCH (CH 2 OH) 2 , the compound represented by the general formula [I] can be produced.
  • the obtained solvent include methanol, ethanol, THF, dimethylformamide and the like, and the reaction temperature is usually from 0 ° C to the boiling point of the solvent.
  • the amount of 3 ⁇ 4NNHCH (CH 2 OH) 2 used is usually 1 to 3 molar equivalents relative to compound [XX], and if necessary, lower or higher amounts can be used.
  • reaction of the compound of the general formula [XXIII] with the compound of the general formula [XXIV] in the step C and the reaction of the compound of the general formula [ ⁇ ] with the compound of the general formula [XXV] in the step E include, for example, dimethylformamide, THF, toluene, in a solvent such as methylene chloride, ⁇ acetonitrile, for example KOH, tert- BuOK :, NaH, K 2 C0 3, can be carried out in the presence of a base such as hexa-methyl disilazide to lithium ⁇ beam.
  • Reaction temperatures range from 0 ° C. to the boiling point of the solvent.
  • Steps B to E can be performed under the same conditions as the reaction conditions in the same kind of reaction used in Step A.
  • the compound represented by the general formula [ ⁇ ] described in the claim (4) can be produced by a method of deprotecting the compound represented by the general formula [XXIV], and the like.
  • the compound represented by the general formula [XIX] can also be produced by culturing the compound represented by the general formula [ ⁇ ] or the compound (28) with a microorganism that glycosylate [Reference] See Examples 1 and 2].
  • the target compound is isolated and purified by a method widely known in the field of organic chemistry (eg, precipitation, solvent extraction, recrystallization, chromatography, etc.).
  • Can be H 2 NNHCH (CH 2 OH) 2 can be produced by the method described in Example 18, and the like.
  • the compound of the general formula [I] provided by the present invention exhibits excellent antitumor activity as shown in the following pharmacological test examples.
  • Cell culture medium containing 1 x 10 3 mouse leukemia cells (P388), human gastric cancer cells (MKN-45), human lung cancer cells (PC-13), or human colon cancer cells (DLD-1) (10% bovine fetal serum-containing - RPMI-1640 medium) was dispensed 50 1 to microplate Bok of 96 min, after 24 hours of incubation at 37 ° C under 5% C0 2, the object to be test solution 50 1 containing the test compound It was added and incubated for 72 hours at still 37 ° C under 5% C0 2. 0.5% Chiazoiruburu 10 1 in addition to the cultures, and fin-incubated over Chillon two hours in 5% C0 2 37 ° C below, was carried out the enzymatic reactions.
  • DLD-1 human colon cancer cells
  • the MKN-45 solid tumor that had been implanted under the skin of a nude mouse in advance and proliferated was minced, and a 3 mm square thereof was implanted under the skin of a test mouse.
  • each dose of the test drug was injected into the tail vein of the mouse once for 5 consecutive days from the time when the tumor grew to 0.3 cm 3 , and then continuously injected for 5 days after the drug was discontinued (treatment schedule: 5Zw x 2 ) Or 4 times every 3-4 days (treatment schedule: 2Zw x 2).
  • Test compound Treatment schedule (mg / kg total) Compound [I -A] 5 / w x 2 27
  • Control Compound 5 / w ⁇ 2 170 The compound provided by the present invention exhibits an even better antitumor effect as shown in the above pharmacological test results than the control compound.
  • the compounds of the present invention show excellent antitumor activity and are useful as antitumor agents for the prevention of diseases, especially for the treatment of cancer.
  • the compound of the present invention is usually formulated into a formulation containing an effective amount of the compound of the present invention together with a pharmaceutically acceptable carrier or excipient. Can be.
  • various forms can be selected, for example, tablets, capsules, oral formulations such as lj, granules or solutions, or solutions or suspensions, for example.
  • oral formulations such as lj, granules or solutions, or solutions or suspensions, for example.
  • examples include sterile liquid parenteral preparations such as suspensions, suppositories, and ointments.
  • Solid preparations can be produced as they are in the form of tablets, capsules, granules or powders, or they can be produced using appropriate additives.
  • additives include, for example, sugars such as lactose or glucose, starches such as corn, wheat or rice, fatty acids such as stearic acid, inorganic salts such as magnesium aluminate metasilicate or anhydrous calcium phosphate, such as polyvinylpyrrole.
  • Synthetic polymers such as oral ridone or polyalkylene glycol; fatty acid salts such as calcium stearate or magnesium stearate; alcohols such as stearyl alcohol or benzyl alcohol; methyl cellulose, carboxymethyl cellulose, ethyl cellulose, Synthetic cellulose derivatives such as hydroxypropylmethylcellulose, and other commonly used additives such as gelatin, talc, vegetable oil, and Arabic rubber
  • Solid preparations such as tablets, capsules, granules and powders are generally
  • liquid preparations use appropriate additives usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil, sesame oil, etc .; suspensions, syrups, injections, infusions It is manufactured in the form of an agent or the like.
  • Particularly suitable solvents for parenteral administration by intramuscular, intravenous or subcutaneous injection include, for example, distilled water for injection, aqueous solution of lidocaine hydrochloride (for intramuscular injection), and physiological saline.
  • Water, aqueous dextrose, ethanol, polyethylene glycol, liquid for intravenous injection (for example, aqueous solutions of citric acid and sodium citrate) or electrolyte solution (for intravenous drip and intravenous injection), or a mixed solution thereof Can be
  • These injections may be in the form of a powder which has been dissolved in advance or a powder to which an appropriate additive has been added, and which is dissolved at the time of use.
  • These injections can usually contain 0.1 to 10% by weight, preferably 1 to 5% by weight of the active ingredient.
  • Liquid preparations such as suspensions and syrups for oral administration can usually contain 0.5 to 10% by weight of active ingredient.
  • the preferred dose of the compound of the present invention depends on the type of compound used, the type of composition formulated, the frequency of application and the specific site to be treated, the severity of the disease, the age of the patient, the diagnosis of a physician, the type of tumor
  • the dose per adult per day can be in the range of 1 to 800 mg for oral administration, and parenteral administration
  • parenteral administration Preferably, for intravenous injection, it can be in the range of 0.1 to 500 mg per word.
  • the frequency of administration varies from once to five times a day depending on the administration method and symptoms.
  • administration methods such as intermittent administration such as alternate day administration and alternate administration can also be used.
  • the present invention will be described more specifically with reference to the following examples, but the present invention is limited to only these examples. It is not something to be done.
  • Boc represents a tert-butoxycarbonyl group; the same applies hereinafter.
  • Example 6-5 compound obtained in) (15) 52m g of copper chloride (II) 26.8 mg and molecular Kyurashibu 50mg for 2 hours ⁇ at room temperature was dissolved in methyl E chill ketone lml. After the reaction solution was filtered through celite, the filtrate was concentrated. The residue was purified by silica gel chromatography (dichloromethane) to obtain 42 mg of the desired compound (16). (Yield: 84%)
  • the reaction solution was distributed with 200 ml of ethyl acetate-100 ml of aqueous ammonium chloride, and the organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water, and then with a saturated saline solution, and then dried and concentrated.
  • the residue was purified using silica gel chromatography (hexane-ethyl acetate: S: 4: 1) to obtain 3.07 g (yield: 91%) of the target compound (19).
  • Microtetraspora sp. A34549 strain cultured on a slope agar medium [Accession number: FERM BP-4206 (Transferred from S. germ fungus No. P-13292 deposited on November 17, 1992) Glucose) 0.2%, dextrin 2.0%, oatmeal 0.5%, defatted rice bran 0.5%, defatted meat-and-bone meal 0.2%, dried yeast 0.1%, magnesium sulfate heptahydrate 0.05%, odorite sodium 0.05%
  • the above culture solution was extracted with 3 L of methyl ethyl ketone (MEK).
  • MEK methyl ethyl ketone
  • the MEK extract was concentrated under reduced pressure.
  • the obtained concentrate was extracted with ethyl acetate.
  • the ethyl acetate extract (850 ml) was dehydrated with anhydrous titanium sulfate and concentrated to dryness.
  • the cells obtained by filtering the above culture solution were extracted twice with methanol (5.1 L, 5.6 L) and twice with tetrahydrofuran (2.2 L, 2.3 L).
  • the combined methanol and tetrahydrofuran extracts were concentrated to about 1600 ml.
  • the aqueous solution obtained by concentration was extracted with hexane (780 ml) to remove impurities, and the aqueous layer was extracted with 3.3 L of ethyl acetate.
  • the ethyl acetate extract was concentrated to dryness, the obtained residue was washed with about 90 ml of ethyl acetate, and the residue was extracted with about 90 ml of methanol.
  • the methanol extract was concentrated to dryness to obtain 694 mg of a yellow-orange solid.
  • the resultant was dissolved in 40 ml and subjected to a column chromatography of Sephadex LH-20 (3.0 ⁇ 53 cm, manufactured by Pharmacia) using methanol as an eluate. Fractions containing the target compound were collected and concentrated to dryness. This was subjected to silica gel column chromatography (1.5 X 46 cm, Kieselgel 60, Merck), washed with black-mouthed form, then with ethyl-form: methanol (10: 1), and then ethyl acetate: methanol (10: 1). Eluted.
  • the compounds of the present invention have excellent antitumor effects and are useful as antitumor agents in the field of medicine.

Abstract

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R?1 and R2¿ represent each OH, R1 being present at the 1- or 2-position while R2 being present at the 10- or 11-position, provided when R1 is present at the 1-position, R2 is present at the 11-position, while when R1 is present at the 2-position, R2 is present at the 10-position. As the compound has an excellent antitumor effect, it is useful as an antitumor drug in the medicinal field.

Description

明 細 書 抗腫瘍性ィンドロピロロカルバゾール誘導体 技術分野  Description Antineoplastic indopyrrololocarbazole derivative Technical field
本発明は医薬の分野で有用であり、 さらに詳細には腫瘍細胞の増殖を阻害 し、 抗腫瘍効果を発揮する新規なインドロピロロカルバゾール誘導体、 その 中間体、 製法及び用途に関する。  The present invention is useful in the field of medicine, and more particularly, relates to a novel indolopyrrolocarbazole derivative which inhibits the growth of tumor cells and exhibits an antitumor effect, an intermediate thereof, a production method thereof, and a use thereof.
背景技術  Background art
癌化学療法の分野においては、 すでに多数の化合物が抗腫瘍剤として実用 化されている。 しかしながら、 様々な種類の腫瘍に対してその効果は必ずし も充分ではなく、 またこれらの薬剤に対する腫瘍細胞の耐性の問題が抗腫瘍 剤の臨床上の使用を複雑にしている [第 47回日本癌学会総会記事、 12~15頁 (1988年） 参照]。  Many compounds have already been put into practical use as antitumor agents in the field of cancer chemotherapy. However, its effect on various types of tumors is not always sufficient, and the problem of tumor cell resistance to these drugs complicates the clinical use of antitumor agents [47th Japan Article of the General Meeting of the Cancer Society, pp. 12-15 (1988)].
このような状況下、 癌治療の分野においては常に新規な制癌物質の開発が 求められている。 特に、 既存の制癌物質に対する耐性を克服し、 既存の制癌 物質が充分に効果を発揮できない種類の癌に対して有効性を示す物質が必要 とされている。  Under these circumstances, the development of new anticancer substances is always required in the field of cancer treatment. In particular, there is a need for a substance that overcomes resistance to existing anticancer substances and is effective against cancers of a type for which existing anticancer substances are not sufficiently effective.
このような現状に鑑み、 本発明者らは広く微生物代謝産物をスクリーニン グした結果、 抗腫瘍活性を有する新規な化合物 BE- 13793C (12，13-ジヒド ロ- 1，1トジヒ ドロキシ- 5H-インドロ [2，3- a] ピロ口 [3,4 - c] カルバゾ一 ノレ- 5，7 (6H) -ジオン） を見出し、 開示した 「日本特開平 3- 20277号公報及 びザ'ジャーナル'ォブ 'アンチピオティクス（J.Antibiotics)第 44巻、 723〜 728頁 （1991年） 参照]。  In view of this situation, the present inventors have screened a wide range of microbial metabolites, and have found that a novel compound having antitumor activity, BE-13793C (12,13-dihydroxy-1,1 todihydroxy-5H- Indolo [2,3-a] pyro-mouth [3,4-c] carbazomono-5,7 (6H) -dione) was discovered and disclosed in “Japanese Patent Application Publication No. 3-20277 and the 'Journal'. J. Antibiotics, Vol. 44, pp. 723-728 (1991)].
その後、 BE- 13793Cに化学修飾を加えて優れた抗腫瘍活性を有するィンド 口ピロロカルバゾール化合物を創製し、 開示した （国際公開 W091ノ 18003 及びヨーロッパ特許公開公報 EP0545195 A1参照)。  After that, BE-13793C was chemically modified to create and disclose a pyrrocarbazole compound having excellent antitumor activity (see International Publication W091-18003 and European Patent Publication EP0545195 A1).
先の特許出願 （国際公開 W091ノ 18003及びヨーロッパ特許公開公報 EP0545195 A1) において開示したインドロピロロカルバゾール系の抗腫瘍 性物質よりもさらに優れた抗腫瘍活性を有する化合物を創製することが本発 明が解決しょうとする課題である。 The present invention is based on the creation of a compound having an antitumor activity that is even better than the indolopyrrolocarbazole-based antitumor substance disclosed in the earlier patent application (International Publication W091 / 18003 and European Patent Publication EP0545195 A1). Akira is the task to be solved.
発明の開示  Disclosure of the invention
本発明者らは、 先に開示したィンドロピロロカルバゾール系の抗腫瘍性化 合物よりもさらに優れた抗腫瘍活性を有する化合物を創製することを目的 に、 インドロピロロカルバゾール誘導体を多数合成し、 その抗腫瘍活性につ いて検討した結果、 今回、 下記一般式 [I] で示される化合物が極めて優れた 抗腫瘍活性、安定性及び安全性を有する新規化合物であることを見い出した。 かくして、 本発明は、 一般式  The present inventors have synthesized a large number of indolopyrrolocarbazole derivatives with the aim of creating a compound having an antitumor activity that is even better than the previously disclosed indlopyrrolocarbazole-based antitumor compounds. However, as a result of examining its antitumor activity, the present inventors have found that the compound represented by the following general formula [I] is a novel compound having extremely excellent antitumor activity, stability and safety. Thus, the present invention provides a compound of the general formula
Figure imgf000004_0001
Figure imgf000004_0001
[式中、 R1及び R2は 0Hを示し、その結合位置は R1は 1位又は 2位であり、 R2 は 10位又は 11位であり、 R1力 位の時、 R2は 11位であり、 R1が 2位の時、 R2は 10位である] で表される化合物又はその製薬学的に許容しうる塩、その 中間体、 製法及び用途に関する。 [Wherein, R 1 and R 2 represent 0H, and the bonding position thereof is R 1 is 1 or 2 position, R 2 is 10 or 11 position, and when R 1 force, R 2 is 11-position, and when R 1 is 2-position, R 2 is 10-position], or a pharmaceutically acceptable salt thereof, an intermediate thereof, production methods and uses.
本発明化合物及び中間体の製造法について説明する。  The method for producing the compound of the present invention and the intermediate will be described.
本発明化合物及び中間体は、 以下の工程 A〜Eに示す方法で製造すること ができる。 工程 A The compound of the present invention and the intermediate can be produced by the methods shown in the following steps A to E. Process A
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000005_0001
Figure imgf000006_0001
工程 B Process B
Figure imgf000007_0001
工程 c
Figure imgf000007_0001
Process c
Figure imgf000008_0001
工程 D
Figure imgf000008_0001
Process D
Figure imgf000008_0002
Figure imgf000008_0002
[IX] 工程 E [IX] Process E
Figure imgf000009_0001
工程 A〜E及び後記請求の範囲において用いられている記号及び用語の意 味は次のとおりである。
Figure imgf000009_0001
The meanings of the symbols and terms used in Steps A to E and the claims set forth below are as follows.
一般式の R1及び R2は OHを示す。 但し、 R1は環上の 1位又は 2位、 R2は 10 位又は 11位にそれぞれ結合し、 R1が 1位の時、 R2は 11位であり、 R1が 2位 の時、 R2は 10位である。 R 1 and R 2 in the general formula represent OH. However, R 1 is bonded to the 1-position or 2-position on the ring, R 2 is bonded to the 10-position or 11-position, respectively, when R 1 is 1-position, R 2 is 11-position, and when R 1 is 2-position , R 2 is in the 10th place.
R3は低級アルキル基、 ベンジルォキシメチル基又はァラルキル基を示し、 低級アルキル基としては、 メチル基、 ェチル基、 プロピル基、 sec-プロピル 基、 ブチル基、 ペンチル基、 へキシル基等の炭素数 1〜6個の直鎖状又は分枝 状のアルキル基を意味し、 ァラルキル基とは、 ベンジル基、 フヱネチル基、 フヱニルプ口ピル基等の炭素数 7〜12個のァラルキル基を意味する。 R 3 represents a lower alkyl group, a benzyloxymethyl group or an aralkyl group, The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a sec-propyl group, a butyl group, a pentyl group, and a hexyl group. The aralkyl group means an aralkyl group having 7 to 12 carbon atoms such as a benzyl group, a phenyl group and a phenyl group.
R4は、 水素原子、 低級アルキル基、 ベンジルォキシメチル基又はァラルキ ノレ基を示し、低級アルキル基及びァラルキル基の意味は R3において記載した 意味と同様である。 R 4 represents a hydrogen atom, a lower alkyl group, a benzyloxymethyl group or an aralkyl group, and the meanings of the lower alkyl group and the aralkyl group are the same as those described for R 3 .
R5及び R6は保護された〇Hを示す。 但し、 R5は環上の 1位又は 2位に結合 し、 R6は 10位又は 11位に結合し、 R5が 1位の時、 R6は 11位であり、 が 2位の時、 R6は 10位である。 R 5 and R 6 show protected ΔH. Provided that R 5 is bonded to the 1- or 2-position on the ring, R 6 is bonded to the 10- or 11-position, and when R 5 is in the 1 position, R 6 is in the 11 position and is in the 2 position , R 6 is 10th.
使用し得る保護基としては、 例えばべンジル基、 トリル基、 パラメ トキシ ベンジル基、 ベンジルォキシメチル基等を挙げることができる。  Examples of the protecting group that can be used include a benzyl group, a tolyl group, a paramethoxybenzyl group, and a benzyloxymethyl group.
R7〜R1Dは、 同一又は異なって OHの保護基を意味し、用い得る保護基とし ては、 例えばべンジル基、 トリル基、 パラメ トキシベンジル基、 ベンジルォ キシメチル基等を挙げることができる。 R 7 to R 1D are the same or different and means a protecting group of the OH, is a protecting group which can be used may include, for example, base Njiru group, a tolyl group, parameters Tokishibenjiru group, a Benjiruo Kishimechiru group.
R11は水素原子又はィンドール骨格のァミノ基の保護基を示し、保護基とし ては、例えば tert-ブトキンカルボニル基、 メチルォキシカルボニル基等の低 級アルコキシカルボニル基、 ベンジル基、 ベンジルォキシメチル基、 トリィ ソプロビルシリル基、 2-トリメチルシリルェチルォキシメチル基、 メシル基、 トシル基等を挙げることができる。 R 11 represents a hydrogen atom or a protecting group for an amino group of an indole skeleton, and examples of the protecting group include lower alkoxycarbonyl groups such as tert-butynecarbonyl group and methyloxycarbonyl group, benzyl group and benzyloxy group. Examples thereof include a methyl group, a trisoprovirsilyl group, a 2-trimethylsilylethyloxymethyl group, a mesyl group, and a tosyl group.
R12はィンドール骨格のァミノ基の保護基を示し、保護基の例は、上記と同 様である。 R 12 represents a protecting group for the amino group of the indole skeleton, and examples of the protecting group are the same as those described above.
Xは脱離基であり、塩素原子、臭素原子、 ヨウ素原子等を挙げることができ る。  X is a leaving group, and examples thereof include a chlorine atom, a bromine atom, and an iodine atom.
X1は脱離基であり、塩素原子、臭素原子、 ヨウ素原子等のハロゲン原子、メ シル基、 トシル基等の有機スルホ二ルォキシ基等を挙げることができる。 一般式 [IX]等で表されるマレイミ ド化合物類と一般式 [X]等で表される インドール化合物類を反応させ、 一般式 [XI] 等で表される化合物を製造す る際に使用する有機金属化合物とは、 例えばブチルリチウム等のアルキルリ チウム類、 リチウムジイソプロピルアミ ド、 リチウムへキサメチルジシラジ ド、 ナトリウムへキサメチルジシラジド、 力リウムへキサメチルジシラジド 等のアル力リ金属へキサアルキルジシラジド類、 ェチルマグネシウムブロミ ド、 メチルマグネシゥムクロリ ド等のグリ二ヤール試薬等を意味する。 X 1 is a leaving group, and examples thereof include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, and an organic sulfonyloxy group such as a mesyl group and a tosyl group. Used to produce compounds represented by the general formula [XI] by reacting maleimide compounds represented by the general formula [IX] etc. with indole compounds represented by the general formula [X] etc. Organometallic compounds include, for example, alkyllithiums such as butyllithium, lithium diisopropylamide, and lithium hexamethyldisilazide. Metal hexaalkyldisilazides, such as sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc., Grignard, such as ethylmagnesium bromide and methylmagnesium chloride Refers to reagents and the like.
