WO2012157744A1 - 1-THIOXO-1,2,3,4-TETRAHYDRO-β-CARBOLINE DERIVATIVE AND ANTI-CANCER AGENT COMPRISING SAME - Google Patents

1-THIOXO-1,2,3,4-TETRAHYDRO-β-CARBOLINE DERIVATIVE AND ANTI-CANCER AGENT COMPRISING SAME Download PDF

Info

Publication number
WO2012157744A1
WO2012157744A1 PCT/JP2012/062775 JP2012062775W WO2012157744A1 WO 2012157744 A1 WO2012157744 A1 WO 2012157744A1 JP 2012062775 W JP2012062775 W JP 2012062775W WO 2012157744 A1 WO2012157744 A1 WO 2012157744A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
tetrahydro
thioxo
aryl
protected
Prior art date
Application number
PCT/JP2012/062775
Other languages
French (fr)
Japanese (ja)
Inventor
敦 加藤
伊佐雄 足立
尚樹 豊岡
聡 鍛冶
由紀子 倉島
友佳子 畑
勤 小倉
Original Assignee
国立大学法人 富山大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人 富山大学 filed Critical 国立大学法人 富山大学
Priority to JP2013515218A priority Critical patent/JPWO2012157744A1/en
Publication of WO2012157744A1 publication Critical patent/WO2012157744A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of compounds and pharmaceutically acceptable salts thereof for the preparation of a medicament for treating solid cancers such as pancreatic cancer. More specifically, the present invention relates to 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivatives and anticancer agents containing them as active ingredients.
  • Solid cancer refers to cancer excluding blood cancer such as leukemia, and includes stomach cancer, lung cancer, breast cancer, colon cancer, pancreatic cancer and the like.
  • blood cancer such as leukemia
  • pancreatic cancer for the treatment of solid cancer, it is common to first remove the cancer by surgery and then treat the cancer that cannot be removed with an anticancer agent.
  • the death toll from pancreatic cancer is more than 23,000, and the 5-year survival rate is only 6.7%, far below the average 5-4.3% survival rate of all cancer types. Is expensive.
  • pancreatic cancer is extremely difficult to detect and is often too late at the time of diagnosis, and only about 20% to 30% of cases can be operated on. Therefore, chemotherapy is an important place for the treatment of pancreatic cancer.
  • Patent Document 1 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivatives having an aldose reductase inhibitory action are known (Patent Document 1).
  • a carboxylic acid form of a 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivative can be a therapeutic agent for cancer in which polyol metabolism is enhanced or aldose reductase is overexpressed.
  • the carboxylic acid form of 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivative has an inhibitory effect on the growth of mouse leukemia adriamycin sensitive strain P388 / S. Has been.
  • pancreatic cancer pancreatic cancer
  • the survival time of non-resected pancreatic cancer patients before the start of use of this drug was only about 3.5 months, whereas after the appearance of gemcitabine, the survival time was extended to 7.8 months.
  • combination treatment with gemcitabine and oxaplatin or erlotinib is performed to improve the survival rate.
  • Pancreatic cancer treatment guidelines recommend gemcitabine monotherapy for locally inoperable cases, but development of next-generation pancreatic cancer therapeutics has hardly progressed for 10 years, and monotherapy At present, no drug exceeding gemcitabine has appeared.
  • An object of the present invention is to provide a compound having a therapeutic effect on solid cancer such as pancreatic cancer and to provide a medicament for treating solid cancer such as pancreatic cancer.
  • the present invention was completed by finding that it has high selectivity for cancer cells such as pancreatic cancer cells. That is, the present invention relates to 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivatives represented by the following general formulas [1] and [1 ′] and physiologically acceptable salts thereof.
  • the present invention provides a therapeutic agent for solid cancer such as pancreatic cancer comprising one or more selected from the group as an active ingredient.
  • the present invention is a new cancer tissue-specific therapeutic approach for cancer that has acquired resistance and survived in a nutrient-starved state, such as pancreatic cancer that grows in an environment with extremely low blood flow.
  • the present invention provides a drug that can be used for “releasing nutritional starvation tolerance”.
  • the present invention will be described in detail.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • an alkyl group is a linear or branched group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl group the chain C 1-12 alkyl group
  • lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl and hexyl groups linear or branched C 1- 6 alkyl group
  • an alkylene group is a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene and isopropylene groups
  • a cycloalkyl group is cyclopropyl
  • hydroxyalkyloxycarbonyl group means the following formula [6]
  • a group represented by “in the formula, Aa represents an alkylene group”
  • hydroxyalkyloxyalkylcarbonyl group means the following formula [7]
  • a group represented by “in the formula, Aa and Ab are the same or different and each represents an alkylene group”;
  • the hydroxyalkyloxy group is an alkoxy group substituted with a hydroxyl group; the hydroxyaryl group is hydroxymethyloxy, hydroxyethyloxy, hydroxypropyloxy, hydroxyisopropyloxy, hydroxybutyloxy, hydroxypentyloxy, hydroxyhexyloxy, C 1 a linear or branched hydroxyl group is substituted such as hydroxy heptyloxy and hydroxy octyloxy group - 12 alkyl group; a hydroxy aryl group, 4-hydroxyphenyl, 3-hydroxyphenyl, 2- By aryl each substituted by one or several hydroxyls such as hydroxyphenyl, hydroxynaphthyl, hydroxyindanyl and hydroxyindenyl groups is meant.
  • Heterocyclic groups include pyrodinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolinyl, tetrahydroisoquinolyl, quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl, quinolyl, quinolyl, , Tetrazolyl, thiadiazolyl, pyronilyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazo
  • the hetero atom forming the ring may contain one or more oxygen atom or sulfur atom, and at least one hetero atom selected from nitrogen, oxygen, or sulfur atom. It means a heterocyclic group having 5 or 6-membered ring, condensed ring or bridged ring atom.
  • the carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups, for example, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl and tert-butyl.
  • Aryl groups such as phenyl and naphthyl; al lower alkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl; acetylmethyl, benzoylmethyl, p-nitro Acyl-lower alkyl groups such as benzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; 2,2,2-trichloroethyl Any halogeno-lower alkyl group; lower alkylsilyl-lower alkyl groups such as 2- (trimethylsilyl) ethyl; acyloxy-lower alkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl
  • the hydroxyl protecting group includes all groups that can be used as protecting groups for ordinary hydroxyl groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphospho) Honio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl,
  • the present invention relates to a general formula [1]
  • R 1 is the same or different and is a hydrogen atom, halogen atom, alkyl group, cycloalkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, cycloalkyloxy group, aryloxy group or protected.
  • R 2 is an optionally protected hydroxyalkyloxycarbonyl, hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl
  • R 3 represents an alkyl group or aryl group substituted with an aryl, cycloalkyl or heterocyclic group optionally substituted with a halogen atom
  • A represents an alkylene group
  • X represents a sulfur atom or oxygen
  • the present invention relates to a general formula [1 ′]
  • R 1 is the same or different and is a hydrogen atom, halogen atom, alkyl group, cycloalkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, cycloalkyloxy group, aryloxy group or protected.
  • R 2 is an optionally protected hydroxyalkyloxycarbonyl, hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl
  • R 3 represents an alkyl group or aryl group substituted with an aryl, cycloalkyl or heterocyclic group optionally substituted with a halogen atom
  • A represents an alkylene group
  • X represents a sulfur atom or oxygen
  • salts of 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivatives of the general formulas [1] and [1 ′] include salts of acidic groups such as hydroxyl groups that are generally known. Can do.
  • salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N-dibenzylethylenediamine And the like.
  • preferred salts include pharmacologically acceptable salts.
  • isomers for example, optical isomers, geometric isomers, and tautomers
  • present invention includes all such isomers as well as hydrates, solvates and all crystal forms.
  • Preferred compounds in the present invention include, for example, the following compounds or salts thereof.
  • R 1a and R 1c are a hydrogen atom or a halogen atom
  • R 1b is a halogen atom, an optionally substituted alkyl or alkoxy group
  • R 2 is an optionally protected hydroxyalkyloxycarbonyl A hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl group
  • R 3a represents an aralkyl group which may be substituted with a halogen atom or a halogeno-substituted lower alkyl group.
  • a 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivative represented by the formula:
  • the 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivatives of the general formulas [1] and [1 ′] can be produced, for example, by the following method. ⁇ Production method
  • R 2a represents an optionally protected hydroxyl, hydroxyalkyloxy or hydroxyaryl group
  • R 2b represents an optionally protected hydroxyalkyloxycarbonyl or hydroxyalkyloxyalkyloxycarbonyl group
  • R 4 represents a carboxyl protecting group
  • Y represents a halogen atom
  • B represents an alkylene group or an alkyleneoxyalkylene group
  • R 1 , R 2 , R 3 , A and X have the same meaning as described above.
  • the compounds of general formula [1a] and general formula [3a] are produced, respectively. can do.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include amides such as N, N-dimethylformamide.
  • Examples of the base used in this reaction include inorganic bases such as sodium hydride, and the amount of the base used is equimolar or more, preferably 1 to 20 times the molar amount of the compound of the general formula [2]. If it is.
  • This reaction is usually carried out at 0 to 200 ° C., preferably 20 to 150 ° C., for 10 minutes to 20 hours.
  • the compound of the general formula [2] can be produced by a method known per se, and examples thereof include the method described in WO2009 / 078423.
  • a compound of the general formula [3b] can be produced by subjecting the compound of the general formula [3a] to a deprotection reaction of a carboxyl protecting group.
  • a deprotection reaction of the carboxyl protecting group a generally known reaction may be used.
  • dealkylation with trimethylsilyl iodide or ester hydrolysis may be performed.
  • the compound of the general formula [1b] can be produced by reacting the compound of the general formula [3b] with the compound of the general formula [4] in the presence of a condensing agent, a base, a catalyst and the like.
  • a condensing agent e.g., a base, a catalyst and the like.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform.
  • Examples of the condensing agent used in this reaction include carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and N, N-dicyclohexylcarbodiimide; halogenating agents such as thionyl chloride; ethyl chloroformate Halogenated alkyl esters such as esters; activated amidating agents such as carbonyldiimidazole; and azidating agents such as diphenylphosphoric azide.
  • the amount of the condensing agent to be used is not less than equimolar, preferably 1 to 5 times mol, relative to the compound of the general formula [3b].
  • Examples of the base used in this reaction include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, tert-butoxypotassium, sodium carbonate, potassium carbonate and Examples thereof include organic bases and inorganic bases such as sodium hydride, and the amount of the base used may be equimolar or more, preferably 1 to 10-fold mol relative to the compound of the general formula [3b].
  • Examples of the catalyst used as necessary in this reaction include N, N-dimethyl-4-aminopyridine and the like.
  • the amount of the catalyst used is 0. 0 with respect to the compound of the general formula [3b]. It may be 1 to 1 mole.
  • This reaction is usually carried out at ⁇ 50 to 200 ° C., preferably ⁇ 30 to 100 ° C., for 10 minutes to 20 hours.
  • the compound of the present invention comprises a solvent, a bulking agent, an isotonic agent, a solubilizer, an emulsifier, a suspending agent, a thickener, an absorption accelerator, a gelation / coagulation accelerator, a light stabilizer, a preservative, and an emulsifier.
  • a solvent a bulking agent
  • an isotonic agent a solubilizer
  • the administration method of the said formulation is not specifically limited, It determines suitably according to the form of a formulation, a patient's age, sex, other conditions, and the grade of a patient's symptom.
  • the dosage of the active ingredient of the preparation of the present invention is appropriately selected according to the usage, patient age, sex, disease form, other conditions, etc., but usually 0.1 to 500 mg per day for an adult. What is necessary is just to divide and administer from 1 time to several times.
  • Test example 1 ⁇ Anticancer activity against pancreatic cancer cells and colon cancer> 1) Cells and culture conditions
  • Cultured cells are 10% Fetal calf serum (MP Biomedicals), 1 ⁇ MEM non-essential amino acid mixture (Sigma), Antibiotic antimycotic solution (Sigma), Glucose (4.5 g / L) and Sodium Pyruvate (110 mg / ml) And cultured in Dulbecco's Modified Eagle (DMEM) medium.
  • the culture conditions were 37 ° C.
  • MTT reagent phosphate buffer PBS: pH 7.4
  • PBS pH 7.4
  • 200 ⁇ L of DMSO was added to dissolve the formatzan, and DMSO alone was used as a blank, and the absorbance of MTT-formazane at 540 nm was measured with FLUOstarOPTIMA (BMG LRBTECH).
  • FLUOstarOPTIMA BMG LRBTECH
  • Test example 2 ⁇ Inhibitory activity of aldose reductase> Contains phosphate buffer 200 mM (pH 6.2), nicotinamide adenine dinucleotide phosphate reduced form (NADPH) 1.5 mM, bovine serum albumin 1 mg / mL, test compound 200 ⁇ g / mL, and DL-glyceraldehyde 100 mM as a substrate
  • aldose reductase 5.1 ⁇ 10 -1 unit / mL was added to start the reaction, and the amount of NADPH decreased by the reaction was measured using a spectrophotometer at an absorption wavelength of 340 nm.
  • Test example 3 ⁇ Comparison of damage to pancreatic cancer (PANC-1 cells) and normal cells (HEL)> Evaluation was made by comparing with 50% cell growth inhibitory concentration against human pancreatic cancer cells and human fetal lung fibroblast HEL. As a result, AR-59 and AR-61 showed cytotoxicity against human pancreatic cancer cell PANC-1 at a concentration of 1/3 or less compared to normal cells.
  • Test example 4 ⁇ Anticancer effect in nutritional starvation> Human pancreatic cancer cells PANC-1 were seeded in 96-well plates at 1.0 ⁇ 10 4 /0.1 ml-well per well, cultured in nutrient-deficient medium NDM, and anticancer activity was evaluated. As a result, in the case of 5-FU and Gemzar, the IC 50 was> 200 ⁇ M in the nutrient-starved state, whereas 5.1 ⁇ 0.7 ⁇ M for AR59 and 3.1 ⁇ 0.6 ⁇ M for AR61. The compound of the present invention exhibits strong cytotoxicity to human pancreatic cancer cell PANC-1 even under nutrient starvation conditions.
  • the 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivatives of the above general formulas [1] and [1 ′] have no aldose reductase inhibitory activity, and as such are solid tumors, In particular, it exerts a cytocidal action on pancreatic cancer cells and colon cancer cells.
  • the compound of the present invention is excellent in selective toxicity to cancer cells and normal cells, and furthermore, the compound of the present invention can cancel the nutrient starvation resistance of cancer cells growing in a hypoxic and low glucose environment.
  • the 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivative of the present invention exhibits a highly selective cytotoxicity against cancer cells such as pancreatic cancer cells. Accordingly, 1-thioxo-1,2,3,4-tetrahydro- ⁇ -carboline derivatives are useful as drugs for treating solid cancers such as pancreatic cancer.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

