WO1997009339A1 - Derives antitumoraux d'indolopyrrolocarbazole - Google Patents

Derives antitumoraux d'indolopyrrolocarbazole Download PDF

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Publication number
WO1997009339A1
WO1997009339A1 PCT/JP1996/002404 JP9602404W WO9709339A1 WO 1997009339 A1 WO1997009339 A1 WO 1997009339A1 JP 9602404 W JP9602404 W JP 9602404W WO 9709339 A1 WO9709339 A1 WO 9709339A1
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protected
group
general formula
meaning
compound
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PCT/JP1996/002404
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English (en)
Japanese (ja)
Inventor
Katsuhisa Kojiri
Hisao Kondo
Hiroharu Arakawa
Mitsuru Ohkubo
Hiroyuki Suda
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Banyu Pharmaceutical Co., Ltd.
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Priority to AU68366/96A priority Critical patent/AU6836696A/en
Publication of WO1997009339A1 publication Critical patent/WO1997009339A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

Definitions

  • the present invention is useful in the field of medicine, and more particularly, relates to a novel indolopyrrolocarbazolyl derivative which inhibits the growth of tumor cells and exhibits an antitumor effect, an intermediate thereof, a production method and a use thereof.
  • BE-13793C was chemically modified to create and disclose an indolopyrrolocarbazole compound having excellent antitumor activity (International Publications WO 91Z18003 and EP 0545 195). A1).
  • the present inventors aimed at creating a compound having an antitumor activity which is even better than the above-disclosed anti-pyrrolocarbazole-based antitumor compounds, with the aim of creating indolopyrrolocarbazole derivatives.
  • the compound represented by the following general formula [I] is a novel compound having extremely excellent antitumor activity, stability and safety.
  • the present invention provides a compound of the general formula
  • R represents an alkyl group having 2 to 4 carbon atoms having 1 to 3 hydroxyl groups
  • R 1 and R 2 represent a hydrogen atom or OH
  • G represents a pentose or hexose. Indicates a group.
  • R 1 and R 2 are not hydrogen atoms at the same time, and R is CH
  • R ′ is 1-position OH and R 2 is 11-position OH
  • R is CH (CH 2 OH) 2
  • R ′ is 2 OH and R 2 is
  • the compound of the present invention and the intermediate can be produced by the methods shown in the following steps A to E.
  • R represents an alkyl group having 2 to 4 carbon atoms having 1 to 3 hydroxyl groups, for example, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 OH, CH 2 CH ⁇ HCH 3 , CH 2 CHOHCHOH, CH (CH 2 OH) 2 , C (CH 3 ) (CH 2 OH) 2 , CH 2 CHOHCHOHCH 2 OH Can be.
  • R 1 and R 2 represent a hydrogen atom or 0 H.
  • R 3 represents a lower alkyl group, a benzyloxymethyl group or an aralkyl group; examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, a sec-propyl group, a butyl group, a pentyl group, and a hexyl group;
  • An alkyl group having 1 to 6 carbon atoms means a linear or branched alkyl group, and an aralkyl group means an aralkyl group having 7 to 12 carbon atoms such as a benzyl group, a phenethyl group and a phenylpropyl group. .
  • R 4 represents a hydrogen atom, a lower alkyl group, a benzyloxymethyl group or an aralkyl group, and the meanings of the lower alkyl group and the aralkyl group are the same as those described for R 3 .
  • R 5 and R 6 represent a hydrogen atom or protected OH.
  • Examples of the protecting group that can be used include a benzyl group, a tolyl group, a paramethoxybenzyl group, and a benzyloxymethyl group.
  • G means pentose or hexose
  • pentose means ribose, arabinose, xylose, etc.
  • hexose means araose, glucose, mannose, galactose, etc. It means dalcosamine, galactosamine, rhamnose, 2-dexoxyglucose, 4-0-methylglucose, glucuronic acid and the like.
  • G 1 represents a protected pentose or hexose group, and examples of a pentose or hexose protecting group include, for example, benzyl, tolyl, paramethoxybenzyl, and benzylo.
