WO2010032582A1 - 成人t細胞白血病治療薬 - Google Patents
成人t細胞白血病治療薬 Download PDFInfo
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- WO2010032582A1 WO2010032582A1 PCT/JP2009/064557 JP2009064557W WO2010032582A1 WO 2010032582 A1 WO2010032582 A1 WO 2010032582A1 JP 2009064557 W JP2009064557 W JP 2009064557W WO 2010032582 A1 WO2010032582 A1 WO 2010032582A1
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- 0 **(CC*1)c(cc2P3CC3)c1cc2N Chemical compound **(CC*1)c(cc2P3CC3)c1cc2N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/11—Aldehydes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a drug used for treating adult T cell leukemia (ATL).
- ATL adult T cell leukemia
- ATL Adult T-cell leukemia
- carriers infected people
- 2-5% of them have ATL during their lifetime. It is said that.
- the survival rate after the onset of ATL is extremely low, and multi-drug combination therapy using various anticancer agents is performed as a treatment, but the treatment results are not good due to the rapid acquisition of drug resistance.
- Patent Document 1 discloses a therapeutic agent containing fucoxanthin or fucoxanthinol as an active ingredient.
- Patent Document 2 discloses an adult T cell leukemia therapeutic agent containing digitoxin as an active ingredient.
- an object of the present invention is to provide a novel therapeutic agent for adult T cell leukemia having an antitumor effect specific to ATL cells.
- the present inventors screened a drug library using the cell line S1T established from an ATL patient and attempted to identify a drug having an antitumor effect specific to ATL cells.
- the inventors have found an ATL cell proliferation inhibitory effect selective to a drug having a specific structure, and have completed the present invention. That is, the gist of the present invention is as follows.
- R 1 is H, OH, an alkoxy group, an acyl group or a thioacyl group
- R 2 is an acyl group, a thioacyl group
- CONR 7 R 8 or CSNR 7 R 8 R 7 and R 8 are each independently H, an alkyl group having 1 to 3 carbon atoms or a phenyl group
- R 1 and R 2 may be combined to form a ring
- X 1 and X 2 are the same Or differently —CR 3 R 4 —, —SiR 3 R 4 — or oxygen
- R 3 and R 4 are the same or different and are alkyl groups having 1 to 6 carbon atoms.
- a therapeutic agent for adult T-cell leukemia comprising a compound represented by the formula or a prodrug thereof:
- R 1 is H or OH
- R 2 is an acyl group
- R 3 to R 6 are the same or different and are alkyl groups having 1 to 6 carbon atoms.
- the therapeutic agent for adult T-cell leukemia according to (2) above which is a compound represented by
- the therapeutic agent for adult T-cell leukemia according to (2) above which is a compound represented by
- the therapeutic agent for adult T cell leukemia which is a compound represented by the formula:
- the compound of the present invention can selectively inhibit the growth of ATL cell lines and is therefore effective as a therapeutic agent for adult T cell leukemia.
- the therapeutic agent for adult T-cell leukemia of the present invention has the formula I
- R 1 is H, OH, an alkoxy group, an acyl group or a thioacyl group
- R 2 is an acyl group, a thioacyl group
- CONR 7 R 8 or CSNR 7 R 8 R 7 and R 8 are each independently Or H 1 is an alkyl group having 1 to 3 carbon atoms or a phenyl group
- R 1 and R 2 may be combined to form a ring
- X 1 and X 2 are the same or Differently, it is —CR 3 R 4 —, —SiR 3 R 4 — or oxygen
- R 3 and R 4 are the same or different and are alkyl groups having 1 to 6 carbon atoms.
- a compound in which X 1 and X 2 are oxygen (O) is sold by Aldrich, and a commercially available product can be obtained.
- the alkoxy group may be linear or branched, and preferably has about 1 to 5 carbon atoms.
- alkoxy groups include methoxy group, ethoxy group, propyloxy group, i-propyloxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group and the like.
- acyl group for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, octanoyl group, decanoyl group, propeonyl group (acryloyl group), butenoyl group, Linear or branched C1-10-saturated or unsaturated aliphatic acyl group such as isobutenoyl group, penteonyl group, hexenoyl group, 4-methyl-2-penteonyl group, preferably C2-10-saturated or unsaturated fat And aromatic acyl groups (aroyl groups) such as benzoyl groups and naphthoyl groups.
- thioacyl group those in which the carbonyl group in the acyl group is a thiocarbonyl group are applicable, and specific examples include a thioformyl group, a thioacetyl group, a thiopropionyl group, a thiobutyryl group, and a thiobenzoyl group.
- acyl group or thioacyl group a carbon atom not adjacent to the carbonyl group or thiocarbonyl group may be substituted with a heteroatom such as nitrogen, sulfur, or oxygen.
- a heteroatom such as nitrogen, sulfur, or oxygen.
- Examples of such an acyl group or thioacyl group substituted by a hetero atom include —COCH ⁇ CHN (CH 3 ) 2 , —CSCH ⁇ CHN (CH 3 ) 2 and the like.