[Problem] To provide a novel therapeutic agent for solid cancer such as pancreatic cancer. [Solution] A 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative represented by general formula [1] wherein R2 represents a hydroxy group, a hydroxyalkylcarbonyl group, a hydroxyaryl group or the like, A represents an alkylene group, and X represents a sulfur atom, which exhibits high cell-killing properties for cancer cells in a highly selective manner and is therefore useful as a therapeutic agent for solid cancer such as pancreatic cancer.

Description

１－チオキソ－１,２,３,４－テトラヒドロ－β－カルボリン誘導体およびそれらを含有する抗がん剤1-Thioxo-1,2,3,4-tetrahydro-β-carboline derivatives and anticancer agents containing them
　本発明は、膵癌などの固形癌を治療する薬物を調製するための化合物および薬学的に許容できるその塩の使用に関する。
　より詳細には、１－チオキソ－１,２,３,４－テトラヒドロ－β－カルボリン誘導体およびそれらを有効成分とする抗がん剤に関する。 The present invention relates to the use of compounds and pharmaceutically acceptable salts thereof for the preparation of a medicament for treating solid cancers such as pancreatic cancer.
More specifically, the present invention relates to 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives and anticancer agents containing them as active ingredients.
　固形癌は、白血病などの血液の癌を除く癌をさし、胃癌、肺癌、乳癌、大腸癌、膵癌などを含む。
　固形癌の治療は、手術によりまず癌を切除し、切除しきれない癌に対して抗癌剤による治療をすることが一般的である。
　ところで、日本では、膵癌による死亡者は、２３０００人以上にのぼり、５年生存率はわずかに６．７％で、全癌種５年生存率の平均５４．３％を大きく下回り、最も難治度が高い。
　更に、膵癌は発見が極めて困難で有り、診断時には既に手遅れとなっている場合も多く、手術可能な症例も全体の約２割から３割に止まっている。従って、膵癌の治療は化学療法が重要な位置を占める。 Solid cancer refers to cancer excluding blood cancer such as leukemia, and includes stomach cancer, lung cancer, breast cancer, colon cancer, pancreatic cancer and the like.
For the treatment of solid cancer, it is common to first remove the cancer by surgery and then treat the cancer that cannot be removed with an anticancer agent.
By the way, in Japan, the death toll from pancreatic cancer is more than 23,000, and the 5-year survival rate is only 6.7%, far below the average 5-4.3% survival rate of all cancer types. Is expensive.
In addition, pancreatic cancer is extremely difficult to detect and is often too late at the time of diagnosis, and only about 20% to 30% of cases can be operated on. Therefore, chemotherapy is an important place for the treatment of pancreatic cancer.
　一方、アルドース還元酵素阻害作用を有する１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体が知られている（特許文献１）。
　特許文献１においては、１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体のカルボン酸体が、ポリオール代謝が亢進またはアルドース還元酵素が過剰発現している癌の治療薬となりうる旨の記載があり、１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体のカルボン酸体が、マウス白血病アドリアマイシン感受性株Ｐ３８８／Ｓの増殖に対し、阻害作用を示すことが記載されている。 Meanwhile, 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives having an aldose reductase inhibitory action are known (Patent Document 1).
In Patent Document 1, a carboxylic acid form of a 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative can be a therapeutic agent for cancer in which polyol metabolism is enhanced or aldose reductase is overexpressed. The carboxylic acid form of 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative has an inhibitory effect on the growth of mouse leukemia adriamycin sensitive strain P388 / S. Has been.
ＷＯ２００９／０７８４２３WO2009 / 078423
　現在、膵癌（膵臓癌）に対する化学療法の中心は、ゲムシタビンである。
　本薬剤が用いられ始める前までの非切除膵癌患者の生存期間が３．５ヶ月程度に過ぎなかったのに対し、ゲムシタビン登場後は、生存期間が７．８ヶ月にまで延長した。
　さらに、ゲムシタビンとオキサプラチンあるいはエルロチニブとの併用治療が行われて、生存率の向上が図られている。
　膵癌治療のガイドラインでは、局所進行で手術不可能な症例に対してゲムシタビン単独治療が推奨されているが、一方で次世代の膵癌治療薬の開発は、１０年間ほとんど進展しておらず、単独療法でゲムシタビンを超える薬剤は登場していないのが現状である。　
　本発明の目的は、膵癌など固形癌に治療効果を有する化合物を提供することおよび膵臓癌など固形癌を治療する医薬を提供することである。 Currently, the center of chemotherapy for pancreatic cancer (pancreatic cancer) is gemcitabine.
The survival time of non-resected pancreatic cancer patients before the start of use of this drug was only about 3.5 months, whereas after the appearance of gemcitabine, the survival time was extended to 7.8 months.
Furthermore, combination treatment with gemcitabine and oxaplatin or erlotinib is performed to improve the survival rate.
Pancreatic cancer treatment guidelines recommend gemcitabine monotherapy for locally inoperable cases, but development of next-generation pancreatic cancer therapeutics has hardly progressed for 10 years, and monotherapy At present, no drug exceeding gemcitabine has appeared.
An object of the present invention is to provide a compound having a therapeutic effect on solid cancer such as pancreatic cancer and to provide a medicament for treating solid cancer such as pancreatic cancer.
　本発明者らは上記目的を達成すべく鋭意研究した結果意外にも、後述する一般式［１］で表される１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体が、膵臓癌細胞などの癌細胞に対して選択性の高い殺細胞性を示すことを見出し、本発明を完成させた。
　すなわち本発明は、下記の一般式［１］および［１’］で表される１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体およびこれらの生理学的に許容される塩からなる群より選ばれる１種または２種以上を有効成分とする膵臓癌などの固形癌の治療剤を提供するものである。 Surprisingly, the present inventors have conducted extensive research to achieve the above object, and a 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative represented by the following general formula [1] is The present invention was completed by finding that it has high selectivity for cancer cells such as pancreatic cancer cells.
That is, the present invention relates to 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives represented by the following general formulas [1] and [1 ′] and physiologically acceptable salts thereof. The present invention provides a therapeutic agent for solid cancer such as pancreatic cancer comprising one or more selected from the group as an active ingredient.
　さらに、本発明は、極端に血流の少ない環境下で増殖する膵臓癌のように、栄養飢餓状態において耐性を獲得し生存しているがんに対する新たながん組織特異的治療のアプローチである「栄養飢餓耐性の解除」に用いることができる薬物を提供するものである。
　以下、本発明を詳細に説明する。 Furthermore, the present invention is a new cancer tissue-specific therapeutic approach for cancer that has acquired resistance and survived in a nutrient-starved state, such as pancreatic cancer that grows in an environment with extremely low blood flow. The present invention provides a drug that can be used for “releasing nutritional starvation tolerance”.
Hereinafter, the present invention will be described in detail.
　本明細書において、特に断らない限り、各用語は、次の意味を有する。
　ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を；アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert－ブチル、ペンチルおよびヘキシル基などの直鎖状または分岐鎖状のＣ１－１２アルキル基を；低級アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert-ブチル、ペンチルおよびヘキシル基などの直鎖状または分岐鎖状のＣ１－６アルキル基を；アルキレン基とは、メチレン、エチレン、プロピレンおよびイソプロピレン基などの直鎖状または分岐鎖状のＣ１－６アルキレン基を；シクロアルキル基とは、シクロプロピル、シクロブチル、シクロペンチルおよびシクロヘキシルなどのＣ３－８シクロアルキル基を；アリール基とは、フェニル、ナフチル、インダニルおよびインデニル基などを；アルアルキルとは、ベンジル、フェネチル、α－メチルフェネチル、ジフェニルメチル、トリチルなどアリール－低級アルキル基を；アルコキシ基とは、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、tert-ブトキシ、ペンチルオキシ、ヘキシルオキシ、ヘプチルオキシおよびオクチルオキシ基などの直鎖状または分岐鎖状のＣ１－１２アルキルオキシ基を；低級アルコキシ基とは、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシおよびヘキシルオキシ基などの直鎖状または分岐鎖状のＣ１－６アルキルオキシ基を；シクロアルキルオキシ基とは、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシおよびシクロヘキシルオキシなどのＣ３－８シクロアルキルオキシ基を；アリールオキシ基とは、フェニルオキシ、ナフチルオキシ、インダニルオキシおよびインデニルオキシ基などを；アルアルキルオキシとは、ベンジルオキシ、フェネチルオキシ、α－メチルフェネチルオキシ、ジフェニルメチルオキシ、トリチルオキシなどアリール－低級アルキルオキシ基を；アシル基とは、ホルミル基、アルキルカルボニル基およびアロイル基を；アルキルカルボニル基とは、アセチルおよびプロピオニルなどのＣ２－６アルキルカルボニル基を；アロイル基とは、ベンゾイルおよびナフチルカルボニル基などのアリールカルボニル基を； In this specification, unless otherwise specified, each term has the following meaning.
A halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkyl group is a linear or branched group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl group the chain C 1-12 alkyl group; and lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl and hexyl groups linear or branched C 1- 6 alkyl group; an alkylene group is a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene and isopropylene groups; a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl and A C 3-8 cycloalkyl group such as cyclohexyl; an aryl group is phenyl An aralkyl is an aryl-lower alkyl group such as benzyl, phenethyl, α-methylphenethyl, diphenylmethyl, trityl; an alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, Linear or branched C 1-12 alkyloxy groups such as butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups; lower alkoxy groups are methoxy, ethoxy, propoxy , isopropoxy, butoxy, isobutoxy, tert- butoxy, straight or branched C 1-6 alkyl group such as pentyloxy and hexyloxy groups; and cycloalkyl group, cyclopropyloxy, cyclobutyl Alkoxy, cyclopentyloxy and C 3-8 cycloalkyloxy group such as cyclohexyloxy; and aryloxy group, phenyloxy, naphthyloxy, indanyloxy and indenyloxy group and the like; and the aralkyloxy, benzyloxy Aryl-lower alkyloxy groups such as phenethyloxy, α-methylphenethyloxy, diphenylmethyloxy, and trityloxy; acyl groups are formyl groups, alkylcarbonyl groups, and aroyl groups; alkylcarbonyl groups are acetyl and propionyl A C 2-6 alkylcarbonyl group such as; an aroyl group means an arylcarbonyl group such as benzoyl and naphthylcarbonyl groups;
ヒドロキシアルキルオキシカルボニル基とは、次式［６］
Figure JPOXMLDOC01-appb-C000003
 The hydroxyalkyloxycarbonyl group means the following formula [6]
Figure JPOXMLDOC01-appb-C000003
「式中、Ａａは、アルキレン基を示す。」で表される基を； A group represented by “in the formula, Aa represents an alkylene group”;
ヒドロキシアルキルオキシアルキルカルボニル基とは、次式［７］
Figure JPOXMLDOC01-appb-C000004
 The hydroxyalkyloxyalkylcarbonyl group means the following formula [7]
Figure JPOXMLDOC01-appb-C000004
　「式中、ＡａおよびＡｂは同一または異なってアルキレン基をそれぞれ示す。」で表される基を； A group represented by “in the formula, Aa and Ab are the same or different and each represents an alkylene group”;
　ヒドロキシアルキルオキシ基とは、ヒドロキシル基が置換したアルコキシ基を；ヒドロキシアリール基とは、ヒドロキシメチルオキシ、ヒドロキシエチルオキシ、ヒドロキシプロピルオキシ、ヒドロキシイソプロピルオキシ、ヒドロキシブチルオキシ、ヒドロキシペンチルオキシ、ヒドロキシヘキシルオキシ、ヒドロキシヘプチルオキシおよびヒドロキシオクチルオキシ基などの直鎖状または分岐鎖状のヒドロキシル基が置換したＣ１－１２アルキルオキシ基を；ヒドロキシアリール基とは、４－ヒドロキシフェニル、３－ヒドロキシフェニル、２－ヒドロキシフェニル、ヒドロキシナフチル、ヒドロキシインダニルおよびヒドロキシインデニル基などの１または数個のヒドロキシルが置換したアリールを、それぞれ意味する。 The hydroxyalkyloxy group is an alkoxy group substituted with a hydroxyl group; the hydroxyaryl group is hydroxymethyloxy, hydroxyethyloxy, hydroxypropyloxy, hydroxyisopropyloxy, hydroxybutyloxy, hydroxypentyloxy, hydroxyhexyloxy, C 1 a linear or branched hydroxyl group is substituted such as hydroxy heptyloxy and hydroxy octyloxy group - 12 alkyl group; a hydroxy aryl group, 4-hydroxyphenyl, 3-hydroxyphenyl, 2- By aryl each substituted by one or several hydroxyls such as hydroxyphenyl, hydroxynaphthyl, hydroxyindanyl and hydroxyindenyl groups is meant.
　複素環式基とは、ピロジニル、ピペリジニル、ピペラジニル、ホモピペラジニル、ホモピペリジニル、モルホリル、チオモルホリル、テトラヒドロキノリニル、テトラヒドロイソキノリル、キヌクリジニル、イミダゾリニル、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリミジル、キノリル、キノリジニル、チアゾリル、テトラゾリル、チアジアゾリル、ピロニリル、ピラゾリニル、ピラゾリジニル、プリニル、フリル、チエニル、ベンゾチエニル、ピラニル、イソベンゾフラニル、オキサゾリル、イソオキサゾリル、ベンゾフラニル、インドリル、ベンズイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、キノキサリル、ジヒドロキノキサリル、２，３－ジヒドロベンゾチエニル、２，３－ジヒドロベンゾピロリル、２，３－４Ｈ－１－チアナフチル、２，３－ジヒドロベンゾフラニル、ベンゾ［ｂ］ジオキサニル、イミダゾ［２，３－ａ］ピリジル、ベンゾ［ｂ］ピペラジニル、クロメニル、イソチアゾリル、イソオキサゾリル、オキサジアゾリル、ピリダジニル、イソインドリルおよびイソキノリル基などの該環を形成する異項原子として一つ以上の酸素原子もしくは硫黄原子を含んでいてもよい、窒素、酸素もしくは硫黄原子から選ばれる少なくとも一つ以上の異項原子を５員もしくは６員環、縮合環または架橋環の複素環式基を意味する。 Heterocyclic groups include pyrodinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolinyl, tetrahydroisoquinolyl, quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl, quinolyl, quinolyl, , Tetrazolyl, thiadiazolyl, pyronilyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl Quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihy Lobenzopyrrolyl, 2,3-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl , Pyridazinyl, isoindolyl, and isoquinolyl group, and the like. The hetero atom forming the ring may contain one or more oxygen atom or sulfur atom, and at least one hetero atom selected from nitrogen, oxygen, or sulfur atom. It means a heterocyclic group having 5 or 6-membered ring, condensed ring or bridged ring atom.
