• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Process for preparing hydroxy-9-ellipticin and derivatives with the following general formula (FORMULA) in which R<u1>u represents hydrogen or an alkyl group and R<u2>u represents hydrogen or an alkyl, aryl, benzyl or benzoyl group, as well as quaternary salts, by the condensation of methoxy-5-indole with hexane-dione 2,5 in order to obtain methoxy-6-dimethyl-1,4-carbazole, followed by demethylation, the protection of the hydroxy group and, eventually, the alkylation of the nitrogen atom and then formylation, condensation of the aminoacetaldehyde with dimethylacetal, cyclisation and removal of the protective group. The ellipticin derivatives thus obtained are extremely pure and can be utilised in the treatment of cancers.
    公开号:SU1053753A3
    申请号:SU802924050
    申请日:1980-05-14
    公开日:1983-11-07
    发明作者:Бернар Ле Пек Жан；Паолетти Клод；Дат-Ксуонг Нгуен
    申请人:Ажанс Насьональ Де Валоризасьон Де Ля Решерш (Фирма)；Анвар,Лябаз (Фирма)；
    IPC主号:
    专利说明:

    b) 6-hydroxy-1,4-dimethylcarbazole. At 180-190s, a solution of 30 g of 6-methoxy-1,4-dimethylcarbazole with 300 g of absolutely 5 anhydrous pyridine hydrochloride is heated at a soft boiling point under reflux. After cooling, the mixture is poured on ice and alkalinized with concentrated ammonia to pH 6, 5, then dried, washed several tO times with water and again crystallized from ethanol / water.
    A thin, colorless crystal is obtained (molecular weight 211.26), code 22 g, m.p. .15
    Elemental analysis for (.
    Euchisleno,%: C 77,84; H 5.60; N 4.32; About 12.35.,
    Found,%: C 77.41; H 5.64; N 3.97-3.92, O 13.20
    c) 6-Benzoshtok-1,4-dimesh1karbazol. 21 g (O, 10 mol) are dissolved.
    6-OXY-1,4-dimethylcarbazole in a mixture of 200 ml of anhydrous acetone in 50 ml of triztilamine, dried over tablets of 25 caustic potash.
    17 g (0.12 mol) of distilled benzoyl chloride are added dropwise with constant stirring of the mixture with a magnetic stirrer. The duration of the AO reaction is 2 hours.
    Deposition of hydrochloric triethylamine is observed. Excess acetone and residual triethylamine are removed by heating in a water bath. C-35 dissolve the product in water and extract it several times with chloroform. The chloroform solution is washed with water, then with 5% sodium bicarbonate solution and again with water, then dried with calcium chloride, filtered. and excess chloroform is distilled off. The product is again crystallized from a minimum amount of chloroform. Pro-g dukt has so pl. 315 + 9®С.
    Elemental analysis for Q, + + 0.5 NuO
    Calculated,%: C 77.84; H 5.60; N 4.32; About 12.35.
    Found,%: C 77.41; H 5.64; 50
    N 3.97-3.92; About 13.
    d) 9-Ethyl-6-benzoyloxo-1,4-dimethylcarbazole. In a calcium chloride trap, dissolved in 120 ml of DMF, dried over 55 molecular sieves, 16 g (0.05 mol) of 6-benzoyl-1,4-dimethylcarbazole. Add there with stirring
    magnetic stirrer 1.35 g of 100% sodium hydride. After about 1 hour, the monosodium derivative is formed.
    With complete external cooling with ice water, 9 g of ethyl iodine is added dropwise over 30 minutes. The mixture was left overnight without stirring. After that, it is heated in a water bath for 1 h.
    The main part of DG1F is removed in deep vacuum. After cooling, the product is again dissolved in ice water and extracted several times with chloroform. The chloroform solution is washed with water, dried over calcium chloride, filtered and the excess x.poroform removed.