- CONR 7 R 8 group and CSNR 7 R 8 CONH 2 , CONH (CH 3 ), CON (CH 3 ) 2 , CONH (CH 2 CH 3 ), CONH (CH 2 CH 2 CH 3 ), CONHC (CH 3 ) 3 , CONHC 6 H 5 , CSNH 2 , CSNH (CH 3 ), CSN (CH 3 ) 2 , CSNH (CH 2 CH 3 ), CSNH (CH 2 CH 2 CH 3 ), CSNHC (CH 3 ) 3 , CSNHC 6 H 5 etc. are mentioned. Among them, CONH 2 is particularly preferable.
- the alkyl group having 1 to 6 carbon atoms may be either a straight chain or branched chain, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Examples thereof include t-butyl group, isobutyl group, n-pentyl group, isopentyl group, neopentyl group and the like.
- the therapeutic agent for adult T-cell leukemia of the present invention has the formula II
- R 1 is H or OH
- R 2 is an acyl group
- R 3 to R 6 are the same or different and are alkyl groups having 1 to 6 carbon atoms.
- acyl group examples are as defined above.
- a linear or branched C1-10-saturated or unsaturated aliphatic acyl group such as butenoyl group, isobutenoyl group, penteonyl group, hexenoyl group, 4-methyl-2-penteonyl group, preferably C2-10-saturated
- an unsaturated aliphatic acyl group (the carbon number is a value including carbon of a carbonyl group)
- aromatic acyl group aroyl group
- benzoyl group and a naphthoyl group such as a benzoyl group and a naphthoyl group.
- the alkyl group having 1 to 6 carbon atoms may be either a straight chain or a branched chain, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n Examples include -butyl group, t-butyl group, isobutyl group, n-pentyl group, isopentyl group, neopentyl group and the like.
- the therapeutic agent for adult T-cell leukemia of the present invention is a compound of formula III among the compounds of formula II described above.
- the compound represented by these is obtained by conventional organic synthesis, for example, Kagechika H, Hashimoto Y, Kawachi E, Shudo K. Affinity gels for purification of retinoid-specific binding protein (RSBP). Biochem. Biophys. Res. Commun. 155: 503-508 (1988). Specifically, as shown in the following reaction formula, 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl ketone is mixed with m-chloroperbenzoic acid in chloroform. (MCPBA) is heated for several hours, and the resulting intermediate is heated with aluminum chloride at 130-140 ° C. to give the desired compound of formula III (5,6,7,8-tetrahydro-3-hydroxy-5 , 5,8,8-tetramethyl-2-naphthylmethylketone).
- MCPBA m-chloroperbenzoic acid in chloroform.
- the acetyl group in the compound of formula III is a thioacetyl group according to the method described in Hupp CD, Tepe JJ. Total Synthesis of a Marine Alkaloid from the Tunicate Dendrodoa grossularia. Org. Lett. 10: 3737-3739 (2008). Can be converted to Specifically, as shown in the following reaction formula, 5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2-naphthylmethylketone together with Lawesson's reagent in toluene By heating to reflux, 5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2-naphthylethanethione can be obtained.
- the therapeutic agent for adult T-cell leukemia of the present invention has formula IV
- This compound can be obtained by conventional organic synthesis, e.g. Kagechika H, Kawachi E, Hashimoto Y, Himi T, Shudo K. Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity. J. Med. Chem. 31: 2182-2192 (1988). Or Buttner MW, Penka M, Doszczak L, Kraft P, Tacke R. Silicon analogues of the musk odorant veralide. Organometallics, 26: 1295-1298 (2007). .
- 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene is reacted with acetyl chloride in dichloroethane in the presence of aluminum chloride.
- the desired compound of formula IV (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethylketone) can be obtained in a yield of about 80%.
- the therapeutic agent for adult T cell leukemia of the present invention has formula V or formula VI.
- the compound of the formula V corresponds to a compound in which an OH group as R 1 and a propionyl group as R 2 form a ring, and a compound of the formula VI has an OH group as R 1 and a propionyl group as R 2 Is equivalent to that formed.
- therapeutic agent for adult T-cell leukemia of the present invention include compounds of formula VII
- Prodrugs of the compounds represented by the formulas I to VII are compounds that are converted into the compounds of the formulas I to VII by reactions with enzymes, gastric acid and the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed.
- prodrugs of the compound of formula III include compounds in which the hydroxyl group of the compound of formula III is acylated, alkylated, phosphorylated, borated (eg, the hydroxyl group of the compound of formula III is acetylated, palmitoylated, propanoyl , Pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylated compounds, etc.).
- These prodrugs can be produced from the compound of formula III by a method known per se.
- prodrugs of compounds of Formula V and Formula VI include
- X is O or S
- R 9 and R 10 are H, CH 3 or the like, or R 9 and R 10 may be combined to form a ring.
- R 11 is an alkyl group such as CH 3 or an acyl group such as COCH 3 .
- prodrugs of the compounds of formulas I to VII are those of formula I to formula VII under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design, 163-198. It may be changed to a compound.
- the above compound or a prodrug thereof can be formulated as a therapeutic agent for adult T cell leukemia in combination with a conventional pharmaceutical carrier.