　カルボキシル保護基としては、通常のカルボキシル基の保護基として使用し得るすべての基を含み、例えば、メチル、エチル、プロピル、イソプロピル、１，１－ジメチルプロピル、ブチルおよびｔｅｒｔ－ブチルなどの低級アルキル基；フェニルおよびナフチルなどのアリール基；ベンジル、ジフェニルメチル、トリチル、ｐ－ニトロベンジル、ｐ－メトキシベンジルおよびビス（ｐ－メトキシフェニル）メチルなどのアル低級アルキル基；アセチルメチル、ベンゾイルメチル、ｐ－ニトロベンゾイルメチル、ｐ－ブロモベンゾイルメチルおよびｐ－メタンスルホニルベンゾイルメチルなどのアシル－低級アルキル基；２－テトラヒドロピラニルおよび２－テトラヒドロフラニルなどの含酸素複素環式基；２，２，２－トリクロロエチルなどのハロゲノ－低級アルキル基；２－（トリメチルシリル）エチルなどの低級アルキルシリル－低級アルキル基；アセトキシメチル、プロピオニルオキシメチルおよびピバロイルオキシメチルなどのアシルオキシ－低級アルキル基；フタルイミドメチルおよびスクシンイミドメチルなどの含窒素複素環式－低級アルキル基；シクロヘキシルなどのシクロアルキル基；メトキシメチル、メトキシエトキシメチルおよび２－（トリメチルシリル）エトキシメチルなどの低級アルコキシ－低級アルキル基；ベンジルオキシメチルなどのアル－低級アルコキシ－低級アルキル基；メチルチオメチルおよび２－メチルチオエチルなどの低級アルキルチオ－低級アルキル基；フェニルチオメチルなどのアリールチオ－低級アルキル基；１，１－ジメチル－２－プロペニル、３－メチル－３－ブテニルおよびアリルなどの低級アルケニル基；並びにトリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ジエチルイソプロピルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジフェニルシリル、ジフェニルメチルシリルおよびｔｅｒｔ－ブチルメトキシフェニルシリルなどの置換シリル基などが挙げられる。 The carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups, for example, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl and tert-butyl. Aryl groups such as phenyl and naphthyl; al lower alkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl; acetylmethyl, benzoylmethyl, p-nitro Acyl-lower alkyl groups such as benzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; 2,2,2-trichloroethyl Any halogeno-lower alkyl group; lower alkylsilyl-lower alkyl groups such as 2- (trimethylsilyl) ethyl; acyloxy-lower alkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; phthalimidomethyl and succinimidomethyl Nitrogen-containing heterocyclic-lower alkyl group; cycloalkyl group such as cyclohexyl; lower alkoxy group such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; al-lower alkoxy group such as benzyloxymethyl Lower alkyl group; lower alkylthio-lower alkyl group such as methylthiomethyl and 2-methylthioethyl; arylthio-lower alkyl group such as phenylthiomethyl; 1,1-dimethyl Lower alkenyl groups such as 2-propenyl, 3-methyl-3-butenyl and allyl; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert -Substituted silyl groups such as butylmethoxyphenylsilyl.
　ヒドロキシル保護基としては、通常のヒドロキシル基の保護基として使用し得るすべての基を含み、例えば、ベンジルオキシカルボニル、４－ニトロベンジルオキシカルボニル、４－ブロモベンジルオキシカルボニル、４－メトキシベンジルオキシカルボニル、３，４－ジメトキシベンジルオキシカルボニル、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、１，１－ジメチルプロポキシカルボニル、イソプロポキシカルボニル、イソブチルオキシカルボニル、ジフェニルメトキシカルボニル、２，２，２－トリクロロエトキシカルボニル、２，２，２－トリブロモエトキシカルボニル、２－（トリメチルシリル）エトキシカルボニル、２－（フェニルスルホニル）エトキシカルボニル、２－（トリフェニルホスホニオ）エトキシカルボニル、２－フルフリルオキシカルボニル、１－アダマンチルオキシカルボニル、ビニルオキシカルボニル、アリルオキシカルボニル、Ｓ－ベンジルチオカルボニル、４－エトキシ－１－ナフチルオキシカルボニル、８－キノリルオキシカルボニル、アセチル、ホルミル、クロロアセチル、ジクロロアセチル、トリクロロアセチル、トリフルオロアセチル、メトキシアセチル、フェノキシアセチル、ピバロイルおよびベンゾイルなどのアシル基；メチル、ｔｅｒｔ－ブチル、２，２，２－トリクロロエチルおよび２－トリメチルシリルエチルなどの低級アルキル基；アリルなどの低級アルケニル基；ベンジル、ｐ－メトキシベンジル、３，４－ジメトキシベンジル、ジフェニルメチルおよびトリチルなどのアル低級アルキル基；テトラヒドロフリル、テトラヒドロピラニルおよびテトラヒドロチオピラニルなどの含酸素および含硫黄複素環式基；メトキシメチル、メチルチオメチル、ベンジルオキシメチル、２－メトキシエトキシメチル、２，２，２－トリクロロエトキシメチル、２－（トリメチルシリル）エトキシメチル、１－エトキシエチルおよび１－メチル－１－メトキシエチルなどの低級アルコキシ－および低級アルキルチオ－低級アルキル基；メタンスルホニルおよびｐ－トルエンスルホニルなどの低級アルキル－およびアリール－スルホニル基；並びにトリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ジエチルイソプロピルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジフェニルシリル、ジフェニルメチルシリルおよびｔｅｒｔ－ブチルメトキシフェニルシリルなどの置換シリル基などが挙げられる。 The hydroxyl protecting group includes all groups that can be used as protecting groups for ordinary hydroxyl groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphospho) Honio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl , Acyl groups such as formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; methyl, tert-butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl Lower alkyl groups such as allyl; lower alkenyl groups such as allyl; al lower groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; Kill groups; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxy Lower alkoxy- and lower alkylthio-lower alkyl groups such as methyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and 1-methyl-1-methoxyethyl; lower alkyl- and aryl such as methanesulfonyl and p-toluenesulfonyl -Sulfonyl group; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl And substituted silyl groups such as tert-butylmethoxyphenylsilyl.
　本発明は、一般式［１］
Figure JPOXMLDOC01-appb-C000005
 The present invention relates to a general formula [1]
Figure JPOXMLDOC01-appb-C000005
　「式中、Ｒ１は、同一または異なって、水素原子、ハロゲン原子、アルキル基、シクロアルキル基、アルキレン基、アルアルキル基、アリール基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基もしくは保護されていてもよいヒドロキシル基から選ばれる１～３個の原子または置換基を；Ｒ２は、保護されていてもよいヒドロキシアルキルオキシカルボニル、ヒドロキシアルキルオキシアルキルオキシカルボニル、ヒドロキシル、ヒドロキシアルキルオキシまたはヒドロキシアリール基を；Ｒ３は、ハロゲン原子で置換されていてもよいアリール、シクロアルキルもしくは複素環式基で置換されたアルキル基またはアリール基を；Ａは、アルキレン基を；Ｘは、硫黄原子または酸素原子を、それぞれ示す。
　但し、Ｒ２がヒドロキシル基、Ｒ３がアリール基であってＸが酸素原子である場合を除く。」
で表される新規な１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体またはその塩である。 Wherein R 1 is the same or different and is a hydrogen atom, halogen atom, alkyl group, cycloalkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, cycloalkyloxy group, aryloxy group or protected. 1 to 3 atoms or substituents selected from an optionally hydroxyl group; R 2 is an optionally protected hydroxyalkyloxycarbonyl, hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl R 3 represents an alkyl group or aryl group substituted with an aryl, cycloalkyl or heterocyclic group optionally substituted with a halogen atom; A represents an alkylene group; X represents a sulfur atom or oxygen Each atom is shown.
However, the case where R 2 is a hydroxyl group, R 3 is an aryl group, and X is an oxygen atom is excluded. "
A novel 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative represented by the formula:
　本発明は、一般式［１’］
Figure JPOXMLDOC01-appb-C000006
 The present invention relates to a general formula [1 ′]
Figure JPOXMLDOC01-appb-C000006
　「式中、Ｒ１は、同一または異なって、水素原子、ハロゲン原子、アルキル基、シクロアルキル基、アルキレン基、アルアルキル基、アリール基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基もしくは保護されていてもよいヒドロキシル基から選ばれる１～３個の原子または置換基を；Ｒ２は、保護されていてもよいヒドロキシアルキルオキシカルボニル、ヒドロキシアルキルオキシアルキルオキシカルボニル、ヒドロキシル、ヒドロキシアルキルオキシまたはヒドロキシアリール基を；Ｒ３は、ハロゲン原子で置換されていてもよいアリール、シクロアルキルもしくは複素環式基で置換されたアルキル基またはアリール基を；Ａは、アルキレン基を；Ｘは、硫黄原子または酸素原子を、それぞれ示す。」
で表される１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体またはその塩を有効成分とする抗がん剤である。 Wherein R 1 is the same or different and is a hydrogen atom, halogen atom, alkyl group, cycloalkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, cycloalkyloxy group, aryloxy group or protected. 1 to 3 atoms or substituents selected from an optionally hydroxyl group; R 2 is an optionally protected hydroxyalkyloxycarbonyl, hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl R 3 represents an alkyl group or aryl group substituted with an aryl, cycloalkyl or heterocyclic group optionally substituted with a halogen atom; A represents an alkylene group; X represents a sulfur atom or oxygen Each atom is shown. "
As an active ingredient, a 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative represented by the formula:
　一般式［１］および［１’］の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体の塩としては、通常知られているヒドロキシル基などの酸性基における塩を挙げることができる。
　酸性基における塩としては、例えば、ナトリウムおよびカリウムなどのアルカリ金属との塩；カルシウムおよびマグネシウムなどのアルカリ土類金属との塩；アンモニウム塩；並びにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ－ベンジル－β－フェネチルアミン、１－エフェナミンおよびＮ，Ｎ－ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などを挙げることができる。
　上記した塩の中で、好ましい塩としては、薬理学的に許容される塩が挙げられる。 Examples of salts of 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives of the general formulas [1] and [1 ′] include salts of acidic groups such as hydroxyl groups that are generally known. Can do.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N-dibenzylethylenediamine And the like.
Among the above-mentioned salts, preferred salts include pharmacologically acceptable salts.
　一般式［１］および［１’］の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体またはその塩において、異性体（例えば、光学異性体、幾何異性体および互変異性体など）が存在する場合、本発明は、それらすべての異性体を包含し、また水和物、溶媒和物およびすべての結晶形を包含するものである。 In the 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives of the general formulas [1] and [1 ′] or salts thereof, isomers (for example, optical isomers, geometric isomers, and tautomers) The present invention includes all such isomers as well as hydrates, solvates and all crystal forms.
　本発明において好ましい化合物は、例えば、以下の化合物またはその塩が挙げられる。
Figure JPOXMLDOC01-appb-C000007
 Preferred compounds in the present invention include, for example, the following compounds or salts thereof.
Figure JPOXMLDOC01-appb-C000007
　「式中、Ｒ１ａおよびＲ１ｃは、水素原子またはハロゲン原子を、Ｒ１ｂはハロゲン原子、置換されていてもよいアルキルまたはアルコキシ基を；Ｒ２は、保護されていてもよいヒドロキシアルキルオキシカルボニル、ヒドロキシアルキルオキシアルキルオキシカルボニル、ヒドロキシル、ヒドロキシアルキルオキシまたはヒドロキシアリール基を；Ｒ３ａは、ハロゲン原子もしくはハロゲノ置換低級アルキル基で置換されていてもよいアルアルキル基を示す。」
で表される１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体またはその塩である。 "Wherein R 1a and R 1c are a hydrogen atom or a halogen atom, R 1b is a halogen atom, an optionally substituted alkyl or alkoxy group; R 2 is an optionally protected hydroxyalkyloxycarbonyl A hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl group; R 3a represents an aralkyl group which may be substituted with a halogen atom or a halogeno-substituted lower alkyl group.
A 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative represented by the formula:
　一般式［１］および［１’］の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体は、例えば、以下の方法により製造することができる。
・製造法 The 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives of the general formulas [1] and [1 ′] can be produced, for example, by the following method.
・ Production method
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　「式中、Ｒ２ａは、保護されていてもよいヒドロキシル、ヒドロキシアルキルオキシまたはヒドロキシアリール基を；Ｒ２ｂは、保護されていてもよいヒドロキシアルキルオキシカルボニルまたはヒドロキシアルキルオキシアルキルオキシカルボニル基を；Ｒ４は、カルボキシル保護基を；Ｙはハロゲン原子を；Ｂは、アルキレン基またはアルキレンオキシアルキレン基を、それぞれ示し、Ｒ１、Ｒ２、Ｒ３、ＡおよびＸは、上記と同様の意味を有する、 “Wherein R 2a represents an optionally protected hydroxyl, hydroxyalkyloxy or hydroxyaryl group; R 2b represents an optionally protected hydroxyalkyloxycarbonyl or hydroxyalkyloxyalkyloxycarbonyl group; R 4 represents a carboxyl protecting group; Y represents a halogen atom; B represents an alkylene group or an alkyleneoxyalkylene group, and R 1 , R 2 , R 3 , A and X have the same meaning as described above. ,
　一般式［２］の化合物に、塩基の存在下、一般式［５ａ］または一般式［５ｂ］の化合物を反応させることにより、それぞれ、一般式［１ａ］、一般式［３ａ］の化合物を製造することができる。
　この反応に用いられる溶媒は、反応に悪影響を及ぼさない限り特に限定されないが、例えば、Ｎ，Ｎ－ジメチルホルムアミドなどのアミド類が挙げられる。
　この反応用いられる塩基としては、例えば、水素化ナトリウムなどの無機塩基が挙げられ、塩基の使用量は、一般式［２］の化合物に対して、等モル以上、好ましくは、１～２０倍モルであればよい。
　この反応は、この反応は、通常、０～２００℃、好ましくは、２０～１５０℃で、１０分～２０時間実施　すればよい。