    The molecular weight product 143.4 has the formula (L JL NO.
    e) 9-Ethyl-6-6-benzoyl-3-formyl-1, 4-dimethylcarbazole. 4 g (0.12 mol) of the product obtained are dissolved in 200 ml of dry ortho-dichlorobenzene, then 22 g (0.7 mol) of freshly distilled N-methylformanidide are added and 22 g (0.14 mol) of phosphorus oxychloride are added in steps.
    ; The whole mixture is heated in a boiling water bath for 3 hours. After cooling, carefully pour the reaction product into a cold solution of 50 g of sodium acetate in 300 ml of water.
    The benzene bed of the decanter is removed and extraction with steam is used to remove orthodichlorobenzene and excess M-methylformanyl. The residue is dissolved in toluene by heating and purified on charcoal.
    The molecular weight product 371,436 has the formula Q, ILNO-.
    e) 0-Ethyl-6-benzosh10ko-3- (, / E dimethyloxyethylimine) -1,4-dimethylcarbazole.
    one .
    In a boiling water bath during
    A mixture of 18.60 g (0.05 mol of the obtained product (aldehyde) and 50 ml of dimethyl acetal aminoacetaldehyde) is heated for 12 hours. Then 100 mp of anhydrous benzene is added and the water formed during the reaction is removed by azeotropic distillation. toluene). A molecular weight product of 458.56 is obtained, which has the form "yWA; g) 9-Benzoyloxo-6-ethylsllipticin
    (base). 22 g (0.05 mol) of the product obtained (azeometina) are introduced into a solution of 600 g of orthophosphoric acid and 20 g of phosphorus pentoxide S1. The mixture is carefully heated to 125-1 and maintained at this temperature for 20 minutes. After cooling, the reaction mixture was poured into 3 liters of ice-water and sharply neutralized with ammonia to a pH of about 7. A mixture of 9 benzoyl-oxo-6-ellipticin and 9-oxo-6-ethylacetic was obtained, which can be separated by column chromatography. . MlO Scele Molecular mass C, the compound is 394.48. h) 9-Oxy-6-ethylellipticin (basis). For 30 minutes, 10 g of a mixture of the obtained 2 ellipticines in 100 ml of 95% ethanol and 10 ml of concentrated hydrochloric acid are heated at a low boiling point in a water bath. After ohpalsdeni. and drying, a chain compound is obtained which is recrystallized from ethanol. The molecular weight is 290.37. and). Iodide 9-hydroxy-2,6-diethyl elipticinium (or iodoethyl-9-OXO-6 ethyl diallipticin). Dissolve in 100 ml of DMF preliminarily dried over molecular sieves, 10 g of 9-OXO-6-ETHYLZLLNPT cin, and after cooling, add another 5 ml of ethyl iodide. The mixture is stirred with a magnetic stirrer for several hours, which facilitates the deposition of the maximum amount of hapogenide. The product is cyiuaT and progressed without anhydrous ether, and then recrystallized from absolute ethanol. Molecular weight C H N.01 equals I f 5 jib at 446. Elemental analysis: Calculated,%: C 56.55; H 5.20; N 6.28; O 3.59; I 28.45. Nschschio,%: C 55.77-55; 73; And 5.2 5.18; N 6.11-6.25; O 3.85-4.10; 28.96-28.89, TLC with Merck F-254 silica gel and solvent with butan-acetic acid / water (4: 1: 5). R.g3iO, 33. k) 9-hydroxy-2,6-ellipticine acetate In the DMF, dissolve the resulting product, adding water all the time in portions to form a solvent. 6 consisting of DMF and water (in equal parts), and obtain a final concentration of about 2-10 mg / ml. Then, it is necessary to degas this solution. Prepare a column from an organic variety Anis Exchange resin Bis-Red resin (acetate form). The exchange capacity of this resin is 1.4 meq / ml resin or 3.2 meq / g dry resin weight i. 0.78 g resin / g product. Accordingly, the amount of the used resin is equal to three times the exact required amount. As an eluent, using a mixture of DMF and (50:50), the resin is suspended in this mixture. The column is then filled and equilibrated, the yo.cyto derivative on this column is eluted to give a solution of 9 oxo-2,6-diethyl ethyl acetate. Water and partially removed from it are completely removed. Z11F is carried out by oily dehydration with ether and, after filtration, the oily and filtered product is dried with ether and dried under vacuum and a desiccator. An orange powder well soluble in water is obtained (yield 95 wt.