  • a xymethyl group and the like can be mentioned. It can also be protected in the form of an acetal or ketal such as an isopropylidene group.
  • R 7 represents a hydrogen atom or a protecting group for an amino group of an indole skeleton; examples of the protecting group include lower alkoxycarbonyl groups such as tert-butoxycarbonyl group and methyloxycarbonyl group, benzyl group, and benzyloxymethyl group; Group, triisopropylsilinole group, 2-trimethylsilylethyloxymethyl group, mesyl group, tosyl group and the like.
  • R 8 represents a protecting group for the amino group of the indole skeleton, and examples of the protecting group are the same as those described above.
  • X is a leaving group, and examples thereof include a chlorine atom, a bromine atom, and an iodine atom.
  • X 1 is a leaving group, and examples thereof include halogen atoms such as chlorine atom, bromine atom and iodine atom, and organic sulfonyloxy groups such as mesyl group and tosyl group.
  • Organic metal compounds include, for example, alkyllithiums such as butyllithium, and alkali metal hexaalkyldisilazides such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide.
  • Mean Grignard reagents such as ethylmagnesium bromide and methylmagnesium chloride.
  • the Mitsunobu reaction refers to organic phosphines such as trifundiyl phosphine and tributyl phosphine and azodicarboxylic acid tert-butyl ester, azodicarboxylic acid ditert-butyl ester, azodicarboxylic acid diisopropyl ester, azodicarboxylic acid di-N, N-dimethylamide, azodicarboxylic acid It refers to a reaction that forms a glycosidic bond using an azodicarboxylic acid derivative such as di-N-methylbiperazine amide [see Synthesis, I, 1981, pp. 1-28].
  • the compound having two indole skeletons represented by the general formula [XV II] can be reacted with an oxidizing agent to convert the compound into an indolopyro-carbazole compound represented by the general formula [XV III] the oxidizing agent, 2, 3-dichloro - 5, 6 Jishiano 1, 4 one base Nzokinon (hereinafter, abbreviated as DDQ), C u C l 2 , C u (OA c) 2, C u (N 0 2 ) 2 , P d C l 2 , P d
  • the reaction between the maleimide compound represented by the general formula [IX] and the indole compound represented by the general formula [X] is carried out by using an alkali metal hexaalkyldialkyl such as lithium hexamethyldisilazide. Shirazide, ethylmagnesium
  • the reaction can be carried out using a Grignard reagent such as bromide.
  • examples of the solvent that can be used include toluene, benzene, tetrahydrofuran (THF), dioxane, and getyl ether.
  • the reaction temperature is usually from ⁇ 78 ° C. to 130 ° C., preferably from 120 ° C. to 11 ° C.
  • the general formula [XI] can be produced by introducing a protecting group into the amino group of the indole skeleton of the compound represented by the general formula [XI].
  • a protecting reagent that can be used at this time a halide or an acid anhydride corresponding to the above-mentioned protecting group can be used.
  • ⁇ 'preferably di-tert-butyl dicarbonate, tert-butyl dicarbonate —Butyloxycarbonyl chloride and the like can be used.
  • reaction temperature is usually -78 ° C to 100 ° C, preferably -25. C to 25 ° C.
  • the reaction between the compound represented by the general formula [XIV] and the compound represented by the general formula [XV] can be carried out by a so-called Mitsunobu reaction.
  • the above-mentioned organic phosphines and azodicarboxylic acid are used.
  • Derivatives can be used, and preferably, organic phosphines such as tributylphosphine and triphenylphosphine and azodicarboxylic acid derivatives such as acetyldicarboxylate dimethyl ester and azodicarboxylate diisopropylester can be used.
  • reaction solvent THF, dioxane, ether and the like can be suitably used, and the reaction temperature is usually from 78 ° C to 50 ° C, preferably from 40 ° C to 20 ° C. It is.