　一般式［２］の化合物は、自体公知の方法の方法で製造することができるが、例えば、ＷＯ２００９／０７８４２３に記載の方法などを挙げることができる。 By reacting the compound of general formula [2] with the compound of general formula [5a] or general formula [5b] in the presence of a base, the compounds of general formula [1a] and general formula [3a] are produced, respectively. can do.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include amides such as N, N-dimethylformamide.
Examples of the base used in this reaction include inorganic bases such as sodium hydride, and the amount of the base used is equimolar or more, preferably 1 to 20 times the molar amount of the compound of the general formula [2]. If it is.
This reaction is usually carried out at 0 to 200 ° C., preferably 20 to 150 ° C., for 10 minutes to 20 hours.
The compound of the general formula [2] can be produced by a method known per se, and examples thereof include the method described in WO2009 / 078423.
　一般式［３ａ］の化合物をカルボキシル保護基の脱保護反応に付すことにより、一般式［３ｂ］の化合物を製造することができる。
　カルボキシル保護基の脱保護反応は、通常公知の反応を用いればよいが、例えば、ヨウ化トリメチルシリルでの脱アルキル化やエステルの加水分解を実施すればよい。 A compound of the general formula [3b] can be produced by subjecting the compound of the general formula [3a] to a deprotection reaction of a carboxyl protecting group.
For the deprotection reaction of the carboxyl protecting group, a generally known reaction may be used. For example, dealkylation with trimethylsilyl iodide or ester hydrolysis may be performed.
　一般式［３ｂ］の化合物に、縮合剤、塩基、触媒などの存在下、一般式［４］の化合物を反応させることにより、一般式［１ｂ］の化合物を製造することができる。
　この反応に用いられる溶媒は、反応に悪影響を及ぼさない限り特に限定されないが、例えば、例えば、塩化メチレンおよびクロロホルムなどのハロゲン化炭化水素類が挙げられる。
　この反応で使用される縮合剤としては、例えば、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド、Ｎ，Ｎ－ジシクロヘキシルカルボジイミドなどのカルボジイミド類；塩化チオニルなどのハロゲン化剤；クロロギ酸エチルエステルなどのハロゲン化アルキルエステル類；カルボニルジイミダゾールなどの活性化アミド化剤；並びにジフェニルリン酸アジドなどのアジド化剤などが挙げられる。
　縮合剤の使用量は、一般式［３ｂ］の化合物に対して、等モル以上、好ましくは、１～５倍モルであればよい。 The compound of the general formula [1b] can be produced by reacting the compound of the general formula [3b] with the compound of the general formula [4] in the presence of a condensing agent, a base, a catalyst and the like.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform.
Examples of the condensing agent used in this reaction include carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and N, N-dicyclohexylcarbodiimide; halogenating agents such as thionyl chloride; ethyl chloroformate Halogenated alkyl esters such as esters; activated amidating agents such as carbonyldiimidazole; and azidating agents such as diphenylphosphoric azide.
The amount of the condensing agent to be used is not less than equimolar, preferably 1 to 5 times mol, relative to the compound of the general formula [3b].
　この反応で使用される塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン（ＤＢＵ）、ピリジン、ｔｅｒｔ－ブトキシカリウム、炭酸ナトリウム、炭酸カリウムおよび水素化ナトリウムなどの有機塩基または無機塩基が挙げられ、塩基の使用量は、一般式［３ｂ］の化合物に対して、等モル以上、好ましくは、１～１０倍モルであればよい。 Examples of the base used in this reaction include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, tert-butoxypotassium, sodium carbonate, potassium carbonate and Examples thereof include organic bases and inorganic bases such as sodium hydride, and the amount of the base used may be equimolar or more, preferably 1 to 10-fold mol relative to the compound of the general formula [3b].
　この反応で必要に応じて使用される触媒としては、例えば、Ｎ，Ｎ－ジメチル－４－アミノピリジンなどが挙げられ、触媒の使用量は、一般式［３ｂ］の化合物に対して、０．１～１倍モルであればよい。
　この反応は、通常、－５０～２００℃、好ましくは、－３０～１００℃で、１０分～２０時間実施すればよい。 Examples of the catalyst used as necessary in this reaction include N, N-dimethyl-4-aminopyridine and the like. The amount of the catalyst used is 0. 0 with respect to the compound of the general formula [3b]. It may be 1 to 1 mole.
This reaction is usually carried out at −50 to 200 ° C., preferably −30 to 100 ° C., for 10 minutes to 20 hours.
　一般式［２］、［３ａ］、［３ｂ］、［４］、［５ａ］、［５ｂ］の化合物において、異性体（例えば、光学異性体、幾何異性体および互変異性体など）が存在する場合、これらすべての異性体を使用することができ、また水和物、溶媒和物およびすべての結晶形を使用することができる。
　また、それらの化合物は、単離せずにそのまま次の反応に用いてもよい。 In the compounds of the general formulas [2], [3a], [3b], [4], [5a], [5b], there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.) If so, all these isomers can be used, and hydrates, solvates and all crystal forms can be used.
These compounds may be used in the next reaction as they are without isolation.
　このようにして得られた一般式［１ａ］および一般式［１ｂ］の化合物は、抽出、晶出、蒸留およびカラムクロマトグラフィーなどの通常の方法によって単離精製することができる。 The compounds of general formula [1a] and general formula [1b] thus obtained can be isolated and purified by ordinary methods such as extraction, crystallization, distillation and column chromatography.
　本発明化合物は、溶剤、増量剤、等張化剤、溶解補助剤、乳化剤、懸濁化剤、増粘剤、吸収促進剤、ゲル化・凝固促進剤、光安定化剤、保存剤、乳化・懸濁・分散安定化剤、着色防止剤、消泡剤、無痛化剤、緩衝剤、ｐＨ調節剤などの各種医薬品添加物を配合して、注射剤、坐剤などの医薬品製剤とすることができる。 The compound of the present invention comprises a solvent, a bulking agent, an isotonic agent, a solubilizer, an emulsifier, a suspending agent, a thickener, an absorption accelerator, a gelation / coagulation accelerator, a light stabilizer, a preservative, and an emulsifier.・ Combination of various pharmaceutical additives such as suspension / dispersion stabilizers, anti-coloring agents, antifoaming agents, soothing agents, buffering agents, pH adjusting agents, etc. to form pharmaceutical preparations such as injections and suppositories. Can do.
　上記製剤の投与方法は、特に限定されないが、製剤の形態、患者の年齢、性別その他の条件、患者の症状の程度に応じて適宜決定される。
　本発明製剤の有効成分の投与量は、用法、患者の年齢、性別、疾患の形態、その他の条件などに応じて適宜選択されるが、通常成人に対して、１日０．１～５００ｍｇを１回から数回に分割して投与すればよい。 Although the administration method of the said formulation is not specifically limited, It determines suitably according to the form of a formulation, a patient's age, sex, other conditions, and the grade of a patient's symptom.
The dosage of the active ingredient of the preparation of the present invention is appropriately selected according to the usage, patient age, sex, disease form, other conditions, etc., but usually 0.1 to 500 mg per day for an adult. What is necessary is just to divide and administer from 1 time to several times.
　次に、本発明の代表的化合物の薬理作用について述べる。
試験例１
＜膵臓癌細胞および大腸癌に対する抗癌活性＞
１）使用細胞および培養条件
　本試験で使用したヒト膵臓癌細胞株であるＰＡＮＣ－１およびＭＩＡ　ＰａＣａ－２および大腸癌ＳＷ４８０は、（独）医薬基盤研究所、ＪＣＲＢ細胞バンクより入手した。
　培養細胞は、10% Fetal calf serum (MP Biomedicals)、1×MEM non-essential amino acid混液（Sigma）、Antibiotic antimycotic溶液（Sigma）、Glucose（4.5 g/L）およびSodium Pyruvate（110 mg/ml）を含むダルベッコ変法イーグル（DMEM）培地中で培養した。
　培養条件は，３７℃，５％　ＣＯ２とした。
　また、培地は３日ごとに交換し，コンフルエンスになる前に細胞を継代した。
２）抗癌活性の測定
　細胞懸濁液（2×104 cells/mL）を９６穴プレートに１００μＬずつ分注した。
　２４時間培養後、被験薬物単独または陽性コントロールの抗がん剤単独を含む培地１００μＬを加え、さらに４８または７２時間培養した。
　各被験薬物または抗がん剤の溶媒はＤＭＳＯを用い、その最終濃度はすべて０．１　％以下とした。
　被験薬物処理後の生細胞数はＭＴＴ（同人化学）を用いて測定した。
　被験薬物処理後、２ｍｇ／ｍＬに調整したＭＴＴ試薬のリン酸緩衝液（ＰＢＳ：ｐＨ　７．４）を１ｗｅｌｌ当たり１０μＬ加え４時間培養し、ＭＴＴ－ｆｏｒｍａｚａｎを生成させた。
　上清を吸引除去した後ＤＭＳＯを２００μＬ加えてｆｏｒｍａｚａｎを溶解し、ブランクとしてはＤＭＳＯのみで、ＭＴＴ－ｆｏｒｍａｚａｎの５４０ｎｍにおける吸光度をFLUOstarOPTIMA (BMG LRBTECH) にて測定した。
　結果を表１および２示す。
　※表１中のＡＲ３およびＡＲ４５は、ＷＯ２００９／０７８４２３に記載された化合物である。 Next, the pharmacological action of representative compounds of the present invention will be described.
Test example 1
<Anticancer activity against pancreatic cancer cells and colon cancer>
1) Cells and culture conditions The human pancreatic cancer cell lines used in this study, PANC-1, MIA PaCa-2 and colon cancer SW480, were obtained from the Pharmaceutical Research Laboratory, JCRB Cell Bank.
Cultured cells are 10% Fetal calf serum (MP Biomedicals), 1 × MEM non-essential amino acid mixture (Sigma), Antibiotic antimycotic solution (Sigma), Glucose (4.5 g / L) and Sodium Pyruvate (110 mg / ml) And cultured in Dulbecco's Modified Eagle (DMEM) medium.
The culture conditions were 37 ° C. and 5% CO 2.
The medium was changed every 3 days and the cells were passaged before confluence.
2) Measurement of anticancer activity 100 μL of cell suspension (2 × 10 4 cells / mL) was dispensed into a 96-well plate.
After culturing for 24 hours, 100 μL of a medium containing a test drug alone or a positive control anticancer agent alone was added, and further cultured for 48 or 72 hours.
DMSO was used as the solvent for each test drug or anticancer agent, and the final concentration was 0.1% or less.
The number of viable cells after treatment with the test drug was measured using MTT (doujinshi).
After treatment with the test drug, MTT reagent phosphate buffer (PBS: pH 7.4) adjusted to 2 mg / mL was added at 10 μL per well and cultured for 4 hours to generate MTT-formazane.
After removing the supernatant by suction, 200 μL of DMSO was added to dissolve the formatzan, and DMSO alone was used as a blank, and the absorbance of MTT-formazane at 540 nm was measured with FLUOstarOPTIMA (BMG LRBTECH).
The results are shown in Tables 1 and 2.
* AR3 and AR45 in Table 1 are compounds described in WO2009 / 078423.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
試験例２
＜アルドースレダクターゼの阻害活性＞
　リン酸緩衝液２００ｍＭ（ｐＨ６．２）、ニコチンアミドアデニンジヌクレオチドリン酸還元型　（ＮＡＤＰＨ）１．５ｍＭ、牛血清アルブミン１ｍｇ／ｍＬ、被験化合物２００μｇ／ｍＬおよび基質としてＤＬ－グリセルアルデヒド１００ｍＭを含む反応溶液を調製した後、アルドースレダクダーゼ5.1×10-1unit/mLを加え反応を開始し、反応によって減少するＮＡＤＰＨ量を、分光光度計を用いて、吸収波長３４０ｎｍにて測定した。
＜結果＞
　ＡＲ５９、ＡＲ６１～ＡＲ６５は、４００μＭ添加でもアルドースレダクターゼに対して阻害活性を示さなかった。一方、ＷＯ２００９／０７８４２３に記載されたＡＲ３の５０％阻害活性は、３７．１μＭである。
　従って、本発明化合物の抗がん活性は、アルドース還元酵素阻害作用によるものではない。 Test example 2
<Inhibitory activity of aldose reductase>
Contains phosphate buffer 200 mM (pH 6.2), nicotinamide adenine dinucleotide phosphate reduced form (NADPH) 1.5 mM, bovine serum albumin 1 mg / mL, test compound 200 μg / mL, and DL-glyceraldehyde 100 mM as a substrate After preparing the reaction solution, aldose reductase 5.1 × 10 -1 unit / mL was added to start the reaction, and the amount of NADPH decreased by the reaction was measured using a spectrophotometer at an absorption wavelength of 340 nm.
<Result>
AR59 and AR61 to AR65 did not show inhibitory activity against aldose reductase even when added at 400 μM. On the other hand, the 50% inhibitory activity of AR3 described in WO2009 / 078423 is 37.1 μM.
Therefore, the anticancer activity of the compound of the present invention is not due to aldose reductase inhibitory action.
試験例３
＜膵臓癌（ＰＡＮＣ－１細胞）と正常細胞（ＨＥＬ）に対する障害性の比較＞
　ヒト膵臓癌細胞とヒト胎児肺繊維芽細胞ＨＥＬに対する５０％細胞増殖抑制濃度と比較し評価した。
　その結果、ＡＲ－５９、ＡＲ－６１は、正常細胞と比して１／３以下の濃度でヒト膵臓癌細胞ＰＡＮＣ－１に対して細胞毒性を示した Test example 3
<Comparison of damage to pancreatic cancer (PANC-1 cells) and normal cells (HEL)>
Evaluation was made by comparing with 50% cell growth inhibitory concentration against human pancreatic cancer cells and human fetal lung fibroblast HEL.
As a result, AR-59 and AR-61 showed cytotoxicity against human pancreatic cancer cell PANC-1 at a concentration of 1/3 or less compared to normal cells.
試験例４
＜栄養飢餓状態における抗がん作用＞
　ヒト膵臓癌細胞ＰＡＮＣ－１を９６ｗｅｌｌプレートに１ウェルあたり1.0×104/0.1ml-wellで細胞を播種し、栄養欠乏培地ＮＤＭにて培養し，抗癌活性を評価した。
その結果、５－ＦＵやジェムザールは、栄養飢餓状態ではＩＣ５０が、＞２００μＭであったのに対し、ＡＲ５９で５．１±０．７μＭ、ＡＲ６１で３．１±０．６μＭであった。
　本発明化合物は、栄養飢餓状態においてもヒト膵臓癌細胞ＰＡＮＣ－１に強力な細胞毒性を示す。 Test example 4
<Anticancer effect in nutritional starvation>
Human pancreatic cancer cells PANC-1 were seeded in 96-well plates at 1.0 × 10 4 /0.1 ml-well per well, cultured in nutrient-deficient medium NDM, and anticancer activity was evaluated.
As a result, in the case of 5-FU and Gemzar, the IC 50 was> 200 μM in the nutrient-starved state, whereas 5.1 ± 0.7 μM for AR59 and 3.1 ± 0.6 μM for AR61.
The compound of the present invention exhibits strong cytotoxicity to human pancreatic cancer cell PANC-1 even under nutrient starvation conditions.
