WO2001049693A1 - 4-o-[2-(n,n-dialkylamino)-2-deoxy-4,6-o,o-beta-d-glucosyl]-4'-o-demethyl-epi-podophyllotoxine, derives, et composition anticancereuse renfermant ces composes - Google Patents

4-o-[2-(n,n-dialkylamino)-2-deoxy-4,6-o,o-beta-d-glucosyl]-4'-o-demethyl-epi-podophyllotoxine, derives, et composition anticancereuse renfermant ces composes Download PDF

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Publication number
WO2001049693A1
WO2001049693A1 PCT/KR2000/000978 KR0000978W WO0149693A1 WO 2001049693 A1 WO2001049693 A1 WO 2001049693A1 KR 0000978 W KR0000978 W KR 0000978W WO 0149693 A1 WO0149693 A1 WO 0149693A1
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WIPO (PCT)
Prior art keywords
compound
deoxy
demethyl
podophyllotoxin
glucosyl
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PCT/KR2000/000978
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English (en)
Inventor
Zaesung No
Gehyeong Lee
Jong Woong Ahn
Chong Ock Lee
Sang Un Choi
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Korea Research Institute Of Chemical Technology
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Publication of WO2001049693A1 publication Critical patent/WO2001049693A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel 4-0-[2-(N,N-dialkylamino)-2- deoxy- ⁇ -D-glucosyl]-4'-O-demethyl-e >/-podophyllotoxin derivatives having excellent anticancer activity, a process for preparing same and an anticancer composition containing same as an active ingredient.
  • etoposide and teniposide have the problem of severe cytotoxicities and insolubility in water, and, therefore, various attempts have been made to develop improved anticancer agents by modifying the structures of etoposide and teniposide.
  • ETOPOPHOSTM G Patent No. 2,207,674 A
  • NK-611 EP publication No. 196,618
  • ETOPOPHOSTM was approved by FDA as an anticancer drug in 1997, while NK-611 which has improved water solubility is now in a clinical test stage.
  • the present inventors have endeavored to develop compounds having a high potency against cancer cells and improved pharmacokinetic properties; and have unexpectedly found that 4-O-[2-(NN-dialkylamino)-2-deoxy- ⁇ -D- glucosyl]-4'-O-demethyl- t-podophyllotoxins containing a double- or triple- bonded acetal in the 4,6-diol positions of 2-aminoglucoside exhibit superior anticancer activity.
  • R and R are, each independently hydrogen, C 0 alkyl or C 5-10 cycloalkyl; or form, together with the nitrogen atom to which they are attached, a nitrogen heterocycle containing 4 to 6 carbon atoms; and R is vinyl, ethynyl, allyl, C 3-10 cycloalkyl, C 5-10 cycloalkenyl, or C 5- ⁇ 0 cycloalkynyl, each having an optional branched or linear C 1-8 alkyl, alkoxy, alkoxyalkyl, or aryl substituent.
  • the compound of formula(l) may be prepared by a process which comprises (a) reacting 4'-O-demethyl-ep/ ' -podophyllotoxin-4-O-[2-amino-2- (tetrachlolopthalimidoil)-2-deoxy- ⁇ -D-glucoside of formula(2) with an aldehyde of formula(3) or an acetal of formula(4) in the presence of a catalyst to obtain a compound of formula(5); (b) removing the amino protecting group of the compound of formula (5) to obtain a compound of formula (6); and (c) alkylating the amino group the compound of formula (6) with the aldehyde in the presence of a reducing agent to obtain the compound of formula (1), as shown in Scheme 1.
  • Scheme 1 Scheme 1
  • R is a lower alkyl group.
  • reaction step (a) the compound of formula(2) may be reacted with an excess amount of the compound of formula(3) or formula(4), from 5 to 50, preferably from 5 to 15 moles per mole of the compound of formula (2), in a suitable solvent at a temperature ranging from 10 to 100 ° C , preferably from 20 to 40 °C , for 3 to 24 hours.
  • Exemplary solvents which may be suitably used in the above reaction step are nitromethane, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, dimethoxyethane, acetonitrile and dimethylformamide, wherein anhydrous acetonitrile and anhydrous nitromethane are preferred.
  • the catalyst which may be used in step (a) is an acid such as sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride and an acidic resin, wherein p-toluenesulfonic acid and methanesulfonic acid are preferred.
  • the catalyst may be used in an amount ranging from 1 to 20 wt%, preferably from 5 to 10 wt% based on the weight of the compound of formula (2).
  • reaction step (a) may be carried out in the absence of a solvent.