%), From which it is easy for mohia to prepare vodsh, a 1H solution with 4 mg / ml. this acetate. The molecular mass of .NiQA is equal to... Ь 2Ь i 3 at 378. Approx 2 ,. Works according to the method of Example 15 but excluding the optional metal-sh stage, one of the products obtained in stages gk does not contain an alkyl group at the nitrogen atom in polo) 9 of the carbazole cycle (or in position 6 of the ellipticin cycle), the product of step 5 has t, pl, 200C. Using thin-layer chromatography (those) with elution with a mixture of mountainous methylene-ethanol (DA: 1), one spot is obtained, which proves the purity of the product; the product of stage E has a mp. 264 ° C; those (benzene-ethyl acetate 5: 1) are one spot; the product of phase e has 238 ° C, TLC (methylene chloride-ethanol 20: 1) is one spot; the product of stage Ж has so-called 245 C. TLC (methylene chloride 20:10) one spot. The resulting 9-hydroxy ellipticin has a molecular weight of 262. Its analysis corresponds to a theoretical, tolerance of the presence of half a molecule of added water. % 1 is 97-98%. EXAMPLE 3. Preparation of 9-hydroxyelipticin from 6-benzyloxy-1,4-dimepsarcarbazole. First, 6-hydroxy-1,4-dnmeti-carbazole is prepared according to the procedure of Example 1. Then, 9-hydroxyheliumine is synthesized. PRI me R 4. 1,4-Dimethyl-6-hydroxy carbazole. 790 (10 mol) of pyridine is loaded into a three-necked flask, then II 2-, 5 g (5, mol) of gaseous hydrogen chloride is bubbled through the immersed tube. The head fraction is distilled off until the temperature of the mass is 192195 ° C. 112.5 g (0.5 mol) of 1,4-dimethyl-b-methoxycarbazole are cooled before and introduced. Increase the temperature to 192-195 s and maintain this temperature for 0.5 hours. 1000 g of ice water is hydrolyzed. Extract three times with 300 cm of sulfuric ether. The combined ether layers are washed twice with 100 cm of water, then dried over sodium sulfate without water. The ester is removed by concentration at atmospheric pressure. 99 g of crude product is collected, yield 94%. The crude product is recrystallized from 10 volumes of a mixture of dichloroethane-p-heptane (50:50 by volume). Output, when cleaning 65% i so pl. 167C Thin-layer chromatography on a Merck F 254 plate with eluent benzene. Appearance: near UV. Rf 0.10-0.12. Demethylation of 1,4-dimethyl-6methoxycarbazole, as opposed to demethylated 9-methoxy-ellipticin, does not cause purity problems for the resulting 1,4-dimethyl-6-oxycarbazole, because the latter is a stable product under the operating conditions encountered in this reaction. PRI me R 5. 1,4-Dimethyl-6-benzyloxycarbazole. 12.6 1,4-dimethyl-6-hydroxycarbazole was charged to a three-neck flask; 100 g of N, M-dimethylformamide; 16.0 g of benzyl chloride and 16.8 g of anhydrous potassium carbonate. Stir for 20 hours at room temperature. The reaction medium is hydrolyzed with 500 g of water. The twenties extracted with 100 cm of sulfuric ether and the combined ether layers were washed twice with 50 cm of water, then dried over sodium sulfate. The ether was removed by concentration at atmospheric pressure. The residue is treated with 30 cm of pentanas. Sucked wasps-dock. It is recrystallized from a 40 cm mixture of -heptane and dich. 11 Oret} 1a (60:40 by volume). The weight of a product is 12.4 g; yield 60%, m.p. That H1C about aloina hrsmatografy on the illumination Lerk F 25 with eluent bepzolom. About vlyshe: near UV. R 0.60. PRI ME 6. I54-Dimethyl-3-formyl 6-benzyloxycarbazole. In a three-necked flask load of 6.02 g of 1,4-dimethyl-6-bepsyloxycarbazole; 20 cm of dichloroethane and 3.7 g of M-dimethylformamide. 