  • the deprotection of the amino group of the indole skeleton of the compound represented by the general formula [XVI] is preferably performed under conditions that allow selective deprotection. For example, under acidic or basic conditions, the protecting group of another moiety is retained. Tert-butoxy of the amino group Conditions that can selectively remove a carbonyl group, 2-trimethylsilylethoxymethyl group and the like are preferable.
  • acids such as trifluoroacetic acid and HF
  • bases such as methylamine, potassium t-tert-butoxide, and tetranormal butylammonium fluoride can be suitably used.
  • the compound represented by the general formula [XV III] can be produced by oxidatively cyclizing the compound represented by the general formula [XVI I].
  • the oxidizing agent used in this case is the above-mentioned DDQ. , C u C l 2, C u (OA c) 2, C u
  • toluene as a reaction solvent include methylene chloride, dimethyl formamidine de, Jiokisan, Ether and the like can be used, and the reaction temperature is usually 0 ° C to 100 ° C.
  • the removal of the protecting group for the phenolic hydroxyl group and the glycosyl group of the compound represented by the general formula [XVIII] can be performed under acidic conditions or a well-known ordinary hydrogenation reaction.
  • the compound represented by the general formula [XX] can be produced by reacting the compound represented by the general formula [XIX] with a base. Salts groups used in this, NaOH, KOH, K 2 C0 3, Na 2 C0 3, NaHC0 3 , etc. can be used.
  • the solvent which can be used water, methanol, ethanol, dimethylformamide And the like.
  • the reaction temperature is usually in the range of 0 ° C to the boiling point of the solvent.
  • the compound represented by the general formula [I] By reacting the compound represented by the general formula [XX] with H 2 NNHR, the compound represented by the general formula [I] can be produced.
  • a solvent that can be used at this time methanol is used. , Ethanol, THF, dimethylformamide and the like, and the reaction temperature is usually from 0 ° C to the boiling point of the solvent.
  • H 2 NNHR The amount of H 2 NNHR to be used is usually 1 to 3 molar equivalents relative to compound [XX], and if necessary, smaller or larger amounts can be used. Description of steps B to E
  • Reaction temperatures range from 0 ° C. to the boiling point of the solvent.
  • Steps B to E can be carried out under the same conditions as the reaction conditions in the same kind of reaction used in Step A.
  • the compound represented by the general formula [II] described in claim 4 can be produced by a method for deprotecting the compound represented by the general formula [XX IV], and the like.
  • the compound represented by [XIX] can also be produced by culturing the compound represented by the general formula [II] or the like with a microorganism that glycosylates.
  • the target compound can be isolated and purified by a method widely known in the field of organic chemistry (eg, precipitation, solvent extraction, recrystallization, chromatography, etc.).
  • the compound of the general formula [I] provided by the present invention exhibits excellent antitumor activity as shown in the following pharmacological test examples.
  • the MKN-45 solid tumor that had been implanted under the skin of a nude mouse in advance and proliferated was minced, and a 3 mm square was implanted under the skin of a test mouse.
  • each dose of the test drug was injected into the tail vein of the mouse once a day for 5 consecutive days from the time the tumor grew to 0.3 cm 3 , and 2 days after the drug was discontinued for another 5 days (treatment schedule: 5ZwX 2) Or 4 times every 3 to 4 days (treatment schedule: 2Zwx 2).
  • the tumor growth inhibition rate was calculated from this volume, and the total dose (GID 75 , mg / kg) that inhibited tumor growth by 75% was determined.
  • the formula 1 1 Bruno 2 X LxW 2
  • the compounds provided by the present invention show more excellent antitumor activity as shown in the above pharmacological test results, as compared with the control compounds.
  • the compounds of the present invention exhibit excellent antitumor activity and are useful as antitumor agents for the prevention and treatment of diseases, particularly for the treatment of cancer.
  • the compound of the present invention is usually formulated into a formulation containing an effective amount of the compound of the present invention together with a pharmaceutically acceptable carrier or excipient. Can be.
  • various forms can be selected, for example, tablets, capsules, powders, granules or liquids.