- the dosage form is not particularly limited, and can be appropriately selected and used as necessary. Tablets, capsules, granules, fine granules, powders, sustained-release preparations, solutions, suspensions, emulsions, syrups And oral agents such as elixirs, and parenteral agents such as injections and suppositories.
- Oral preparations are produced according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like.
- binders In addition to the various excipients described above, binders, disintegrants, surfactants, lubricants, fluidity promoters, corrigents, colorants, fragrances, and the like can be added as appropriate.
- binder examples include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol and the like.
- disintegrant examples include starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted hydroxypropylcellulose.
- surfactant examples include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, and polysorbate 80.
- lubricant examples include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.
- fluidity promoter examples include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
- Injections are produced according to conventional methods, and generally used as diluents are distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like. Further, if necessary, bactericides, preservatives, stabilizers, tonicity agents, soothing agents and the like may be added.
- the injection can be frozen after filling into a vial or the like, the water can be removed by a normal freeze-drying technique, and the solution can be re-prepared from the freeze-dried product immediately before use.
- the proportion of the compound of formula I to formula VII or prodrug thereof in the injection can vary between 5 and 50% by weight, but is not limited thereto.
- parenterals include suppositories for rectal administration and are manufactured according to conventional methods.
- the formulated therapeutic drug varies depending on the dosage form, administration route, etc., but can be administered 1 to 4 times a day for a period of 1 week to 3 months.
- the weight of the compound of Formula I to Formula VII or a prodrug thereof in order to exert the desired effect as a parenteral agent, it varies depending on the age, body weight, and degree of disease of the patient. In general, in the case of an adult, as the weight of the compound of Formula I to Formula VII or a prodrug thereof, for example It is appropriate to administer 0.1 to 1000 mg, preferably 1 to 500 mg by intravenous injection, intravenous drip injection, subcutaneous injection or intramuscular injection.
- S1T ATL patient-derived cell line
- MT-2 HTLV-1-infected cell line
- MOLT-4 acute lymphoblastic leukemia cell line
- CEM acute lymphoblastic cell line
- HL-60 acute promyelocytic leukemia cell line
- Jurkat acute T cell leukemia cell line
- TMNAA is described in Kagechika H, Hashimoto Y, Kawachi E, Shudo K. Affinity gels for purification of retinoid-specific binding protein (RSBP). Biochem. Biophys. Res. Commun. 155: 503-508 (1988). Based on the synthesis. As shown in FIG. 1, it was revealed that TMNAA, which is a compound of the present invention, selectively inhibits the proliferation of ATL cells as compared with the control at a concentration of 4 ⁇ M or more.
- RSBP retinoid-specific binding protein
- Table 1 also shows the results regarding TMNAA, the compound of formula IV (TMN (COCH 3 )), which showed a high SI value, and other derivatives.
- TMNAA, TMN (COCH 3 ) and TMN (OCH 3 ) (COCH 3 ), which are the compounds of the present invention have selectivity for ATL cells compared to other derivatives having similar structures. I understood. Among these, it became clear that TMNAA and TMN (COCH 3 ), which are the compounds of the present invention, have a higher selectivity for ATL cells than other derivatives having a similar structure.
- the reaction solution was poured into cold water and extracted with ethyl acetate.
- the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
- the crude product was purified by recrystallization using hexane as a solvent. Yield 1.83 g (83%).
- the reaction solution was diluted with dichloromethane, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
- the crude product was purified by silica gel chromatography using hexane: ethyl acetate (40: 3) as an elution solvent. Yield 53.6 mg (9.0%).
- the reaction solution was filtered through Celite, and hydrochloric acid was added to the filtrate to make the solution acidic. After extraction with ethyl acetate, the extract was dried over magnesium sulfate and concentrated under reduced pressure.
- the crude product was purified by silica gel chromatography using hexane: ethyl acetate (4: 1) as an elution solvent. Yield 141.6 mg (3%).
- the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate.
- the extract was washed with dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the crude product was purified by silica gel chromatography using hexane: ethyl acetate (10: 1) as an elution solvent. Yield 139 mg (50%).
- the residue was roughly purified by silica gel chromatography using hexane: ethyl acetate (20: 1) as an elution solvent.
- Methanol (5 mL) and acetic acid (1 mL) were added to the crude product, and the mixture was heated at 95 ° C. for 30 hours.
- the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
- the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
- the crude product was purified by silica gel chromatography using hexane: ethyl acetate (4: 1) as an elution solvent. Yield 153 mg (23%).