  • the reaction may be terminated by adding an organic base such as trialkylamine or a pyridine derivative to neutralize the acid catalyst employed.
  • 4'-O-demethyl- -podophyllotoxin-4-O-[2-amino-2-(tetracUoropthal_midoil)- 2-deoxy- ⁇ -D-glucoside of formula(2) may be prepared in accordance with a known method(see J. S. Debenham, S. D. Debenham and B. Freiser-Reid, Bioorg. Med. Chem.. 4, 1909( 1996)).
  • Exemplary aldehydes of formula (3) which may be suitably used in the process of the present invention include cyclopropancarboxaldehyde, 1,2,5,6- tetrahydrobenzaldehyde, trans-cinnamaldehyde and the like.
  • Representative acetals of formula (4) are acrolein dimethyl acetal, 3-butenal diethyl acetal, propiolaldehyde diehyl acetal, 2-butyne-l -aldehyde diethyl acetal and the like.
  • reaction step (b) the tetrachloropthalimidoil amino protecting group of the compound of formula (5) is removed by the action of an excess amount of a primary alkylamine such as hydrazine and ethylenediamine to produce the compound of formula(6).
  • reaction step (c) the compound of formula(6) is alkylated with the corresponding aldehydes in the presence of a reducing agent, e.g., lithium aluminiumhydride, sodium borohydride, or sodium cyanoborohydride.
  • a reducing agent e.g., lithium aluminiumhydride, sodium borohydride, or sodium cyanoborohydride.
  • the compound of formula(l) of the present invention may be converted into a pharmaceutically acceptable salt thereof by a process which comprises treating the compound of formula(l) with an organic or inorganic acid in a suitable solvent at a temperature ranging from -20 to 50 ° C , preferably from 0 to 20 °C to obtain a precipitated solid; filtering the solid; and drying.
  • organic acids which may be suitably used in this process are form acid, acetic acid, oxalic acid, malonic acid, lactic acid, and tartaric acid; and representative inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, and iodic acid may also be used therein.
  • Solvent, such as ether, chloroform and dichloromethane may be suitably used in this process.
  • the present invention also includes within its scope a pharmaceutical composition comprising the compound of formula (1) as an active ingredient, in association with a pharmaceutically acceptable carrier, excipient or other additives, if necessary.
  • the pharmaceutical composition of the present invention may be formulated for oral administration or, preferably, for injection.
  • the composition for oral administration may take various forms such as tablets and gelatin capsules, which may contain conventional additives such as a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), a lubricant (e.g., silica, talc, stearic acid or its magnesium and calcium salts and polyethylene glycol).
  • a diluent e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • a lubricant e.g., silica, talc, stearic acid or its magnesium and calcium salts and polyethylene glycol.
  • the composition may further comprise a binder (e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and polyvinyl picolidine) and optionally a disintegrant (e.g., starch, agar and alginic acid or its sodium salt), absorbent, colorant, flavor and sweetener.
  • a binder e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and polyvinyl picolidine
  • a disintegrant e.g., starch, agar and alginic acid or its sodium salt
  • composition for injection may be an isotonic solution or a suspension containing the inventive compound.
  • the inventive pharmaceutical composition may be administered daily.
  • a typical daily dose of the active ingredient ranges from about 1 to 100 mg kg, preferably 1 to 20 mg/kg, and can be administered in a single dose or in divided doses.
  • the amount of the active ingredient actually administered should be determined in light of various relevant factors including the condition to be treated, the chosen route of administration, the age and weight of the individual patient, and the severity of the patient's symptoms; and, therefore, the dosage suggested above should not be construed to limit the scope of the invention in any way.
  • Compound 6a 4'-O-demethyl-epi-podophyllotoxin-4-O-[4,6-O,0-
  • Human cancer cell lines A-549(non-molding type cell lung cancer derived from human), SK-OV-3(adenocarcinoma, ovary malignant hydroperitoneum), SK-MEL-2(malignant melanoma, transferred to femoral skin), XF498(cancer of central nervous system) and HCT15(colonic cancer), were obtained from U.S. National Cancer Institute and subcultured in Korea Research Institute of Chemical Technology. Each of these cell lines was cultured in a RPMI(Rosewell Park Medium)
  • a phosphate buffer containing 0.25% trypsin and 3 mM trans- l,2-diamino-cyclohexane-N,N,N,N-tetraacetic acid (CDTA)(trypsin-CDTA solution) to separate the cells from the incubator
  • the cells were subjected to serial subcultures.
  • the serial subcultures were carried out at an interval of three or four days.