3.7 g of phosphorus oxychloride is introduced into this medium during 0.5 hours. Maintain the reaction mass in a water bath for 5 hours with a npi-Te.isnepaType mass of 50 C. The reaction medium is hydrolyzed with a solution of 12.3 g sodium acetate trihydrate. 350 g 15ODY. The precipitate is filtered off, washed with plenty of water, the mixture is treated with stirring with 50 cm of sulfuric ether. Sucked off again and dried. The weight of the resulting product 5, 25 g; yield 80%; m.p. . Thin layer chromatography on a Merck 254 stick with elution with benzene (60 cm) and acetone (20 cm3). About vle1she: melee 5F. Rf D, 80. EXAMPLE 7,., - Dimethyl-3- (N, M-Dimethox1-1: Ethylpminomett) -6-benzyloxycarbazole. In a three-necked flask load of 6.6 g of 154 dimethyl-3-formsh1-6-benzyloxycarbazole; 50 g of benzene and 2.4 g of dimethyl acetal a shnocetaldehyde. The mixture is heated to reflux and the aqueous fraction is removed by azeotropic distillation for 2 hours. The mixture is cooled to 10 ° C and the precipitate is filtered off with suction. Wash the resulting crystals with 50 cm of n-heptane and dry. Weight 6.6 g; yield 79%; m.p. 1-30 C. Approx 8. 9-Benz1-lexielliptic. A3 g of 85% phosphoric acid and 5.7 i of phosphoric anhydride are loaded into a three-necked flask. The solution is heated with stirring to 80-90 ° C, then a solution of 3.7 g of I, 4-dimethyl-3 (jb, fb-dimethoxyethylimine methyl) 6 benzyloxycarbazole in 25 cm of benzene is added. The reaction medium is hydrolyzed with 100 g of water, then neutralized to a pH of 9 minutes by slowly adding 50% sodium hydroxide solution. The precipitate is filtered off with suction, washed extensively with water and dried. The weight of the obtained product 3.0 g; yield 95 Thin-layer chromatography on a Merck 254 plate with eluent benzene (72 cm) and ethanol (18 cm). Appearance: near UV. Kf-0.50 (C H5-CH20H) and 35 (BUT). The crude product is a mixture of 70% benzyl derivative and 30% hydroxyl derivative due to insufficient acidity of the medium. It can be recrystallized from 200 volumes of acetone, which results in a product containing less than 5% hydroxyl derivative, which is not a contamination because it is a product obtained in the next stage. PRI me R 8. 9-Hydroxylipticine 500 ml of ethanol are charged to an Erlenmeyer flask; 0.5 g of palladium carbon containing 10% palladium, then 3. About 5 g of 9-benzsh1oksielliptitsina. After purging with nitrogen, hydrogenolysis is carried out at a pressure of 150 g and room temperature. After uptake of the theoretical amount of hydrogen, palladium carbon is removed. Evaporated to dryness on a rotary evaporator with a residual pressure created by a water-jet pump. The weight of the obtained product is 3 ± 7 g. The yield is 100%. The product is purified in 100 volumes of ethanol when the insoluble product is removed during heating. Exit after cleaning 85%; m.p. . Anhydro-titrimetric titer not less than 98%. The percentage of dimer ke is more than 2%, (liquid chromatography). The proposed method allows to obtain the desired products with high yield and degree of purity, which can be used to prepare compositions with anti-cancer activity or as intermediate products to obtain such compounds.
