EP0873347A2 - Amine derivative von 2", 3"-dideoxyglycosiden von epipodophyllotoxin, ihre verfahren zur herstellung, inre verwendung als arzneimitteln, und ihre verwendung als anti-krebsmitteln - Google Patents

Amine derivative von 2", 3"-dideoxyglycosiden von epipodophyllotoxin, ihre verfahren zur herstellung, inre verwendung als arzneimitteln, und ihre verwendung als anti-krebsmitteln

Info

Publication number
EP0873347A2
EP0873347A2 EP96934895A EP96934895A EP0873347A2 EP 0873347 A2 EP0873347 A2 EP 0873347A2 EP 96934895 A EP96934895 A EP 96934895A EP 96934895 A EP96934895 A EP 96934895A EP 0873347 A2 EP0873347 A2 EP 0873347A2
Authority
EP
European Patent Office
Prior art keywords
epipodophyllotoxin
compound
demethyl
ethylidene
dideoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96934895A
Other languages
English (en)
French (fr)
Inventor
Claude Monneret
Laurent Daley
Yves Guminski
Thierry Imbert
Bridget Hill
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP0873347A2 publication Critical patent/EP0873347A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • New amino derivatives of 2 ", 3" dideoxygiycosides of epipodophyllotoxin, their preparation process, their use as a medicament and their use intended for anticancer treatments.
  • the present invention relates to new amino derivatives 2 ", 3" dideoxygiycosides of epipodophyllotoxin, their preparation process, their use as a medicament and their use intended for anticancer treatments.
  • epipodophylloids having the basic skeleton of podophyllotoxin. It includes hemi-synthetic derivatives such as Etoposide or Teniposide which are commonly used in the preparation of drugs for the treatment of cancer. They are considered major products in this area.
  • Etoposide has anti-tumor properties and is used to treat in particular small cell lung cancer and testicular cancer.
  • the object of the present invention is to show that derivatives of 4'-demethyl epipodophyllotoxin, having in position 4, a substitution of structure 2 "-deoxyglycoside, allows, by the incorporation of one or more nitrogen, to form compounds whose addition salts have an aqueous solubility which makes it possible to respond to the problem and show the desired anticancer activity.
  • Patent EP-0 196 618 relates to water-soluble derivatives of 4'-demethyl epipodophyllotoxin of formula:
  • R 1 and R 2 identical or different represent a hydrogen atom, a C 1 to C 6 alkyl group, which can form a ring, this ring possibly comprising a heteroatom such as oxygen or nitrogen, a C 1 to C 6 aminoalkyl group or cyanomethyl.
  • X and Y can be the same or different and represent an OH, CH 3 , CH 2 - NH 2 , X and Y can also be linked and form a ring, such as, for example, 2-methyl 1,3 dioxane, thus forming a 4,2-ethylidene 3-amino-2,3-dideoxy- ⁇ -D arabino or ribo-hexo pyranoside type bicyclic osidic skeleton.
  • the NR 1 R 2 group is an NH 2 or N (CH 3 ) 2 group .
  • the NR 1 R 2 group can also be an amino group substituted once or twice with methyl, CH 2 CN, CH 2 -CH 2 -NH 2 , forming a ring such as morpholine.
  • the compounds of general formula I will be chosen with a glycoside for which X and Y form a ring with a chain OCH (CH 3 ) OCH 2 , such as 4,6 ethylidene-3-amino-2,3 -dideoxy- ⁇ -D arabino-hexo pyranoside or else 4.6 ethylidene-3-amino-2,3-de ⁇ oxy- ⁇ -D-ribo-hexopyranoside.
  • the compounds according to the invention are selected from the following compounds:
  • the present invention also relates to pharmaceutical compositions comprising at least one compound of general formula I according to the invention and an appropriate excipient.
  • compositions can be presented in a suitable manner by administration by the injectable route or by the oral route in the form of capsules, capsules, tablets at the dosage of 1 to 200 mg / m 2 by injection and from 5 to 500 mg. / m 2 orally per 24 h period.
  • These derivatives can thus be administered in human clinic to treat different forms of cancer such as small cell lung cancer, testicular cancer, embryonic tumors, neuroblastomas, kidney cancer, Hodgkin's and non-Hodgkin's lyphomas, acute leukemias, colorectal cancers, melanomas, placental choriocarcinomas and breast adenocarcinomas.
  • cancer such as small cell lung cancer, testicular cancer, embryonic tumors, neuroblastomas, kidney cancer, Hodgkin's and non-Hodgkin's lyphomas, acute leukemias, colorectal cancers, melanomas, placental choriocarcinomas and breast adenocarcinomas.
  • the present invention also relates to processes for the preparation of the compounds of formula I as well as their addition salts with pharmaceutically acceptable mineral or organic acids.
  • the present invention therefore relates to the processes for preparing the compounds of general formula I according to the invention, in which a compound of formula III or IV or V is reacted
  • the substituent in position 3 can be ⁇ or ⁇
  • NR 1 R 2 can be an amino protected by a group Z
  • P represents an alcohol protecting group and the products resulting from this condensation are deprotected and hydrogenated to provide the compounds of formula I,
  • the primary amines in position 3 of the glycosyl are methylated by formalin and sodium cyanoborohydride.