  • Step 2 In vitro anticancer activity
  • SRB serum-sulforhodamin B
  • the subcultured cells were treated with a tripsin-CDTA solution to separate the cells, which were added to the wells of a 96 well microplate(Falcon Co., U.S.) in an amount of 5 x 103 (A549, HCT15), 1 x 104(SK-MEL-2, XF498), 2 x 104(SK-OV-3) cells per well.
  • the cells were incubated under a C02 atmosphere for 24 hours to be affixed on the well bottom and the culture medium was removed with an aspirator.
  • test compounds la to lh of the present invention and etoposide(BMS, U.S.A) were used as test compounds.
  • Each of the test compounds was dissolved in water to obtain a test solution.
  • a small amount of dimethylsulfoxide was used to dissolve the compound, if necessary.
  • the test solution was diluted with the culture medium(pH 7.2) by factors of 1, 10 "1 , 10 "2 , 10 "3 , 10 "4 and 10 "5 , respectively. After filtering through a 0.22 ⁇ l filter, 100 ⁇ £(x3) each of the diluted test solutions was added to the cell containing wells and the cells were cultured for another 48 hours.
  • TCA trichloroacetic acid
  • the anticancer activities(A.A.) of a test compound was calculated by equation (1) or (2).
  • A. A. [(T-Tz)/(C-Tz)] x 100 (Tz>T) Eq. (1)
  • A. A. [(T-Tz)/Tz] x 100 (Tz ⁇ T) Eq. (2)
  • Tz is the number of cells before adding a culture medium
  • C is the number of cells after incubation for 48 hours in a culture medium containing no test compound
  • T is the number of cells after incubation for 48 hours in a culture medium containing a measured amount of a test compound.
  • ED 50 the concentration of a compound at which the growth of cancer cell, is inhibited by 50%, was calculated by a regression method using LOTUS program. The results are shown in Table I.
  • Test Example 2 Inhibition of human topoisomerase II
  • Step 1 Preparation of topoisomerase II HeLa cell line provided by ATCC( American Type Culture Collection) was used in preparing topoisomerase II of the cancer cell.
  • the HeLa cells were cultured in a RPMI 1640 culture medium enriched with 10% fetal bovine serum at 37 ° C under an atmosphere of 5% CO 2 and the cultured HeLa cells were collected. Added thereto was a 3-fold volume of 50 mM KH 2 PO 4 buffer solution(pH 7.0) containing 1 mM ethylenediamine tetraacetic acid(EDTA), ImM mercaptoethanol, 0.5 mM phenylmethylsulfonylchloride(PMSF) and 10% glycerol and the resulting mixture was homogenized with Polytron for 30 seconds in a ice bath.
  • EDTA ethylenediamine tetraacetic acid
  • PMSF phenylmethylsulfonylchloride
  • a 2M KH 2 P0 4 buffer solution(pH 7.0) was added thereto to a KH 2 PO 4 concentration of 0.3M and the resultant was homogenized for 30 seconds, placed in an ice bath for 1 hour, and then, centrifuged at 30,000 xg for 30 minutes.
  • the supernatant was purified by phosphocellulose column chromatography(eluent: linear gradient from 0.3M to 0.5M KH 2 P0 buffer(pH 7.0) to obtain topoisomerase II.
  • IC 50 values of the test compounds for topoisomerase II were measured by an unknotting assay.
  • Topo II obtained above and 0.4 ⁇ g of P4 knotted DNA were added to a 50 mM N-[2-hydroxyethyl]-piperazine-N'-[2-ethanesulfonic acid] (HEPES) buffer solution (pH 7.0) containing 50 mM KCl, 0.1 mM EDTA, 100 mM NaCl, 10 mM MgCl 2 , 100 g/ml of fetal bovine serum albumin and 1 mM adenosine triphosphate(ATP) to a final volume of 20 ⁇ l and the mixture was reacted at 37 °C for 30 minutes.
  • HEPES N-[2-hydroxyethyl]-piperazine-N'-[2-ethanesulfonic acid]
  • the reaction was terminated by adding sodium dodecyl sulfate(SDS) to a SDS concentration of 1%.
  • SDS sodium dodecyl sulfate
  • the resultant was subjected to electrophoresis using 1% agarose gel equilibrated with a 50 mM tris borate buffer solution(pH 8.3) containing 2.5mM EDTA, and then, dyed with ethidium bromide.
  • Topo II The activity of Topo II was assessed using photographs taken under UV radiation.
  • the Topo II activity measured when 50% of 0.4 ⁇ g of knotted P4 DNA was unknotted was defined as 1 unit activity.
  • IC 50 was the concentration of a compound at which the activity of Topo II is inhibited by 50%. The results are shown in Table I.