- S1T ATL patient-derived cell line
- MOLT-4 acute lymphoblastic leukemia cell line
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Abstract
Description
で表される化合物又はそのプロドラッグを含有する成人T細胞白血病治療薬。
で表される化合物である上記(1)に記載の成人T細胞白血病治療薬。
種々の薬剤存在下で、S1T(ATL患者由来細胞株)、MT-2(HTLV-1感染細胞株)、その対照としてMOLT-4(急性リンパ芽球性白血病細胞株)、CEM(急性リンパ芽球性白血病細胞株)、HL-60(急性前骨髄球性白血病細胞株)、そしてJurkat(急性T細胞白血病細胞株)を4日間培養後、MTT法により化合物の各細胞に対する増殖阻害効果を評価した。
また、TMNAAと、同様に高いSI値を示した式IVの化合物(TMN(COCH3))、及びその他の誘導体に関する結果を表1に示す。表1から、本発明の化合物であるTMNAA、TMN(COCH3)及びTMN(OCH3)(COCH3)が、類似構造を有する他の誘導体に比べてATL細胞に対する選択性を有していることが分かった。その中でも、本発明の化合物であるTMNAA及びTMN(COCH3)が、類似構造を有する他の誘導体に比べてATL細胞に対する高い選択性を有していることが明らかとなった。なお、これらの化合物に関係する薬剤として、サリチル酸ナトリウムの抗ATL効果が報告されているが(Portis T, Harding JC, Ratner L. The contribution of NF-κB activity to spontaneous proliferation and resistance to apoptosis in human T-cell leukemia virus type 1 Tax-induced tumors. Blood 98: 1200-1208 (2001).)、表1に示す通り、実験ではS1Tに対する選択性は認められなかった。さらに、SIが10以上を示した式IIIの化合物について、MT-2、CEM、HL-60、Jurkatに対する増殖阻害効果を検討した結果、MT-2に対してのみ、特異的な抑制効果を示した。
(1)5,6,7,8-テトラヒドロ-2-ヒドロキシ-5,5,8,8-テトラメチルナフタレン(a)の合成
合成工程は下記の化学反応式に示す通りである。反応経路中、AlCl3は塩化アルミニウムを表す。フェノール(1.02g、10.8mmol)に無水ジクロロメタン(5mL)と塩化アルミニウム(144mg、1.08mmol)、2,5-ジクロロ-2,5-ジメチルヘキサン(2.18g、11.9mmol)を加え、19時間室温で攪拌した。反応溶液を冷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物を、ヘキサンを溶媒として再結晶により精製した。収量1.83g(83%)。
FAB-MS m/z 204(M+H)+;1H-NMR(500 MHz, CDCl3)δ 7.17 (d, 1H, J = 8.5 Hz), 6.75 (d, 1H, J = 3.0 Hz), 6.62 (dd, 1H, J = 5.5, 3.0 Hz), 4.49 (s, 1H), 1.66 (s, 4H), 1.25 (s、6H), 1.24 (s, 6H).
5,6,7,8-テトラヒドロ-2-ヒドロキシ-5,5,8,8-テトラメチルナフタレン(204mg、1.00mmol)に無水ジクロロメタン(1mL)と塩化アルミニウム(148mg、1.12mmol)、塩化プロピオニル(101.7mg、1.10mmol)を加え、16時間60℃で攪拌した。反応溶液を冷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物を、ヘキサン:酢酸エチル(20:1)を溶出溶媒としてシリカゲルカラムクロマトグラフィーにより精製した。収量117mg(45%)。
FAB-MS m/z 247(M+H)+;1H-NMR(500 MHz, CDCl3)δ 11.96 (s, 1H), 7.68 (s, 1H), 6.90 (s, 1H), 3.03 (q, 2H), 1.68 (s, 4H), 1.28 (s, 6H), 1.27 (s, 6H), 1.25 (t, 3H, J = 7.3 Hz).
合成工程は下記の化学反応式に示す通りである。5,6,7,8-テトラヒドロ-2-ヒドロキシ-5,5,8,8-テトラメチルナフタレン(204mg、1.00mol)に無水ジクロロメタン(1mL)と塩化アルミニウム(148mg、1.12mmol)、塩化イソブチリル(117mg、1.10mmol)を加え、2時間60℃で攪拌した。反応溶液を冷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(20:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量128mg(47%)。
FAB-MS m/z 261(M+H)+;1H-NMR(500 MHz, CDCl3)δ 12.11 (s, 1H), 7.71 (s, 1H), 6.91 (s, 1H), 3.60 (septet, 1H, J = 7.0 Hz), 1.68 (s, 4H), 1.29 (s, 6H), 1.27 (s, 6H), 1.24 (d, 6H, J = 6.7 Hz).
合成工程は下記の化学反応式に示す通りである。反応経路中、TiCl4は塩化チタンを表す。5,6,7,8-テトラヒドロ-2-ヒドロキシ-5,5,8,8-テトラメチルナフタレン(409mg、2.00mmol)に塩化チタニウム(417mg、2.20mmol)と塩化ピバロイル(361mg、2.99mmol)を加え、1時間120℃で攪拌した。反応溶液をジクロロメタンで希釈し、有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(40:3)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量53.6mg(9.0%)。
FAB-MS m/z 289(M+H)+;1H-NMR(500 MHz, CDCl3)δ 12.30 (s, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 2.05 (s, 1H), 1.68 (s, 4H), 1.45 (s, 9H), 1.29 (s, 6H), 1.27 (s, 6H).