　上記の一般式［１］および［１’］の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体は、アルドース還元酵素阻害活性をもたず、それ自体で、固形癌、とりわけ膵臓癌細胞および大腸癌細胞に対し、殺細胞作用を発揮する。
　また、本発明化合物は、癌細胞と正常細胞に対する選択毒性に優れ、さらに、本発明化合物により、低酸素状態、低グルコース環境下で増殖する癌細胞の栄養飢餓状態耐性を解除することができる。
　次に実施例で本発明を説明するが、本発明はこれらに限定されない。 The 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives of the above general formulas [1] and [1 ′] have no aldose reductase inhibitory activity, and as such are solid tumors, In particular, it exerts a cytocidal action on pancreatic cancer cells and colon cancer cells.
In addition, the compound of the present invention is excellent in selective toxicity to cancer cells and normal cells, and furthermore, the compound of the present invention can cancel the nutrient starvation resistance of cancer cells growing in a hypoxic and low glucose environment.
EXAMPLES Next, although an Example demonstrates this invention, this invention is not limited to these.
(2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)-acetic acid 2-hydroxy-ethyl ester [AR59]
Figure JPOXMLDOC01-appb-C000012
 (2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) -acetic acid 2-hydroxy-ethyl ester [AR59]
Figure JPOXMLDOC01-appb-C000012
(2-Benzyl-5,7-difluoro-１-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) acetic acid [AR3]
の塩化メチレン溶液にエチレングリコール（２．０ｍｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（２．０ｍｍｏｌ），　Ｎ，Ｎ－ジメチル－４－アミノピリジン　（０．２　ｍｍｏｌ），トリエチルアミン（２．０　ｍｍｏｌ）を加え室温にて３時間撹拌した。
　その後、塩化メチレンで希釈し１０％塩酸を加えた。
　塩化メチレンで抽出し、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を留去したらシリカゲルカラムクロマトグラフィー(溶離液：塩化メチレン)にて精製し、(2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)-acetic acid 2-hydroxy-ethyl esterを得た。 (2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) acetic acid [AR3]
Of ethylene glycol (2.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.0 mmol), N, N-dimethyl-4-aminopyridine (0.2 mmol) ), Triethylamine (2.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours.
Thereafter, the mixture was diluted with methylene chloride and 10% hydrochloric acid was added.
Extracted with methylene chloride, washed with saturated brine, dried over magnesium sulfate, evaporated and purified by silica gel column chromatography (eluent: methylene chloride) to give (2-Benzyl-5,7-difluoro -1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) -acetic acid 2-hydroxy-ethyl ester was obtained.
収率：６１％
1H-NMR (300MHz, CDCl3):δ7.26-7.36 (5H, m), 6.77 (1H, dd, J = 1.78 Hz, 9.20 Hz), 6.67 (1H, t, J = 9.54 Hz), 5.72 (2H, s), 5.43 (2H, s), 4.34 (2H, t, J = 4.67 Hz), 3.85 (2H, t, J = 4.67 Hz) , 3.75 (2H, t, J = 7.00 Hz) , 3.10 (2H, t, J = 7.00 Hz) Yield: 61%
1 H-NMR (300 MHz, CDCl 3 ): δ7.26-7.36 (5H, m), 6.77 (1H, dd, J = 1.78 Hz, 9.20 Hz), 6.67 (1H, t, J = 9.54 Hz), 5.72 (2H, s), 5.43 (2H, s), 4.34 (2H, t, J = 4.67 Hz), 3.85 (2H, t, J = 4.67 Hz), 3.75 (2H, t, J = 7.00 Hz), 3.10 (2H, t, J = 7.00 Hz)
実施例１と同様にして以下の化合物を得た。
・[1-Thioxo-2-(4-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-β-carbolin-9-yl]-acetic acid 2-hydroxy-ethyl ester　[AR61]
Figure JPOXMLDOC01-appb-C000013
 In the same manner as in Example 1, the following compounds were obtained.
・ [1-Thioxo-2- (4-trifluoromethyl-benzyl) -1,2,3,4-tetrahydro-β-carbolin-9-yl] -acetic acid 2-hydroxy-ethyl ester [AR61]
Figure JPOXMLDOC01-appb-C000013
収率：５５％
1H-NMR (300MHz, CDCl3):δ7.61 (3H, m), 7.47 (2H, d, J = 8.0 Hz), 7.36-7.42 (1H, m), 7.30 (1H, d, J = 8.5 Hz), 7.17-7.22 (1H, m), 5.79 (2H, s), 5.50 (2H, s) , 4.31 (2H, t, J = 4.7 Hz) , 3.81 (2H, t, J = 4.7 Hz) , 3.77 (2H, t, J = 7.1 Hz) , 3.02 (2H, t, J = 7.1 Hz);  Yield: 55%
1 H-NMR (300 MHz, CDCl 3 ): δ7.61 (3H, m), 7.47 (2H, d, J = 8.0 Hz), 7.36-7.42 (1H, m), 7.30 (1H, d, J = 8.5 Hz), 7.17-7.22 (1H, m), 5.79 (2H, s), 5.50 (2H, s), 4.31 (2H, t, J = 4.7 Hz), 3.81 (2H, t, J = 4.7 Hz), 3.77 (2H, t, J = 7.1 Hz), 3.02 (2H, t, J = 7.1 Hz);
・[6-Fluoro-2-(4-fluoro-benzyl)-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl]-acetic acid 2-hydroxy-ethyl ester [AR62]
Figure JPOXMLDOC01-appb-C000014
 ・ [6-Fluoro-2- (4-fluoro-benzyl) -1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl] -acetic acid 2-hydroxy-ethyl ester [AR62]
Figure JPOXMLDOC01-appb-C000014
収率：７２％
1H-NMR (300MHz, CDCl3):δ7.33-7.38 (2H, m), 7.19-7.25 (2H, m), 7.09-7.16 (1H, m), 7.03 (2H, t, J = 8.5 Hz), 5.77 (2H, s), 5.40 (2H, s), 4.32 (2H, t, J = 4.5 Hz) , 3.83 (2H, t, J = 4.5 Hz) , 3.75 (2H, t, J = 7.1 Hz) , 2.93 (2H, t, J = 7.1 Hz)  Yield: 72%
1 H-NMR (300 MHz, CDCl 3 ): δ7.33-7.38 (2H, m), 7.19-7.25 (2H, m), 7.09-7.16 (1H, m), 7.03 (2H, t, J = 8.5 Hz ), 5.77 (2H, s), 5.40 (2H, s), 4.32 (2H, t, J = 4.5 Hz), 3.83 (2H, t, J = 4.5 Hz), 3.75 (2H, t, J = 7.1 Hz) ), 2.93 (2H, t, J = 7.1 Hz)
・[5,7-Difluoro-2-(4-fluoro-benzyl)-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl]-acetic acid 2-hydroxy-ethyl ester [AR63]
Figure JPOXMLDOC01-appb-C000015
 ・ [5,7-Difluoro-2- (4-fluoro-benzyl) -1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl] -acetic acid 2-hydroxy-ethyl ester [ AR63]
Figure JPOXMLDOC01-appb-C000015
収率：６３％
1H-NMR (300MHz, CDCl3):δ7.35 (2H, dt, J = 2.9 Hz, 5.9 Hz ), 7.00-7.06 (2H, m), 6.77 (1H, dd, J = 1.9 Hz, 9.1 Hz), 6.65 (1H, dt, J = 1.9 Hz, 10.3 Hz), 5.70 (2H, s), 5.38 (2H, s), 4.32-4.35 (2H, m) , 3.84-3.85 (2H, m) , 3.73 (2H, t, J = 7.1 Hz) , 3.10 (2H, t, J = 7.1 Hz) Yield: 63%
1 H-NMR (300 MHz, CDCl 3 ): δ 7.35 (2H, dt, J = 2.9 Hz, 5.9 Hz), 7.00-7.06 (2H, m), 6.77 (1H, dd, J = 1.9 Hz, 9.1 Hz) ), 6.65 (1H, dt, J = 1.9 Hz, 10.3 Hz), 5.70 (2H, s), 5.38 (2H, s), 4.32-4.35 (2H, m), 3.84-3.85 (2H, m), 3.73 (2H, t, J = 7.1 Hz), 3.10 (2H, t, J = 7.1 Hz)
・[5,7-Difluoro-2-(4-fluoro-benzyl)-1-oxo-1,2,3,4-tetrahydro-β-carbolin-9-yl]-acetic acid 2-hydroxy-ethyl ester [AR64]
Figure JPOXMLDOC01-appb-C000016
 ・ [5,7-Difluoro-2- (4-fluoro-benzyl) -1-oxo-1,2,3,4-tetrahydro-β-carbolin-9-yl] -acetic acid 2-hydroxy-ethyl ester [ AR64]
Figure JPOXMLDOC01-appb-C000016
収率：６１％
1H-NMR (300MHz, CDCl3):δ7.27-7.30 (2H, m ), 7.00-7.05 (2H, m), 6.79 (1H, dd, J = 1.9 Hz, 9.3 Hz), 6.63 (1H, dt, J = 1.9 Hz, 9.9 Hz), 5.21 (2H, s), 4.66 (2H, s), 4.35-4.38 (2H, m) , 3.82-3.83 (2H, m) , 3.61 (2H, t, J = 7.1 Hz) , 3.14 (2H, t, J = 7.1 Hz) Yield: 61%
1 H-NMR (300 MHz, CDCl 3 ): δ 7.27-7.30 (2H, m), 7.00-7.05 (2H, m), 6.79 (1H, dd, J = 1.9 Hz, 9.3 Hz), 6.63 (1H, dt, J = 1.9 Hz, 9.9 Hz), 5.21 (2H, s), 4.66 (2H, s), 4.35-4.38 (2H, m), 3.82-3.83 (2H, m), 3.61 (2H, t, J = 7.1 Hz), 3.14 (2H, t, J = 7.1 Hz)
(2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)-acetic acid 2-(2-hydroxy-ethoxy)-ethyl ester　[AR65]
Figure JPOXMLDOC01-appb-C000017
 (2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) -acetic acid 2- (2-hydroxy-ethoxy) -ethyl ester [AR65 ]
Figure JPOXMLDOC01-appb-C000017
(2-Benzyl-5,7-difluoro-１-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) acetic acid [AR3]
の塩化メチレン溶液にジエチレングリコール（２．０　ｍｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（２．０　ｍｍｏｌ），　Ｎ，Ｎ－ジメチル－４－アミノピリジン　（０．２　ｍｍｏｌ），トリエチルアミン（２．０　ｍｍｏｌ）を加え室温にて３時間撹拌した。
　その後、塩化メチレンで希釈し10%塩酸を加えた。
　塩化メチレンで抽出し、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を留去したらシリカゲルカラムクロマトグラフィー(溶離液：塩化メチレン)にて精製し、
 (2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)-acetic acid 2-(2-hydroxy-ethoxy)-ethyl ester を得た。 (2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) acetic acid [AR3]
Diethylene glycol (2.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.0 mmol), N, N-dimethyl-4-aminopyridine (0.2 mmol) and triethylamine (2.0 mmol) were added, and the mixture was stirred at room temperature for 3 hours.
Thereafter, the mixture was diluted with methylene chloride and 10% hydrochloric acid was added.
Extracted with methylene chloride, washed with saturated brine, dried over magnesium sulfate, evaporated and purified by silica gel column chromatography (eluent: methylene chloride)
(2-Benzyl-5,7-difluoro-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) -acetic acid 2- (2-hydroxy-ethoxy) -ethyl ester It was.
収率：６４％
1H-NMR (300MHz, CDCl3):δ7.26-7.35 (5H, m ), 6.77 (1H, dd, J = 1.9 Hz, 9.3 Hz), 6.66 (1H, dt, J = 1.9 Hz, 9.9 Hz), 5.78 (2H, s), 5.41 (2H, s), 4.37 (2H, t, J = 4.67 Hz) , 3.71-3.75 (6H, m) , 3.57-3.60 (2H, m) , 3.08 (2H, t, J = 7.1 Hz)  Yield: 64%
1 H-NMR (300 MHz, CDCl 3 ): δ7.26-7.35 (5H, m), 6.77 (1H, dd, J = 1.9 Hz, 9.3 Hz), 6.66 (1H, dt, J = 1.9 Hz, 9.9 Hz ), 5.78 (2H, s), 5.41 (2H, s), 4.37 (2H, t, J = 4.67 Hz), 3.71-3.75 (6H, m), 3.57-3.60 (2H, m), 3.08 (2H, t, J = 7.1 Hz)
・(2-Benzyl-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)-acetic acid 2-hydroxy-ethyl ester 　[AR69]
Figure JPOXMLDOC01-appb-C000018
 ・ (2-Benzyl-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl) -acetic acid 2-hydroxy-ethyl ester [AR69]
Figure JPOXMLDOC01-appb-C000018
収率：７０％
1H-NMR (300MHz, CDCl3): 7.59 (1H, d, J = 8.0 Hz), 7.38-7.28 (7H, m), 7.20 (1H, d, J = 7.7 Hz), 5.80 (2H, s), 5.46 (2H, s), 4.32 (2H, t, J = 4.5 Hz), 3.83-3.74 (4H, m), 2.99 (2H, t, J = 7.0 Hz) Yield: 70%
1 H-NMR (300MHz, CDCl 3 ): 7.59 (1H, d, J = 8.0 Hz), 7.38-7.28 (7H, m), 7.20 (1H, d, J = 7.7 Hz), 5.80 (2H, s) , 5.46 (2H, s), 4.32 (2H, t, J = 4.5 Hz), 3.83-3.74 (4H, m), 2.99 (2H, t, J = 7.0 Hz)
2-Benzyl-9-(4-hydroxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione　[AR66]
Figure JPOXMLDOC01-appb-C000019
 2-Benzyl-9- (4-hydroxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione [AR66]
Figure JPOXMLDOC01-appb-C000019
（１）2-Benzyl-2,3,4,9-tetrahydro-β-carbolin-1-thione （３５．２ｍｇ，０．１２ｍｍｏｌ） のジメチルホルムアミド（１．４　ｍＬ）　溶液に水素化ナトリウム （１．５ｅｑ，７．２ｍｇ，０．１８ｍｍｏｌ）を０℃で加えそのまま１時間撹拌後、4-Methoxybenzylchloride　（１．５ｅｑ，０．０３ｍＬ，０．１８ｍｍｏｌ）を加え室温にて一晩撹拌した。
　その後、水を加えジエチルエーテルで抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を留去し、シリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：酢酸エチル＝１０：１）にて精製し、2-Benzyl-9-(4-methoxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thioneを得た。 (1) Sodium hydride (1. 2-Benzyl-2,3,4,9-tetrahydro-β-carbolin-1-thione (35.2 mg, 0.12 mmol) in a dimethylformamide (1.4 mL) solution. 5 eq, 7.2 mg, 0.18 mmol) was added at 0 ° C., and the mixture was stirred as it was for 1 hour. 4-Methoxybenzylchloride (1.5 eq, 0.03 mL, 0.18 mmol) was added, and the mixture was stirred overnight at room temperature.
Thereafter, water was added and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 10: 1). Benzyl-9- (4-methoxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione was obtained.
収率：７３％
1H-NMR (300MHz, CDCl3):δ 7.52-7.56 (2H, m), 7.40-7.30 (6H, m), 7.14 (1H, t, J = 7.6 Hz), 5.50 (2H, s), 5.22 (2H, t, J = 5.7 Hz), 4.00 (2H, t, J = 5.7 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.60 (2H, m), 3.52 (2H, t, J = 4.1 Hz), 2.95 (2H, t, J = 7.1 Hz) Yield: 73%
1 H-NMR (300MHz, CDCl 3 ): δ 7.52-7.56 (2H, m), 7.40-7.30 (6H, m), 7.14 (1H, t, J = 7.6 Hz), 5.50 (2H, s), 5.22 (2H, t, J = 5.7 Hz), 4.00 (2H, t, J = 5.7 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.60 (2H, m), 3.52 (2H, t, J = 4.1 Hz), 2.95 (2H, t, J = 7.1 Hz)
（２）2-Benzyl-9-(4-methoxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione（３０ｍｇ，０．０７ｍｍｏｌ） の塩化メチレン（０．２ｍＬ）溶液に三臭化ほう素（３ｅｑ，０．２２ｍＬ，０．２２ｍｍｏｌ）を加え室温にて一晩攪拌した。