  • Test Example 3 In vivo anticancer activity
  • mice were observed daily and the survival period of each mouse was checked.
  • the anticancer activity was assessed by calculating the ratio (I.R.) by equation 3.
  • At is the average survival days of mice in a test group and Ac is the average survival days of mice in the control group.
  • the compounds of the present invention possess excellent anticancer activity against leukemia cells, much higher than that of etoposide and NK-611.
  • Test Example 4 Acute toxicity test
  • mice When the mice became five- week old, etoposide, NK-611 HC1, and compounds la, lb and lg • HC1 of the present invention were dissolved in distilled water and respective solutions were injected into the abdominal cavities of mice of respective test groups at the doses of 68.3. 88.8 and 115.4 mg/kg body weight. The solution was injected once and the mice were observed for 7 days for signs of adverse effects and the weight change according to the amount of the test compound. The LD 50 value was determined by Probit method(Innovative Origramming Associates Inc., New Jersey, USA). Further, the anticancer activity was assessed by calculating the therapeutic index by equation 4.
  • C is the lowest concentration of a test compound at which anticancer activity is manifest.
  • the compounds of the present invention possess higher therapeutic index values than etoposide or NK-611.
  • the inventive compounds can therefore be used as a drug for treating cancers.

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Abstract

Cette invention concerne un composé à forte activité anticancéreuse représenté par la formule (1) dans laquelle R1 et R2 sont chacun indépendamment hydrogène, alkyle en C¿1-10? ou cycloalkyle en C5-10; ou bien forment, avec l'atome d'azote auquel ils sont reliés, un hétérocycle azote renfermant de 4 à 6 atomes de carbone; et R?3¿ est vinyle, éthynyle, allyle, cycloalkyle en C¿3-10?, cycloalkynyle en C5-10 cycloalkynyl, chacun ayant en option un substituant akyle en C1-8, alkoxy, alkoxyalkyle, ou aryle ramifié ou linéaire.
PCT/KR2000/000978 2000-01-03 2000-08-30 4-o-[2-(n,n-dialkylamino)-2-deoxy-4,6-o,o-beta-d-glucosyl]-4'-o-demethyl-epi-podophyllotoxine, derives, et composition anticancereuse renfermant ces composes WO2001049693A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2900154A1 (fr) * 2006-04-25 2007-10-26 Inst Nat Sciences Appliq Nouveaux composes c-glycosides gem-difluores derives de la podophyllotoxine, leur preparation et leurs applications.
CN106995449A (zh) * 2017-04-13 2017-08-01 遵义医学院 鬼臼毒素‑维甲酸杂合物合成方法和应用于预防、治疗肿瘤的药物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0366122A2 (fr) * 1988-10-26 1990-05-02 Warner-Lambert Company Dérivés de la deméthylépipodophyllotoxine
EP0423747A2 (fr) * 1989-10-20 1991-04-24 BEHRINGWERKE Aktiengesellschaft Prodrogues glycosyl-étoposide, leur procédé de préparation et leur utilisation en combinaison avec des conjugats enzymatiques conjugués fonctionnalisés spécifiques aux tumeurs
JPH05310775A (ja) * 1992-05-15 1993-11-22 Nippon Kayaku Co Ltd Ｎ−モノメチルアミノエトポシド類及びその塩並びにそれらを含む抗腫瘍剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0366122A2 (fr) * 1988-10-26 1990-05-02 Warner-Lambert Company Dérivés de la deméthylépipodophyllotoxine
EP0423747A2 (fr) * 1989-10-20 1991-04-24 BEHRINGWERKE Aktiengesellschaft Prodrogues glycosyl-étoposide, leur procédé de préparation et leur utilisation en combinaison avec des conjugats enzymatiques conjugués fonctionnalisés spécifiques aux tumeurs
JPH05310775A (ja) * 1992-05-15 1993-11-22 Nippon Kayaku Co Ltd Ｎ−モノメチルアミノエトポシド類及びその塩並びにそれらを含む抗腫瘍剤

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2900154A1 (fr) * 2006-04-25 2007-10-26 Inst Nat Sciences Appliq Nouveaux composes c-glycosides gem-difluores derives de la podophyllotoxine, leur preparation et leurs applications.
WO2007125194A1 (fr) 2006-04-25 2007-11-08 Institut National Des Sciences Appliquees De Rouen (Insa) Nouveaux composes c-glycosides gem-difluores derives de la podophyllotoxine, leur preparation et leurs applications
CN106995449A (zh) * 2017-04-13 2017-08-01 遵义医学院 鬼臼毒素‑维甲酸杂合物合成方法和应用于预防、治疗肿瘤的药物

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