ミツノブ反応とは、 トリフヱニルホスフィン、 トリブチルホスフィン等の 有機ホスフィン類とァゾジカルボン酸ジェチルエステル、 ァゾジ力ルポン酸 ジ tert -ブチルェステル、ァゾジカルボン酸ジイソプロピルエステル、 ァゾジ カルボン酸 ジ- N，N-ジメチルアミ ド、 ァゾジカルボン酸 ジ- N-メチルビ ペラジンァミ ド等のァゾジカルボン酸誘導体を用いて、 グリコシド結合を形 成する反応をいう [シンセシス （Synthesis)，1， 1981年 ,p.l〜28参照]。 一般式 [XVII] 等で表されるィンドール骨格を二個有する化合物に酸化剤 を反応させて、一般式 [XVIII]等で表されるィンドロピロロカルバゾールイ匕 合物に変換する際に用い得る酸化剤とは、 2,3-ジクロロ- 5,6-ジシァノ- 1，4- ベンゾキノン（以下、 DDQと略す）、 CuCl2、 Cu (OAc)2、 Cu (N02)2、 PdCl2、 Pd (OAc)2、 Pd (CF3COO)2等を意味する。 The Mitsunobu reaction is defined as triphosphinyl phosphine, tributyl phosphine, and other organic phosphines and azodicarboxylic acid dimethyl ester, azodicarboxylic acid ditert-butylester, azodicarboxylic acid diisopropyl ester, azodicarboxylic acid di-N, N-dimethylamide, Azodicarboxylic acid Refers to a reaction that forms a glycosidic bond using an azodicarboxylic acid derivative such as di-N-methylbiperazine amide [see Synthesis, 1, 1981, pl-28]. It is used when a compound having two indole skeletons represented by the general formula [XVII] is reacted with an oxidizing agent to convert the compound to an indopyrrolocarbazole derivative represented by the general formula [XVIII]. the obtained oxidizing agent, 2,3-dichloro - 5,6 Jishiano - 1,4-benzoquinone (hereinafter, abbreviated as DDQ), CuCl 2, Cu ( OAc) 2, Cu (N0 2) 2, PdCl 2, Pd (OAc) 2 , Pd (CF 3 COO) 2 and the like.
工程 Aの説明 Description of process A
一般式 [IX] で表されるマレイミ ド化合物と、一般式 [X] で表されるィン ドール化合物との反応は、 前記で述べた如く、 リチウムへキサメチルジシラ ジド等のアル力リ金属へキサアルキルジシラジド、 ェチルマグネシウムブロ ミ ド等のグリニャール試薬等を用いて行うことができ、 この際に使用し得る 溶媒としては、 トルエン、ベンゼン、 テトラヒドロフラン （THF)、 ジォキサ ン、 ジェチルエーテル等を挙げることができる。  As described above, the reaction between the maleimide compound represented by the general formula [IX] and the indole compound represented by the general formula [X] is carried out using an alkali metal hexane such as lithium hexamethyldisilazide. The reaction can be carried out using a Grignard reagent such as alkyldisilazide and ethylmagnesium bromide. In this case, solvents that can be used include toluene, benzene, tetrahydrofuran (THF), dioxane, and dimethyl ether. Can be mentioned.
反応温度は、通常、- 78°C〜130°Cであり、好適には- 20°C〜110°Cである。 一般式 [XI] で表される化合物のインドール骨格のァミノ基に保護基を導 入して一般式 [ΧΠ] を製造することができる。 この際に使用し得る保護試剤 としては、 上記の保護基に相当するハロゲン化物又は酸無水物等を使用する ことができ、例えば好適には、二炭酸ジ- tert -プチル、 tert-ブチルォキシ力 ルポニルクロライド等が使用できる。  The reaction temperature is generally -78 ° C to 130 ° C, preferably -20 ° C to 110 ° C. By introducing a protecting group into the amino group of the indole skeleton of the compound represented by the general formula [XI], the general formula [式] can be produced. As the protecting reagent that can be used in this case, a halide or an acid anhydride corresponding to the above-mentioned protecting group can be used. For example, di-tert-butyl dicarbonate, tert-butyloxyl alcohol and the like are preferably used. Nyl chloride and the like can be used.
この際、 4- N，N-ジメチルァミノピリジン等の塩基の存在下に行うことが好 ましく、 また使用し得る溶媒としては、 トルエン、 ベンゼン、 THF、 ジォキ サン、エーテル等を挙げることができる。 反応温度は、通常、 - 78°C〜100°C、 好ましくは- 25 °C〜25 °Cである。 In this case, it is preferable to carry out the reaction in the presence of a base such as 4-N, N-dimethylaminopyridine. Examples of usable solvents include toluene, benzene, THF, dioxane and ether. it can. The reaction temperature is usually -78 ° C to 100 ° C, Preferably it is −25 ° C. to 25 ° C.
一般式 [XII] で表される化合物と一般式 [XIII] で表される化合物を反応 させる、 一般式 [XIV] で表される化合物の製造は、 上記一般式 [IX] で表 される化合物と一般式 [XI] で表される化合物との反応と同様に行うことが できる。  The compound represented by the general formula [XIV] is produced by reacting the compound represented by the general formula [XII] with the compound represented by the general formula [XIII]. And the compound represented by the general formula [XI].
一般式 [XIV] で表される化合物と一般式 [XV] で表される化合物との反 応は、 いわゆるミツノブ反応によって行うことができ、 この際には、 上記の 有機ホスフィン類及びァゾジカルボン酸誘導体を用いることができ、 好適に は、 トリブチルホスフィン、 トリフエニルホスフィン等の有機ホスフィン類 及びァゾジカルボン酸ジェチルエステル、 ァゾジカルボン酸ジイソプロピル エステル等のァゾジ力ルポン酸誘導体を用いることができる。  The reaction between the compound represented by the general formula [XIV] and the compound represented by the general formula [XV] can be performed by a so-called Mitsunobu reaction. In this case, the above-mentioned organic phosphines and azodicarboxylic acid derivatives are used. Preferably, organic phosphines such as tributylphosphine and triphenylphosphine and azodicarboxylic acid derivatives such as azodicarboxylic acid getyl ester and azodicarboxylic acid diisopropyl ester can be used.
反応溶媒としては、 THF、 ジォキサン、 エーテル等が好適に使用すること ができ、 反応温度は、 通常、- 78°C〜50 °Cであり、 好適には、- 40 °C〜20 °C である。  As the reaction solvent, THF, dioxane, ether and the like can be suitably used, and the reaction temperature is generally -78 ° C to 50 ° C, preferably -40 ° C to 20 ° C. is there.
—般式 [XVI] で表される化合物のィンドール骨格のァミノ基の脱保護は、 選択的に脱保護できる条件が好ましく、 例えば酸性又は塩基性の条件下にお いて、他の部分の保護基を保持しつつ、ァミノ基の tert-ブトキシカルボニル 基、 2-トリメチルシリルェトキシメチル基等を選択的に除去し得るような条 件が好ましい。  — The deprotection of the amino group of the indole skeleton of the compound represented by the general formula [XVI] is preferably performed under conditions that allow selective deprotection. For example, under acidic or basic conditions, the protecting group of another moiety may be removed. It is preferable that the conditions are such that the tert-butoxycarbonyl group, 2-trimethylsilylethoxymethyl group and the like of the amino group can be selectively removed while maintaining the above.
例えば、 トリフルォロ酢酸、 HF等の酸、 メチルァミン、 tert-ブトキシカ リウム、 テトラノルマルブチルアンモニゥムフルオリ ド等の塩基等を好適に 使用することができる。  For example, acids such as trifluoroacetic acid and HF, and bases such as methylamine, tert-butoxylium, and tetra-n-butylammonium fluoride can be suitably used.
一般式 [XVIII] で表される化合物は、 一般式 [XVII] で表される化合物 を酸化的に環化して製造することができ、 この際に使用できる酸化剤として は、 上記の DDQ、 CuCl2、 Cu (〇Ac)2、 Cu (N02)2、 PdCl2、 Pd (OAc)2、 Pd (CF3COO)2等を挙げることができ、 反応溶媒としてはトルエン、 塩化メ チレン、 ジメチルホルムアミ ド、 ジォキサン、 エーテル等が使用でき、 また 反応温度は、 通常、 0 °C〜100 °Cである。 The compound represented by the general formula [XVIII] can be produced by oxidatively cyclizing the compound represented by the general formula [XVII]. As the oxidizing agent used in this case, the above-mentioned DDQ, CuCl 2 , Cu (〇Ac) 2 , Cu (N0 2 ) 2 , PdCl 2 , Pd (OAc) 2 , Pd (CF 3 COO) 2 etc., and the reaction solvent is toluene, methylene chloride, dimethyl Formamide, dioxane, ether and the like can be used, and the reaction temperature is usually 0 ° C to 100 ° C.
一般式 [XVIII]で表される化合物のフェノール性水酸基及びグリコシル基 の保護基の除去は、 酸性の条件又はよく知られた通常の水素添加反応等によ り行うことができる。 The removal of the protecting groups for the phenolic hydroxyl group and the glycosyl group of the compound represented by the general formula [XVIII] is carried out under acidic conditions or a well-known ordinary hydrogenation reaction. Can be performed.
一般式 [XIX] で表される化合物に塩基を反応させることにより一般式 [XX] で表される化合物を製造することができる。 この際に使用される塩基 としては、 NaOH、 K0H、 K2C03、 Na2C〇3、 NaHC03等を使用することがで き、 また使用できる溶媒としては水、 メタノール、 エタノール、 ジメチルホ ルムアミ ド等を挙げることができる。 また反応温度は通常 o°c〜溶媒の沸点 の範囲である。 The compound represented by the general formula [XX] can be produced by reacting the compound represented by the general formula [XIX] with a base. The base used in this, NaOH, K0H, K 2 C0 3, Na 2 C_〇 3, Ki is permitted to use NaHCO 3 and the like. As the solvent which can be used water, methanol, ethanol, Jimechiruho Rumuami And the like. The reaction temperature is usually in the range of o ° c to the boiling point of the solvent.
一般式 [XX] で表される化合物に H2NNHCH (CH2OH)2を反応させるこ とにより、一般式 [I] で表される化合物を製造することができ、 この際に使 用し得る溶媒としては、 メタノール、 エタノール、 THF、 ジメチルホルムァ ミ ド等であり、 反応温度は通常 0 °C〜溶媒の沸点範囲である。 By reacting the compound represented by the general formula [XX] with H 2 NNHCH (CH 2 OH) 2 , the compound represented by the general formula [I] can be produced. Examples of the obtained solvent include methanol, ethanol, THF, dimethylformamide and the like, and the reaction temperature is usually from 0 ° C to the boiling point of the solvent.
使用する ¾NNHCH (CH2OH)2の量は、化合物 [XX] に対して通常 1〜3 モル当量であり、 必要に応じてこれ以下、 これ以上の量を使用することもで さる。 The amount of ¾NNHCH (CH 2 OH) 2 used is usually 1 to 3 molar equivalents relative to compound [XX], and if necessary, lower or higher amounts can be used.
工程 B〜Eの説明 Description of steps B to E
工程 Cにおける一般式 [XXIII] の化合物と一般式 [XXIV] の化合物との 反応、 及び工程 Eにおける一般式 [ΧΧΙΠ] と一般式 [XXV] の化合物との 反応は、 例えばジメチルホルムアミ ド、 THF、 トルエン、 塩化メチレン、 ァ セトニトリル等の溶媒中、 例えば KOH、 tert- BuOK：、 NaH、 K2C03、 リチ ゥムへキサメチルジシラジド等の塩基の存在下に行うことができる。 The reaction of the compound of the general formula [XXIII] with the compound of the general formula [XXIV] in the step C and the reaction of the compound of the general formula [ΧΧΙΠ] with the compound of the general formula [XXV] in the step E include, for example, dimethylformamide, THF, toluene, in a solvent such as methylene chloride, § acetonitrile, for example KOH, tert- BuOK :, NaH, K 2 C0 3, can be carried out in the presence of a base such as hexa-methyl disilazide to lithium © beam.
反応温度は 0 °C〜溶媒の沸点の範囲である。  Reaction temperatures range from 0 ° C. to the boiling point of the solvent.
また、工程 B〜Eにおける他の各工程は、工程 Aで用いた同種の反応におけ る反応条件と同様の条件で行うことができる。  The other steps in Steps B to E can be performed under the same conditions as the reaction conditions in the same kind of reaction used in Step A.
尚、 請求の範囲 （4) に記載される一般式 [Π] で表される化合物は、 一般 式 [XXIV] で表される化合物を脱保護する方法等により製造することがで き、 また、一般式 [XIX] で表される化合物は、一般式 [Π] で表される化合 物又は化合物 （28) 等をグリコシレーシヨンする微生物と培養することによ つても製造することができる [参考例 1及び 2参照]。  The compound represented by the general formula [Π] described in the claim (4) can be produced by a method of deprotecting the compound represented by the general formula [XXIV], and the like. The compound represented by the general formula [XIX] can also be produced by culturing the compound represented by the general formula [Π] or the compound (28) with a microorganism that glycosylate [Reference] See Examples 1 and 2].
反応終了後は、 有機化学の分野で広く知られた方法 （例えば、 沈澱法、 溶 媒抽出法、 再結晶、 クロマトグラフィー等） により、 目的物を単離 ·精製す ることができる。 また、 H2NNHCH (CH2OH)2は実施例 18に記載の方法等 製造することができる。 本発明により提供される一般式 [I] の化合物は、以下の薬理試験例に示さ れる如く優れた抗腫瘍作用を示す。 After completion of the reaction, the target compound is isolated and purified by a method widely known in the field of organic chemistry (eg, precipitation, solvent extraction, recrystallization, chromatography, etc.). Can be H 2 NNHCH (CH 2 OH) 2 can be produced by the method described in Example 18, and the like. The compound of the general formula [I] provided by the present invention exhibits excellent antitumor activity as shown in the following pharmacological test examples.
(1) 各種癌細胞に対する増殖阻害活性 （CTX)  (1) Growth inhibitory activity against various cancer cells (CTX)
測定方法：  Measuring method:
1 X 103個のマウス白血病細胞 （P388)、 ヒト胃癌細胞 （MKN- 45)、 ヒト 肺癌細胞（PC- 13)又はヒト大腸癌細胞（DLD- 1)を含む細胞培養用培地（10 %牛胎児血清含有- RPMI- 1640培地） 50 1を 96穴のマイクロプレー卜に 分注し、 5 % C02下で 37°Cにおいて 24時間培養した後、供試化合物を含む被 検液 50 1を加え、 5 % C02下でさらに 37°Cにおいて 72時間培養した。 培養 液に 0.5 %チアゾィルブルー 10 1を加え、 5 % C02下で 37 °Cにおいて 2時 間ィンキュベーシヨンし、酵素反応を行わせた。 20 %ドデシル硫酸ナトリゥ ム （SDS) を加えて、 反応を停止し、 さらに 37 °Cにおいて 16時間インキュ ベーシヨンして生成した色素を溶解した後、 560nmにおける吸光度を測定し て対照群と比較した。 また、 対照化合物としては、 式 Cell culture medium containing 1 x 10 3 mouse leukemia cells (P388), human gastric cancer cells (MKN-45), human lung cancer cells (PC-13), or human colon cancer cells (DLD-1) (10% bovine fetal serum-containing - RPMI-1640 medium) was dispensed 50 1 to microplate Bok of 96 min, after 24 hours of incubation at 37 ° C under 5% C0 2, the object to be test solution 50 1 containing the test compound It was added and incubated for 72 hours at still 37 ° C under 5% C0 2. 0.5% Chiazoiruburu 10 1 in addition to the cultures, and fin-incubated over Chillon two hours in 5% C0 2 37 ° C below, was carried out the enzymatic reactions. After adding 20% sodium dodecyl sulfate (SDS) to stop the reaction and further incubating at 37 ° C. for 16 hours to dissolve the formed dye, the absorbance at 560 nm was measured and compared with the control group. In addition, as a control compound, the formula
Figure imgf000014_0001
の化合物を用いた。 その結果を第 1表に示す 第 1表 各種癌細胞に対する増殖阻害活性
Figure imgf000014_0001
Was used. The results are shown in Table 1. Table 1 Growth inhibitory activity against various cancer cells
CTX (〃M) CTX (〃M)
供試化合物  Test compound
P388 MKN-45 PC- 13 DLD- 1 化合物 [ I - A] 0.037 0.29 0.34 0.67 化合物 [ I -B] 0.0020. 0.011 0.035 0.10 対照化合物 0.12 0.50 1.4 73  P388 MKN-45 PC-13 DLD-1 Compound [I-A] 0.037 0.29 0.34 0.67 Compound [I-B] 0.0020.0.011 0.035 0.10 Control compound 0.12 0.50 1.4 73
(2) ヒト胃癌 MKN- 45に対する効果 (2) Effect on human gastric cancer MKN-45
予めヌードマウス皮下に移植し、増殖させた MKN- 45固型腫瘍を細切し、 その 3mm角を被験マウス皮下に移植した。 移植後、 腫瘍が 0.3cm3に増殖し た時点より各量の試験薬物をマウス尾静脈に 1曰 1回 5日間連続注射し、 2曰 休薬後更に 5日間注射 （治療スケジュール： 5Zw x 2) 又は 3〜4日毎に 4回 (治療スケジュール： 2Zw x 2)注射し治療した。 治療開始 20曰後又は 32曰 後に腫瘍の長径（L)及び短径（W) を測定し、その体積（V) を求めた （V = 1/2 X L X W2)。 この体積より腫瘍増殖阻害率を算出し、腫瘍増殖を 75 %抑 制する投与総量 （GID75,mg/kg) を求めた。 結果を第 2表に示した。 第 2表 本発明化合物のヒト胃癌 MKN- 45に対する効果 The MKN-45 solid tumor that had been implanted under the skin of a nude mouse in advance and proliferated was minced, and a 3 mm square thereof was implanted under the skin of a test mouse. After transplantation, each dose of the test drug was injected into the tail vein of the mouse once for 5 consecutive days from the time when the tumor grew to 0.3 cm 3 , and then continuously injected for 5 days after the drug was discontinued (treatment schedule: 5Zw x 2 ) Or 4 times every 3-4 days (treatment schedule: 2Zw x 2). Twenty or thirty days after the start of treatment, the major axis (L) and minor axis (W) of the tumor were measured, and the volume (V) was determined (V = 1/2 XLXW 2 ). The tumor growth inhibition rate was calculated from this volume, and the total dose (GID 75 , mg / kg) that inhibited tumor growth by 75% was determined. The results are shown in Table 2. Table 2 Effect of the compound of the present invention on human gastric cancer MKN-45
GID75 GID 75
供試化合物 治療スケジュール (mg/kg total) 化合物 [ I -A] 5/w x 2 27  Test compound Treatment schedule (mg / kg total) Compound [I -A] 5 / w x 2 27
化合物 [ I -B] 2/w x 2 3.0  Compound [I -B] 2 / w x 2 3.0
対照化合物 5/w x 2 170 本発明により提供される化合物は、 対照化合物に比べ、 上記の薬理試験結 果に示される如く更に優れた抗腫瘍作用を示す。  Control Compound 5 / w × 2 170 The compound provided by the present invention exhibits an even better antitumor effect as shown in the above pharmacological test results than the control compound.
上記の薬理試験の結果から明らかなように、 本発明の化合物は優れた抗腫 瘍作用を示し、 抗腫瘍剤として疾病の予防 '治療のため、 殊に癌の処置のた めに有用である。 本発明の化合物をかかる用途に使用する場合、 本発明の化 合物は、 通常、 本発明の化合物の有効量を製薬学的に許容されうる担体又は 賦形剤と共に含んでなる製剤とすることができる。 As is evident from the results of the above pharmacological tests, the compounds of the present invention show excellent antitumor activity and are useful as antitumor agents for the prevention of diseases, especially for the treatment of cancer. Useful for When the compound of the present invention is used for such purposes, the compound of the present invention is usually formulated into a formulation containing an effective amount of the compound of the present invention together with a pharmaceutically acceptable carrier or excipient. Can be.
本発明の化合物を抗腫瘍剤として使用する際の投与形態としては各種の形 態を選択でき、 例えば錠剤、 カプセル剤、 散斉 lj、 顆粒剤若しくは液剤等の経 口製剤、 又は例えば溶液若しくは懸濁液等の殺菌した液状の非経口製剤、 坐 剤、 軟膏剤等が挙げられる。  When the compound of the present invention is used as an antitumor agent, various forms can be selected, for example, tablets, capsules, oral formulations such as lj, granules or solutions, or solutions or suspensions, for example. Examples include sterile liquid parenteral preparations such as suspensions, suppositories, and ointments.
固体の製剤は、 そのまま錠剤、 カプセル剤、 顆粒剤又は粉末の形態として 製造することもできるが、 適当な添加物を使用して製造することもできる。 そのような添加物としては、 例えば乳糖若しくはブドウ糖等の糖類、 例えば トウモロコシ、小麦若しくは米等の澱粉類、例えばステアリン酸等の脂肪酸、 例えばメタケイ酸アルミン酸マグネシウム若しくは無水リン酸カルシウム等 の無機塩、 例えばポリビニルピ口リ ドン若しくはポリアルキレングリコール 等の合成高分子、 例えばステアリン酸カルシウム若しくはステアリン酸マグ ネシゥム等の脂肪酸塩、 例えばステアリルアルコール若しくはベンジルアル コール等のアルコール類、 例えばメチルセルロース、 カルボキシメチルセル ロース、 ェチルセルロース若しくはヒドロキシプロピルメチルセルロース等 の合成セルロース誘導体、 その他、 ゼラチン、 タルク、 植物油、 アラビアゴ ム等通常用いられる添加物が挙げられる。  Solid preparations can be produced as they are in the form of tablets, capsules, granules or powders, or they can be produced using appropriate additives. Such additives include, for example, sugars such as lactose or glucose, starches such as corn, wheat or rice, fatty acids such as stearic acid, inorganic salts such as magnesium aluminate metasilicate or anhydrous calcium phosphate, such as polyvinylpyrrole. Synthetic polymers such as oral ridone or polyalkylene glycol; fatty acid salts such as calcium stearate or magnesium stearate; alcohols such as stearyl alcohol or benzyl alcohol; methyl cellulose, carboxymethyl cellulose, ethyl cellulose, Synthetic cellulose derivatives such as hydroxypropylmethylcellulose, and other commonly used additives such as gelatin, talc, vegetable oil, and Arabic rubber
これらの錠剤、 カプセル剤、 顆粒剤及び粉末等の固形製剤は一般的には Solid preparations such as tablets, capsules, granules and powders are generally
0.1〜100重量％、好ましくは 5〜100重量％の有効成分を含むことができる。 液状製剤は、 水、 アルコール類又は例えば大豆油、 ピーナツ油、 ゴマ油等 の植物由来の油等の液状製剤において通常用いられる適当な添加物を使用 し、 懸濁液、 シロップ剤、 注射剤、 点滴剤等の形態として製造される。 It may contain from 0.1 to 100% by weight, preferably from 5 to 100% by weight, of the active ingredient. For liquid preparations, use appropriate additives usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil, sesame oil, etc .; suspensions, syrups, injections, infusions It is manufactured in the form of an agent or the like.