　その後、０℃で１０％塩酸を加え塩化メチレンで抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を留去し、シリカゲルカラムクロマトグラフィー（溶離液；ヘキサン:酢酸エチル＝６：１）にて精製し、2-Benzyl-9-(4-hydroxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thioneを得た。 (2) 2-Benzyl-9- (4-methoxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione (30 mg, 0.07 mmol) in methylene chloride (0.2 mL) Was added boron tribromide (3 eq, 0.22 mL, 0.22 mmol) and stirred at room temperature overnight.
Thereafter, 10% hydrochloric acid was added at 0 ° C., and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and silica gel column chromatography (eluent: hexane: ethyl acetate = 6: 1) was used. Purification was performed to obtain 2-Benzyl-9- (4-hydroxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione.
収率：５０％
1H-NMR (300MHz, CDCl3):δ 7.37-7.30 (8H, m), 7.15-7.04 (3H, m), 6.75 (2H, d, J = 8.5 Hz), 5.40 (2H, s), 3.99 (2H, s), 3.74 (2H, t, J = 7.4 Hz), 2.97 (2H, t, J = 7.4 Hz) Yield: 50%
1 H-NMR (300 MHz, CDCl 3 ): δ 7.37-7.30 (8H, m), 7.15-7.04 (3H, m), 6.75 (2H, d, J = 8.5 Hz), 5.40 (2H, s), 3.99 (2H, s), 3.74 (2H, t, J = 7.4 Hz), 2.97 (2H, t, J = 7.4 Hz)
2-Benzyl-9-(3-hydroxy-propyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione　[AR68]
Figure JPOXMLDOC01-appb-C000020
 2-Benzyl-9- (3-hydroxy-propyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione [AR68]
Figure JPOXMLDOC01-appb-C000020
（１）2-Benzyl-2,3,4,9-tetrahydro-β-carbolin-1-thione（２１．１ｍｇ，０．０７ｍｍｏｌ）のジメチルホルムアミド（０．５ｍＬ）溶液に水素化ナトリウム（２．０ｅｑ，４．３ｍｇ，０．１４ｍｍｏｌ　を０℃で加えそのまま１時間撹拌後、tetrabutyl ammonium iodide （０．２ｅｑ，５．３ｍｇ，０．０１ｍｍｏｌ）、2-(3-Bromo-propoxy)-tetrahydro- pyran（１．５ｅｑ，２４ｍｇ，０．１１ｍｍｏｌ）を加え室温にて一晩撹拌した。
　その後、水を加えジエチルエーテルで抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を留去し、シリカゲルカラムクロマトグラフィー（溶離液；ヘキサン:酢酸エチル＝１０　：１）にて精製し2-Benzyl-9-[3- (tetrahydro- pyran-2-yloxy)propyl]-2,3,4,9-tetrahydro-β-carbolin-1-thione（ＴＨＰ保護体：１６．８ｍｇ）を得た。 (1) 2-Benzyl-2,3,4,9-tetrahydro-β-carbolin-1-thione (21.1 mg, 0.07 mmol) in a dimethylformamide (0.5 mL) solution with sodium hydride (2.0 eq) , 4.3 mg, 0.14 mmol was added at 0 ° C. and stirred as it was for 1 hour, and then tetrabutyl ammonium iodide (0.2 eq, 5.3 mg, 0.01 mmol), 2- (3-Bromo-propoxy) -tetrahydro-pyran ( 1.5 eq, 24 mg, 0.11 mmol) was added, and the mixture was stirred overnight at room temperature.
Then, water was added and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 10: 1). -9- [3- (tetrahydro-pyran-2-yloxy) propyl] -2,3,4,9-tetrahydro-β-carbolin-1-thione (THP protector: 16.8 mg) was obtained.
　（２）THP保護体（１６．８ｍｇ，０．０４ｍｍｏｌ） のエタノール（０．１ｍＬ）溶液にパラトルエンスルホン酸ピリジニウム（０．１ｅｑ，１．０ｍｇ，０．００４ｍｍｏｌ）を加え５０℃にて３２時間攪拌した。
　その後、水を加え酢酸エチルで抽出し、有機層をＭｇＳＯ４で乾燥後、溶媒を留去し、シリカゲルカラムクロマトグラフィー（溶離液；ヘキサン:酢酸エチル＝３：１）にて精製し2-Benzyl-9-(3-hydroxy-propyl)-2,3,4,9- tetrahydro-β-carbolin-1-thioneを得た 。 (2) Pyridinium paratoluenesulfonate (0.1 eq, 1.0 mg, 0.004 mmol) was added to a solution of THP protector (16.8 mg, 0.04 mmol) in ethanol (0.1 mL) at 50 ° C. for 32 hours. Stir.
Thereafter, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO 4 , the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1). -9- (3-hydroxy-propyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione was obtained.
収率：７８％
1H-NMR (300MHz, CDCl3):δ 7.56 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.40-7.30 (6H, m), 7.15 (1H, t, J = 7.6 Hz), 5.52 (2H, s), 5.23 (2H, t, J = 6.7 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.64 (2H, t, J = 6.6 Hz), 2.96, (2H, t, J = 7.0 Hz), 2.17 (2H, quint, J = 6.3 Hz) Yield: 78%
1 H-NMR (300 MHz, CDCl 3 ): δ 7.56 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.40-7.30 (6H, m), 7.15 (1H, t , J = 7.6 Hz), 5.52 (2H, s), 5.23 (2H, t, J = 6.7 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.64 (2H, t, J = 6.6 Hz), 2.96, (2H, t, J = 7.0 Hz), 2.17 (2H, quint, J = 6.3 Hz)
実施例５と同様にして以下の化合物を得た。
・2-Benzyl-9-(3-hydroxy-ethyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione　[AR67]
Figure JPOXMLDOC01-appb-C000021
 The following compounds were obtained in the same manner as in Example 5.
・ 2-Benzyl-9- (3-hydroxy-ethyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione [AR67]
Figure JPOXMLDOC01-appb-C000021
1H-NMR (300MHz, CDCl3):δ 7.50 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 8.1 Hz), 7.40-7.28 (6H, m), 7.15 (1H, t, J = 7.0 Hz), 5.49 (2H, s), 5.21 (2H, t, J = 5.5 Hz), 4.18 (2H, q, J = 4.9 Hz), 3.73 (2H, t, J = 7.1 Hz), 2.96 (2H, t, J = 7.1 Hz) 1 H-NMR (300 MHz, CDCl 3 ): δ 7.50 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 8.1 Hz), 7.40-7.28 (6H, m), 7.15 (1H, t , J = 7.0 Hz), 5.49 (2H, s), 5.21 (2H, t, J = 5.5 Hz), 4.18 (2H, q, J = 4.9 Hz), 3.73 (2H, t, J = 7.1 Hz), 2.96 (2H, t, J = 7.1 Hz)
・2-Benzyl-9-(3-hydroxy-pentyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione　[AR70]
Figure JPOXMLDOC01-appb-C000022
 ・ 2-Benzyl-9- (3-hydroxy-pentyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione [AR70]
Figure JPOXMLDOC01-appb-C000022
1H-NMR (300MHz, CDCl3):δ 7.55 (1H, d, J = 8.0 Hz), 7.41-7.26 (7H, m), 7.13 (1H, t, J = 7.3 Hz), 5.51 (2H, s), 4.99 (2H, t, J = 7.8 Hz), 3.72 (2H, t, J = 7.0 Hz), 3.66 (2H, t, J = 6.5 Hz), 2.94 (2H, t, J = 7.0 Hz), 1.96-1.91 (2H, quint, J = 7.1 Hz), 1.66 (2H, quint, J = 6.9 Hz), 1.46 (2H, quint, J = 7.7 Hz) 1 H-NMR (300 MHz, CDCl 3 ): δ 7.55 (1H, d, J = 8.0 Hz), 7.41-7.26 (7H, m), 7.13 (1H, t, J = 7.3 Hz), 5.51 (2H, s ), 4.99 (2H, t, J = 7.8 Hz), 3.72 (2H, t, J = 7.0 Hz), 3.66 (2H, t, J = 6.5 Hz), 2.94 (2H, t, J = 7.0 Hz), 1.96-1.91 (2H, quint, J = 7.1 Hz), 1.66 (2H, quint, J = 6.9 Hz), 1.46 (2H, quint, J = 7.7 Hz)
・2-Benzyl-9-[2-(2-hydroxy-ethoxy)ethyl]-2,3,4,9-tetrahydro-β-carbolin-1-thione　[AR71]
Figure JPOXMLDOC01-appb-C000023
 ・ 2-Benzyl-9- [2- (2-hydroxy-ethoxy) ethyl] -2,3,4,9-tetrahydro-β-carbolin-1-thione [AR71]
Figure JPOXMLDOC01-appb-C000023
1H-NMR (300MHz, CDCl3):δ7.52-7.56 (2H, m), 7.40-7.30 (6H, m), 7.14 (1H, t, J = 7.6 Hz), 5.50 (2H, s), 5.22 (2H, t, J = 5.7 Hz), 4.00 (2H, t, J = 5.7 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.60 (2H, m), 3.52 (2H, t, J = 4.1 Hz), 2.95 (2H, t, J = 7.1 Hz) 1 H-NMR (300MHz, CDCl 3 ): δ7.52-7.56 (2H, m), 7.40-7.30 (6H, m), 7.14 (1H, t, J = 7.6 Hz), 5.50 (2H, s), 5.22 (2H, t, J = 5.7 Hz), 4.00 (2H, t, J = 5.7 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.60 (2H, m), 3.52 (2H, t, J = 4.1 Hz), 2.95 (2H, t, J = 7.1 Hz)
・2-Benzyl-9-(2-hydroxy- ethyl)-2,3,4,9-tetrahydro-β-carbolin-1-one　[AR72]
Figure JPOXMLDOC01-appb-C000024
 ・ 2-Benzyl-9- (2-hydroxy-ethyl) -2,3,4,9-tetrahydro-β-carbolin-1-one [AR72]
Figure JPOXMLDOC01-appb-C000024
1H-NMR (300MHz, CDCl3):δ 7.57 (1H, d, J = 8.0 Hz), 7.40-7.27 (7H, m), 7.16 (1H, t, J = 8.0 Hz), 4.79 (2H, s), 4.77 (2H, t, J = 5.1 Hz), 4.05 (2H, m), 3.63 (2H, t, J = 7.0 Hz), 3.00 (2H, t, J = 7.0 Hz) 1 H-NMR (300 MHz, CDCl 3 ): δ 7.57 (1H, d, J = 8.0 Hz), 7.40-7.27 (7H, m), 7.16 (1H, t, J = 8.0 Hz), 4.79 (2H, s ), 4.77 (2H, t, J = 5.1 Hz), 4.05 (2H, m), 3.63 (2H, t, J = 7.0 Hz), 3.00 (2H, t, J = 7.0 Hz)
（１）実施例４（１）と同様にして以下の化合物を得た。
・2-Benzyl-9-(3-methoxymethoxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione
収率７８％
1H-NMR (400MHz, CDCl3):δ 7.57 (1H, d, J = 7.8 Hz), 7.35-7.28 (6H, m), 7.14 (2H, t, J = 7.6 Hz), 6.88 (1H, d, J = 6.8 Hz), 6.80 (1H, s), 6.72 (1H, d, J = 7.1 Hz), 6.37 (2H, s), 5.49 (2H, s), 5.10 (2H, s), 3.73 (2H, t, J = 7.0 Hz), 2.98 (2H, t, J = 7,0 Hz) (1) In the same manner as in Example 4 (1), the following compound was obtained.
・ 2-Benzyl-9- (3-methoxymethoxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione
Yield 78%
1 H-NMR (400MHz, CDCl 3 ): δ 7.57 (1H, d, J = 7.8 Hz), 7.35-7.28 (6H, m), 7.14 (2H, t, J = 7.6 Hz), 6.88 (1H, d , J = 6.8 Hz), 6.80 (1H, s), 6.72 (1H, d, J = 7.1 Hz), 6.37 (2H, s), 5.49 (2H, s), 5.10 (2H, s), 3.73 (2H , t, J = 7.0 Hz), 2.98 (2H, t, J = 7,0 Hz)
・2-Benzyl-6-iodo-9-(4-methoxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione
収率５２％
1H-NMR (400MHz, CDCl3):δ 7.90 (1H, d, J = 1.5 Hz), 7.49 (1H, dd, J = 1.5 Hz, 8.8 Hz), 7.34-7.29 (5H, m), 7.09 (1H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.5 Hz), 6.27 (2H, s), 5.47 (2H, s), 3.75 (3H, s), 3.70 (2H, t, J = 7.1 Hz), 2.91 (2H, t, J = 7,1 Hz) ・ 2-Benzyl-6-iodo-9- (4-methoxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione
Yield 52%
1 H-NMR (400 MHz, CDCl 3 ): δ 7.90 (1H, d, J = 1.5 Hz), 7.49 (1H, dd, J = 1.5 Hz, 8.8 Hz), 7.34-7.29 (5H, m), 7.09 ( 1H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.5 Hz), 6.27 (2H, s), 5.47 (2H, s), 3.75 ( 3H, s), 3.70 (2H, t, J = 7.1 Hz), 2.91 (2H, t, J = 7,1 Hz)
・2-Benzyl-6-methoxy-9-(4-methoxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione
収率４７％
1H-NMR (500MHz, CDCl3):δ 7.34-7.29 (3H, m), 7.21 (1H, d, J = 9.1 Hz), 7.07 (2H, d, J = 9.2 Hz), 6.95-6.91 (3H, m), 6.79-6.77 (3H, m), 6.27 (2H, s), 5.49 (2H, s), 3.83 (3H, s), 3.75 (3H, s), 3.71 (2H, t, J = 6.9 Hz), 2.93 (2H, t, J = 6.9 Hz) ・ 2-Benzyl-6-methoxy-9- (4-methoxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione
Yield 47%
1 H-NMR (500 MHz, CDCl 3 ): δ 7.34-7.29 (3H, m), 7.21 (1H, d, J = 9.1 Hz), 7.07 (2H, d, J = 9.2 Hz), 6.95-6.91 (3H , m), 6.79-6.77 (3H, m), 6.27 (2H, s), 5.49 (2H, s), 3.83 (3H, s), 3.75 (3H, s), 3.71 (2H, t, J = 6.9 Hz), 2.93 (2H, t, J = 6.9 Hz)
・2-Benzyl-9-(3-methoxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione
1H-NMR (400MHz, CDCl3):δ 7.57 (1H, d, J = 8.1 Hz), 7.35-7.27 (7H, m), 7.19-7.11 (2H, m), 6.74 (1H, d, J = 8.1 Hz), 6.70 (2H, m), 6.37 (2H, s), 5.49 (2H, s), 3.73 (2H, t, J = 6.8 Hz),3.72 (3H, s), 2.98 (2H, t, J = 6.8 Hz) ・ 2-Benzyl-9- (3-methoxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione
1 H-NMR (400 MHz, CDCl 3 ): δ 7.57 (1H, d, J = 8.1 Hz), 7.35-7.27 (7H, m), 7.19-7.11 (2H, m), 6.74 (1H, d, J = 8.1 Hz), 6.70 (2H, m), 6.37 (2H, s), 5.49 (2H, s), 3.73 (2H, t, J = 6.8 Hz), 3.72 (3H, s), 2.98 (2H, t, (J = 6.8 Hz)
（２）実施例４（１）と同様にして以下の化合物を得た。
・2-Benzyl-9-(3-hydroxy-benzyl)-2,3,4,9-tetrahydro-β-carbolin-1-thione[AR73]
Figure JPOXMLDOC01-appb-C000025
 (2) In the same manner as in Example 4 (1), the following compound was obtained.
・ 2-Benzyl-9- (3-hydroxy-benzyl) -2,3,4,9-tetrahydro-β-carbolin-1-thione [AR73]
Figure JPOXMLDOC01-appb-C000025
収率５２％
1H-NMR (400MHz, CDCl3):δ 7.57 (1H, d, J = 8.1 Hz), 7.45-7.26 (7H, m), 7.13 (2H, t, J = 7.2 Hz), 6.73 (1H, d, J = 7.6 Hz), 6.68 (1H, d, J = 7.8 Hz), 6.57 (1H, s), 6.34 (2H, s), 5.48 (2H, s), 3.73 (2H, t, J = 7.1 Hz), 2.97 (2H, t, J = 7,1 Hz) Yield 52%
1 H-NMR (400 MHz, CDCl 3 ): δ 7.57 (1H, d, J = 8.1 Hz), 7.45-7.26 (7H, m), 7.13 (2H, t, J = 7.2 Hz), 6.73 (1H, d , J = 7.6 Hz), 6.68 (1H, d, J = 7.8 Hz), 6.57 (1H, s), 6.34 (2H, s), 5.48 (2H, s), 3.73 (2H, t, J = 7.1 Hz ), 2.97 (2H, t, J = 7,1 Hz)
　本発明の１－チオキソ－１,２,３,４－テトラヒドロ－β－カルボリン誘導体は、膵臓癌細胞などのがん細胞に対して選択性の高い殺細胞性を示す。
　従って、１－チオキソ－１,２,３,４－テトラヒドロ－β－カルボリン誘導体は、膵臓癌などの固形癌を治療するための薬剤として有用である。 The 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative of the present invention exhibits a highly selective cytotoxicity against cancer cells such as pancreatic cancer cells.
Accordingly, 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivatives are useful as drugs for treating solid cancers such as pancreatic cancer.