合成工程は下記の化学反応式に示す通りである。5,6,7,8-テトラヒドロ-2-ヒドロキシ-5,5,8,8-テトラメチルナフタレン(204mg、1.00mmol)に無水ジクロロメタン(1mL)と塩化アルミニウム(148mg、1.12mmol)、塩化ベンゾイル(155mg、1.10mmol)を加え、1時間60℃で攪拌した。反応溶液を冷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(20:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量27.3mg(9%)。
FAB-MS m/z 309(M+H)+;1H-NMR(500 MHz, CDCl3)δ 11.63 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.59 (m, 2H), 7.55 (m, 3H), 6.99 (s, 1H), 2.05 (s, 1H), 1.68 (m, 4H), 1.30 (s, 6H), 1.17 (s, 6H).
合成工程は下記の化学反応式に示す通りである。5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチルナフタレン(188mg、1mmol)に無水ジクロロメタン(1mL)と塩化アルミニウム(148mg、1.12mmol)、塩化プロピオニル(101mg、1.10mmol)を加え、3時間60℃で攪拌した。反応溶液を冷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(30:1)を溶出溶媒としたシリカゲルクロマトグラフィーにより精製した。収量66.4mg(27%)。
FAB-MS m/z 245(M+H)+;1H-NMR(500 MHz, CDCl3)δ 7.94 (d, 1H, J = 2.0 Hz), 7.70 (dd, 1H, J = 6.0, 2.0 Hz), 7.38 (d, 1H, J = 8.5 Hz), 2.97 (q, 2H, J = 7.3 Hz), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H), 1.22 (t, 3H, J = 7.3 Hz).
合成工程は下記の化学反応式に示す通りである。5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチルナフタレン(188mg、1.00mmol)に無水ジクロロメタン(1mL)と塩化アルミニウム(140mg、1.05mmol)、塩化イソブチリル(112mg、1.05mmol)を加え、3時間室温で攪拌した。反応溶液を冷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(20:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量97.4mg(38%)。
FAB-MS m/z 259(M+H)+;1H-NMR(500 MHz, CDCl3)δ 7.95 (d, 1H, J = 1.8 Hz), 7.70 (dd, 1H, J = 6.0, 1,8 Hz), 7.38 (d, 2H, J = 2.4 Hz), 3.54 (septet, 1H, J = 7.0 Hz), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H), 1.21 (d, 6H, J = 7.0 Hz).
5,6,7,8-テトラヒドロ-3-ヒドロキシ-5,5,8,8-テトラメチル-2-ナフチルメチルケトン(13.3mg、53.9μmol)に無水トルエン(1mL)とローソン試薬(32.0mg、80.9mmol)を加え、24時間120℃で攪拌した。反応溶液を冷水に注ぎ、ジクロロメタンで抽出し、集めた有機層を減圧濃縮した。粗生成物を、ヘキサン:酢酸エチル(12:1)を溶出溶媒としてシリカゲルカラムクロマトグラフィーにより精製した。収量4.2mg(30%)。
FAB-MS m/z 263(M+H)+;1H-NMR(500 MHz, CDCl3)δ 12.99 (s, 1H), 7.82 (s, 1H), 6.99 (s, 1H), 3.12 (s, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.29 (s, 6H).
(1)5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-メチルナフタレン(b)の合成
合成工程は下記の化学反応式に示す通りである。無水トルエン(10mL)に塩化アルミニウム(200mg、1.5mmol)、2,5-ジクロロ-2,5-ジメチルヘキサン(4.70g、25.7mmol)を加え、24時間室温で攪拌した。反応溶液を冷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。収量4.90g(94%)。
1H-NMR(500 MHz, CDCl3)δ 7.20 (d, 1H, J = 8.0 Hz), 7.10 (d, 1H, J = 1.2 Hz), 6.95 (dd, 1H, J = 6.5, 1.2 Hz), 2.29 (s, 3H), 1.67 (s, 4H), 1.28 (s, 6H), 1.26 (s, 6H).
合成工程は下記の化学反応式に示す通りである。反応経路中、KMnO4は過マンガン酸カリウムを表す。5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-メチルナフタレン(3.52g、17.4mmol)にピリジン(12mL)と過マンガン酸カリウム(6.70g、42.4mmol)、水酸化ナトリウム(1.00g、25.0mmol)を加え、5時間95℃で攪拌した。反応溶液をセライト濾過し、濾液に塩酸を加えて液性を酸性にした。酢酸エチルで抽出した後に、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(4:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量141.6mg(3%)。
FAB-MS m/z 233(M+H)+;1H-NMR(500 MHz, CDCl3)δ 8.05 (d, 1H, J = 1.8 Hz), 7.82 (dd, 1H, J = 6.0, 1.8 Hz), 7.40 (d, 1H, J = 8.0 Hz), 1.71 (s, 4H), 1.32 (s, 6H), 1.30 (s, 6H).