特に、 非経口的に筋肉内注射、 静脈内注射又は皮下注射の形で投与する場 合の適当な溶剤としては、 例えば注射用蒸留水、 塩酸リ ドカイン水溶液 （筋 肉内注射用）、生理食塩水、 ブドウ糖水溶液、 エタノール、 ポリェチレングリ コール、 静脈内注射用液体 （例えばクェン酸及びクェン酸ナトリウム等の水 溶液） 若しくは電解質溶液 （点滴静注及び静脈内注射用） 等、 又はこれらの 混合溶液が挙げられる。 これらの注射剤は予め溶解したものの他、 粉末のまま或いは適当な添加物 を加えたものを用時溶解する形態もとり得る。 これらの注射液は、通常 0.1〜 10重量％、 好ましくは 1〜5重量％の有効成分を含むことができる。 Particularly suitable solvents for parenteral administration by intramuscular, intravenous or subcutaneous injection include, for example, distilled water for injection, aqueous solution of lidocaine hydrochloride (for intramuscular injection), and physiological saline. Water, aqueous dextrose, ethanol, polyethylene glycol, liquid for intravenous injection (for example, aqueous solutions of citric acid and sodium citrate) or electrolyte solution (for intravenous drip and intravenous injection), or a mixed solution thereof Can be These injections may be in the form of a powder which has been dissolved in advance or a powder to which an appropriate additive has been added, and which is dissolved at the time of use. These injections can usually contain 0.1 to 10% by weight, preferably 1 to 5% by weight of the active ingredient.
また、経口投与用の懸濁剤、 シロップ剤等の液剤は、通常、 0.5〜10重量％ の有効成分を含むことができる。  Liquid preparations such as suspensions and syrups for oral administration can usually contain 0.5 to 10% by weight of active ingredient.
本発明の化合物の好ましい投与量は、 使用される化合物の種類、 配合され た組成物の種類、 適用頻度及び治療すべき特定部位、 病気の軽重、 患者の年 令、 医師の診断、 腫瘍の種類等によって変えることができるが、 一応の目安 として、 例えば、 1日当りの成人 1人当りの投与量は、 経口投与の場合、 1な いし 800mgの範囲内とすることができ、 また非経口投与、好ましくは静脈内 注射の場合、 1曰当り 0.1ないし 500mgの範囲内とすることができる。 なお、 投与回数は投与方法及び症状により異なるカ^ 1日 1回ないし 5回である。 ま た、 隔日投与、 隔々曰投与などの間歇投与等の投与方法も用いることができ 以下に実施例を挙げて本発明をより具体的に説明するが、 本発明はこれら 実施例のみに限定されるものではない。  The preferred dose of the compound of the present invention depends on the type of compound used, the type of composition formulated, the frequency of application and the specific site to be treated, the severity of the disease, the age of the patient, the diagnosis of a physician, the type of tumor As a rough guide, for example, the dose per adult per day can be in the range of 1 to 800 mg for oral administration, and parenteral administration Preferably, for intravenous injection, it can be in the range of 0.1 to 500 mg per word. The frequency of administration varies from once to five times a day depending on the administration method and symptoms. In addition, administration methods such as intermittent administration such as alternate day administration and alternate administration can also be used.The present invention will be described more specifically with reference to the following examples, but the present invention is limited to only these examples. It is not something to be done.
実施例 1 Example 1
式：  Formula:
Figure imgf000017_0001
で表される化合物の製造。
Figure imgf000017_0001
Production of the compound represented by
下記工程 1) 〜9) に示される方法で製造した c  Manufactured by the method shown in the following steps 1) to 9) c
1) 式： (1) Bn〇 1 set: (1) Bn〇
(式中、 Bnはベンジル基を示す。 以下、 同じ。） で表される化合物の製造。  (Wherein, Bn represents a benzyl group; the same applies hereinafter).
7-ベンジルォキシインドール gを THF150mlに溶解し、 リチウムへキサ メチルジシラジド （1M : THF溶液） 161.3mlを加え窒素雰囲気下 0 °Cで 30 分間攪拌した後、 2，3 -ジブロモ - N -メチルマレイミ ド 18.1gの THF溶液 180mlを 10分かけて滴下した。  Dissolve 7-benzyloxyindole g in 150 ml of THF, add 161.3 ml of lithium hexamethyldisilazide (1M: THF solution), stir at 0 ° C for 30 minutes under nitrogen atmosphere, and then add 2,3-dibromo-N-methylmaleimide 180 ml of a 18.1 g THF solution was added dropwise over 10 minutes.
滴下終了後、 0 °Cにて 0.5時間攪拌した後、反応液を 2N塩酸 1Lに注ぎ込み、 酢酸ェチル 2Lで抽出した。 有機層を飽和炭酸水素ナトリゥム水溶液ついで飽 和食塩水で洗浄後、乾燥、濃縮し残渣を酢酸ェチル -へキサンを用いて再結晶 することにより目的化合物 （1) 26.9gを得た。 （収率： 97 %) After completion of the dropwise addition, the mixture was stirred at 0 ° C. for 0.5 hour, poured into 1 L of 2N hydrochloric acid, and extracted with 2 L of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried and concentrated, and the residue was recrystallized from ethyl acetate-hexane to obtain 26.9 g of the desired compound (1). (Yield: 97%)
HRMS (m/z) ： found 410.0273， calcd 410.0248 [C2。H N2O3Brとして] IR (KBr) ： cm" 1 1705, 1628, 1576, 1433, 1383, 1259, 1247, 1076,762,739 Ή- NMR (300MHz,CDCl3)： δ ppm 9.03 (lH，brs)，7.94 (lH，d，J = 3.0 Hz) ,7.64 (lH,d,J = 8.0Hz) .7.30- 7.53 (5H，m) .7.15 (lH.t.J = 8.0Hz) , 6,82 ( lH,d,J = 8.0Hz) ,5.22 (2H，s)，3.16 (3H,s) HRMS (m / z): found 410.0273, calcd 410.0248 [C 2. HN 2 O 3 Br] IR (KBr): cm " 1 1705, 1628, 1576, 1433, 1383, 1259, 1247, 1076,762,739 Ή-NMR (300 MHz, CDCl 3 ): δ ppm 9.03 (lH, brs) , 7.94 (lH, d, J = 3.0 Hz), 7.64 (lH, d, J = 8.0 Hz) .7.30-7.53 (5H, m) .7.15 (lH.tJ = 8.0 Hz), 6,82 (lH, d, J = 8.0Hz), 5.22 (2H, s), 3.16 (3H, s)
2) 式： 2) Formula:
Figure imgf000018_0001
Figure imgf000018_0001
(式中、 Bocは tert-ブトキシカルボ二ル基を示す。 以下、 同じ。） で表される 化合物の製造。  (In the formula, Boc represents a tert-butoxycarbonyl group; the same applies hereinafter.)
実施例 1 - 1) で得られた化合物 （1) 29g、 二炭酸ジ- tert-ブチル 169g及 び 4- N，N-ジメチルァミノピリジン 136mgを THF200mlに溶解し室温にて 1時間攪拌した。 反応液を濃縮後、残渣をシリカゲルクロマトグラフィー（ク ロロホルム） を用いて精製し、 さらにクロ口ホルム-酢酸ェチル -へキサンを 用いて再結晶し目的化合物 （2) 32.9gを得た。 （収率： 92 %) 29 g of the compound (1) obtained in Example 1-1), 169 g of di-tert-butyl dicarbonate and 136 mg of 4-N, N-dimethylaminopyridine were dissolved in 200 ml of THF and stirred at room temperature for 1 hour. After concentrating the reaction mixture, the residue was subjected to silica gel chromatography (C The residue was purified using chloroform and further recrystallized from chloroform-ethyl acetate-hexane to obtain 32.9 g of the desired compound (2). (Yield: 92%)
IR (KBr) ： cm" 1 1765, 1712,1438,1369, 1261,1228, 1149,739 IR (KBr): cm " 1 1765, 1712,1438,1369, 1261,1228, 1149,739
HRMS (m/z)： found 510.0815, calcd 510.0790に H23N205Brとして] Ή- NMR (300MHz，CDCl3)： (5 ppm 8.04 (lH,s) ,7.20-7.62 (7H,m)，6.95HRMS (m / z): found 510.0815, as H 23 N 2 0 5 Br in calcd 510.0790] Ή- NMR (300MHz, CDCl 3): (5 ppm 8.04 (lH, s), 7.20-7.62 (7H, m) , 6.95
(lH,d,J = 7.9Hz),5.23 (2H，s),3.18 (3H，s)，1.53 (9H,s) (lH, d, J = 7.9Hz), 5.23 (2H, s), 3.18 (3H, s), 1.53 (9H, s)
3) 式： 3) Formula:
(3)
Figure imgf000019_0001
(3)
Figure imgf000019_0001
で表される化合物の製造。 Production of the compound represented by
7-ベンジルォキシィンドール 107.2mgを THF3mlに溶解し、 リチウムへキ サメチルジシラジド （1M： THF溶液） 0.48mlを加え窒素雰囲気下 0°Cで 15 分間攪拌した後、 実施例 1 - 2) で得た化合物 （2) 102.2mgの THF溶液 2ml を 20分かけて滴下した。 滴下終了後、 室温にて 0.5時間攪拌した後、 反応液 を 2N塩酸 10mLに注ぎ込み、酢酸ェチル 30mLで抽出した。 有機層を水、飽 和炭酸水素ナトリウム水溶液ついで飽和食塩水で洗浄後、 乾燥、 濃縮し残渣 をシリカゲルクロマトグラフィ （へキサン-酢酸ェチル = 4 : 1) を用いて精製 し、 目的化合物 (3) 112.7mgを得た。 (収率： 86 %)  107.2 mg of 7-benzyloxyindole was dissolved in 3 ml of THF, 0.48 ml of lithium hexamethyldisilazide (1M: THF solution) was added, and the mixture was stirred under a nitrogen atmosphere at 0 ° C for 15 minutes. A compound (2) obtained in 2) (2) 10 ml of a THF solution (2 ml) was added dropwise over 20 minutes. After the completion of the dropwise addition, the mixture was stirred at room temperature for 0.5 hour, then poured into 10 mL of 2N hydrochloric acid, and extracted with 30 mL of ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and then with saturated saline, dried and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 4: 1) to give the target compound (3) 112.7 mg was obtained. (Yield: 86%)
HRMS (m/z)： found 653.2529, calcd 653.2526 [C4。H35N306として] IR (KBr) : cm - 1 1759,1734,1579,1498,1430,1261,1217,1149,752,733 Ή- NMR (300MHz,CDCl3) ： <5 ppm 8.78 (lH，brs)，7.90 (lH,s),7.75 (lH，s) ,7.29- 7.52 (10H,m)，6.58- 6.82 (6H，m)，5.17 (2H，s)，5.15 (2H, s)，3.19 (3H,s),1.53 (9H，s) HRMS (m / z): found 653.2529, calcd 653.2526 [C 4. H 35 N 3 0 as 6] IR (KBr): cm - 1 1759,1734,1579,1498,1430,1261,1217,1149,752,733 Ή- NMR (300MHz, CDCl 3): <5 ppm 8.78 (lH, brs), 7.90 (lH, s), 7.75 (lH, s), 7.29-7.52 (10H, m), 6.58-6.82 (6H, m), 5.17 (2H, s), 5.15 (2H, s), 3.19 (3H, s), 1.53 (9H, s)
4) 式：
Figure imgf000020_0001
で表される化合物の製造。 4) Formula:
Figure imgf000020_0001
Production of the compound represented by
実施例 1 - 3) で得た化合物 （3) 300mg、 2，3,4，6- 0-テトラベンジル- D - グルコビラノース 746.2mg及びトリフェニルホスフィン 543mgを THF15ml {こ溶解し、- 78 °Cにてァゾジカルボン酸ジイソプロピルエステル 0.419mlを加 ぇ徐々に室温まで昇温しながら 3時間攪拌した。 反応液を酢酸ェチル 40ml- 2N塩酸 20mlで分配し、有機層を水、飽和炭酸水素ナトリウム水溶液、水、次 C、で飽和食塩水で洗浄後、乾燥濃縮した.残渣をシリ力ゲルクロマトグラフィ The compound (3) obtained in Example 1-3) (3) 300 mg, 2,3,4,6-0-tetrabenzyl-D-glucoviranose 746.2 mg and triphenylphosphine 543 mg were dissolved in THF (15 ml) and dissolved at -78 ° In C, 0.419 ml of azodicarboxylic acid diisopropyl ester was added, and the mixture was stirred for 3 hours while gradually warming to room temperature. The reaction solution was partitioned between 40 ml of ethyl acetate and 20 ml of 2N hydrochloric acid, and the organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and then concentrated to dryness.
(トルエン-酢酸ェチル：50 : 1) を用いて精製し目的化合物（4) 459.3mg (収 率： 85 % ) を得た。 Purification was performed using (toluene-ethyl acetate: 50: 1) to obtain 459.3 mg (yield: 85%) of the target compound (4).
HRMS (m/z) ： found 1175.4950, calcd 1175.4932 [C74H69N30„とし て] HRMS (m / z): found 1175.4950, calcd 1175.4932 [as C 74 H 69 N 30 „]
IR (KBr) ： cm" 1 1759， 1701，1579, 1454， 1440， 1384， 1358， 1259, 1232， IR (KBr): cm "1 1759, 1701,1579, 1454, 1440, 1384, 1358, 1259, 1232,
1149,1087,752,735,662  1149,1087,752,735,662
Ή- NMR (300MHz，CDCl3)： 5 ppm 8.19 (lH,s),7.91 (lH，s)，7.45 (2H， d，J = 6.6Hz)，6.96- 7.39 (25H,m) ,6.54- 6.71 (7H，m)，6.48 (2H，dd，J = 1.6，8.5Hz)，6.43 (lH.d.J = 8.9Hz),5.13 (2H，s)，5.02 (lH,d，J = 11.4 Hz) ,4.90 (lH，d，J = 10.7Hz), 4.84 (lH，d，J = 10.8Ηζ)，4·83 (lHd，J =Ή-NMR (300 MHz, CDCl 3 ): 5 ppm 8.19 (lH, s), 7.91 (lH, s), 7.45 (2H, d, J = 6.6 Hz), 6.96 to 7.39 (25H, m), 6.54-6.71 (7H, m), 6.48 (2H, dd, J = 1.6, 8.5Hz), 6.43 (lH.dJ = 8.9Hz), 5.13 (2H, s), 5.02 (lH, d, J = 11.4Hz), 4.90 (lH, d, J = 10.7Hz), 4.84 (lH, d, J = 10.8Ηζ), 4.83 (lHd, J =
11.4Hz),4.80 (lH，d，J = 10.8Hz)，4.60 (lH.d.J = 12.7Hz),4.59 (1H, d，J = 10.8Hz),4.53 (lH.dJ = 11.4Hz),4,39 (lH，d，J = 9.9Hz)，3.80 (lH,U = 8.9Hz) ,3.64- 3.76 (4H，m)，3.56 (lH,t,J = 9.1Hz) ,3.38- 3.46 (lH,m),3.19 (3H，s)，1.53 (9H,s) 11.4Hz), 4.80 (lH, d, J = 10.8Hz), 4.60 (lH.dJ = 12.7Hz), 4.59 (1H, d, J = 10.8Hz), 4.53 (lH.dJ = 11.4Hz), 4, 39 (lH, d, J = 9.9Hz), 3.80 (lH, U = 8.9Hz), 3.64-3.76 (4H, m), 3.56 (lH, t, J = 9.1Hz), 3.38-3.46 (lH, m ), 3.19 (3H, s), 1.53 (9H, s)
5) 式：
Figure imgf000021_0001
で表される化合物の製造。 5) Formula:
Figure imgf000021_0001
Production of the compound represented by
実施例 1 - 4) で得られた化合物 （4) 459.3mgをメチルァミン （40 %メタ ノール溶液） 20mlに溶解し室温にて 30分間攪拌した。 反応液を濃縮後、 残 渣をシリカゲルクロマトグラフィ （へキサン-酢酸ェチル：4 : 1) を用いて精 製し目的化合物 （5) 395.2mgを得た。 （収率： 94 %)  459.3 mg of the compound (4) obtained in Example 1-4) was dissolved in 20 ml of methylamine (40% methanol solution) and stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue was purified by silica gel chromatography (hexane-ethyl acetate: 4: 1) to obtain 395.2 mg of the desired compound (5). (Yield: 94%)
HRMS (m/z)： found 1075.4445, calcd 1075.4408 [C69H61N309として] IR (KBr)： cm" 1 1697, 1577, 1569， 1497, 1454， 1436， 1257, 1083,752,753, HRMS (m / z): found 1075.4445, calcd 1075.4408 [C 69 as H 61 N 3 0 9] IR (KBr): cm "1 1697, 1577, 1569, 1497, 1454, 1436, 1257, 1083,752,753,
696  696
Ή- NMR (300MHz，CDCl3) ： δ ppm 8.61 (lH,brs),8.07 (lH,s),7.56 (lH,d,J = 2.7Hz) ,6.95- 7.50 (27H，m)，6.85 (lH，d,J = 7.2Hz)，6.40- 6.70 (9H，m)，5.13 (2H，s)，5.06 (lH.d.J = l l.lHz),4.91 (lH,d,J = 11.1 Hz) ,4.90 (lH,d，J = 11.1 Hz)，4.84 (lH，d，J = 9.6Hz),4.80 (lH，d,J =Ή-NMR (300 MHz, CDCl 3 ): δ ppm 8.61 (lH, brs), 8.07 (lH, s), 7.56 (lH, d, J = 2.7 Hz), 6.95 to 7.50 (27H, m), 6.85 (lH , D, J = 7.2 Hz), 6.40-6.70 (9H, m), 5.13 (2H, s), 5.06 (lH.dJ = l l.lHz), 4.91 (lH, d, J = 11.1 Hz), 4.90 (lH, d, J = 11.1 Hz), 4.84 (lH, d, J = 9.6 Hz), 4.80 (lH, d, J =
11.1Hz)，4.48- 4.62 (3H,m),4.41 (lH，d，J = 10.3Hz)，3.64- 3.83 (4H, m)，3.57 (2H，t，J = 8.97Hz)，3.40— 3.48 (lH,m),3.18 (3H,m) 6) 式：
Figure imgf000022_0001
で表される化合物の製造。 11.1Hz), 4.48-4.62 (3H, m), 4.41 (lH, d, J = 10.3Hz), 3.64-3.83 (4H, m), 3.57 (2H, t, J = 8.97Hz), 3.40-3.48 ( lH, m), 3.18 (3H, m) 6) Formula:
Figure imgf000022_0001
Production of the compound represented by
実施例 1-5) で得た化合物 （5) 52mgを DMF2.5mlに溶解し、 トリフルォ 口酢酸 ラジウム 49.9mgを加ん 90 °Cにて 3時間攪拌した。 反応液を酢酸ェ チル- 2N塩酸で分配し、有機層を水、飽和炭酸水素ナトリゥム水溶液、水、次 いで飽和食塩水で洗浄後、 乾燥濃縮した。 残渣をシリカゲルクロマトグラ フィ （へキサン-酢酸ェチル：4 : 1) を用いて精製し目的化合物（6) 26mgを 得た。 （収率： 50 %)  52 mg of the compound (5) obtained in Example 1-5) was dissolved in 2.5 ml of DMF, and 49.9 mg of radium acetate trifluoride was added thereto, followed by stirring at 90 ° C for 3 hours. The reaction solution was partitioned with ethyl acetate-2N hydrochloric acid, and the organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and then with a saturated saline solution, and then dried and concentrated. The residue was purified using silica gel chromatography (hexane-ethyl acetate: 4: 1) to obtain 26 mg of the desired compound (6). (Yield: 50%)
HRMS (m/z)： found 1073.4269, calcd 1073.4251 [C69H59N309として] IR (KBr) ： cm" 1 2617,1699, 1581,1377,1257,1097,1072,754,696 Ή- NMR (300MHz,CDCl3)： 5 ppm 10.55 (lH,s),9.08 (lH，d，J = 7.3Hz), 8.87 (lH，d，J = 8.3Hz),6.90- 7.51 (31H，m)，6.86 (2H,t，J = 7.6Hz)，6.17 (2H,d，J = 6.9Hz),5.30 (lH,d,J = 11.5Hz),5.20 (2H,d，J = 11.5Hz)，5.14HRMS (m / z): found 1073.4269, calcd 1073.4251 [C 69 as H 59 N 3 0 9] IR (KBr): cm "1 2617,1699, 1581,1377,1257,1097,1072,754,696 Ή- NMR ( 300 MHz, CDCl 3 ): 5 ppm 10.55 (lH, s), 9.08 (lH, d, J = 7.3 Hz), 8.87 (lH, d, J = 8.3 Hz), 6.90-7.51 (31H, m), 6.86 ( 2H, t, J = 7.6Hz), 6.17 (2H, d, J = 6.9Hz), 5.30 (lH, d, J = 11.5Hz), 5.20 (2H, d, J = 11.5Hz), 5.14
(lH，d，J = 11.5Hz) ,4.73 (lH，d，J = 10.9Hz)，4.64 (lH.d.J = 10.9Hz), 4.59 (lH，d，J = 11.0Hz),4,57 (lH，d，13.1Hz)，4.52 (lH，d，J = 13.1Hz)， 4.10 (lH，d，J = 11.0Hz)，4.00 (lH,t，J = 9.1Hz)，3.83 (lH.dJ = 9.6Hz), 3.52- 3.76 (5H,m)，3.49 (3H,s)，2.95 (lH，d，J = 9.6Hz) (lH, d, J = 11.5Hz), 4.73 (lH, d, J = 10.9Hz), 4.64 (lH.dJ = 10.9Hz), 4.59 (lH, d, J = 11.0Hz), 4,57 (lH , D, 13.1 Hz), 4.52 (lH, d, J = 13.1 Hz), 4.10 (lH, d, J = 11.0 Hz), 4.00 (lH, t, J = 9.1 Hz), 3.83 (lH.dJ = 9.6 Hz), 3.52- 3.76 (5H, m), 3.49 (3H, s), 2.95 (lH, d, J = 9.6Hz)
7) 式：
Figure imgf000023_0001
で表される化合物の製造。 7) Formula:
Figure imgf000023_0001
Production of the compound represented by
実施例 1-6) で得た化合物（6) 270mgをクロ口ホルム -メタノール（1 : 1) 270 mg of the compound (6) obtained in Example 1-6) was added to chloroform-methanol (1: 1)
15mlに溶解し、 パラジウム黒を触媒量加え、 水素雰囲気下 4時間攪拌した。 触媒を濾過した後濾液を濃縮し残渣をメタノール-クロ口ホルム -へキサンを 用いて再結晶し目的化合物 （7) 130mgを得た。 （収率： 98 %) The mixture was dissolved in 15 ml, palladium black was added in a catalytic amount, and the mixture was stirred under a hydrogen atmosphere for 4 hours. After filtering the catalyst, the filtrate was concentrated, and the residue was recrystallized from methanol-form-form-hexane to obtain 130 mg of the desired compound (7). (Yield: 98%)
HRMS (mZz)： found 533.1419， calcd 533.1434 [C27H23N309として] IR (KBr) : cm - 1 3371 , 1741 , 1638, 1587, 1577, 1387， 1321 , 1261 , 1238， HRMS (mZz): found 533.1419, calcd 533.1434 [C 27 as H 23 N 3 0 9] IR (KBr): cm - 1 3371, 1741, 1638, 1587, 1577, 1387, 1321, 1261, 1238,
1081,754  1081,754
Ή- NMR (300MHz,DMSO-d6)： 5 pm 10.89 (lH,s), 10.34 (lH,s),9.95 (lH，s),8.71 (lH,d,J = 7.7Hz),8.53 (lH'd'J = 7.7Hz)，7.18 (2H't，J = 7.7Hz),7.05 (lH，d,J = 9.1Hz)，7.01 (lH，d，J = 7.7Hz)，6.99 (lH.d.J = 7.7Hz)，4.50- 5.80 (4H,br) ,3.95 - 4.08 (2H,m)，3.58- 3.80 (3H，m),3.Ή-NMR (300 MHz, DMSO-d 6 ): 5 pm 10.89 (lH, s), 10.34 (lH, s), 9.95 (lH, s), 8.71 (lH, d, J = 7.7 Hz), 8.53 (lH 'd'J = 7.7Hz), 7.18 (2H't, J = 7.7Hz), 7.05 (lH, d, J = 9.1Hz), 7.01 (lH, d, J = 7.7Hz), 6.99 (lH.dJ = 7.7Hz), 4.50-5.80 (4H, br), 3.95-4.08 (2H, m), 3.58-3.80 (3H, m), 3.