  • oral preparations sterile liquid parenteral preparations such as solutions and suspensions, suppositories, ointments and the like.
  • Solid preparations can be produced as they are in the form of tablets, capsules, granules or powders, or they can be produced using appropriate additives.
  • additives include sugars such as lactose and glucose; starches such as corn, wheat and rice; fatty acids such as stearic acid; inorganics such as magnesium aluminate metasilicate and calcium phosphate anhydrous; Salts, for example, synthetic polymers such as polyvinyl pyridone or polyalkylene glycol; fatty acid salts, for example, calcium stearate or magnesium stearate; alcohols, for example, stearyl alcohol or benzyl alcohol; for example, methyl cellulose, carboxymethyl cellulose; Synthetic cellulose derivatives such as ethylcellulose or hydroxypropylmethylcellulose, and other commonly used additives such as gelatin, talc, vegetable oil, and gum arabic. .
  • Solid preparations such as tablets, capsules, granules and powders are generally
  • It may contain from 0.1 to 100% by weight, preferably from 5 to 100% by weight, of the active ingredient.
  • liquid preparations use appropriate additives usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil, sesame oil, etc .; suspensions, syrups, injections, infusions It is manufactured in the form of an agent or the like.
  • Particularly suitable solvents for parenteral administration by intramuscular injection, intravenous injection or subcutaneous injection include, for example, distilled water for injection, lidocaine hydrochloride aqueous solution (for intramuscular injection), and physiological saline.
  • aqueous glucose solution for example, aqueous solution of citric acid and sodium citrate
  • electrolyte solution for intravenous drip and intravenous injection
  • a mixed solution thereof can be
  • injections may be in the form of a powder which has been dissolved in advance or a powder to which an appropriate additive has been added, and which is dissolved at the time of use. These injections may contain usually 0.1 to 10% by weight, preferably 1 to 5% by weight of the active ingredient. Liquid preparations such as suspensions and syrups for oral administration are usually 0.5 to 10 It can contain active ingredients by weight.
  • the preferred dose of the compound of the present invention depends on the type of compound used, the type of composition formulated, the frequency of application and the specific site to be treated, the severity of the disease, the age of the patient, the diagnosis of a physician, the type of tumor
  • the dosage per adult per oral administration can be in the range of 1 to 80 O mg in the case of oral administration.
  • the dosage per adult per oral administration can be in the range of 1 to 80 O mg in the case of oral administration.
  • For oral administration preferably for intravenous injection, it can be in the range of 0.1 to 50 mg per day.
  • the number of administrations varies depending on the administration method and symptoms, but is 1 to 5 times.
  • administration methods such as intermittent administration such as alternate-day administration and alternately administration can also be used.
  • G lc represents an S—D-glucovilanosyl group. The same applies to the following.
  • Bn represents a benzyl group.
  • Bn represents a benzyl group.
  • 6 Dissolve 284 g of monobenzyloxyindole in 3 L of THF, add 2.7 L of lithium hexamethyldisilazide (1M: THF solution), stir at 110 under nitrogen atmosphere for 45 minutes, A solution of 340 g of 2,3-dibromo-N-methylmaleimide in 3 L of THF was added dropwise over 1 hour.
  • Boc represents a Tert-butoxycarbonyl group. The same applies to the following.
  • Example 11-1 1.00 g of the compound obtained in Example 11-1), 637 mg of di-tert-butyltinole dicarbonate and 3 mg of 4-N, N-dimethylaminopyridine were dissolved in 200 ml of THF, and dissolved at room temperature in 1 ml. Stirred for hours. After concentrating the reaction solution, the residue was recrystallized from ethyl acetate-hexane to obtain 1.18 g of the desired compound.
  • G 1 c (OBn) 2,3,4,6-di-tetrabenzyl- ⁇ -D-glucoviranosyl group is shown. The same applies to the following.
  • Compound (1) 4.0 g, 2,3,4,6-O-tetrabenzyl-yS-D-glucoviranose 11.8 g and triphenylphosphine 5.74 g The residue was dissolved in 160 ml of THF, and 4.3 ml of diazopropyl ester azodicarboxylate was added at room temperature, followed by stirring for 1 hour.