合成工程は下記の化学反応式に示す通りである。反応経路中、DMFはN,N-ジメチルホルムアミド、(COCl)2は塩化オキサリル、HN(OMe)MeはN-メトキシ-N-メチルアミン塩酸塩、Et3Nはトリエチルアミンを表す。5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフタレンカルボン酸(c)(232mg、1.00mol)に無水ジクロロメタン(10mL)と塩化オキサリル(294mg、2.40mmol)、N,N-ジメチルホルムアミド(1滴)を加え、5時間室温で攪拌した。反応溶液を減圧濃縮した。粗生成物に無水ジクロロメタン(10mL)とN-メトキシ-N-メチルアミン塩酸塩(116mg、1.20mmol)、トリエチルアミン(4.00mL,28.7mmol)を加え、17時間室温で攪拌した。反応液を減圧濃縮し、酢酸エチルで希釈した。希塩酸、水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、粗生成物をヘキサン:酢酸エチル(10:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量139mg(50%)。
FAB-MS m/z 276(M+H)+;1H-NMR(500 MHz, CDCl3)δ 7.34 (d, 1H, J = 1.8 Hz), 7.30 (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J = 6.1, 1.8 Hz), 3.10 (br s, 1H), 3.00 (br s, 1H), 1.68 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H).
合成工程は下記の化学反応式に示す通りである。5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフタレンカルボン酸(c)(465mg、2.00mmol)に、DMF(3滴)、無水ジクロロメタン(5mL)、塩化オキサリル(0.25mL、2.95mmol)を加え、1時間0℃にて撹拌した。濃アンモニア水(30mL)を加え、15時間室温で撹拌した。反応液に水を加え、ジクロロメタンで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、減圧濃縮した。粗生成物を酢酸エチルで再結晶することにより精製した。収量453mg(98%)。
FAB-MS m/z 232(M+H)+;1H-NMR(500 MHz, CDCl3)δ 7.81(d, 1H, J = 2.0 Hz), 7.49(dd, 1H, J = 8.0, 2.0 Hz), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H ).
合成工程は下記の化学反応式に示す通りである。反応経路中、PhBrは臭化ベンゼンを表す。臭化ベンゼン(1.17g、7.50mmol)に無水テトラヒドロフラン(10mL)とマグネシウム(911mg、37.5mol)、ヨウ素を加え、80℃で攪拌した。室温まで冷却した後、5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフチル-N-メトキシ-N-メチルアミド(J)(55.0mg、0.200mmol)を無水ジエチルエーテル(2mL)に溶解させたものに加え、22時間室温で攪拌した。反応液を飽和塩化アンモニウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(2:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量14.9mg(25%)。
FAB-MS m/z 293(M+H)+;1H-NMR(500 MHz, CDCl3)δ 7.80 (d, 1H, J = 7.3 Hz), 7.79(s, 1H), 7.57 (t, 1H, J = 7.5 Hz), 7.55 (dd, 1H, J = 6.1, 1.8 Hz), 7.47 (t, 1H, J = 8.0 Hz), 7.39 (d, 1H, J = 8.0 Hz), 1.72 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H).
合成工程は下記の化学反応式に示す通りである。反応経路中、CANは硝酸アンモニウムセリウムを表す。5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-メチルナフタレン(b)(202mg、1.00mol)に酢酸(8.2mL)と硝酸アンモニウムセリウム(2.40g、4.37mol)を加え、1時間100℃で攪拌した。反応溶液を氷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(15:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量106mg(49%)。
FAB-MS m/z 217(M+H)+;1H-NMR(500 MHz, CDCl3)δ 9.95 (s, 1H), 7.83 (d, 1H, J = 2.0 Hz), 7.62 (dd, 1H, J = 7.0, 2.0 Hz), 7.46 (d, 1H, J = 8.0 Hz), 1.72 (s, 4H), 1.32 (s, 6H), 1.31 (s, 6H).
合成工程はButtner M. W, Penka M, Doszczak L,Kraft P, Tacke R. Silicon Analogues of the Musk Odorant Versalide. Organometallics 26: 1295-1298 (2007).の記載に従って下記に示される通りである。
1,2-ビス(エチニルジメチルシリル)エタン(486mg、2.50mmol)と3-(トリメチルシロキシ)-1-ブチン(498mg、3.50mol)に無水キシレン(5mL)とシクロペンタジエニルコバルトジカルボニル(135mg、0.750mmol)を加え、9時間170℃に加熱した。反応溶液を減圧濃縮した。残渣をヘキサン:酢酸エチル(20:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより粗精製した。粗生成物にメタノール(5mL)と酢酸(1mL)加え、30時間95℃で加熱した。反応液を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、減圧濃縮した。粗生成物をヘキサン:酢酸エチル(4:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量153mg(23%)。
1H-NMR(500 MHz, CDCl3)δ 7.50 (m, 2H), 7.36 (dd, 1H, J = 6.0, 2.0 Hz), 4.87 (m, 1H), 1.51 (d, 3H), 1.00 (s, 4H), 0.23 (d, 6H, J = 2.0 Hz), 0.22 (s, 6H).
5,6,7,8-テトラヒドロ-5,8-ジシラ-5,5,8,8-テトラメチル-2-ナフチルエタン-1-オール(d)(153mg、0.577mmol)にジクロロメタン(2mL)と二クロム酸ピリジニウム(376mg、1.00mmol)を加え、2時間室温で攪拌した。反応溶液をセライト濾過し、ジクロロメタンで洗浄した後に減圧濃縮した。粗生成物をヘキサン:酢酸エチル(8:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量67.9mg(45%)。
FAB-MS m/z 263(M+H)+;1H-NMR(500 MHz, CDCl3)δ 8.05 (d, 1H , J = 6.0, 2.0 Hz), 7.86 (dd, 1H, J = 6.0, 2.0 Hz), 7.60 (d, 1H , J = 7.0 Hz), 2.60 (s, 3H), 1.03 (s, 4H), 0.26 (s, 6H), 0.24 (s, 6H).