39 (lH,dd,J = 8.6,9.1Hz),3.18 (3H,s) 39 (lH, dd, J = 8.6,9.1Hz), 3.18 (3H, s)
8) 式： 8) Formula:
(8)
Figure imgf000023_0002
で表される化合物の製造。 (8)
Figure imgf000023_0002
Production of the compound represented by
実施例 1 - 7) で得られた化合物 （7) 70mgを 10 %水酸化カリウム水溶液 2mlに溶解し、室温にて 0.5時間攪拌した。 反応液に 2N塩酸 lmlを加えて中 和した後、 メチルェチルケトン-酢酸ェチル（1： 1) で抽出した。 有機層を飽 和食塩水で洗浄後、乾燥濃縮した.残渣をジクロロメタンで洗浄し表題の化合 物 （8) 65mg得た。 （収率： 95 %)  70 mg of the compound (7) obtained in Example 1-7) was dissolved in 2 ml of a 10% aqueous potassium hydroxide solution and stirred at room temperature for 0.5 hour. The reaction mixture was neutralized by adding 1 ml of 2N hydrochloric acid, and extracted with methyl ethyl ketone-ethyl acetate (1: 1). The organic layer was washed with saturated saline and dried and concentrated. The residue was washed with dichloromethane to obtain 65 mg of the title compound (8). (Yield: 95%)
HRMS (mZz)： found 520.1117， calcd 520.1118 [C26H2。N2O10として] IR (KBr) ： cm" 1 3353,1816,1743,1587,1388,1249,1072,800,748,609 Ή- NMR (300MHz,DMSO- d6) ： δ ppm 11.11 (lH.s), 10.52 (lH，s), 10.13 (lH，s)，8.51 (lH，d,J = 7,6Hz),8.36 (lH.d.J = 7.6Hz),7.40 (1H， d,J = 7.8Hz) ,7.20 (lH.dJ = 7.8Hz),7.09 (lH,d，J = 8.0Hz)，7.06 (2H, dd,J = 7.6,7.8Hz) ,5.32 (lH,dd,4.9,5.1Hz),5.24 (lH，d，J = 5.4Hz)，495 (lH，d,J = 4.6Hz)，3.95- 4.10 (2H,m),3.76 (lH'm)，3.56- 3.70 (2H,m), 3.42 (lH，m) HRMS (mZz): found 520.1117, calcd 520.1118 [C 26 H 2. N 2 as O 10] IR (KBr): cm "1 3353,1816,1743,1587,1388,1249,1072,800,748,609 Ή- NMR (300MHz, DMSO- d 6): δ ppm 11.11 (lH.s), 10.52 (lH, s), 10.13 (lH, s), 8.51 (lH, d, J = 7,6Hz), 8.36 (lH.dJ = 7.6Hz), 7.40 (1H, d, J = 7.8Hz), 7.20 (lH.dJ = 7.8Hz), 7.09 (lH, d, J = 8.0Hz), 7.06 (2H, dd, J = 7.6,7.8Hz), 5.32 (lH, dd, 4.9,5.1Hz), 5.24 (lH , D, J = 5.4 Hz), 495 (lH, d, J = 4.6 Hz), 3.95 to 4.10 (2H, m), 3.76 (lH'm), 3.56 to 3.70 (2H, m), 3.42 (lH, m)
9) 実施例卜 8) で得られた化合物 （8) lOOmgを DMFlOmlに溶解し 2-ヒ ドラジノ- 1,3-プロパンジオール 61mgを加え 80 °Cにて 1時間攪拌した。 反 応液を濃縮後残渣をセフアデックス LH- 20を用いて展開しメ夕ノ一ルで溶出 し表題化合物 [I- A] 89mgを得た。 （収率： 77 %) 9) The compound obtained in Example 8) (8) lOOmg was dissolved in DMFlOml, 61mg of 2-hydrazino-1,3-propanediol was added, and the mixture was stirred at 80 ° C for 1 hour. After concentrating the reaction solution, the residue was developed using Sephadex LH-20 and eluted with a solvent to obtain 89 mg of the title compound [IA]. (Yield: 77%)
HRMS (m/z)： found 609.1826, calcd 609.1833 [C29H28N40„として] IR (KBr) ： cm— 1 3309， 1695, 1567, 1540, 1521,1456.1417,1398, 1087,609HRMS (m / z): found 609.1826, [ as C 29 H 28 N 4 0 " ] calcd 609.1833 IR (KBr): cm- 1 3309, 1695, 1567, 1540, 1521,1456.1417,1398, 1087,609
Ή- NMR (300MHz,DMSO-d6)： 5 ppm 10.91 (lH，brs)， 10.30 (lH.brs), 9.90 (lH,s),8.70 (lH.d.J = 8.0Hz) ,8.52 (lH,d，J = 7.9Hz)，7.16- 7.21 (2H,m) ,6.98- 7.05 (3H,m)，5.59 (lH,d,J = 2.3Hz),5.41 (lH.d.J = 5.7 Hz), 5.20- 5.40 (2H，m),5.20 (lH,d,J = 5.3Hz),4.90 ClH.br) ,4.50-4.60 (3H，m)，3.98— 4.15 (2H，m)，3.35- 3.80 (7H,m) Ή-NMR (300 MHz, DMSO-d 6 ): 5 ppm 10.91 (lH, brs), 10.30 (lH.brs), 9.90 (lH, s), 8.70 (lH.dJ = 8.0 Hz), 8.52 (lH, d , J = 7.9 Hz), 7.16-7.21 (2H, m), 6.98-7.05 (3H, m), 5.59 (lH, d, J = 2.3 Hz), 5.41 (lH.dJ = 5.7 Hz), 5.20-5.40 (2H, m), 5.20 (lH, d, J = 5.3Hz), 4.90 ClH.br), 4.50-4.60 (3H, m), 3.98—4.15 (2H, m), 3.35- 3.80 (7H, m)
実施例 2 Example 2
式：
Figure imgf000025_0001
formula:
Figure imgf000025_0001
で表される化合物の製造。 Production of the compound represented by
実施例 1 -3) で得られた化合物 (3) 69mgをメチルアミン （40 %メタノー ル溶液） lmUこ溶解し、室温にて 10分間攪拌した。 反応溶液を濃縮後、残渣 を酢酸ェチル -へキサンを用いて再結晶し目的の化合物 （9) 55.2mを得た。 69 mg of the compound (3) obtained in Example 1-3) was dissolved in lmU of methylamine (40% methanol solution) and stirred at room temperature for 10 minutes. After concentrating the reaction solution, the residue was recrystallized from ethyl acetate-hexane to obtain 55.2 m of the desired compound (9).
(95 %) (95%)
HRMS (m/z)： found 55 1982, calcd 553.2002 [C35H27N304として] IR (KBr) ： cm" ' 1691,1577 ,1531,1423,1384,1259,1083,752,715,694 Ή- NMR (300MHz,CDCl3) ： 5 ppm 8.73 (2H，brs)，7.69 (2H'd,J = 2.1 Hz) ,7.30- 7.49 (10H,m) ,6.60- 6.75 (6H，m)，5.16 (4H,s),3.17 (3H，s) 実施例 3 HRMS (m / z): found 55 1982, calcd 553.2002 [C 35 H 27 N 3 0 4 as] IR (KBr): cm "'1691,1577, 1531,1423,1384,1259,1083,752,715,694 Ή- NMR (300MHz, CDCl 3 ): 5 ppm 8.73 (2H, brs), 7.69 (2H'd, J = 2.1 Hz), 7.30-7.49 (10H, m), 6.60-6.75 (6H, m), 5.16 (4H, s), 3.17 (3H, s) Example 3
式：  Formula:
Figure imgf000025_0002
Figure imgf000025_0002
で表される化合物の製造。 Production of the compound represented by
実施例 2で得られた化合物 （9) 30mg及びトリフルォ口酢酸ノ、。ラジウム 49.9mgを加え 90 °Cにて 0.5時間攪拌した。 反応液を酢酸ェチル- 2N塩酸で 分配し、 有機層を水、 飽和炭酸水素ナトリウム水溶液、 水、 次いで飽和食塩 水で洗浄後、乾燥濃縮した.残渣をセフアデックス LH- 20を用いて展開しメ夕 ノールで溶出し目的化合物 （10) 14.6mgを得た。 （収率： 49 %) Compound (9) obtained in Example 2 (9 mg) and trifluoroacetate. 49.9 mg of radium was added and the mixture was stirred at 90 ° C for 0.5 hour. The reaction solution was partitioned with ethyl acetate-2N hydrochloric acid, and the organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water, and then with saturated saline, and concentrated by drying, and the residue was developed using Sephadex LH-20. The residue was eluted with toluene to obtain 14.6 mg of the desired compound (10). (Yield: 49%)
HRMS (m/z) ： found 551.1839, calcd 551.1845 [C35H25N304として] IR (KBr) ： cm" ' 1742, 1695, 1684, 1577, 1406, 1377, 1251, 1103,776,737, HRMS (m / z): found 551.1839, calcd 551.1845 [C 35 H 25 N 3 0 4 as] IR (KBr): cm "'1742, 1695, 1684, 1577, 1406, 1377, 1251, 1103,776,737,
696 Ή- NMR (300MHz，DMSO- d6)： 5 ppm 11.67 (2H,s) ,8.52- 8.55 (2H, m),7.62 (4H,d,J = 7.1Hz) ,7.46 (4H,t,J = 7.1Hz),7.40 (2H(d,J = 7.1 Hz) ,7.23- 7.28 (4H，m),5.37 (4H，s)，3.30 (3H，s) 696 Ή-NMR (300 MHz, DMSO-d 6 ): 5 ppm 11.67 (2H, s), 8.52-8.55 (2H, m), 7.62 (4H, d, J = 7.1Hz), 7.46 (4H, t, J = 7.1Hz), 7.40 (2H ( d, J = 7.1 Hz), 7.23- 7.28 (4H, m), 5.37 (4H, s), 3.30 (3H, s)
実施例 4 Example 4
式：  Formula:
Figure imgf000026_0001
で表される化合物の製造。
Figure imgf000026_0001
Production of the compound represented by
水酸化力リゥム 360mg及び硫酸ナトリゥム 2.2gをァセトニトリル 40mlに 懸濁させ、 実施例 3で得られた化合物 （10) 483mgを加え室温にて 0.5時間 攪拌した後 1 -クロ口- 2，3，4,6-テトラ- 0-ベンジル- D -ダルコピラノシド 1.06gのァセトニトリル溶液 12mlを滴下した。 室温にて終夜攪拌した後、反 応液を 2N塩酸 50mlに注ぎ込み酢酸ェチル 200mlで抽出した。 有機層を水、 飽和炭酸水素ナトリウム水溶液、 水、 次いで飽和食塩水で洗浄後、 乾燥濃縮 した。 残渣をシリカゲルクロマトグラフィ （へキサン-酢酸ェチル = 10 : 1,ト ルェン -酢酸ェチル = 90： 1) を用いて精製し目的化合物 （6) 840mgを得た。 (収率： 90 %) 360 mg of hydroxylating water and 2.2 g of sodium sulfate were suspended in 40 ml of acetonitrile, 483 mg of the compound (10) obtained in Example 3 was added, and the mixture was stirred at room temperature for 0.5 hour, and then stirred at room temperature for 1-chloro-2,3,4. A solution of 1.06 g of, 6-tetra-0-benzyl-D-darcopyranoside in 12 ml of acetonitrile was added dropwise. After stirring overnight at room temperature, the reaction solution was poured into 50 ml of 2N hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water, and then with saturated saline, and then dried and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 10: 1, toluene-ethyl acetate = 90: 1) to obtain 840 mg of the desired compound (6). (Yield: 90%)
物性データは実施例 1 - 6) で得たのものと一致した。  Physical property data were consistent with those obtained in Examples 1-6).
実施例 5 Example 5
式：
Figure imgf000027_0001
formula:
Figure imgf000027_0001
で表される化合物の製造。 Production of the compound represented by
臭化工チルマグネシウム （1M THF溶液） 2.24mlをトルエン 2.2mlに溶 解し 45 °Cにて 7 -ベンジルォキシインドール 500mgを加え 130 °Cまで昇温し た。 反応溶液に 2,3-ジブロモ -N-メチルマレイミ ド 201.7mgのトルエン溶液 2.8mlを加え、 130°Cで 4時間攪拌した。 反応液を 2N塩酸 5mlに注ぎ込み酢 酸ェチル 20mlで抽出した。 有機層を水、 飽和炭酸水素ナトリウム水溶液、 水、 次いで飽和食塩水で洗浄後、乾燥濃縮した.残渣をシリ力ゲルクロマトグ ラフィ （へキサン-酢酸ェチル = 4 : 1 -2 : 1) を用いて精製し目的化合物 （9) 6mgを得た。 （収率： 38 %)  2.24 ml of butylmagnesium bromide (1M THF solution) was dissolved in 2.2 ml of toluene, and 500 mg of 7-benzyloxyindole was added at 45 ° C and the temperature was raised to 130 ° C. To the reaction solution was added 2.8 ml of a toluene solution of 201.7 mg of 2,3-dibromo-N-methylmaleimide, and the mixture was stirred at 130 ° C for 4 hours. The reaction mixture was poured into 5 ml of 2N hydrochloric acid and extracted with 20 ml of ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, water, and saturated saline, and then dried and concentrated. The residue was purified using silica gel chromatography (hexane-ethyl acetate = 4: 1 -2: 1). Purification gave 6 mg of the desired compound (9). (Yield: 38%)
物性データは実施例 2) で得たのものと一致した。  Physical property data were consistent with those obtained in Example 2).
実施例 6 Example 6
式：  Formula:
Figure imgf000027_0002
で表される化合物 [I- B] の製造。
Figure imgf000027_0002
Production of the compound [IB] represented by the formula:
下記工程 1) 〜9) に示される方法で製造した c C manufactured by the method shown in the following steps 1) to 9)
1) 式：
Figure imgf000028_0001
で表される化合物の製造。 1 set:
Figure imgf000028_0001
Production of the compound represented by
6-ベンジルォキシインドール 284gを THF3Lに溶解し、 リチウムへキサメ チルジシラジド （1M : THF溶液） 2.7Lを加え窒素雰囲気下- 10°Cで 45分間 攪拌した後、 2，3-ジブロモ- N-メチルマレイミ ド 340gの THF溶液 3Lを 1時 間かけて滴下した。 Was dissolved 6-benzyl O carboxymethyl indoles 284g to THF3L, Kisame Chirujishirajido to lithium: - After stirring 10 ° C for 45 minutes, 2,3-dibromo - (1M THF solution) 2.7 L was added under a nitrogen atmosphere N- Mechirumareimi 340 g of THF solution (3 L) was added dropwise over 1 hour.