  • reaction solution was distributed between 300 ml of ethyl acetate and 2N hydrochloric acid, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and then with saturated saline, and then dried and concentrated.
  • the residue is purified by silica gel chromatography (ethyl acetate: 50: 1) to give the desired compound (2) 6.
  • 2-deoxyGlc represents a 2-dexoxy- ⁇ - ⁇ -glucopyranosyl group. Hereinafter the same).
  • Example 14 The compounds of Examples 14 to 20 were produced in the same manner as in Example 13.
  • Example 14
  • Xy 1 pyrra represents an SD—xylobyranosyl group. The same applies to the following.
  • Xylpyra (OBn) 3 represents a 2,3,4-tri-O-benzyl-1- / 3-D-xylobilanosyl group.
  • OBn 2,3,4-tri-O-benzyl-1- / 3-D-xylobilanosyl group.
  • 2.43 g of potassium hydroxide and 9.24 g of anhydrous sodium sulfate were suspended in 190 ml of acetonitrile, and 2.21 g of the compound obtained in Example 21-3) was added, followed by stirring at room temperature for 30 minutes.
  • a compound obtained by chlorinating 2.36 g of 2,3-, 4-tree O-benzyl D-xylobiranose with thionyl chloride in 32 ml of acetonitrile was added.
  • reaction solution was diluted with 220 ml of ethyl acetate, and washed with 150 ml of 1N hydrochloric acid.
  • the separated organic layer was left for a while to precipitate crystals, which were collected by filtration.
  • the crystals are washed with a small amount of water and then with ethyl acetate-hexane, dried and then dried.
  • Example 23 The compounds of Examples 23 to 34 were produced in the same manner as in Example 21.
  • Example 23
  • A11ofura represents a yS-D-arofuranosyl group.
  • G a1 pyr a — represents a D-galactopyranosyl group.
  • 6-deoxyGlc represents a 6-doxy / S—D-dalcoviranosyl group.
  • a 11 opy ra represents a S—D-aroviranosyl group. Hereinafter the same).
  • Ribofura represents a / 3-D-ribofuranosyl group. Hereinafter the same).
  • Glcfuura represents ⁇ -D-dalcofuranosyl group.
  • Example 36 The compound of Example 36 was produced in the same manner as in Example 35.c
  • Allopyra COBn represents a 2,3,4,6-tetra-O-benzyl-3-D-arovilanosyl group.
  • the crude product of the compound (61) was dissolved in 10 mL of a 2N aqueous hydroxide aqueous solution and stirred at room temperature for 1 hour. After adding 20 mL of 2N hydrochloric acid to the reaction solution and stirring for 30 minutes, the mixture was extracted with 100 mL of ethyl acetate-methylethyl ketone (1: 1) and 5 OmL (twice). The organic layer was washed with saturated saline, dried and concentrated, and the residue was purified by Sephadex LH20 (methanol) to obtain 68 mg of the desired compound (62).
  • R f value 0.3 1 (Merck, Kieselgel 60 F 254 , developing solvent;
  • R f value 0.56 (manufactured by Merck, Kieselgel 60 F 23 , developing solvent;
  • R f value 0.33 (Merck, Kieselgel 60 F 254 , developing solvent;
  • R f value 0.33 (Merck, Kieselgel 60 F 254 , developing solvent;
  • N, N-dimethylformamide was obtained by adding 129 mg of (2R) — 3-hydrazino 1,2-propanediol obtained from 25 Omg of compound of Reference Example 1 and 2) to N, N-dimethylformamide.
  • Tetrahydrofuran methanol: n-hexane: diformate 10: 2:
  • the compounds of the present invention have excellent antitumor effects and are useful as antitumor agents in the field of medicine.