  • the intermediate of formula IV is prepared by reacting a mixture of diacetoxy azido glycoside VI
  • glycosidic intermediate azide ⁇ 12 follows the same reaction sequence as its epimer and provides in an identical manner the coupling derivative with DMEPT4'OZ from the azide 3 " ⁇ 13, in this case the coupling is carried out more easily according to two techniques.
  • the first technique consists in treating the ribohexopyranoside derivative 13 with trimethyl silyl trifluoromethane sulfonate (TMSOTf) at - 40 ° C in CH 2 Cl 2 .
  • TMSOTf trimethyl silyl trifluoromethane sulfonate
  • the second technique consists in using the etherate of BF 3 in CH 2 Cl 2 at - 15 ° C.
  • the silylated ⁇ azide 12 is selectively tosylated with tosyl chloride in pyridine at 21, the primary alcohol tosylate is exchanged for iodo derivative 22.
  • the secondary alcohol in position 4 is protected by a chloroacetate to provide the functionalized 2-desoxysugre 23 ready to be condensed with DMEPT 4'-OZ under the usual conditions with the etherate of BF 3 in methylene chloride at low temperature.
  • the salts formed from the nitrogen compounds are, for example, hydrochlorides and are formed conventionally by treating a methanolic solution of the nitrogen compound with a stoichiometric solution with respect to sites to be salified with hydrochloric methanol previously dosed
  • the crystallized hydrochloride can optionally be obtained by precipitation in the reaction medium by addition of ethyl ether.
  • aqueous phase is extracted with CH 2 Cl 2 (200 ml) then after drying over MgSO 4 , the organic phase is concentrated under reduced pressure and the residue (18.7 g) is chromatographed on silica gel (cyclohexane / AcOEt: 9/1). 10.7 g of 3 (syrup; 48%) and 4.7 g of 4 (syrup; 21%) are thus isolated; however, intermediate fractions contain a mixture of 3 and 4 (3.3 g; 15%).
  • reaction medium After stirring for 8 h, the reaction medium is poured into 100 ml H 2 O and the aqueous phase is extracted with CH 2 C1 2 (100 ml). The organic phase is dried over MgSO 4 , concentrated under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane / AcOEt: 6/1 and 4/1) in order to isolate 1.9 g of 8 (72% ).
  • reaction medium After reaction for 5 h at 20 ° C, the reaction medium is filtered and then concentrated under reduced pressure to provide 59 mg of pure 28 (94%).
  • the molecules have been tested in biological experiments and have shown their interest as an anticancer agent in tests for P 388 leukemia in vivo in mice. This test is commonly used in the field of anti-cancer substances research (Protocols for screening chemical agents and natural products against animal tumors and other biological Systems, R. Geran, NH Greenberg, MM MacDonald, AM Schumacher and BJ Abbott, Cancer Chemotherapy reports 1972, 3, No. 2).
  • ED 50 the effective dose 50 which represents the single minimum dose of the compound to be administered in order to obtain significant animal survival compared to the untreated control animals
  • P 388 leukemia was chemically induced in 1955 by 3-methylcholanthrene in a DBA / 2 mouse (Am. J. Pathol. 33, 603, 1957).
  • the tumors are maintained by weekly passages in the form of ascites in the peritoneum of DBA / 2 mice (original line) and the experiments are carried out on CDF ⁇ hybrid female mice (bal b / c female XDBA / 2 males) of 20 ⁇ 2 g (Cancer chemother. Rep. 3, 9, 1972).
  • the tumor cells are implanted intravenously (106 cells per mouse) on day 0.
  • the animals are randomized and divided into groups of 2 for each series.
  • Anti-tumor substances are administered intraperitoneally (ip) one day after inoculation of the leukemia cells (acute treatment).
  • the solutions are injected at the rate of 10 ml / kg of mouse.
  • the criterion for evaluating anti-tumor activity is the prolongation of the survival of the animals treated. 86% of the mice die on the 7th day after the tumor transplant. A substance will be considered active if it induces survival longer than 8 days.
  • the compounds of the invention have retained the level of activity of the reference compounds such as Etoposide and have the additional advantage of having an aqueous solubility which is advantageous for formulation and administration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
EP96934895A 1995-10-12 1996-10-11 Amine derivative von 2", 3"-dideoxyglycosiden von epipodophyllotoxin, ihre verfahren zur herstellung, inre verwendung als arzneimitteln, und ihre verwendung als anti-krebsmitteln Withdrawn EP0873347A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9511978A FR2739857B1 (fr) 1995-10-12 1995-10-12 Nouveaux derives amines de 2",3"-didesoxyglycosides d'epipodophyllotoxine, leur procede de preparation, leur utilisation comme medicament et leur utilisation destinee aux traitements anticancereux
FR9511978 1995-10-12
PCT/FR1996/001588 WO1997013776A2 (fr) 1995-10-12 1996-10-11 Nouveaux derives amines de 2', 3' didesoxyglycosides d'epipodophyllotoxine, leur procede de preparation, leur utilisation comme medicament et leur utilisation destinee aux traitements anticancereux