滴下終了後、 0°Cにて 15分間攪拌した後、反応液を 2N塩酸 10Lに注ぎ込み、 酢酸ェチル 30Lで抽出した。 有機層を飽和炭酸水素ナトリゥム水溶液ついで 飽和食塩水で洗浄後、 乾燥、 濃縮し残渣をメタノールを用いて再結晶するこ とにより目的化合物 （11) 482gを得た。 （収率： 93 %) After completion of the dropwise addition, the mixture was stirred at 0 ° C for 15 minutes, and then poured into 2N hydrochloric acid (10 L) and extracted with ethyl acetate (30 L). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried and concentrated, and the residue was recrystallized from methanol to obtain 482 g of the desired compound (11). (Yield: 93%)
HRMS (m/z)： found 410.0292, calcd 410.0266 [C2。H15N203Brとして]HRMS (m / z): found 410.0292, calcd 410.0266 [C 2. H 15 N 2 0 3 Br]
IR (KBr)： cm - 1 3330,3318, 1762, 1701 , 1606, 1511 , 1450, 1165, 1135, IR (KBr): cm- 1 3330,3318, 1762, 1701, 1606, 1511, 1450, 1165, 1135,
1041,794  1041,794
Ή- NMR (300MHz,CDCl3)： (5 ppm 8.60 (lH,brs),7.96 (lH,d'J = 8.1 Hz) ,7.94 (lH，d，J = 2.5Hz) ,7.33- 7.47 (5H,m)，7.00 (lH，dd,J = 2.5, 8.8Hz),6.97 (lH，d，J = 2.5Hz),5.13 (2H，s)，3.16 (3H，s) Ή-NMR (300 MHz, CDCl 3 ): (5 ppm 8.60 (lH, brs), 7.96 (lH, d'J = 8.1 Hz), 7.94 (lH, d, J = 2.5 Hz), 7.33-7.47 (5H, m), 7.00 (lH, dd, J = 2.5, 8.8 Hz), 6.97 (lH, d, J = 2.5 Hz), 5.13 (2H, s), 3.16 (3H, s)
2) 式：  2) Formula:
Figure imgf000028_0002
Figure imgf000028_0002
で表される化合物の製造。 Production of the compound represented by
実施例 6- 1)で得られた化合物（11) 1.00g、二炭酸ジ -tert-ブチル 637mg 及び 4-Ν,Ν-ジメチルァミノピリジン 3mgを THF200mlに溶解し室温にて 1 時間攪拌した。 反応液を濃縮後、残渣を酢酸ェチル -へキサンを用いて再結晶 し目的化合物 （12) 1.18gを得た。 （収率： 96%) 1.00 g of the compound (11) obtained in Example 6-1), 637 mg of di-tert-butyl dicarbonate and 3 mg of 4-Ν, Ν-dimethylaminopyridine were dissolved in 200 ml of THF and stirred at room temperature for 1 hour. After concentrating the reaction mixture, the residue was recrystallized using ethyl acetate-hexane. Thus, 1.18 g of the target compound (12) was obtained. (Yield: 96%)
IR (KBr) ： cm" 1 1740, 1714,1614,1527, 1487, 1443, 1373, 1227, 1153 HRMS (m/z)： found 510.0771, calcd 510.0791 [C H23N205Brとして] Ή-NMR (300MHz,CDCl3)： δ ppm 8.10 (lH，s),7.91 (lH.d.J = 2.3Hz), 7.73 (lH,d,J = 8.9Hz) ,7.34- 7.50 (5H,m),7.03 (lH.dd.J = 2.3,8.5Hz), 5.16 (2H,s)，3.18 (3H，s)，1.68 (9H,s) IR (KBr): cm "1 1740, 1714,1614,1527, 1487, 1443, 1373, 1227, 1153 HRMS (m / z): found 510.0771, [ a CH 23 N 2 0 5 Br] calcd 510.0791 Ή-NMR (300MHz, CDCl 3 ): δ ppm 8.10 (lH, s), 7.91 (lH.dJ = 2.3Hz), 7.73 (lH, d, J = 8.9Hz), 7.34-7.50 (5H, m), 7.03 (lH .dd.J = 2.3,8.5Hz), 5.16 (2H, s), 3.18 (3H, s), 1.68 (9H, s)
3) 式： 3) Formula:
Figure imgf000029_0001
Figure imgf000029_0001
で表される化合物の製造。 Production of the compound represented by
6 -ベンジルォキシィンドール 218.4mgを THF20mlに溶解し、 リチウムへ キサメチルジシラジド （1M： THF溶液） 2.35mlを加え窒素雰囲気下 0°Cで 15分間攪拌した後、 実施例 6-2) で得られた化合物 （12) 500mgの THF溶 液 10mlを 10分かけて滴下した。 滴下終了後、室温にて 0.5時間攪拌した後、 反応液を 2N塩酸 lOOmLに注ぎ込み、 酢酸ェチル 400mLで抽出した。 有機 層を水、飽和炭酸水素ナトリゥム水溶液ついで飽和食塩水で洗浄後、乾燥、濃 縮し残渣をトルエン-へキサンを用いて再結晶し目的化合物 （13) 580mgを 得た。 （収率： 91 %)  218.4 mg of 6-benzyloxyindole was dissolved in 20 ml of THF, 2.35 ml of lithium hexamethyldisilazide (1M: THF solution) was added, and the mixture was stirred at 0 ° C. for 15 minutes under a nitrogen atmosphere. 10 ml of a THF solution of 500 mg of the compound (12) obtained in) was added dropwise over 10 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 0.5 hour, then poured into 2N hydrochloric acid (100 mL), and extracted with 400 mL of ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and then with saturated saline, dried and concentrated, and the residue was recrystallized from toluene-hexane to obtain 580 mg of the desired compound (13). (Yield: 91%)
HRMS (mZz)： found 653.2556， calcd 653.2526 [C4。H35N306として] IR (KBr) ： cm' 1 1740,1701,1646,1623,1543,1445,1155 HRMS (mZz): found 653.2556, calcd 653.2526 [C 4. H 35 N 3 0 as 6] IR (KBr): cm '1 1740,1701,1646,1623,1543,1445,1155
Ή-NMR (300MHz，CDCl3) ： <5 ppm 8.41 (lH，brs)，7.97 (lH，s)，7.84 (lH，brs)，7.68 (lH,brs)，7.16- 7.43 (10H，m)，6.98 (lH,d,J = 9.2Hz), 6.85 (lH,brs)，6.74 (lH.d.J = 9.2Hz),6.58 (lH，d，J = 9.2Ηζ)，6·52 (1H, d,J = 9.2Hz),5.05 (2H,s),5.02 (2H,s)，3.19 (3H,s),1.67 (9H,s) 4) 式：
Figure imgf000030_0001
で表される化合物の製造。 Ή-NMR (300 MHz, CDCl 3 ): <5 ppm 8.41 (lH, brs), 7.97 (lH, s), 7.84 (lH, brs), 7.68 (lH, brs), 7.16-7.43 (10H, m), 6.98 (lH, d, J = 9.2Hz), 6.85 (lH, brs), 6.74 (lH.dJ = 9.2Hz), 6.58 (lH, d, J = 9.2Ηζ), 6652 (1H, d, J = 9.2Hz), 5.05 (2H, s), 5.02 (2H, s), 3.19 (3H, s), 1.67 (9H, s) 4) Formula:
Figure imgf000030_0001
Production of the compound represented by
実施例 6- 3) で得られた化合物 （13) 50mg、 2,3，4，6- 0-テトラべンジル- D -グルコビラノース 186mg及びトリフエニルホスフィ ン 90mgを THF3ml \こ溶解し、 0 °Cにてァゾジカルボン酸ジェチルエステル 0.054mlを加え 1時間 攪拌した。 反応液を酢酸ェチル 40ml- 2N塩酸 20mlで分配し、 有機層を水、 飽和炭酸水素ナトリウム水溶液、 水、 次いで飽和食塩水で洗浄後、 乾燥濃縮 した.残渣をシリカゲルクロマトグラフィ （へキサン-酢酸ェチル = 4： 1) を 用いて精製し目的化合物 （14) 36.4mgを得た。 （収率： 62 %)  50 mg of the compound (13) obtained in Example 6-3), 186 mg of 2,3,4,6-0-tetrabenzyl-D-glucoviranose and 90 mg of triphenylphosphine were dissolved in 3 ml of THF, and dissolved. At 0 ° C, 0.054 ml of azodicarboxylic acid getyl ester was added, and the mixture was stirred for 1 hour. The reaction solution was partitioned between 40 ml of ethyl acetate and 20 ml of 2N hydrochloric acid, and the organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water, and then with saturated saline, and concentrated by drying. The residue was subjected to silica gel chromatography (hexane-ethyl acetate = hexane). Purification was performed using 4: 1) to obtain 36.4 mg of the desired compound (14). (Yield: 62%)
HRMS (m/z) ： found 1175.4955, calcd 1175.4932 [C74H69N30„とし て] HRMS (m / z): found 1175.4955, calcd 1175.4932 [as C 74 H 69 N 30 „]
IR (KBr)： cm- ' 2360, 1736, 1701 , 1616, 1543, 1489, 1454, 1363, 1219, 1153 Ή- NMR (300MHz，CDCl3)： <5 ppm 8.03 (lH，s),7.95 (lH,s) ,7.78- 7.82 (lH,m) ,7.04- 7.38 (30H,m)，6.84 (lH,d,J = 8.7Hz) ,6.76- 6.84 (1H， m),6.79 (lH,d,J = 8.9Hz)，6.32 (lH.dd.J = 2.2,8.9Hz) ,6.28 (lH，dd， J = 2.4,8.7Hz),5.33 (lH,d,J = 8.7Hz) ,4.82- 4.94 (7H,m),4.67 (1H, d,J = 10.6Hz),4.63 (lH，d,J = 12.1H)，4.55 (lH，d，J = 12.1Hz),4.10 (lH，d，J = 10.2Hz),3.69- 3.95 (6H,m),3.40 (lH，d，J = 10.2Hz)，3.20 (3H，s),1.66 (9H，s) IR (KBr): cm- '2360, 1736, 1701, 1616, 1543, 1489, 1454, 1363, 1219, 1153 Ή-NMR (300 MHz, CDCl 3 ): <5 ppm 8.03 (lH, s), 7.95 (lH , s), 7.78-7.82 (lH, m), 7.04-7.38 (30H, m), 6.84 (lH, d, J = 8.7Hz), 6.76-6.84 (1H, m), 6.79 (lH, d, J = 8.9Hz), 6.32 (lH.dd.J = 2.2,8.9Hz), 6.28 (lH, dd, J = 2.4, 8.7Hz), 5.33 (lH, d, J = 8.7Hz), 4.82-4.94 (7H , m), 4.67 (1H, d, J = 10.6Hz), 4.63 (lH, d, J = 12.1H), 4.55 (lH, d, J = 12.1Hz), 4.10 (lH, d, J = 10.2Hz) ), 3.69-3.95 (6H, m), 3.40 (lH, d, J = 10.2Hz), 3.20 (3H, s), 1.66 (9H, s)
5) 式
Figure imgf000031_0001
で表される化合物の製造。 5) Expression
Figure imgf000031_0001
Production of the compound represented by
実施例 6- 4) で得られた化合物 （14) 141mgをメチルァミン （40 %メタ ノール溶液） 5mlに溶解し室温にて 30分間攪拌した。 反応液を濃縮後、残渣 をシリカゲルクロマトグラフィー （へキサン-酢酸ェチル：7 : 3) を用いて精 製し目的化合物 （15) 12.3mgを得た。 （収率： 96 %)  141 mg of the compound (14) obtained in Example 6-4) was dissolved in 5 ml of methylamine (40% methanol solution) and stirred at room temperature for 30 minutes. After concentration of the reaction solution, the residue was purified by silica gel chromatography (hexane-ethyl acetate: 7: 3) to obtain 12.3 mg of the desired compound (15). (Yield: 96%)
HRMS (m/z)： found 1075.4392, calcd 1075.4408 [C69H61N309として] IR (KBr)： cm- 1 3311 ,3030,2927, 1697, 1621 , 1533, 1454, 1385, 1159, 1093HRMS (m / z): found 1075.4392, calcd 1075.4408 [C 69 as H 61 N 3 0 9] IR (KBr): cm- 1 3311, 3030,2927, 1697, 1621, 1533, 1454, 1385, 1159, 1093
Ή- NMR (300MHz,CDCl3)： δ ppm 8.29 (lH.d.J = 2.7Ηζ),7.96 (1H， s) ,7.52 (lH.d.J = 2.7Hz) ,7.19- 7.40 (25H,m)，7.03- 7.16 (5H,m) , 6.78-6.84 (3H,m),6.67 (lH.d.J = 8.8Hz),6.45 ( lH.dd, J = 2.2,8.8Hz), 6.34 (lH,dd,J = 2.2,8.8Hz),5.34 (lH.dJ = 8.7Hz) ,4.82-4.94 (7H，m)， 4.67 (lH,d,J = 10.7Hz),4.62 (lH.dJ = 12.2Hz),4.53 (lH,d,J = 12.2Ή-NMR (300 MHz, CDCl 3 ): δ ppm 8.29 (lH.dJ = 2.7Ηζ), 7.96 (1H, s), 7.52 (lH.dJ = 2.7 Hz), 7.19-7.40 (25H, m), 7.03- 7.16 (5H, m), 6.78-6.84 (3H, m), 6.67 (lH.dJ = 8.8Hz), 6.45 (lH.dd, J = 2.2,8.8Hz), 6.34 (lH, dd, J = 2.2, 8.8Hz), 5.34 (lH.dJ = 8.7Hz), 4.82 to 4.94 (7H, m), 4.67 (lH, d, J = 10.7Hz), 4.62 (lH.dJ = 12.2Hz), 4.53 (lH, d , J = 12.2
Hz),4.12 (lH,d,J = 10·2Ηζ)，3·67- 3.98 (7H，m)，3.18 (3H，m) 6) 式： Hz), 4.12 (lH, d, J = 10 · 2), 3 · 67-3.98 (7H, m), 3.18 (3H, m) 6) Equation:
Figure imgf000031_0002
で表される化合物の製造。
Figure imgf000031_0002
Production of the compound represented by
実施例 6-5) で得られた化合物 （15) 52mg塩化銅 （II) 26.8mg及びモレ キュラーシーブ 50mgをメチルェチルケトン lmlに溶解し室温にて 2時間攪 拌した。 反応液をセライ ト濾過した後濾液を濃縮した。 残渣をシリカゲルク 口マトグラフィー （ジクロロメタン） を用いて精製し目的化合物 （16) 42mg を得た。 （収率： 84%) Example 6-5 compound obtained in) (15) 52m g of copper chloride (II) 26.8 mg and molecular Kyurashibu 50mg for 2 hours攪拌at room temperature was dissolved in methyl E chill ketone lml. After the reaction solution was filtered through celite, the filtrate was concentrated. The residue was purified by silica gel chromatography (dichloromethane) to obtain 42 mg of the desired compound (16). (Yield: 84%)
HRMS (m/z)： found 1073.4237, calcd 1073.4251 [C69H5gN309として] IR (KBr) ： cm—1 3311,3030,2927,1697,1621,1533,1454,1385,1159,1093 Ή-NMR (300MHz,CDCl3)： ppm 10.6 (lH，s)，9.24 (lH.dJ = 9.5Hz), 9.13 (lH，d，J = 9.5Hz)，7.0 '，-7.50 (29H,m)，6.98- 7.03 (lH，m),6.83 - 6.91 (2H,m)，6.18- 6.22 H，m),5.84 (lH，d，J = 8.9Hz), 5.12- 5.22 (2H,m),5.18 (lH,d,J= 11.0Hz),5.08 (lH，d,J = 11.5Hz),4.97 (lH，d, J = 10.7Hz)，4.89 (lH,d,J= 10.7Hz),4.84 (lH，d，J= 10.7Hz),4.74 (1H, d，J = 13.0Hz),4.67 (lH，dJ = 10.7Hz) ,4.56 (lH,d,J = 13.0Hz), 4.32 (lH.dd.J = 9.6,9.6Hz), 3.98 -4.07 (2H,m), 3.82- 3.97 (3H,m)，3.79 (lH,dd，J = 2.7, 10.2Hz)，3.33 (3H,s),3.00 (lH.d.J = 9.7Hz) HRMS (m / z): found 1073.4237, calcd 1073.4251 [C 69 as H 5g N 3 0 9] IR (KBr): cm- 1 3311,3030,2927,1697,1621,1533,1454,1385,1159,1093 Ή-NMR (300 MHz, CDCl 3 ): ppm 10.6 (lH, s), 9.24 (lH.dJ = 9.5 Hz), 9.13 (lH, d, J = 9.5 Hz), 7.0 ', -7.50 (29H, m) , 6.98-7.03 (lH, m), 6.83-6.91 (2H, m), 6.18-6.22 H, m), 5.84 (lH, d, J = 8.9 Hz), 5.12- 5.22 (2H, m), 5.18 ( lH, d, J = 11.0Hz), 5.08 (lH, d, J = 11.5Hz), 4.97 (lH, d, J = 10.7Hz), 4.89 (lH, d, J = 10.7Hz), 4.84 (lH, d, J = 10.7Hz), 4.74 (1H, d, J = 13.0Hz), 4.67 (lH, dJ = 10.7Hz), 4.56 (lH, d, J = 13.0Hz), 4.32 (lH.dd.J = 9.6,9.6Hz), 3.98 -4.07 (2H, m), 3.82- 3.97 (3H, m), 3.79 (lH, dd, J = 2.7, 10.2Hz), 3.33 (3H, s), 3.00 (lH.dJ = 9.7Hz)
7) 式 : 7) Formula:
Figure imgf000032_0001
で表される化合物の製造。
Figure imgf000032_0001
Production of the compound represented by
実施例 6- 6) で得られた化合物 （16) lOOmgをクロ口ホルム-メタノール (2 : 1) 6mlに溶解し、パラジウム黒を触媒量加え、 水素雰囲気下 2時間攪拌 した。 触媒を濾過した後濾液を濃縮し残渣をメタノール-ァセトン-酢酸ェチ ル—へキサンを用 L、て結晶化しさらにセフアデックス LH- 20を用 L、て展開し クロ口ホルム -メタノール-エタノール-テトラヒ ドロフラン （5： 2： 2： 1) で 溶出しアセトン-メタノール-へキサンから再結晶し目的化合物（17) 43.8mg を得た。 （収率： 88%) 100 mg of the compound (16) obtained in Example 6-6) was dissolved in 6 ml of chloroform-methanol (2: 1), a catalytic amount of palladium black was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. After filtering the catalyst, the filtrate was concentrated, and the residue was crystallized using methanol-acetone-ethyl acetate-hexane, and then developed using Sephadex LH-20. The residue was eluted with chloroform-methanol-ethanol-tetrahydrofuran (5: 2: 2: 1) and recrystallized from acetone-methanol-hexane to obtain 43.8 mg of the desired compound (17). (Yield: 88%)
HRMS (m/z)： found 533.1429, calcd 533.1434 [C27H23N3〇9として] IR (KBr) : cm— 1 3328,1733,1683,1678,1540,1417,1126,1081,611 Ή-NMR (300MHz,DMSO-d6)： 5 ppm 11.20 (lH,s),9.76 (lH,s)，9.74 (lH，s)，8.88 (lH,d，J = 8.6Hz) ,8.80 (lH.d.J = 8.6Hz),7.18 (lH，d，J = 2.1Hz),6.99 (lH,d,J = 2.1Hz) ,6.82 (lH,dd,J = 2.1,8.6Hz) ,6.80 (1H, dd,J = 2.1,8.6Hz) ,5.97 (lH.d.J = 8.9Hz),5.86 (1H.U = 4.0Hz) ,5.33 (lH,d,J = 4.9Hz),5.12 (lH，d，J = 4.3Hz)，4.94 (lH，d，J = 5.2Hz)，4.02 (lH,dd,J = 3.0,10.7Hz) ,3.94 (lH,m),3.78 (lH，m),3.52 (2H，m)，3.16 (3H，s) HRMS (m / z): found 533.1429, calcd 533.1434 [as C 27 H 23 N 3 〇 9 ] IR (KBr): cm— 1 3328,1733,1683,1678,1540,1417,1126,1081,611 Ή- NMR (300 MHz, DMSO-d 6 ): 5 ppm 11.20 (lH, s), 9.76 (lH, s), 9.74 (lH, s), 8.88 (lH, d, J = 8.6 Hz), 8.80 (lH.dJ = 8.6 Hz), 7.18 (lH, d, J = 2.1 Hz), 6.99 (lH, d, J = 2.1 Hz), 6.82 (lH, dd, J = 2.1, 8.6 Hz), 6.80 (1H, dd, J = 2.1,8.6Hz), 5.97 (lH.dJ = 8.9Hz), 5.86 (1H.U = 4.0Hz), 5.33 (lH, d, J = 4.9Hz), 5.12 (lH, d, J = 4.3Hz) , 4.94 (lH, d, J = 5.2 Hz), 4.02 (lH, dd, J = 3.0, 10.7 Hz), 3.94 (lH, m), 3.78 (lH, m), 3.52 (2H, m), 3.16 ( 3H, s)
8) 式： 8) Formula:
Figure imgf000033_0001
で表される化合物の製造。
Figure imgf000033_0001
Production of the compound represented by
実施例 6- 7) で得られた化合物 （17) 1.2gを 10%水酸化カリウム水溶液 40mlに溶解し、室温にて 1時間攪拌した。 反応液に 2N塩酸 40mlを加えて中 和した後、 メチルェチルケトン 1Lで抽出した。 有機層を飽和食塩水で洗浄 後、 乾燥濃縮した.残渣をアセトン-ヘプタンにて再結晶し目的化合物 （18) 1.2g得た。 （収率： 100%) 1.2 g of the compound (17) obtained in Example 6-7) was dissolved in 40 ml of a 10% aqueous potassium hydroxide solution and stirred at room temperature for 1 hour. The reaction solution was neutralized by adding 40 ml of 2N hydrochloric acid, and extracted with 1 L of methyl ethyl ketone. The organic layer was washed with brine, dried and concentrated. The residue was recrystallized from acetone-heptane to obtain 1.2 g of the desired compound (18). (Yield: 100%)
HRMS (m/z) ： found 520.1147, calcd 520.1118 [C HSONSO,。として] IR (KBr) ： cm" 1 3311,1810,1739,1652,1626,1558,1405,1091,611 Ή-NMR (300MHz,DMSO-d6) ： <5 ppm 11.4 (lH,s),9.95 (lH，s)，9.92 OS HRMS (m / z): found 520.1147, calcd 520.1118 [C HSONSO. As] IR (KBr): cm " 1 3311,1810,1739,1652,1626,1558,1405,1091,611 Ή-NMR (300MHz, DMSO-d 6): <5 ppm 11.4 (lH, s), 9.95 (lH, s), 9.92 OS
Figure imgf000034_0001
Figure imgf000034_0001
(吨 υ οε·ε- os's'(ui'H9) 09·ε- o S'( HI)
Figure imgf000034_0002
(吨 υ οεε-os's '(ui'H9) 09ε-o S' (HI)
Figure imgf000034_0002
ΉΖ) 36'ε-98'ε'(^Ήΐ) Z0Y(mV = S:'VHZ) S T(zHI'S = f'P'HT)  ΉΖ) 36'ε-98'ε '(^ Ήΐ) Z0Y (mV = S:' VHZ) S T (zHI'S = f'P'HT)
T6r(zHe*9
Figure imgf000034_0003
ΓΡ'Ηΐ) T6r (zHe * 9
Figure imgf000034_0003
ΓΡ'Ηΐ)
99'9'(zH8'8 = f'P'HT) 98"9'(ZH8"8 = Γ'Ρ'Ηΐ) 6'S'(ZH9'8'0'Z = ΓΡΡ 99'9 '(zH8'8 = f'P'HT) 98 "9'(ZH8" 8 = Γ'Ρ'Ηΐ) 6'S '( Z H9'8'0'Z = ΓΡΡ
'Ηΐ) 08"9'(ZH9"8'0"2 = f'PP'HT) Z8'9'(zH0-2 = Γ'Ρ'Ηΐ) 86·9'(ΖΗ0 st = ΓΡ'ΗΙ) 8r '(zH9"8 = f'P'HT) 6 "8'(ZH9'8 = f'P'HT) 8'8'(s'HI) 'Ηΐ) 08 "9' ( Z H9"8'0"2 = f'PP'HT) Z8'9 '( z H0-2 = Γ'Ρ'Ηΐ) 869' ( Ζ Η0 st = ΓΡ ' ΗΙ) 8r '(zH9 "8 = f'P'HT) 6"8'(ZH9'8 = f'P'HT) 8'8 '(s'HI)
W6'(s'HI) 8 "6'(s'HI) 0ΖΊΙ : (9P- OS ' ZHWOOS)腦 N - H【W6 '(s'HI) 8 "6'(s'HI) 0ΖΊΙ: ( 9 P-OS 'ZHWOOS) Brain N-H 【
Figure imgf000034_0004
Figure imgf000034_0004
Oつ？ ,lO'N8ZH6Z3] ε88Γ609 Ρ。ΐΒ。 '9ΐ8ΐ·609 Ρ画 ί： S爾 Η O one? , l O'N 8Z H 6Z 3] ε88Γ609Ρ. ΐ Β . '9ΐ8ΐ · 609 Project Ρ ： S S Η
(%ιι - 01 。二 ^ sm8^ [g -i] [^^ ^ m u ^ (i 氺： 一 . (% ιι - 01 two ^ sm 8 ^ [g -i] [^^ ^ mu ^ (i氺: A
τ： 一 ：マ ψαπι ）
Figure imgf000034_0005
Figure imgf000034_0006
τ: one: Ma ψαπι)
Figure imgf000034_0005
Figure imgf000034_0006
(吨 9) 3 0Γ — OS'S'(zHS'S = f'P'HD 66r(zHZ'9 = f'P'HO 9Γ9'(ΖΗΓ9 = f'P (吨 9) 3 0Γ — OS'S '( z HS'S = f'P'HD 66r ( z HZ'9 = f'P'HO 9Γ9' ( Ζ ΗΓ9 = f'P
'Ηΐ) 8S'S'(ZH9 = η'Ηΐ) S6'S'(ZH0'8'P'HI) 90·9'(ΖΗΛ· 'S'l = f'P 'Ηΐ) 8S'S' ( Z H9 = η'Ηΐ) S6'S '( Z H0'8'P'HI) 909' ( Ζ ''S'l = f'P
'ΗΌ) Z8 '(ZH - '9'T = f'PP'HT) 06 '(ZHS = f'P'HT) SO' '（ZHS'I 'ΗΌ) Z8' ( Z H-'9'T = f'PP'HT) 06' ( Z HS = f'P'HT) SO ''(ZHS'I
= f'P'HT) 2' '(ZHZ"Z = f'P'HT) S9'8'(zHi/ = f'P'HI) 69'8'(s'HI)  = f'P'HT) 2 '' (ZHZ "Z = f'P'HT) S9'8 '(zHi / = f'P'HI) 69'8' (s'HI)
Z£一 Z £ 1
89800/S6df/I3d Z890£/S6 ΟΛ\ 実施例 6-1) で得られた化合物 （11) 1.00g、 2，3，4，6- 0-テトラべンジル- D -ダルコビラノ一ス 6.57g及びトリフェニルホスフィ ン 3.19gを THF40ml に溶解し、 0°Cにてァゾジカルボン酸ジェチルエステル 1.91mlを加え徐々に 室温まで昇温しながら 1時間攪拌した。 反応液を酢酸ェチル 200ml-塩化ァン モニァ水 100mlで分配し、有¾層を水、飽和炭酸水素ナトリウム水溶液、水、 次いで飽和食塩水で洗浄後、 乾燥濃縮した。 残渣をシリカゲルクロマトグラ フィー （へキサン-酢酸ェチル：S :卜 4 : 1) を用いて精製し目的化合物（19) 3.07g (収率： 91 %) を得た。 89800 / S6df / I3d Z890 £ / S6 ΟΛ \ 1.00 g of the compound (11) obtained in Example 6-1), 6.57 g of 2,3,4,6-0-tetrabenzyl-D-dalcoviranos and 3.19 g of triphenylphosphine were dissolved in 40 ml of THF. Then, 1.91 ml of azodicarboxylic acid getyl ester was added at 0 ° C., and the mixture was stirred for 1 hour while gradually warming to room temperature. The reaction solution was distributed with 200 ml of ethyl acetate-100 ml of aqueous ammonium chloride, and the organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water, and then with a saturated saline solution, and then dried and concentrated. The residue was purified using silica gel chromatography (hexane-ethyl acetate: S: 4: 1) to obtain 3.07 g (yield: 91%) of the target compound (19).