Abstract

Composés représentés par la formule générale (I) ou sels pharmaceutiquement acceptables de ces composés. Dans la formule, R représente C2-4 alkyle renfermant de 1 à 3 groupes hydroxyles; R1 et R2 représentent individuellement l'hydrogène ou OH; et G représente un pentose ou un hexose, sous réserve que R1 et R2 ne représentent pas simultanément l'hydrogène, et étant exclu le cas où R1 est OH en position 1 et R2 est OH en position 11 lorsque R est CH(CH¿2?OH)2, ainsi que le cas où R?1¿ est OH en position 2 et R2 est OH en position 10 lorsque R est CH(CH¿2?OH)2. Grace à leur activité antitumorale remarquable, ces composés se révèlent utiles comme agents antitumoraux dans le domaine des médicaments.
PCT/JP1996/002404 1995-09-05 1996-08-28 Derives antitumoraux d'indolopyrrolocarbazole WO1997009339A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064917A2 (fr) * 1999-04-26 2000-11-02 Advanced Life Sciences Inc. Regioisomeres d'indolocarbazoles synthetiques et leurs utilisations
WO2001062769A1 (fr) * 2000-02-24 2001-08-30 Banyu Pharmaceutical Co., Ltd. Procede de preparation de derives d'indolopyrrolocarbazole, leurs intermediaires, et procede de preparation des intermediaires
US6605596B2 (en) 2000-10-31 2003-08-12 Advanced Life Sciences, Inc. Indolocarbazole anticancer agents and methods of using them
US7122526B2 (en) 2000-10-31 2006-10-17 Nanosphere, Inc. Indolocarbazole anticancer agents and methods of using same

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JPH01233281A (ja) * 1988-02-10 1989-09-19 F Hoffmann La Roche Ag ピロール類
JPH06128283A (ja) * 1991-11-29 1994-05-10 Banyu Pharmaceut Co Ltd 抗腫瘍性インドロピロロカルバゾール誘導体
WO1995030682A1 (fr) * 1994-05-09 1995-11-16 Banyu Pharmaceutical Co., Ltd. Derive d'indolopyrolocarbazole antitumoral

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JPS63198695A (ja) * 1986-11-21 1988-08-17 ブリストル―マイアーズ　スクイブ　コムパニー レベカマイシン類似体
JPH01233281A (ja) * 1988-02-10 1989-09-19 F Hoffmann La Roche Ag ピロール類
JPH06128283A (ja) * 1991-11-29 1994-05-10 Banyu Pharmaceut Co Ltd 抗腫瘍性インドロピロロカルバゾール誘導体
WO1995030682A1 (fr) * 1994-05-09 1995-11-16 Banyu Pharmaceutical Co., Ltd. Derive d'indolopyrolocarbazole antitumoral

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Title
J. ORG. CHEM., 1993, Vol. 58, GALLANT, M. LINK, J.T. and DANISHEFSKY, S.J., "A Stereoselective Synthesis of Indole-beta-N-Glycosides: An Application to the Synthesis of Rebeccamycin", pages 343-349. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064917A2 (fr) * 1999-04-26 2000-11-02 Advanced Life Sciences Inc. Regioisomeres d'indolocarbazoles synthetiques et leurs utilisations
WO2000064917A3 (fr) * 1999-04-26 2002-09-26 Advanced Life Sciences Inc Regioisomeres d'indolocarbazoles synthetiques et leurs utilisations
WO2001062769A1 (fr) * 2000-02-24 2001-08-30 Banyu Pharmaceutical Co., Ltd. Procede de preparation de derives d'indolopyrrolocarbazole, leurs intermediaires, et procede de preparation des intermediaires
US6790836B2 (en) 2000-02-24 2004-09-14 Banyu Pharmaceutical Co., Ltd. Process for preparing indolopyrrolocarbazole derivatives, intermediates therefor, and preparation process of the intermediates
US6605596B2 (en) 2000-10-31 2003-08-12 Advanced Life Sciences, Inc. Indolocarbazole anticancer agents and methods of using them
US7122526B2 (en) 2000-10-31 2006-10-17 Nanosphere, Inc. Indolocarbazole anticancer agents and methods of using same

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