合成工程は下記の化学反応式に示す通りである。5,6,7,8-テトラヒドロ-3-ヒドロキシ-5,5,8,8-テトラメチル-2-ナフチルメチルケトン(TMNAA)(129mg、0.50mmol)にN,N-ジメチルホルムアミド(0.5mL)とN,N-ジメチルホルムアミドジメチルアセタール(135μl、1.01mmol)を加え、100℃で3.5時間攪拌した。反応溶液を氷水に注ぎ、ジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。収量151mg(100%)。
FAB-MS m/z 302(M+H)+;1H-NMR(500 MHz, CDCl3)δ 13.42 (s, 1H), 7.87 (d, 1H, J = 12.0 Hz), 7.59 (s, 1H), 6.86 (s, 1H), 5.76 (d, 1H, J = 12.0 Hz), 3.18 (s, 3H), 2.99 (s, 3H), 1.67 (s, 4H), 1.29 (s, 6H), 1.27 (s, 6H).
6,7,8,9-テトラヒドロ-6,6,9,9-テトラメチル-4H-ナフト[2,3-b]ピラン-4-オン(N)の合成
合成工程は下記の化学反応式に示す通りである。5,6,7,8-テトラヒドロ-3-ヒドロキシ-5,5,8,8-テトラメチル-2-ナフチル β-(N,N-ジメチルアミノ)ビニルケトン(上記化合物M、149mg、0.50mmol)に3規定硫酸(0.5ml)を加え、105℃で3.5時間攪拌した。反応溶液を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮した。収量125mg(98%)。
FAB-MS m/z 257(M+H)+;1H-NMR(500 MHz, CDCl3)δ 8.14 (s, 1H), 7.79 (d, 1H, J = 6.0 Hz), 7.36 (s, 1H), 6.26 (d, 1H, J = 6.0 Hz), 1.73 (s, 4H), 1.34 (s, 6H), 1.33 (s, 6H).
2,3,6,7,8,9-ヘキサヒドロ-6,6,9,9-テトラメチル-4H-ナフト[2,3-b]ピラン-4-オン(O)の合成
合成工程は下記の化学反応式に示す通りである。6,7,8,9-テトラヒドロ-6,6,9,9-テトラメチル-4H-ナフト[2,3-b]ピラン-4-オン(上記化合物N、124mg、0.48mmol)にメタノール(4.0ml)と酢酸エチル(4.0ml)と10%パラジウム-炭素(40mg)を加え、水素雰囲気下、室温で10時間攪拌した。反応溶液をセライト濾過し、濾液を減圧濃縮した。粗生成物をヘキサン:酢酸エチル(4:1~2:1)を溶出溶媒としてシリカゲルクロマトグラフィーにより精製した。収量80.0mg(64%)。
FAB-MS m/z 259(M+H)+;1H-NMR(500 MHz, CDCl3)δ 7.85 (s, 1H), 6.89 (s, 1H), 4.50 (t, 2H, J = 6.0 Hz), 2.77 (t, 2H, J = 6.0 Hz), 1.67 (s, 4H), 1.27 (s, 6H), 1.26 (s, 6H).
種々の濃度の薬剤存在下で、S1T(ATL患者由来細胞株)と、その対照としてMOLT-4(急性リンパ芽球性白血病細胞株)を4日間培養後、MTT法により化合物の各細胞に対する増殖阻害効果を評価した。その結果を表2に示す。
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PCT/JP2009/064557 WO2010032582A1 (ja) | 2008-09-22 | 2009-08-20 | 成人t細胞白血病治療薬 |
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US (1) | US8765719B2 (ja) |
EP (1) | EP2345409A4 (ja) |
JP (1) | JP5516894B2 (ja) |
BR (1) | BRPI0919348A2 (ja) |
WO (1) | WO2010032582A1 (ja) |
ZA (1) | ZA201101778B (ja) |
Citations (7)
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JPH0436240A (ja) | 1990-05-29 | 1992-02-06 | Shionogi & Co Ltd | 成人t細胞白血病治療剤 |
JPH07505607A (ja) * | 1991-08-23 | 1995-06-22 | ザ ソールク インスチチュート フォア バイオロジカル スタディズ | ステロイドあるいはステロイド様ホルモン応答性病態に対する治療用選択性リガンドの使用 |
WO2004048391A1 (en) * | 2002-11-25 | 2004-06-10 | Amedis Pharmaceuticals Ltd. | Silicon compounds to be used as ligands for retinoid receptors |
JP2008019174A (ja) | 2006-07-11 | 2008-01-31 | Tropical Technology Center Ltd | ウイルス関連悪性腫瘍治療剤 |
JP2008242867A (ja) | 2007-03-27 | 2008-10-09 | Fujitsu Ltd | 抽選処理用のプログラム |
JP2008256620A (ja) | 2007-04-06 | 2008-10-23 | Matsushita Electric Ind Co Ltd | 地図データ修正装置、地図データ修正方法、及び地図データ修正プログラム |
JP2009068750A (ja) | 2007-09-12 | 2009-04-02 | Sanyo Electric Co Ltd | 空気調和機の室外ユニット |
Family Cites Families (2)
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JP2004523571A (ja) * | 2001-03-08 | 2004-08-05 | マキシア・ファーマシューティカルズ・インコーポレイテッド | Rxr活性化分子 |
IL152904A0 (en) * | 2002-01-24 | 2003-06-24 | Gamida Cell Ltd | Utilization of retinoid and vitamin d receptor antagonists for expansion of renewable stem cell populations |
-
2009
- 2009-08-20 EP EP09814427A patent/EP2345409A4/en not_active Withdrawn
- 2009-08-20 BR BRPI0919348A patent/BRPI0919348A2/pt not_active IP Right Cessation