    权利要求:
    Claims (1)
    [1]
    A method of producing 9-hydroxyellipticin or its derivatives of the general formula or their salts quaternized at the nitrogen atom in position 2, general form where R
    R is hydrogen or lower alkyl; hydrogen, benzyl, benzoyl or lower alkyl;
    lower alkyl;
    quaternizing anion, especially with 5, methoxyivdol is reacted with 2,5-hexanedione, the obtained 6-methoxy-1,4-dimethylcarbazole is demethylated, and the hydroxyl group is protected by benzylation or benzoylation
    6-hydroxy-1,4-dimethylcarbazole, then, if necessary, the product is metallized ^: treatment with nodiside alkyl, formylation, condensation with dimethylacetal aminoacetal dehydrate, cyclization of the obtained product, saponification of 9-benzoyloxoellipticin. Or hydrogenolysis of 9-benzyl oxoellipt or 9-benzyloxo-6-alkyl ~ ellipticin with isolation of the target product or subsequent reaction with haloalkyl and isolation of the product in free form or after anion exchange in the form of a salt, respectively quaternized at the nitrogen atom in the floor May 2.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1053753A3|1983-11-07|Process for preparing 9-oxyellipiticine or its derivatives or their salts
    EP0103553B1|1989-02-22|Intermediates for the preparation of omeprazole
    EP1161434B1|2003-01-29|Pyridopyranoazepine derivatives, preparation and therapeutic use
    Kuck1994|Benzoanellated Centropolyquinanes, 15. Benzoanellated Fenestranes with [5.5. 5],[5.5. 5.6], and [5.5. 5.5] Frameworks: The Route from 1, 3‐Indandione to Fenestrindan
    CH633796A5|1982-12-31|THERAPEUTICALLY ACTIVE DIPYRIDOINDOLES.
    McEwen et al.1971|1, 3-Dipolar addition reactions of Reissert compounds
    JP3119872B2|2000-12-25|Intermediates for chelating agents with pre-fixed symmetry and methods for their preparation
    FR2553409A1|1985-04-19|NOVEL BENZENESULFONYL-LACTAMES, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS ACTIVE SUBSTANCES OF PHARMACEUTICAL COMPOSITIONS
    SU479290A3|1975-07-30|The method of obtaining 2- | -6,7 benzomorfan
    HU196801B|1989-01-30|Process for producing orto-condensed pirrol derivatives and pharmaceutical compositions containing them
    Kimoto et al.1980|New histamine and histidine analogs via transformations of the 2-trifluoromethyl group
    Yang et al.1988|Neihumicin, a new cytotoxic antibiotic from Micromonospora neihuensis II. Structural determination and total synthesis
    Chen et al.2007|d-Glucosamine trimethylene dithioacetal derivatives: formation of six-and seven-membered ring amino carbasugars. Synthesis of |-calystegine B3
    US4036841A|1977-07-19|Indolo[2,3α]quinolizine derivatives
    KR20110091534A|2011-08-11|Synthesis of morphine-6-glucuronide or one of the derivatives thereof
    SU587863A3|1978-01-05|Method of obtaining aminoimidazoisoquinolines or their salts
    Pyman1912|LXI.—The synthesis of glyoxaline derivatives allied to pilocarpine
    US4044012A|1977-08-23|Indolo-quinolizidine derivatives
    SU474978A3|1975-06-25|The method of obtaining derivatives of 11 -methyl steroids