HRMS (m/z)： found 932.2694, calcd 932.2627 [CS4H49N208Brとして] IR (KBr) : cm— ' 1767, 170' M 603, 1454, 1379, 1090, 1026 HRMS (m / z): found 932.2694, calcd 932.2627 IR [ as C S4 H 49 N 2 0 8 Br] (KBr): cm- '1767, 170' M 603, 1454, 1379, 1090, 1026
Ή-NMR (300MHz，CDCl3) δ ppm 7.96 (lH，d,J = 8.9Ηζ)，7·93 (1H, s)，7.17 - 7.41 (20H,m),6.97-7.17 (5H，m),6.71 (2H,dd, J = 1.3,8.9Hz), 5.29 (lH,d,J = 8.4Hz),5.00 (lH,d,J = 7.8Hz),4.97 (lH.dJ = 7.8Hz), 4.93 (lH，d,J= 11.9Hz),4.92 (lH，d，J = 10.8Hz)，4.90 (lH,d,J = 11.9 Hz) ,4.68 (lH,d,J = 10.8Fz),4.61 (lH,d,J= 11.9Hz),4.52 (lH.d.J = 11.9Hz),4.17 (lH,d,J = 10.0Hz) ,3.75- 3,96 (5H,m),3.71 (lH，brd,J = 9.6Hz) 3.56 (lH.d.J = 10.0Hz),3.16 (3H,s) Ή-NMR (300 MHz, CDCl 3 ) δ ppm 7.96 (lH, d, J = 8.9Ηζ), 7.93 (1H, s), 7.17-7.41 (20H, m), 6.97-7.17 (5H, m), 6.71 (2H, dd, J = 1.3,8.9Hz), 5.29 (lH, d, J = 8.4Hz), 5.00 (lH, d, J = 7.8Hz), 4.97 (lH.dJ = 7.8Hz), 4.93 ( lH, d, J = 11.9Hz), 4.92 (lH, d, J = 10.8Hz), 4.90 (lH, d, J = 11.9Hz), 4.68 (lH, d, J = 10.8Fz), 4.61 (lH, d, J = 11.9Hz), 4.52 (lH.dJ = 11.9Hz), 4.17 (lH, d, J = 10.0Hz), 3.75- 3,96 (5H, m), 3.71 (lH, brd, J = 9.6 Hz) 3.56 (lH.dJ = 10.0Hz), 3.16 (3H, s)
実施例 8 Example 8
式：  Formula:
Figure imgf000035_0001
で表される化合物の製造。
Figure imgf000035_0001
Production of the compound represented by
6 -ベンジルォキシィンドール 350.6mgを THF5mlに溶解し、 リチウムへキ サメチルジシラジド （1M : THF溶液） 3.45mlを加え窒素雰囲気下 0°Cで 分間攪拌した後、化合物 （19) 1470mgの THF溶液 15mlを 10分かけて滴下 した。 滴下終了後、 室温にて 1時間攪拌した後、 反応液を 2N塩酸 lOOmLに 注ぎ込み、酢酸ェチル 200mLで抽出した。 有機層を水、飽和炭酸水素ナトリ ゥム水溶液ついで飽和食塩水で洗浄後、 乾燥、 濃縮し残渣をシリ力ゲルク口 マトグラフィー （へキサン-酢酸ェチル = 4 : 1- 1： 1) を用いて精製し目的化 合物 （15) 1234mg (収率： 73 %) を得た。 Dissolve 350.6 mg of 6-benzyloxyindole in 5 ml of THF, add 3.45 ml of lithium hexamethyldisilazide (1 M solution in THF) and add nitrogen atmosphere at 0 ° C. After stirring for 1 minute, 15 ml of a THF solution of 1470 mg of compound (19) was added dropwise over 10 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, poured into 100 mL of 2N hydrochloric acid, and extracted with 200 mL of ethyl acetate. The organic layer is washed with water, a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried and concentrated, and the residue is subjected to gel chromatography (hexane-ethyl acetate = 4: 1-1-1: 1). Purification yielded 1234 mg (yield: 73%) of the desired compound (15).
物性デー夕は実施例 6- 5) で得られたものと一致した。  The physical properties were consistent with those obtained in Example 6-5).
実施例 9 Example 9
式：  Formula:
Figure imgf000036_0001
で表される化合物の製造。
Figure imgf000036_0001
Production of the compound represented by
実施例 6- 3) で得られた化合物 （13) 100mgをメチルァミン （40 %メタ ノール溶液） 10mlに溶解し、 室温にて 30分間攪拌した。  100 mg of the compound (13) obtained in Example 6-3) was dissolved in 10 ml of methylamine (40% methanol solution) and stirred at room temperature for 30 minutes.
反応溶液を濃縮後、 残渣をジクロロメタン-ァセトン -へキサンを用いて再結 晶し目的の化合物 （20) 68.6mを得た。 （収率： 84 %) After concentrating the reaction solution, the residue was recrystallized from dichloromethane-acetone-hexane to obtain 68.6 m of the desired compound (20). (Yield: 84%)
HRMS (m/z)： found 553.1982, calcd 553.2002 [C35H27N304として] IR (KBr)： cm— ' 3419,3350, 1759, 1697, 1620, 1533, 1454, 1383, 1292, 1167 Ή- NMR (300MHz，DMSO- d6)： 5 ppm 11.48 (2H,s),7.62 (2H，s)，7.28 - 7.45 (10H，m)，6.95 (2H，d，J = 1·2Ηζ),6·70 (2H,d,J = 8.7Hz),6.39 (2H, dd,J = 1.2,8.7Hz),5.04 (4H,s),3.03 (3H，s) HRMS (m / z): found 553.1982, [ as C 35 H 27 N 3 0 4 ] calcd 553.2002 IR (KBr): cm- '3419,3350, 1759, 1697, 1620, 1533, 1454, 1383, 1292, 1167 Ή-NMR (300 MHz, DMSO-d 6 ): 5 ppm 11.48 (2H, s), 7.62 (2H, s), 7.28-7.45 (10H, m), 6.95 (2H, d, J = 1.2Ηζ), 6.70 (2H, d, J = 8.7Hz), 6.39 (2H, dd, J = 1.2,8.7Hz), 5.04 (4H, s), 3.03 (3H, s)
実施例 10 Example 10
式：
Figure imgf000037_0001
formula:
Figure imgf000037_0001
で表される化合物の製造。 Production of the compound represented by
実施例 9で得られた化合物 （20) l.Olg及び 2，3-ジクロロ- 5，6- 1，4-ベンゾキノン 456.1mgをトルエン 50mlに溶解 110 °Cにて 40分間攪拌し た。 反応液を室温に戻した後不溶物を濾過しメタノール 30mlで洗浄した。 残渣をジメチルスルフォキシド-ジクロロメタン-メタノールを用いて再結晶 し目的化合物 (21) 981mgを得た。 (収率： 98 %)  Compound (20) obtained in Example 9 (20) l.Olg and 2,3-dichloro-5,6-1,4-benzoquinone (456.1 mg) were dissolved in toluene (50 ml), and the mixture was stirred at 110 ° C for 40 minutes. After the temperature of the reaction solution was returned to room temperature, insolubles were filtered and washed with 30 ml of methanol. The residue was recrystallized from dimethyl sulfoxide-dichloromethane-methanol to obtain 981 mg of the desired compound (21). (Yield: 98%)
HRMS (m/z)： found 551.1829, calcd 551.1845 [C35H25N304として] IR (KBr) ： cm— ' 3257, 1740, 1675, 1620, 1571 , 1402, 1246, 1178 HRMS (m / z): found 551.1829, [ as C 35 H 25 N 3 0 4 ] calcd 551.1845 IR (KBr): cm- '3257, 1740, 1675, 1620, 1571, 1402, 1246, 1178
Ή- NMR (300MHz,DMSO- d6)： 5 ppm 11.46 (2H，s)，8.79 (2H,d，J = 8.5Hz) ,7.53 (4H,d,8.5Hz) ,7.35 - 7.44 (8H，m)，7.02 (2H,dd，8.5,0.8Ή-NMR (300 MHz, DMSO-d 6 ): 5 ppm 11.46 (2H, s), 8.79 (2H, d, J = 8.5 Hz), 7.53 (4H, d, 8.5 Hz), 7.35-7.44 (8H, m ), 7.02 (2H, dd, 8.5,0.8
Hz) ,5.25 (4H,s),3.13 (3H,s) Hz), 5.25 (4H, s), 3.13 (3H, s)
実施例 11 Example 11
式：  Formula:
Figure imgf000037_0002
で表される化合物の製造。
Figure imgf000037_0002
Production of the compound represented by
水酸化力リウム 5.7g及び硫酸ナトリウム 22gをァセトニトリル 380mlに懸 濁させ、 実施例 10で得られた化合物 （21) 5.51gを加え室温にて 1時間攪拌 した後 1 -クロ口- 2,3，4，6-テトラ -〇-ベンジル- D-グノレコピラノシド 11.5gの ァセトニトリル溶液 170mlを滴下した。 室温にて 7時間攪拌した後、 反応液 を 1N塩酸 360mlに注ぎ込み酢酸ェチル 360mlで抽出した。 有機層を水、 飽 和炭酸水素ナトリウム水溶液、 水、 次いで飽和食塩水で洗浄後、 乾燥濃縮し た.残渣をシリ力ゲルクロマトグラフィー （トルェン-酢酸ェチル： 30： 1) を 用いて精製し目的化合物 (16) 7.8gを得た。 (73 %) 5.7 g of lithium hydroxide and 22 g of sodium sulfate were suspended in 380 ml of acetonitrile, 5.51 g of the compound (21) obtained in Example 10 was added, and the mixture was stirred at room temperature for 1 hour. 4,6-tetra-〇-benzyl-D-gunolecopyranoside 11.5 g 170 ml of an acetonitrile solution was added dropwise. After stirring at room temperature for 7 hours, the reaction solution was poured into 1N hydrochloric acid (360 ml) and extracted with ethyl acetate (360 ml). The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and then dried and concentrated. The residue was purified by silica gel chromatography (toluene-ethyl acetate: 30: 1) for the purpose. 7.8 g of compound (16) was obtained. (73%)
物性デ一タは実施例 6- 6) で得られたものと一致した。  Physical property data were consistent with those obtained in Example 6-6).
実施例 12 Example 12
式：  Formula:
Figure imgf000038_0001
で表される化合物の製造。
Figure imgf000038_0001
Production of the compound represented by
臭化工チルマグネシウム （0.9Μ THF溶液） 50mlをトルエン 50mlに溶解 し 45°Cにて 6-ベンジルォキシインドール 10gを加え 1時間攪拌した。 反応溶 液に 2,3-ジブロモ- N-メチルマレイミ ド 4.02gのトルエン溶液 50mlを加え、 110 °Cで終夜攪拌した。 反応液を 2N塩酸 500mlに注ぎ込みメチルェチルケ トン 900mlで抽出した。 有機層を水、飽和炭酸水素ナトリウム水溶液、水、次 いで飽和食塩水で洗浄後、 乾燥濃縮した.残渣をシリカゲルクロマ卜グラ フィ一 （ジクロロメタン） を用いて精製しさらにジクロロメタン-アセトン - へキサンを用いて再結晶し目的化合物 （20) 5.65gを得た。 （収率： 69 %) 物性データは実施例 9で得られたものと一致した。  50 ml of chlormagnesium bromide (0.9 （THF solution) was dissolved in 50 ml of toluene, and 10 g of 6-benzyloxyindole was added at 45 ° C., followed by stirring for 1 hour. To the reaction solution was added 50 ml of a toluene solution of 4.03 g of 2,3-dibromo-N-methylmaleimide, and the mixture was stirred at 110 ° C overnight. The reaction solution was poured into 500 ml of 2N hydrochloric acid and extracted with 900 ml of methylethyl ketone. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and then with saturated saline, dried and concentrated, and the residue was purified using silica gel chromatography (dichloromethane), and further diluted with dichloromethane-acetone-hexane. The obtained compound was recrystallized to give 5.65 g of the desired compound (20). (Yield: 69%) Physical data were consistent with those obtained in Example 9.
実施例 13 Example 13
式：
Figure imgf000039_0001
formula:
Figure imgf000039_0001
(式中、 SEMは 2-トリメチルシリルエトキシメチル基を示す。 以下、 同じ。） で表される化合物の製造。  (Wherein, SEM represents a 2-trimethylsilylethoxymethyl group; the same applies hereinafter).
実施例 6- 1) で得られた化合物 （11) 2.00g、 2-トリメチルシリルェトキシ メチルクロライド lg及び水素化ナトリウム 300mgを THF30mlに溶解し室 温にて 0.5時間攪拌した。 反応液を 2N塩酸 200mlに注ぎ込み酢酸ェチル 300mlで抽出した。 有機層を水、 飽和炭酸水素ナトリウム水溶液、 水、 次い で飽和食塩水で洗浄後、 乾燥濃縮した。 残渣をシリカゲルクロマトグラ フィー（へキサン-酢酸ェチル = 4 : 1)を用いて精製し目的化合物（22) 1.96g を得た。 （収率： 77 %)  2.00 g of the compound (11) obtained in Example 6-1), 2-trimethylsilylethoxymethyl chloride lg and 300 mg of sodium hydride were dissolved in 30 ml of THF and stirred at room temperature for 0.5 hour. The reaction solution was poured into 200 ml of 2N hydrochloric acid and extracted with 300 ml of ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and then with a saturated saline solution, and then dried and concentrated. The residue was purified using silica gel chromatography (hexane-ethyl acetate = 4: 1) to obtain 1.96 g of the desired compound (22). (Yield: 77%)
Ή- NMR (300MHz, CDC13) ： δ ppm 7.96 (lH,d，J = 8.9Hz)，7.89 (1H, s) ,7.33- 7.50 (5H,m)，7.10 (lH.d.J = 2.2Hz)，7.01 (lH，dd，J = 2.2,8.9 Hz), 5.48 (2H,s)，5.15 (2H，s),3.52 (2H，t，J = 8.1Hz),3.16 (3H，s)，0.90 (2H，t，J = 8.1Hz)，- 0.04 (9H,s) Ή- NMR (300MHz, CDC1 3) : δ ppm 7.96 (lH, d, J = 8.9Hz), 7.89 (1H, s), 7.33- 7.50 (5H, m), 7.10 (lH.dJ = 2.2Hz), 7.01 (lH, dd, J = 2.2, 8.9 Hz), 5.48 (2H, s), 5.15 (2H, s), 3.52 (2H, t, J = 8.1 Hz), 3.16 (3H, s), 0.90 (2H , T, J = 8.1Hz), -0.04 (9H, s)
実施例 14 Example 14
式  Expression
Figure imgf000039_0002
で表される化合物の製造。
Figure imgf000039_0002
Production of the compound represented by
6 -べンジルォキシインドール 1.25gを THF20mlに溶解し、 リチウムへキ サメチルジシラジド （1M： THF溶液） 2.35mlを加え窒素雰囲気下 0°Cで 30 分間攪拌した後、実施例 13で得られた化合物 （22) L96gの THF溶液 20ml を滴下した。 滴下し 2時間攪拌した。 反応液を 2N塩酸 lOOmLに注ぎ込み、 酢酸ェチル 200mLで抽出した。 有機層を水、飽和炭酸水素ナトリウム水溶液 ついで飽和食塩水で洗浄後、 乾燥、 濃縮し残渣をシリカゲルクロマトグラ フィー （へキサン-酢酸ェチル = 4： 1) を用いて精製しさらに酢酸ェチル-ァ セトン-へキサンを用いて再結晶し目的化合物（23) 2.21gを得た。 （収率： 911.25 g of 6-benzyloxyindole was dissolved in 20 ml of THF, and 2.35 ml of lithium hexamethyldisilazide (1M: THF solution) was added. The mixture was stirred at 0 ° C. for 30 minutes under a nitrogen atmosphere. 20 ml of a THF solution of the obtained compound (22) L96g was added dropwise. The mixture was added dropwise and stirred for 2 hours. The reaction solution was poured into 2N hydrochloric acid (100 mL), Extracted with 200 mL of ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and then with saturated saline, dried and concentrated. The residue was purified using silica gel chromatography (hexane-ethyl acetate = 4: 1), and further purified with ethyl acetate-acetone. Recrystallization from hexane gave 2.21 g of the desired compound (23). (Yield: 91
%) %)
IR (KBr) ： cm- 1 3369, 1697, 1621 , 1533, 1456, 1385, 1246, 1164, 1091 , IR (KBr): cm- 1 3369, 1697, 1621, 1533, 1456, 1385, 1246, 1164, 1091,
1025,837,737,696  1025,837,737,696
Ή- NMR (300MHz,CDCl3) ： δ ppm 8.55 (lH.d.J = 2.0Hz),7.67 (1H， s),7.57 (lH，d，J = 2.0Hz)，7.27- 7.46 (lOH'm)J.OO (lH.d.J = 2.0Hz), 6.89 (lH，d,J = 8.9Hz)，6.80 (2H,d,J = 8.9Hz)，6.49 (2H，dd,J = 2.0,8.9 Hz),5.41 (2H，s)，5.01 (2H,s),4.96 (2H，s)，3.50 (2H,t，J = 8.9Hz)，3.17 (3H,s),0.90 (2H,t,J = 8.9Hz),- 0.02 (9H，s) Ή-NMR (300 MHz, CDCl 3 ): δ ppm 8.55 (lH.dJ = 2.0 Hz), 7.67 (1H, s), 7.57 (lH, d, J = 2.0 Hz), 7.27-7.46 (lOH'm) J .OO (lH.dJ = 2.0Hz), 6.89 (lH, d, J = 8.9Hz), 6.80 (2H, d, J = 8.9Hz), 6.49 (2H, dd, J = 2.0, 8.9Hz), 5.41 (2H, s), 5.01 (2H, s), 4.96 (2H, s), 3.50 (2H, t, J = 8.9Hz), 3.17 (3H, s), 0.90 (2H, t, J = 8.9Hz) ,-0.02 (9H, s)
実施例 15 Example 15
式：  Formula:
Figure imgf000040_0001
Figure imgf000040_0001
で表される化合物の製造。 Production of the compound represented by
実施例 14で得られた化合物 （23) l .Og及び炭酸カルシウム 2.0gを DMF50mlに溶解し、 塩化パラジウム 1.09gを加え 80 °Cにて 0.5時間攪拌し た。 反応液をセライト濾過した後濾液を酢酸ェチル 200πύ-2Ν塩酸 100mlで 分配し、 有機層を水、 飽和炭酸水素ナトリウム水溶液、 水、 次いで飽和食塩 水で洗浄後、乾燥濃縮した。 残渣をシリ力ゲルクロマトグラフィ （へキサン- 酢酸ェチル：6 : 1-3 : 1) を用いて精製しさらにアセトン-へキサンを用いて 再結晶し目的化合物 （24) 689mgを得た。 （収率： 69 %)  Compound (23) l.Og and 2.0 g of calcium carbonate obtained in Example 14 were dissolved in 50 ml of DMF, and 1.09 g of palladium chloride was added, followed by stirring at 80 ° C for 0.5 hour. After the reaction solution was filtered through celite, the filtrate was partitioned with 100 ml of ethyl acetate 200πύ-2Ν hydrochloric acid, and the organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and then with a saturated saline solution, and then dried and concentrated. The residue was purified using silica gel chromatography (hexane-ethyl acetate: 6: 1-3: 1), and recrystallized from acetone-hexane to obtain 689 mg of the desired compound (24). (Yield: 69%)
IR (KBr) ： cm- 1 1747， 1697， 1621 , 1581 , 1454， 1429， 1376， 1338, 1282， IR (KBr): cm- 1 1747, 1697, 1621, 1581, 1454, 1429, 1376, 1338, 1282,
1251,1214,1187,1132,1066  1251,1214,1187,1132,1066
Ή- NMR (300MHz，CDCl3) ： 5 ppm 9.66 (lH,brs),9.00 (2H，t，J = 8.7 Hz) ,7.35- 7.53 (10H,m),7.08 (2H,dd，J = 2.2，8·7Ηζ)，7.06 (lH，d,J = 2.2Hz),7.03 (lH，d'J = 2.2Hz)，5.72 (2H，s),5.22 (2H,s),5.21 (2H,s)， 3.70 (2H，t，J = 8.1Hz),3.09 (3H，s)，0.96 (2H,U = 8.1Hz) -0.05 (9H， s) Ή-NMR (300 MHz, CDCl 3 ): 5 ppm 9.66 (lH, brs), 9.00 (2H, t, J = 8.7 Hz), 7.35-7.53 (10H, m), 7.08 (2H, dd, J = 2.2,8.7Ηζ), 7.06 (lH, d, J = 2.2Hz), 7.03 (lH, d'J = 2.2Hz) , 5.72 (2H, s), 5.22 (2H, s), 5.21 (2H, s), 3.70 (2H, t, J = 8.1 Hz), 3.09 (3H, s), 0.96 (2H, U = 8.1 Hz) -0.05 (9H, s)
実施例 16 Example 16
式：  Formula:
Figure imgf000041_0001
で表される化合物の製造。
Figure imgf000041_0001
Production of the compound represented by
tert-ブトキシカリウム 30mg及び硫酸ナトリウム 200mgをトルェン 2ml に懸濁させ、 実施例 15で得られた化合物 （24) 50mgを加え室温にて 0.5時 間攪拌した後 1 -クロ口- 2,3,4,6-テトラ- 0-ベンジル- D-グルコピラノシド 130mgのトルエン溶液 lmlを滴下した。 50°Cにて終夜攪拌した後、反応液を 1N塩酸 50mlに注ぎ込み酢酸ェチル 100mlで抽出した。 有機層を水、飽和炭 酸水素ナトリウム水溶液、水、次いで飽和食塩水で洗浄後、乾燥濃縮した。 残 渣をシリカゲルクロマトグラフィー （へキサン-酢酸ェチル = 8： 1- 6： 1) を 用いて精製し目的化合物 （25) 58.6mgを得た。 （収率： 65 %) 30 mg of potassium tert-butoxide and 200 mg of sodium sulfate were suspended in 2 ml of toluene, and 50 mg of the compound (24) obtained in Example 15 was added. The mixture was stirred at room temperature for 0.5 hour, and then stirred at room temperature for 1-chloro-2,3,4. A solution of 130 mg of 1,6-tetra-0-benzyl-D-glucopyranoside in 1 ml of toluene was added dropwise. After stirring at 50 ° C. overnight, the reaction solution was poured into 50 ml of 1N hydrochloric acid and extracted with 100 ml of ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water, and then saturated brine, and then dried and concentrated. The residue was purified by silica gel chromatography (hexane - acetic Echiru = 8: 1 - 6: 1) to give the purified target compound (25) 58.6m g using. (Yield: 65%)
Ή- NMR (300MHz,CDCl3) ： 5 ppm 9.03 (lH,d，J = 9·5Ηζ),8.99 (1Η, d,J = 9.5Hz) ,6.77- 7.57 (32H,m),6.07 (2H，d，J = 7.5Hz),5.30 (lH,d，Ή-NMR (300 MHz, CDCl 3 ): 5 ppm 9.03 (lH, d, J = 9.5Ηζ), 8.99 (1Η, d, J = 9.5 Hz), 6.77-7.57 (32H, m), 6.07 (2H, d, J = 7.5 Hz), 5.30 (lH, d,
J = 8.9Hz),5.26 (2H，s)，5.13 (2H,s) ,3.47- 5.02 (15H,m),3.42 (2H，t, J = 8.9Hz),3.12 (3H，s)，2.61 (lH.d.J = 9.5Hz),0.93 (2H,t,J = 8.9Hz), - 0.07 (9H，s) J = 8.9Hz), 5.26 (2H, s), 5.13 (2H, s), 3.47-5.02 (15H, m), 3.42 (2H, t, J = 8.9Hz), 3.12 (3H, s), 2.61 ( lH.dJ = 9.5Hz), 0.93 (2H, t, J = 8.9Hz),-0.07 (9H, s)
実施例 17 Example 17
式： formula:
Figure imgf000042_0001
で表される化合物の製造。
Figure imgf000042_0001
Production of the compound represented by
実施例 16で得られた化合物 （25) 45mg、 モレキュラーシーブ 50mg及び テトラブチルァンモニゥムフ口リ ド （1M THF溶液） 0.9mlをテトラヒドロ フラン lmlに溶解し 50°Cにて 2時間攪拌した。 反応液をセライト濾過した後 濾液を 1N塩酸 50mlに注ぎ込み酢酸ェチル 100mlで抽出した。 有機層を水、 飽和炭酸水素ナトリウム水溶液、 水、 次いで飽和食塩水で洗浄後、 乾燥濃縮 した。 残渣をシリカゲルクロマトグラフィー（へキサン-酢酸ェチル = 10 : 1) を用いて精製し目的化合物 （16) 26.7mgを得た。 （85 %)  45 mg of the compound (25) obtained in Example 16, 50 mg of molecular sieve and 0.9 ml of tetrabutylammonium fluoride (1 M THF solution) were dissolved in 1 ml of tetrahydrofuran and stirred at 50 ° C. for 2 hours. . After the reaction solution was filtered through celite, the filtrate was poured into 50 ml of 1N hydrochloric acid and extracted with 100 ml of ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and then with a saturated saline solution, and then dried and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 10: 1) to obtain 26.7 mg of the desired compound (16). (85%)
物性データは実施例 6- 6) で得られたものと一致した。  Physical property data were consistent with those obtained in Example 6-6).