Claims (14)

  1. 下記一般式［１］
    Figure JPOXMLDOC01-appb-C000001
     　「式中、Ｒ１は、同一または異なって、水素原子、ハロゲン原子、アルキル基、シクロアルキル基、アルキレン基、アルアルキル基、アリール基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基もしくは保護されていてもよいヒドロキシル基から選ばれる１～３個の原子または置換基を；Ｒ２は、保護されていてもよいヒドロキシアルキルオキシカルボニル、ヒドロキシアルキルオキシアルキルオキシカルボニル、ヒドロキシル、ヒドロキシアルキルオキシまたはヒドロキシアリール基を；Ｒ３は、ハロゲン原子で置換されていてもよいアリール、シクロアルキルもしくは複素環式基で置換されたアルキル基またはアリール基を；Ａは、アルキレン基を；Ｘは、硫黄原子または酸素原子を、それぞれ示す。但し、Ｒ２がヒドロキシル基、Ｒ３がアリール基であってＸが酸素原子である場合を除く。」
    で表される１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体。     The following general formula [1]
    Figure JPOXMLDOC01-appb-C000001
     Wherein R 1 is the same or different and is a hydrogen atom, halogen atom, alkyl group, cycloalkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, cycloalkyloxy group, aryloxy group or protected. 1 to 3 atoms or substituents selected from an optionally hydroxyl group; R 2 is an optionally protected hydroxyalkyloxycarbonyl, hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl R 3 represents an alkyl group or aryl group substituted with an aryl, cycloalkyl or heterocyclic group optionally substituted with a halogen atom; A represents an alkylene group; X represents a sulfur atom or oxygen Atoms are shown respectively, provided that R 2 is hydro Excluding the case of a xyl group, R 3 is an aryl group and X is an oxygen atom. "
    A 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative represented by:
  2. 　Ｒ２が、保護されていてもよいヒドロキシアルキルオキシカルボニルまたはヒドロキシアルキルオキシアルキルオキシカルボニル基である請求項１記載の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体。 The 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative according to claim 1, wherein R 2 is an optionally protected hydroxyalkyloxycarbonyl or hydroxyalkyloxyalkyloxycarbonyl group.
  3. 　Ｒ２が、保護されていてもよいヒドロキシまたはヒドロキシアルキルオキシ基である請求項１記載の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体。 The 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative according to claim 1, wherein R 2 is a hydroxy or hydroxyalkyloxy group which may be protected.
  4. 　Ｒ２が、保護されていてもよいヒドロキシアリール基である請求項１記載の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体。 The 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative according to claim 1, wherein R 2 is an optionally protected hydroxyaryl group.
  5. 　Ｒ３が、ハロゲン原子で置換されていてもよいアリールで置換されたアルキル基である請求項１～４のいずれかの項記載の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体。 The 1-thioxo-1,2,3,4-tetrahydro-β- according to any one of claims 1 to 4, wherein R 3 is an alkyl group substituted with an aryl which may be substituted with a halogen atom. Carboline derivatives.
  6. 　Ｘが硫黄原子である請求項１～５のいずれかの項記載の１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体。 6. The 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative according to any one of claims 1 to 5, wherein X is a sulfur atom.
  7. 下記一般式［１’］
    Figure JPOXMLDOC01-appb-C000002
     　「式中、Ｒ１は、同一または異なって、水素原子、ハロゲン原子、アルキル基、シクロアルキル基、アルキレン基、アルアルキル基、アリール基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基もしくは保護されていてもよいヒドロキシル基から選ばれる１～３個の原子または置換基を；Ｒ２は、保護されていてもよいヒドロキシアルキルオキシカルボニル、ヒドロキシアルキルオキシアルキルオキシカルボニル、ヒドロキシル、ヒドロキシアルキルオキシまたはヒドロキシアリール基を；Ｒ３は、ハロゲン原子で置換されていてもよいアリール、シクロアルキルもしくは複素環式基で置換されたアルキル基またはアリール基を；Ａは、アルキレン基を；Ｘは、硫黄原子または酸素原子を、それぞれ示す。」
    で表される１－チオキソ－１，２，３，４－テトラヒドロ－β－カルボリン誘導体またはその塩を有効成分とする抗がん剤。     The following general formula [1 ']
    Figure JPOXMLDOC01-appb-C000002
     Wherein R 1 is the same or different and is a hydrogen atom, halogen atom, alkyl group, cycloalkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, cycloalkyloxy group, aryloxy group or protected. 1 to 3 atoms or substituents selected from an optionally hydroxyl group; R 2 is an optionally protected hydroxyalkyloxycarbonyl, hydroxyalkyloxyalkyloxycarbonyl, hydroxyl, hydroxyalkyloxy or hydroxyaryl R 3 represents an alkyl group or aryl group substituted with an aryl, cycloalkyl or heterocyclic group optionally substituted with a halogen atom; A represents an alkylene group; X represents a sulfur atom or oxygen Each atom is shown. "
    An anticancer agent comprising a 1-thioxo-1,2,3,4-tetrahydro-β-carboline derivative represented by the formula:
  8. 　Ｒ２が、保護されていてもよいヒドロキシアルキルオキシカルボニルまたはヒドロキシアルキルオキシアルキルオキシカルボニル基である請求項７記載の抗がん剤。 The anticancer agent according to claim 7, wherein R 2 is an optionally protected hydroxyalkyloxycarbonyl or hydroxyalkyloxyalkyloxycarbonyl group.
  9. 　Ｒ２が、保護ほごされていてもよいヒドロキシまたはヒドロキシアルキルオキシ基である請求項７記載の抗がん剤。 The anticancer agent according to claim 7, wherein R 2 is a hydroxy or hydroxyalkyloxy group which may be protected.
  10. 　Ｒ２が、保護ほごされていてもよいヒドロキシアリール基である請求項７記載の抗がん剤。 The anticancer agent according to claim 7, wherein R 2 is a hydroxyaryl group which may be protected.
  11. 　Ｒ３が、ハロゲン原子で置換されていてもよいアリールで置換されたアルキル基である請求項７～１０のいずれかの項記載の抗がん剤。 The anticancer agent according to any one of claims 7 to 10, wherein R 3 is an alkyl group substituted with an aryl optionally substituted with a halogen atom.
  12. 　Ｘが硫黄原子である請求項７～１１のいずれかの項記載の抗がん剤。 The anticancer agent according to any one of claims 7 to 11, wherein X is a sulfur atom.
  13. 　対象とするがんが、固形癌である請求項７～１２のいずれかの項記載の抗がん剤。 The anticancer agent according to any one of claims 7 to 12, wherein the target cancer is a solid cancer.
  14. 　固形癌が、膵臓癌または大腸癌である請求項１３記載の抗がん剤。 The anticancer agent according to claim 13, wherein the solid cancer is pancreatic cancer or colon cancer.
PCT/JP2012/062775 2011-05-19 2012-05-18 1-THIOXO-1,2,3,4-TETRAHYDRO-β-CARBOLINE DERIVATIVE AND ANTI-CANCER AGENT COMPRISING SAME WO2012157744A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2013515218A JPWO2012157744A1 (en) 2011-05-19 2012-05-18 1-Thioxo-1,2,3,4-tetrahydro-β-carboline derivatives and anticancer agents containing them