- 2009-08-20 US US13/120,114 patent/US8765719B2/en not_active Expired - Fee Related
- 2009-08-20 WO PCT/JP2009/064557 patent/WO2010032582A1/ja active Application Filing
- 2009-08-20 JP JP2010529695A patent/JP5516894B2/ja active Active
-
2011
- 2011-03-08 ZA ZA2011/01778A patent/ZA201101778B/en unknown
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JPH0436240A (ja) | 1990-05-29 | 1992-02-06 | Shionogi & Co Ltd | 成人t細胞白血病治療剤 |
JPH07505607A (ja) * | 1991-08-23 | 1995-06-22 | ザ ソールク インスチチュート フォア バイオロジカル スタディズ | ステロイドあるいはステロイド様ホルモン応答性病態に対する治療用選択性リガンドの使用 |
WO2004048391A1 (en) * | 2002-11-25 | 2004-06-10 | Amedis Pharmaceuticals Ltd. | Silicon compounds to be used as ligands for retinoid receptors |
JP2008019174A (ja) | 2006-07-11 | 2008-01-31 | Tropical Technology Center Ltd | ウイルス関連悪性腫瘍治療剤 |
JP2008242867A (ja) | 2007-03-27 | 2008-10-09 | Fujitsu Ltd | 抽選処理用のプログラム |
JP2008256620A (ja) | 2007-04-06 | 2008-10-23 | Matsushita Electric Ind Co Ltd | 地図データ修正装置、地図データ修正方法、及び地図データ修正プログラム |
JP2009068750A (ja) | 2007-09-12 | 2009-04-02 | Sanyo Electric Co Ltd | 空気調和機の室外ユニット |
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"Pharmaceutical Research and Development", vol. 7, 1990, HIROKAWASHOTEN, pages: 163 - 198 |
BUTTNER M. W, PENKA M, DOSZCZAK L, KRAFT P, TACKE R: "Silicon Analogues of the Musk Odorant Versalide", ORGANOMETALLICS, vol. 26, 2007, pages 1295 - 1298 |
BUTTNER MW, PENKA M, DOSZCZAK L, KRAFT P, TACKE R: "Silicon analogues of the musk odorant veralide", ORGANOMETALLICS, vol. 26, 2007, pages 1295 - 1298 |
HUPP CD, TEPE JJ: "Total Synthesis of a Marine Alkaloid from the Tunicate Dendrodoa grossularia", ORG. LETT., vol. 10, 2008, pages 3737 - 3739 |
KAGECHIKA H, HASHIMOTO Y, KAWACHI E, SHUDO K: "Affinity gels for purification of retinoid-specific binding protein (RSBP)", BIOCHEM. BIOPHYS. RES. COMMUN., vol. 155, 1988, pages 503 - 508 |
KAGECHIKA H, KAWACHI E, HASHIMOTO Y, HIMI T, SHUDO K: "Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity", J. MED. CHEM., vol. 31, 1988, pages 2182 - 2192 |
KAGECHIKA, H. ET AL.: "Retinobenzoic acids. 2. Structure-activity relationships of chalcone-4- carboxylic acids and flavone-4'-carboxylic acids", JOURNAL OF MEDICINAL CHEMISTRY, vol. 32, no. 4, 1989, pages 834 - 840, XP000569539 * |
NAKAMURA, M. ET AL.: "Discovery of tetrahydrotetramethyl naphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 17, no. 13, July 2009 (2009-07-01), pages 4740 - 4746, XP008146581 * |
PORTIS T, HARDING JC, RATNER L: "The contribution of NF-KB activity to spontaneous proliferation and resistance to apoptosis in human T-cell leukemia virus type 1 Tax-induced tumors", BLOOD, vol. 98, 2001, pages 1200 - 1208 |
See also references of EP2345409A4 * |
Also Published As
Publication number | Publication date |
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BRPI0919348A2 (pt) | 2015-12-29 |
ZA201101778B (en) | 2012-06-27 |
US20110172185A1 (en) | 2011-07-14 |
EP2345409A4 (en) | 2012-03-28 |
US8765719B2 (en) | 2014-07-01 |
EP2345409A1 (en) | 2011-07-20 |
JPWO2010032582A1 (ja) | 2012-02-09 |
JP5516894B2 (ja) | 2014-06-11 |
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