    Ong et al.1973|Photocyclizations. III. Synthesis of 3, 6-dimethyl-8-hydroxy-3, 4, 5, 6-tetrahydro-3-benzazocin-2 |-one
    US4338320A|1982-07-06|Esters of 6&#39;-hydroxycinchonine, and a method of treating arrythmia with them
    CS219347B2|1983-03-25|Method of preparation of the 1-hydroxyaporfin derivative
    SU793404A3|1980-12-30|Method of preparing vincinic acid derivatives or their salts or their quaternary salts
    US3657270A|1972-04-18|1-phenyl-1h-indazole-4-acetic acids
    JP2880203B2|1999-04-05|Preparation of furanone derivatives
    同族专利:
    公开号 | 公开日
    ES484181A1|1980-05-16|
    EP0009445A1|1980-04-02|
    HU183081B|1984-04-28|
    DE2965444D1|1983-07-07|
    AT3427T|1983-06-15|
    WO1980000564A1|1980-04-03|
    EP0009445B1|1983-05-18|
    US4310667A|1982-01-12|
    JPS55500630A|1980-09-11|
    JPS6141917B2|1986-09-18|
    JPS6045579A|1985-03-12|
    JPS5951956B2|1984-12-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2248828B1|1973-10-29|1977-04-15|Anvar|
    US3933827A|1974-10-29|1976-01-20|Hoffmann-La Roche Inc.|9-Acyloxy-5,11-dimethyl-6H-pyrido[4,3-B]carbazoles|
    FR2308365B2|1975-04-25|1978-08-25|Anvar|JPH0548236B2|1984-07-31|1993-07-20|Suntory Ltd|
    FR2584409B1|1985-07-04|1987-11-20|Sanofi Sa|CHLORHYDRATES OF AMINOALKYL-2 HYDROXY-9 ELLIPTICINIUM CHLORIDE CHLORIDES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
    US4851417A|1988-05-26|1989-07-25|Rensselaer Polytechnic Institute|9-substituted 6H-pyrido[4,3-b]carbazoles|
    JPH02121545U|1989-03-17|1990-10-03|
    CA2064853C|1990-06-05|1999-08-24|Hiroshi Nagase|Indole derivatives|
    US5272146A|1992-10-02|1993-12-21|The United States Of America As Represented By The United States Department Of Health And Human Services|1,2-dihydroellipticines with activity against CNS specific cancer cell lines|
    AU666416B2|1993-01-29|1996-02-08|Tanabe Seiyaku Co., Ltd.|Ellipticine derivative and process for preparing the same|
    US5424315A|1993-08-02|1995-06-13|Sri International|Benzothiophen analogs as antiviral agents|
    JPH0861498A|1995-08-29|1996-03-08|S T K Shokai:Kk|Hydraulic cylinder|
    AU5339898A|1996-12-26|1998-07-31|Sekisui Chemical Co., Ltd.|Foamable thermoplastic sheet-like synthetic resin, thermoplastic foame d resin and their production method|
    JP4299375B2|1996-05-31|2009-07-22|積水化学工業株式会社|Foamable thermoplastic resin sheet, thermoplastic resin foam, and methods for producing the same|
    AU2976497A|1996-06-04|1998-01-05|Tanabe Seiyaku Co., Ltd.|Process for preparing 9-hydroxyellipticine|
    US20070027175A1|2005-07-27|2007-02-01|Shaughnessy John Jr|Antineoplastic activities of ellipticine and its derivatives|
    JP2009537626A|2006-05-22|2009-10-29|ビオアリアンスファルマ|Reversion of malignant phenotype by 9-hydroxy ellipticine derivatives|
    PL2508207T3|2011-03-31|2013-09-30|Bioalliance Pharma|Nanoparticles loaded with chemotherapeutic antitumoral Drug|
    CA2883320A1|2012-08-30|2014-03-06|The Scripps Research Institute|Small molecules targeting repeat r sequences|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/942,793|US4310667A|1976-04-22|1978-09-15|2-N Quaternary ammonium salt derivatives of 9-hydroxy ellipticine|
    [返回顶部]