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2011111973 2011-05-19
JP2011-111973 2011-05-19
JP2011-247369 2011-11-11
JP2011247369 2011-11-11

Publications (1)

Publication Number Publication Date
WO2012157744A1 true WO2012157744A1 (en) 2012-11-22

Family

ID=47177058

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/062775 WO2012157744A1 (en) 2011-05-19 2012-05-18 1-THIOXO-1,2,3,4-TETRAHYDRO-β-CARBOLINE DERIVATIVE AND ANTI-CANCER AGENT COMPRISING SAME

Country Status (2)

Country Link
JP (1) JPWO2012157744A1 (en)
WO (1) WO2012157744A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009129A2 (en) * 1999-08-03 2001-02-08 Novuspharma S.P.A. 1h-pirido[3, 4-b]indol-1-one derivatives
WO2006011750A1 (en) * 2004-07-27 2006-02-02 C & C Research Laboratories Tetrahydro-beta-carbolinone derivatives and process for preparing the same
WO2009078423A1 (en) * 2007-12-18 2009-06-25 National University Corporation University Of Toyama Fused tricyclic compound having aldose reductase inhibitory activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009129A2 (en) * 1999-08-03 2001-02-08 Novuspharma S.P.A. 1h-pirido[3, 4-b]indol-1-one derivatives
WO2006011750A1 (en) * 2004-07-27 2006-02-02 C & C Research Laboratories Tetrahydro-beta-carbolinone derivatives and process for preparing the same
WO2009078423A1 (en) * 2007-12-18 2009-06-25 National University Corporation University Of Toyama Fused tricyclic compound having aldose reductase inhibitory activity

Also Published As

Publication number Publication date
JPWO2012157744A1 (en) 2014-07-31

Similar Documents

Publication Publication Date Title
KR101831005B1 (en) Tetrahydrocarboline derivative
SA05250449B1 (en) Thiophene derivatives as CHK 1 inihibitors
BG61485B1 (en) N-oxycarbonylsubstituted 5&#39;-deoxy-5-fluorocytidines
ES2965264T3 (en) 3-Phosphoglycerate dehydrogenase inhibitors and their uses
JPH08504765A (en) Anti-proliferative substituted 5-thiapyrimidinone and 5-selenopyrimidinone compounds
CN103370311A (en) Pochoxime conjugates useful for the treatment of HSP90 related pathologies
EP4032890A1 (en) Heterocyclic amide compound, pharmaceutically acceptable salt thereof, and preparation method therefor and use thereof
JP5366211B2 (en) Condensed tricyclic compounds having aldose reductase inhibitory activity
CN112047944A (en) Selective kinase inhibition compound and application thereof
US20220041616A1 (en) Spiro compound and medical uses thereof
AU2007304881B2 (en) Novel chromenone potassium channel blockers and uses thereof
WO2012157744A1 (en) 1-THIOXO-1,2,3,4-TETRAHYDRO-β-CARBOLINE DERIVATIVE AND ANTI-CANCER AGENT COMPRISING SAME
JP2016037472A (en) Novel semaphorin 3a inhibitory agent
US9901641B2 (en) Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety
US5162350A (en) Benzothiazolinone compounds
US10227374B2 (en) Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety
JP5640256B2 (en) PPARγ agonist
US8362240B2 (en) Taxol derivatives with antitumor activity
JP4061059B2 (en) N-alkoxyalkyl-N-alkylamine derivatives or salts thereof
CN115594686A (en) Millpuline A derivatives, and preparation method and medical application thereof
WO1994008961A1 (en) Prostaglandin e1 analog
WO2007102368A1 (en) Novel 3-(1-aminoalkylidene)furan-2,4(3h,5h)-dione derivative, method for producing the same, and pharmaceutical composition containing the same as active ingredient
JP2003055373A (en) C7 ester substituted taxane
US20030220385A1 (en) Treatment of disorder related to low cyclic GMP levels
JPS6316398B2 (en)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12785291

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2013515218

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12785291

Country of ref document: EP

Kind code of ref document: A1