実施例 18 Example 18
式： H2NNHCH (CH2OH)2 (26) Formula: H 2 NNHCH (CH 2 OH) 2 (26)
で表される化合物の製造。 Production of the compound represented by
1) ジヒドロキシアセトン二量体 10.0g、 カルバジン酸 tert-ブチルエステル 14.7gをエタノール 500mlに溶解し、室温で 15時間攪拌した。 反応液を減圧 濃縮し、残渣を酢酸ェチルより再結晶させ、 2- (tert-ブチルォキシカルボ二 ノレ） ヒドラゾノ- 1,3-プロパンジオールを 18.67g無色固体として得た。  1) 10.0 g of dihydroxyacetone dimer and 14.7 g of tert-butyl carbazate were dissolved in 500 ml of ethanol and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 18.67 g of 2- (tert-butyloxycarbinole) hydrazono-1,3-propanediol as a colorless solid.
Ή- NMR (300MHZ.DMSO- d6)， 5 (ppm)： 1.49 (9H，s)，3.92 (2H,d，J = Ή- NMR (300MHZ.DMSO- d 6), 5 (ppm): 1.49 (9H, s), 3.92 (2H, d, J =
5.2Hz),4.24 (2H，d，J = 5.0Hz)，4.88 (1H，U = 5.8Hz),5.61 (lH，t，J =5.2Hz), 4.24 (2H, d, J = 5.0Hz), 4.88 (1H, U = 5.8Hz), 5.61 (lH, t, J =
5.1 Hz)，9.98 (lH.brs) 5.1 Hz), 9.98 (lH.brs)
2) 2- (tert-ブチルォキシカルボニル） ヒドラゾノ- 1,3-プロパンジオール 5.00gを 0°C下、ボラン-テトラヒドロフラン錯体 50mlを加えた後、室温で 0.5 時間攪拌した。 反応液に 6規定塩酸 25mlを室温で加え、 1.5時間加熱還流し た。 反応液を減圧濃縮し、得られた残留物をダウエックス 50W X 4の H—タイ プに吸着させ、水洗した後、 0.5規定アンモニア水で溶出した。 目的物を含む 画分を集めて減圧濃縮し、 得られる油状物を、 IRC- 50の ΝΗ4 τタイプに吸 着させ水で溶出した。 目的物を含む画分を集めて減圧濃縮し、 2-ヒドラジノ- 1，3-プロパンジオール 2.26gを無色固体として得た。 2) 2- (tert-butyloxycarbonyl) hydrazono-1,3-propanediol (5.00 g) was added at 0 ° C. at 50 ° C., and the mixture was stirred at room temperature for 0.5 hour after adding 50 ml of borane-tetrahydrofuran complex. Add 25 ml of 6N hydrochloric acid to the reaction solution at room temperature, and heat to reflux for 1.5 hours. Was. The reaction solution was concentrated under reduced pressure, and the obtained residue was adsorbed on an H-type Dowex 50W × 4, washed with water, and eluted with 0.5N aqueous ammonia. The fractions containing the desired product were concentrated under reduced pressure, the resulting oil was eluted with water to adsorb to ΝΗ 4 τ type IRC-50. The fractions containing the desired product were collected and concentrated under reduced pressure to obtain 2.26 g of 2-hydrazino-1,3-propanediol as a colorless solid.
FAB- MS (m/z) ： 107 (M + H) "  FAB-MS (m / z): 107 (M + H) "
Ή-NMR (200MHz,CD3OD), (5 (ppm) : 2.78 (lH，m) ,3.50- 3.75 (4H,m) 参考例 1 Ή-NMR (200MHz, CD 3 OD), (5 (ppm): 2.78 (lH, m), 3.50-3.75 (4H, m) Reference Example 1
式：  Formula:
Figure imgf000043_0001
で表される化合物の製造。
Figure imgf000043_0001
Production of the compound represented by
斜面寒天培地に培養したミクロテトラスボラ'エスピー（Microtetraspora sp.) A34549株 [受託番号： FERM BP- 4206 (平成 4年 11月 17日に寄託 された微ェ研菌寄第 P- 13292号より移管した微生物) ] をグルコース 0.2 %、 デキストリン 2.0 %、 オートミ-ル 0.5 %、 脱脂米ヌカ 0.5 %、 脱脂肉骨粉 0.2 %、乾燥酵母 0.1 %、硫酸マグネシウム ·7水和物 0.05 %、臭ィヒナトリウム 0.05 %、塩化ナトリゥム 0.5 %、 リン酸水素二力リゥム 0.1 %からなる培地 （滅菌 前 pH7.2) 110mlを含む 500ml容の培養用三角フラスコ 1本に接種し、 28 °C で 8日間、 回転振盪機 （毎分 180回転） 上で培養した。 この培養液 2mlを上 記組成の培地 110mlを含む 500ml容の培養用三角フラスコ 20本に接種し、 28 °Cで回転振盪機 （毎分 180回転） 上で培養した。 9日間培養した時点で、 1フ ラスコあたり 12,13-ジヒ ドロ- 1,11-ジヒ ドロキシ -5H-インドロ [2,3- a] ピ ロロ [3，4- c] 力ルバゾール -5,7 (6H) -ジオン [化合物（28)；特開平 3- 2077 号参照] の 20mgZmlジメチルスルホキシド溶液 0.5mlを添加し、 同上条件' 下で更に 15日間培養した。 Microtetraspora sp. A34549 strain cultured on a slope agar medium [Accession number: FERM BP-4206 (Transferred from S. germ fungus No. P-13292 deposited on November 17, 1992) Glucose) 0.2%, dextrin 2.0%, oatmeal 0.5%, defatted rice bran 0.5%, defatted meat-and-bone meal 0.2%, dried yeast 0.1%, magnesium sulfate heptahydrate 0.05%, odorite sodium 0.05% Inoculate a 500 ml Erlenmeyer flask for culture containing 110 ml of a medium consisting of 0.5% sodium chloride and 0.1% hydrogen phosphate biphosphate (pH 7.2 before sterilization), and shake at 28 ° C for 8 days on a rotary shaker. (180 rotations per minute). 2 ml of this culture was inoculated into 20 500 ml Erlenmeyer flasks for culture containing 110 ml of the medium having the above composition, and cultured at 28 ° C on a rotary shaker (180 rotations per minute). At the time of culturing for 9 days, 12,13-dihydro-1,11-dihydroxy-5H-indolo [2,3-a] pyrrolo [3,4-c] pyrazole-5,7 per flask (6H) -dione [Compound (28); JP-A-3-2077 Was added and 0.5 ml of a 20 mg Zml dimethyl sulfoxide solution was added, and the cells were further cultured under the same conditions as described above for 15 days.
上記培養液をメチルェチルケトン （MEK) 3Lで抽出した。 MEK抽出液を 減圧下で濃縮した。 得られた濃縮液を酢酸ェチルを用いて抽出した。 酢酸ェ チル抽出液（850ml)を無水硫酸チトリゥムで脱水後、濃縮乾固した。 これを シリ力ゲルの力ラムクロマトグラフィー （内径 2cm，長さ 30cm，BW-350シリ 力ゲル.富士デヴィソン化学社製） に付し、 クロ口ホルム -メタノール-テトラ ヒ ドロフラン- 28 %アンモニア水 （2 : 1 : 3 : 0.2) で洗浄後、 クロ口ホルム- メタノ一ル-テトラヒドロフラン （3 : 1 : 1) で溶出した。 目的物を含む分画 を濃縮乾固した後、少量のテトラヒドロフラン-エタノール（1： 3)に溶解し、 セフアデックス LH- 20のカラムク口マトグラフィー （内径 1.5cm,長さ 87cm) に付し、エタノールで溶出し、 目的物を含む分画を濃縮乾固すること により表題化合物 （27)、 12，13-ジヒドロ- 1，11 -ジヒドロキシ- 13- ( /3- D- ダルコビラノシル） - 5H-インドロ [2,3- a] ピロ口 [3,4- c] カルバゾール- 5,7 (6H) -ジオン 53.9mgを得た。  The above culture solution was extracted with 3 L of methyl ethyl ketone (MEK). The MEK extract was concentrated under reduced pressure. The obtained concentrate was extracted with ethyl acetate. The ethyl acetate extract (850 ml) was dehydrated with anhydrous titanium sulfate and concentrated to dryness. This was subjected to power column chromatography on a silica gel (inner diameter 2 cm, length 30 cm, BW-350 silica gel, manufactured by Fuji Devison Chemical Co., Ltd.), and the chromate form-methanol-tetrahydrofuran-28% ammonia water After washing with (2: 1: 3: 0.2), elution was carried out with chloroform-methanol-tetrahydrofuran (3: 1: 1). The fraction containing the target compound was concentrated to dryness, dissolved in a small amount of tetrahydrofuran-ethanol (1: 3), and subjected to column chromatography on Sephadex LH-20 (1.5 cm ID, 87 cm length). The title compound (27), 12,13-dihydro-1,11-dihydroxy-13-(/ 3-D-darcoviranosyl) -5H-indolo was eluted with ethanol and the fraction containing the target compound was concentrated to dryness. 53.9 mg of [2,3-a] pyro [3,4-c] carbazole-5,7 (6H) -dione was obtained.
HR FAB- MS (m/z) ： 519.1313  HR FAB-MS (m / z): 519.1313
Ή- NMR (400MHz,DMSO-d6), (5 (ppm)： 11.0 (lH,s),10.9 (lH,s),10.3 (lH,brs)，9.93 (lH，brs)，8.69 (lH.d.J = 7.8Hz),8.51 (lH，d，J = 7.8Hz)， 7.17 (2H,t,J = 7.8Hz)，7.05 (lH,d，J二 9.3Hz),7.01 (lH.d.J = 7.8Hz), 6.99 (lH,d，J = 7.8Hz),5.41 (lH，d，J = 5.9Hz),5.34 (lH，brs),5.20 (1H, d,J = 5.4Hz),4.89 (lH,brs),4.02 (2H,m),3.74 (lH,m)，3.63 (2H,m)， 3.41 (lH.m) Ή-NMR (400 MHz, DMSO-d 6 ), (5 (ppm): 11.0 (lH, s), 10.9 (lH, s), 10.3 (lH, brs), 9.93 (lH, brs), 8.69 (lH. dJ = 7.8 Hz), 8.51 (lH, d, J = 7.8 Hz), 7.17 (2H, t, J = 7.8 Hz), 7.05 (lH, d, J 9.3 Hz), 7.01 (lH.dJ = 7.8 Hz) ), 6.99 (lH, d, J = 7.8 Hz), 5.41 (lH, d, J = 5.9 Hz), 5.34 (lH, brs), 5.20 (1H, d, J = 5.4 Hz), 4.89 (lH, brs) ), 4.02 (2H, m), 3.74 (lH, m), 3.63 (2H, m), 3.41 (lH.m)
参考例 2 Reference example 2
式：
Figure imgf000045_0001
で表される化合物の製造。 formula:
Figure imgf000045_0001
Production of the compound represented by
斜面寒天培地に培養したサッカロスリクス ェャロコロニジヱネス Saccharomyces serocolorigenicity cultured on slope agar
(Saccharothrix aerocolonigenes) ATCC 39243株をグルコース 3.0 %、 ソーャフラワー 1.0 %、 綿実粕 1.0 %及び炭酸カルシウム 0.3 %からなる培地 (滅菌前 ρΗ7.2) 110mlを含む 500ml容の培地用三角フラスコ 7本に接種し、 28°Cで 48時間、回転振還機（毎分 180回転）上で培養した。 この培養液 4ml ずつをグルコース 1.0 %、 デキストリン 6.0 %、亜麻仁粕 1.5 %、粉末酵母 0.5 %、 硫酸第一鉄 7水和物 0.1 %、 リン酸二水素アンモニゥム 0.1 %、 硫酸アン モニゥム 0.1 %及び炭酸カルシウム 1.0%からなる培地（滅菌前 pH7.2) 110ml を含む 500ml容の培地用三角フラスコ 150本に接種し、 28 °Cで回転振盪機 (毎分 180回転） 上で培養した。 120時間培養した時点で、 1フラスコあたり 12，13-ジヒドロ- 1,11 -ジヒドロキシ- 5H-インドロ [2,3- a] ピロ口 [3，4- c] 力ノ ゾール- 5,7 (6H) -ジオン [特開平 3 - 2077号参照] の 22mg/ml ジ メチルスルホキシド（DMSO)溶液 0.5mlを添加し、同上条件下で更に 120時 間培養した。 (Saccharothrix aerocolonigenes) ATCC 39243 strain was inoculated into seven 500 ml Erlenmeyer flasks containing 110 ml of a medium consisting of 3.0% glucose, 1.0% soya flour, 1.0% cottonseed meal and 0.3% calcium carbonate (ρ 滅菌 7.2 before sterilization). Then, the cells were cultured at 28 ° C. for 48 hours on a rotary shaker (180 rotations per minute). Add 4 ml of this culture solution to glucose 1.0%, dextrin 6.0%, linseed cake 1.5%, powdered yeast 0.5%, ferrous sulfate heptahydrate 0.1%, ammonium dihydrogen phosphate 0.1%, ammonium sulfate 0.1% and carbonate The medium was inoculated into 150 500 ml Erlenmeyer flasks for medium containing 110 ml of a medium containing 1.0% of calcium (pH 7.2 before sterilization), and cultured at 28 ° C. on a rotary shaker (180 rotations per minute). At the time of culturing for 120 hours, 12,13-dihydro-1,11-dihydroxy-5H-indolo [2,3-a] pyro-mouth [3,4-c] pyrrole-5,7 (6H 0.5 ml of a 22 mg / ml solution of-)-dione (see JP-A-3-2077) in 22 mg / ml of dimethylsulfoxide (DMSO) was added, and the cells were further cultured under the same conditions as above for 120 hours.
上記培養液を濾過して得られた菌体をメタノールで 2回（5.1L，5.6L)、テト ラヒドロフランで 2回 （2.2L，2.3L) 抽出した。 メ夕ノール及びテトラヒドロ フラン抽出液を合わせて約 1600mlまで濃縮した。 濃縮して得られた水溶液 をへキサン（780ml)で抽出して不純物を除去し、この水層を酢酸ェチル 3.3L を用いて抽出した。 酢酸ェチル抽出液を濃縮乾固し、 得られた残澄を酢酸ェ チル約 90mlで洗浄した後の残渣をメタノール約 90mlで抽出した。 メタノー ル抽出液を濃縮乾固して、 694mgの黄橙色固体を得た。 これをメタノール 40mlに溶解し、 メタノールを溶出液としたセフアデックス LH- 20 (3.0 x 53cm，フアルマシア社製）のカラムクロマ卜に付し、目的の化合物を含む分画 を集めて濃縮乾固した。 これをシリカゲルのカラムクロマトグラフィー (1.5 X 46cm，キーゼルゲル 60，メルク社） に付し、 クロ口ホルム、次いでクロ 口ホルム：メタノール （10： 1) で洗浄後、酢酸ェチル： メタノール （10： 1) で溶出した。 溶出液を濃縮乾固して目的の表題化合物 （27)、 12,13-ジヒド 口- 1，11 -ジヒドロキシ - 13- (/?- D-グルコビラノシル）- 5H-インドロ [2，3- a] ピロ口 [3,4- c] 力ルバゾール - 5,7 (6H) -ジオン （169mg) を得た。 こうして得られた表題化合物の物性データは、 参考例 1で得られた化合物 の物性データと同一である。 The cells obtained by filtering the above culture solution were extracted twice with methanol (5.1 L, 5.6 L) and twice with tetrahydrofuran (2.2 L, 2.3 L). The combined methanol and tetrahydrofuran extracts were concentrated to about 1600 ml. The aqueous solution obtained by concentration was extracted with hexane (780 ml) to remove impurities, and the aqueous layer was extracted with 3.3 L of ethyl acetate. The ethyl acetate extract was concentrated to dryness, the obtained residue was washed with about 90 ml of ethyl acetate, and the residue was extracted with about 90 ml of methanol. The methanol extract was concentrated to dryness to obtain 694 mg of a yellow-orange solid. This is methanol The resultant was dissolved in 40 ml and subjected to a column chromatography of Sephadex LH-20 (3.0 × 53 cm, manufactured by Pharmacia) using methanol as an eluate. Fractions containing the target compound were collected and concentrated to dryness. This was subjected to silica gel column chromatography (1.5 X 46 cm, Kieselgel 60, Merck), washed with black-mouthed form, then with ethyl-form: methanol (10: 1), and then ethyl acetate: methanol (10: 1). Eluted. The eluate is concentrated to dryness and the desired title compound (27), 12,13-dihydrido-1,11-dihydroxy-13-(/?-D-glucoviranosyl) -5H-indolo [2,3-a] [3,4-c] pyrazole-pyrazole-5,7 (6H) -dione (169 mg) was obtained. The physical property data of the title compound thus obtained is the same as the physical property data of the compound obtained in Reference Example 1.
参考例 3 Reference example 3
式：  Formula:
Figure imgf000046_0001
で表される化合物の製造。
Figure imgf000046_0001
Production of the compound represented by
参考例 1又は 2で製造された 12,13-ジヒドロ- 1,11-ジヒドロキシ- 13- { β - D-グルコビラノシル） - 5Η-インドロ [2，3- a] ピロ口 [3,4- c] カルバゾー ル- 5,7 (6H) -ジオン 3.4gを 10 %水酸化カリウム水溶液 120mlに溶解し、室 温にて 2時間撹拌した。 反応液に 2N塩酸 120mlを加えて中和した後、析出し た赤色結晶を濾過し、水洗、乾燥することにより、表題の化合物 （8) 3.0gを ,こ o  12,13-Dihydro-1,11-dihydroxy-13- {β-D-glucoviranosyl) -5Η-indolo [2,3-a] produced in Reference Example 1 or 2 [3,4-c] 3.4 g of carbazole-5,7 (6H) -dione was dissolved in 120 ml of a 10% aqueous potassium hydroxide solution and stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2N hydrochloric acid (120 ml), and the precipitated red crystals were filtered, washed with water and dried to give 3.0 g of the title compound (8).
FAB- MS (m/z) ： 520 (M) \521 (M + H) '  FAB-MS (m / z): 520 (M) \ 521 (M + H) '
1 H- NMR (400MHz，DMSO- d6)，5 (ppm) : 3.42 (lH,m) ,3.56-3.70 (2H， m),3.76 (lH,m) ,3.95-4.10 (2H，m)，4.95 (lH.dJ = 4.6Hz),5.24 (1H， d，J = 5.4Hz)，5.32 (lH，dd，J = 4.9，5·1Ηζ)，7.06 (2H,dd, J = 7.6,7.8Hz), 7.09 (lH,d，J = 8.0Hz)，7.20 (lH.d.J = 7.8Hz),7.40 (lH'd'J = 7.8Hz)， 8.36 (lH,d，J = 7·6Ηζ)，8，51 (lH，d，J = 7.6Hz)，10.13 (lH，s)，10.52 (lH,s),l l.l l (lH，s) 産業上の利用可能性 1 H-NMR (400 MHz, DMSO-d 6 ), 5 (ppm): 3.42 (lH, m), 3.56-3.70 (2H, m), 3.76 (lH, m), 3.95-4.10 (2H, m), 4.95 (lH.dJ = 4.6Hz), 5.24 (1H, d, J = 5.4 Hz), 5.32 (lH, dd, J = 4.9, 5.1Ηζ), 7.06 (2H, dd, J = 7.6, 7.8 Hz), 7.09 (lH, d, J = 8.0 Hz), 7.20 (lH.dJ = 7.8Hz), 7.40 (lH'd'J = 7.8Hz), 8.36 (lH, d, J = 7.6Ηζ), 8, 51 (lH, d, J = 7.6Hz), 10.13 ( lH, s), 10.52 (lH, s), llll (lH, s) Industrial applicability
本発明の化合物は、 優れた抗腫瘍効果を有することから医薬の分野におい て抗腫瘍剤として有用である。  The compounds of the present invention have excellent antitumor effects and are useful as antitumor agents in the field of medicine.

Claims

請 求 の 範 囲 The scope of the claims
(1) 一般式  (1) General formula
Figure imgf000048_0001
Figure imgf000048_0001
[式中、 R1及び R2は OHを示し、その結合位置は R1は 1位又は 2位であり、 R2 は 10位又は 11位であり、 R1が 1位の時、 R2は 11位であり、 R1が 2位の時、 R2は 10位である] で表される化合物又はその製薬学的に許容しうる塩。 [Wherein, R 1 and R 2 represent OH, and the bonding position thereof is R 1 is 1 or 2; R 2 is 10 or 11; and when R 1 is 1, R 2 Is at the 11-position, and when R 1 is at the 2-position, R 2 is at the 10-position.] Or a pharmaceutically acceptable salt thereof.
(2) 式 Equation (2)
Figure imgf000048_0002
で表される化合物又はその製薬学的に許容しうる塩。
Figure imgf000048_0002
Or a pharmaceutically acceptable salt thereof.
(3) 式
Figure imgf000049_0001
で表される化合物又はその製薬学的に許容しうる塩 Equation (3)
Figure imgf000049_0001
Or a pharmaceutically acceptable salt thereof
(4) 一般式  (4) General formula
Figure imgf000049_0002
Figure imgf000049_0002
[式中、 R3は低級アルキル基、ベンジルォキシメチル基又はァラルキル基を示 し、 R1及び R2は請求項 1に記載の意味を有する] で表される化合物。 [Wherein, R 3 represents a lower alkyl group, a benzyloxymethyl group or an aralkyl group, and R 1 and R 2 have the meanings according to claim 1].
(5) 一般式 (5) General formula
Figure imgf000049_0003
Figure imgf000049_0003
[式中、 R4は水素原子、低級アルキル基、ベンジルォキシメチル基又はァラル キル基を示し、 R5及び R6は保護された OHを示し （その結合位置は、 R5が 1 位又は 2位であり、 R6は 10位又は 11位であり、 R5が 1位の時、 R6は 11位で あり、 R5が 2位の時、 R6は 10位である）、 R7〜R1Qは、 同一又は異なって、水 酸基の保護基を示し、 R'1は水素原子又はィンドール骨格のァミノ基の保護基 を示す] で表される化合物。 Wherein R 4 is a hydrogen atom, a lower alkyl group, a benzyloxymethyl group or an aryl R 5 and R 6 represent a protected OH (R 5 is 1 or 2 position, R 6 is 10 or 11 position, R 5 is 1 position In the formula, R 6 is 11-position, and when R 5 is 2-position, R 6 is 10-position), R 7 to R 1Q are the same or different and each represents a hydroxyl-protecting group; ' 1 represents a hydrogen atom or an amino group-protecting group for an indole skeleton.]
(6) 一般式 (6) General formula
Figure imgf000050_0001
Figure imgf000050_0001
[式中、 R4〜R"は請求項 5に記載の意味を有する] で表される化合物 c [Wherein R 4 to R ″ have the meanings according to claim 5].
(7) 一般式 (7) General formula
Figure imgf000050_0002
中、 Xは脱離基を示し、 R5は 1位又は 2位に結合する保護された 0Hを示 し、 R4、 R7〜Rl°は請求項 5に記載の意味を有する] で表される化合物。
Figure imgf000050_0002
Wherein X represents a leaving group, R 5 represents a protected 0H bonded to the 1-position or 2-position, and R 4 , R 7 to R l ° have the meaning according to claim 5]. The compound represented.
(8) 一般式
Figure imgf000051_0001
(8) General formula
Figure imgf000051_0001
[式中、 R4〜R6、 R11は請求項 5に記載の意味を有する] で表される化合物 c Wherein R 4 to R 6 and R 11 have the meanings described in claim 5.
(9) 一般式 (9) General formula
Figure imgf000051_0002
Figure imgf000051_0002
K中、 R4〜R6、 R11は請求項 5に記載の意味を有する] で表される化合物 c During K, R 4 ~R 6, R 11 is compounds c represented by 'have the meanings given in claim 5
(10) 一般式 (10) General formula
[观][观]
Figure imgf000051_0003
Figure imgf000051_0003
中、 R R6及び R11は請求項 5に記載の意味を有し、 Xは請求項 7に記載 の意味を有する] で表される化合物。 Wherein RR 6 and R 11 have the meanings according to claim 5, and X has the meanings according to claim 7].
(11) 式 Equation (11)
Figure imgf000051_0004
Figure imgf000051_0004
[式中、 ま請求項 5に記載の意味を有し、 Xは請求項 7に記載の意味を有す る] で表される化合物に、 一般式
Figure imgf000052_0001
[Wherein, has the meaning described in claim 5, and X has the meaning described in claim 7.] To the compound represented by the general formula
Figure imgf000052_0001
[式中、 R6は請求項 5に記載の意味を有する] で表される化合物を有機金属化 合物の存在下反応させ、 一般式 [Wherein R 6 has the meaning of claim 5], and reacted in the presence of an organometallic compound;
Figure imgf000052_0002
Figure imgf000052_0002
[式中、 R4、 R6及び Xは前記の意味を有する] で表される化合物を製造し、次 いでィンドール骨格のァミノ基の水素原子を保護し、 一般式 Wherein R 4 , R 6 and X have the same meanings as defined above, and then protecting the hydrogen atom of the amino group of the indole skeleton by the general formula
Figure imgf000052_0003
Figure imgf000052_0003
[式中、 R4、 R6及び Xは前記の意味を有し、 R12はィンドール骨格のァミノ基 の保護基を示す] で表される化合物を製造し、 次いで、 この化合物に有機金 属化合物の存在下、 一般式
Figure imgf000052_0004
[Wherein R 4 , R 6 and X have the above-mentioned meanings, and R 12 represents a protecting group for an amino group of the indole skeleton]. In the presence of the compound, the general formula
Figure imgf000052_0004
中、 R5は請求項 5に記載の意味を有する] で表される化合物を反応させ、 —般式
Figure imgf000053_0001
Wherein R 5 has the meaning described in claim 5],
Figure imgf000053_0001
[式中、 R4、 Rs、 R6及び R12は前記の意味を有する] で表される化合物を製造 し、 次 、でミツノブ反応により、 一般式 [Wherein R 4 , R s , R 6 and R 12 have the above-mentioned meaning], and a compound represented by the general formula:
Figure imgf000053_0002
Figure imgf000053_0002
[式中、 R7〜RIQは請求項 5に記載の意味を有する]で表される化合物を反応さ せ、 一般式 Wherein R 7 to R IQ have the meaning according to claim 5, and a compound represented by the general formula:
Figure imgf000053_0003
ぼ中、 R4〜R1<5及び R12は前記の意味を有する] で表される化合物を製造し、 次いでィンドール骨格のァミノ基の保護基を除去し、 一般式
Figure imgf000053_0003
In the formula, R 4 to R 1 <5 and R 12 have the same meaning as described above], and the protecting group for the amino group of the indole skeleton is removed.
Figure imgf000054_0001
[式中、 R -〜 R'°は前記の意味を有する] で表される化合物を製造し、 次いで この化合物を酸化剤を用いて環化させることにより、 一般式
Figure imgf000054_0001
Wherein R-to R '° have the above-mentioned meaning, and then cyclizing the compound with an oxidizing agent to obtain a compound represented by the general formula
Figure imgf000054_0002
Figure imgf000054_0002
[式中、 R4〜R1C)は前記の意味を有する] で表される化合物を製造し、 OHの保 護基を除去することにより、 一般式 Wherein R 4 to R 1C have the above-mentioned meanings, and the protecting group of OH is removed to obtain a compound of the general formula
Figure imgf000055_0001
[式中、 R1及び R2は請求項 1に記載の意味を有し、 Ι¾Ίま前記の意味を有する] で表される化合物を製造し、 この化合物に塩基を反応させることにより、一 般式
Figure imgf000055_0001
[Wherein, R 1 and R 2 have the meanings of claim 1 and have the above-mentioned meanings], and the compound is reacted with a base to obtain a general compound. formula
Figure imgf000055_0002
Figure imgf000055_0002
[式中、 R1及び R2は前記の意味を有する] で表される化合物を製造し、 次い で H2NNHCH (C¾OH)2を反応させることを特徴とする請求項 1に記載の化 合物の製造法。 Wherein R 1 and R 2 have the above-mentioned meanings, and then reacting with H 2 NNHCH (C¾OH) 2 . Manufacturing method of compound.
(12) —般式
Figure imgf000056_0001
(12) —General formula
Figure imgf000056_0001
[式中、 R'1及び R5は請求項 5に記載の意味を有し、 Xは請求項 7に記載の意味 を有する] で表される化合物に、 ミツノブ反応により、 一般式 [Wherein, R ′ 1 and R 5 have the meaning described in claim 5 and X has the meaning described in claim 7] to the compound represented by the general formula
Figure imgf000056_0002
Figure imgf000056_0002
[式中、 R7〜R'°は請求項 5に記載の意味を有する]で表される化合物を反応さ せ、 一般式 Wherein R 7 to R ′ ° have the meaning described in claim 5, and a compound represented by the general formula:
Figure imgf000056_0003
Figure imgf000056_0003
[式中、 R4〜R5、 R7〜R8及び Xは前記の意味を有する] で表される化合物を 製造し、 次いで有機金属化合物の存在下に一般式
Figure imgf000056_0004
Wherein R 4 to R 5 , R 7 to R 8 and X have the same meaning as described above, and then a compound represented by the general formula
Figure imgf000056_0004
[式中、 R6は請求項 5に記載の意味を有する] で表される化合物を反応させる ことを特徴とする一般式
Figure imgf000057_0001
[式中、 R4〜R1Qは前記の意味を有する] で表される化合物の製造法 c [Wherein R 6 has the meaning of claim 5].
Figure imgf000057_0001
[Wherein, R 4 to R 1Q have the above-mentioned meanings]
(13) 一般式 (13) General formula
Figure imgf000057_0002
Figure imgf000057_0002
[式中、 R4〜R6は請求項 5に記載の意味を有し、 R'2は請求項 11に記載の意味 を有する]で表される化合物のィンドール骨格のァミノ基の保護基を除去し、 一般式 [Wherein, R 4 to R 6 have the meaning described in claim 5, and R ′ 2 has the meaning described in claim 11]. Remove, general formula
Figure imgf000057_0003
ぼ中、 R''〜R6は前記の意味を有する]で表される化合物を製造し、 この化合 物に酸化剤を反応させることにより環化し、 一般式
Figure imgf000058_0001
Figure imgf000057_0003
In the formula, R ″ to R 6 have the same meanings as defined above], and cyclized by reacting the compound with an oxidizing agent to obtain a compound represented by the general formula
Figure imgf000058_0001
[式中、 R4〜R6は前記の意味を有する]で表される化合物を製造し、 この化合 物に塩基の存在下、 一般式 [Wherein, R 4 to R 6 have the same meaning as described above], and a compound represented by the general formula:
Figure imgf000058_0002
Figure imgf000058_0002
ぼ中、 X1は脱離基を示し、 R7〜R'°は請求項 5に記載の意味を有する] で表 される化合物を反応させることを特徴とする、 一般式 In the formula, X 1 represents a leaving group, and R 7 to R ′ ° have the meaning according to claim 5].
Figure imgf000058_0003
Figure imgf000058_0003
[式中、 R4〜Rieは前記の意味を有する] で表される化合物の製造法 c [Wherein, R 4 to R ie have the same meanings as above] c
(14) 一般式 (14) General formula
Figure imgf000058_0004
Figure imgf000058_0004
[式中、 R4は請求項 5に記載の意味を有し、 Xは請求項 7に記載の意味を有す る] で表される化合物に、 有機金属化合物の存在下、 一般式
Figure imgf000059_0001
Wherein R 4 has the meaning as defined in claim 5 and X has the meaning as defined in claim 7 To the compound represented by the general formula
Figure imgf000059_0001
[式中、 R5は請求項 5に記載の意味を有する] で表される化合物を 2分子付加 させることを特徴とする一般式 Wherein, in the formula, R 5 has the meaning described in claim 5, and two molecules of the compound represented by the formula are added.
Figure imgf000059_0002
Figure imgf000059_0002
[式中、 及び R5は前記の意味を有し、 R6は請求項 5に記載の意味を有する] で表される化合物の製造法。 [Wherein, and R 5 have the meanings described above, and R 6 has the meanings according to claim 5].
(15) —般式 (15) —General formula
Figure imgf000059_0003
Figure imgf000059_0003
[式中、 R4〜R6は請求項 5に記載の意味を有し、 R12は請求項 11に記載の意味 を有する] で表される化合物を製造し、 次いで酸化剤を反応させることによ り、 一般式
Figure imgf000060_0001
Wherein R 4 to R 6 have the meaning described in claim 5, and R 12 has the meaning described in claim 11, and then reacting with an oxidizing agent. By the general formula
Figure imgf000060_0001
[式中、 R4〜R6及び R12は前記の意味を有する] で表される化合物を製造し、 この化合物に塩基の存在下、 一般式 [Wherein, R 4 to R 6 and R 12 have the above-mentioned meanings].
Figure imgf000060_0002
Figure imgf000060_0002
[式中、 R7〜R1Qは請求項 5に記載の意味を有し、 X1は請求項 13に記載の意味 を有する] で表される化合物を反応させ、 一般式 Wherein R 7 to R 1Q have the meaning described in claim 5, and X 1 has the meaning described in claim 13.
Figure imgf000060_0003
Figure imgf000060_0003
[式中、 R4〜Rie及び R12は前記の意味を有する] で表される化合物を製造し、 次いでィンドール骨格のァミノ基の保護基を除去することを特徴とする一般 式
Figure imgf000061_0001
Wherein R 4 to R ie and R 12 have the same meaning as described above, and then removing the protecting group for the amino group of the indole skeleton.
Figure imgf000061_0001
[式中、 R4〜R1Qは前記の意味を有する] で表される化合物の製造法。 [Wherein, R 4 to R 1Q have the above-mentioned meanings].
(16) 式： H2NNHCH (CH2OH)2 で表される化合物。 (16) A compound represented by the formula: H 2 NNHCH (CH 2 OH) 2 .
(17) 請求項 1〜3のいずれかに記載の化合物を含有することを特徴とする抗  (17) An anti-drug comprising the compound according to any one of claims 1 to 3.
PCT/JP1995/000868 1994-05-09 1995-05-02 Antitumor indolopyprolocarbazole derivative WO1995030682A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU23535/95A AU683749B2 (en) 1994-05-09 1995-05-02 Antitumor indolopyprolocarbazole derivative
AT95917506T ATE255121T1 (en) 1994-05-09 1995-05-02 ANTITUMOR INDOLOPYROLOCARBAZOLE DERIVATIVE
US08/737,382 US5804564A (en) 1994-05-09 1995-05-02 Antitumor indolopyrrolocarbazole derivatives
EP95917506A EP0760375B1 (en) 1994-05-09 1995-05-02 Antitumor indolopyprolocarbazole derivative
JP7528838A JP3038921B2 (en) 1994-05-09 1995-05-02 Antineoplastic indolopyrrolocarbazole derivatives
DE69532198T DE69532198T2 (en) 1994-05-09 1995-05-02 ANTI-TUMOR INDOLOPYROLOCARBAZOLDERIVAT
DK95917506T DK0760375T3 (en) 1994-05-09 1995-05-02 The antitumor indolopyrrolocarbazole derivatives
DK02018235T DK1264836T3 (en) 1994-05-09 1995-05-02 Process for the preparation of indolopyrrolocarbaxol derivatives
CA002190007A CA2190007C (en) 1994-05-09 1995-05-02 Antitumor indolopyrrolocarbazole derivatives
KR1019960706296A KR100312473B1 (en) 1994-05-09 1995-05-02 Antitumor Indolopyrolocarbazole Derivatives
HK97102485A HK1000890A1 (en) 1994-05-09 1997-12-17 Antitumor indolopyrolocarbazole derivative

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP6/119483 1994-05-09
JP11948394 1994-05-09
JP6/145648 1994-06-03
JP14564894 1994-06-03
US08/255,980 US5591842A (en) 1991-11-29 1994-06-08 Indolopyrrolocarbazole derivatives

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WO1995030682A1 true WO1995030682A1 (en) 1995-11-16

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WO1997009339A1 (en) * 1995-09-05 1997-03-13 Banyu Pharmaceutical Co., Ltd. Antitumor indolopyrrolocarbazole derivatives
US6610727B2 (en) 2000-10-06 2003-08-26 Bristol-Myers Squibb Company Anhydro sugar derivatives of indolocarbazoles
US6653290B2 (en) 2000-10-06 2003-11-25 Bristol-Myers Squibb Company Tumor proliferation inhibitors
US6677450B2 (en) 2000-10-06 2004-01-13 Bristol-Myers Squibb Company Topoisomerase inhibitors
US6790836B2 (en) 2000-02-24 2004-09-14 Banyu Pharmaceutical Co., Ltd. Process for preparing indolopyrrolocarbazole derivatives, intermediates therefor, and preparation process of the intermediates
US6855698B2 (en) 2001-03-22 2005-02-15 Bristol-Myers Squibb Company Topoisomerase I selective cytotoxic sugar derivatives of indolopyrrolocarbazoles
WO2009125042A1 (en) 2008-04-08 2009-10-15 Universidad De Oviedo Glycosylated indolecarbazoles, method for obtaining same and uses thereof
US7713969B2 (en) 2005-02-09 2010-05-11 Arqule, Inc. Compositions and methods for treatment of cancer
US8232285B2 (en) 2007-06-22 2012-07-31 Arqule, Inc. Quinazolinone compounds and methods of use thereof
US8304425B2 (en) 2007-06-22 2012-11-06 Arqule, Inc. Pyrrolidinone, pyrrolidine-2,5-dione, pyrrolidine and thiosuccinimide derivatives, compositions and methods for treatment of cancer
US8513292B2 (en) 2007-06-22 2013-08-20 Arqule, Inc. Compositions and methods for the treatment of cancer

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009339A1 (en) * 1995-09-05 1997-03-13 Banyu Pharmaceutical Co., Ltd. Antitumor indolopyrrolocarbazole derivatives
US6790836B2 (en) 2000-02-24 2004-09-14 Banyu Pharmaceutical Co., Ltd. Process for preparing indolopyrrolocarbazole derivatives, intermediates therefor, and preparation process of the intermediates
US6610727B2 (en) 2000-10-06 2003-08-26 Bristol-Myers Squibb Company Anhydro sugar derivatives of indolocarbazoles
US6653290B2 (en) 2000-10-06 2003-11-25 Bristol-Myers Squibb Company Tumor proliferation inhibitors
US6677450B2 (en) 2000-10-06 2004-01-13 Bristol-Myers Squibb Company Topoisomerase inhibitors
US6686385B2 (en) 2000-10-06 2004-02-03 Bristol-Myers Squibb Company Anhydro sugar derivatives of indolocarbazoles
US7138377B2 (en) 2000-10-06 2006-11-21 Bristol-Myers Squibb Company Topoisomerase inhibitors
US6855698B2 (en) 2001-03-22 2005-02-15 Bristol-Myers Squibb Company Topoisomerase I selective cytotoxic sugar derivatives of indolopyrrolocarbazoles
US8377927B2 (en) 2005-02-09 2013-02-19 Arqule, Inc. Compositions and methods for treatment of cancer
US7713969B2 (en) 2005-02-09 2010-05-11 Arqule, Inc. Compositions and methods for treatment of cancer
US8754078B2 (en) 2005-02-09 2014-06-17 Arqule, Inc. Compositions and methods for treatment of cancer
US9447088B2 (en) 2005-02-09 2016-09-20 Arqule, Inc. Compositions and methods for treatment of cancer
US8232285B2 (en) 2007-06-22 2012-07-31 Arqule, Inc. Quinazolinone compounds and methods of use thereof
US8304425B2 (en) 2007-06-22 2012-11-06 Arqule, Inc. Pyrrolidinone, pyrrolidine-2,5-dione, pyrrolidine and thiosuccinimide derivatives, compositions and methods for treatment of cancer
US8513292B2 (en) 2007-06-22 2013-08-20 Arqule, Inc. Compositions and methods for the treatment of cancer
WO2009125042A1 (en) 2008-04-08 2009-10-15 Universidad De Oviedo Glycosylated indolecarbazoles, method for obtaining same and uses thereof

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