Publications (1)

Publication Number Publication Date
EP0873347A2 true EP0873347A2 (de) 1998-10-28

Family

ID=9483465

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96934895A Withdrawn EP0873347A2 (de) 1995-10-12 1996-10-11 Amine derivative von 2", 3"-dideoxyglycosiden von epipodophyllotoxin, ihre verfahren zur herstellung, inre verwendung als arzneimitteln, und ihre verwendung als anti-krebsmitteln

Country Status (10)

Country Link
EP (1) EP0873347A2 (de)
JP (1) JP2000505053A (de)
KR (1) KR19990064166A (de)
CN (1) CN1202173A (de)
AU (1) AU7304096A (de)
BR (1) BR9610851A (de)
CA (1) CA2234484A1 (de)
FR (1) FR2739857B1 (de)
NZ (1) NZ320323A (de)
WO (1) WO1997013776A2 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2800374B1 (fr) * 1999-10-28 2002-06-28 Adir Nouveaux derives de 9-(3,5-dimethoxyphenyl)-5,8,8a,9- tetrahydrofuro[3',4':6,7]naphto[2,3-d] [1,3]dioxol-6(5ah)- one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
TWI307341B (en) * 2002-10-11 2009-03-11 Plantaceutica Inc Anticancer compounds
FR2859208B1 (fr) 2003-09-02 2006-01-21 Servier Lab Nouveaux derives de 9-amino-podophyllotoxine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
CN102115483B (zh) * 2009-12-30 2014-12-17 苏州天人合生物技术有限公司 卤代双去氧糖衍生物及其制备方法与应用
CN109369667B (zh) * 2018-12-05 2021-04-13 南通大学 2，3，6-三脱氧糖基去甲表鬼臼毒素化合物及其制备方法和用途
CN110294764B (zh) * 2019-07-15 2021-04-20 中国科学院兰州化学物理研究所 一种偶氮键连接的鬼臼毒素衍生物及其制备方法
CN112079879B (zh) * 2020-08-21 2022-01-14 华润双鹤药业股份有限公司沧州分公司 一种替尼泊苷中间体的合成新方法及替尼泊苷的合成方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6032799A (ja) * 1983-07-29 1985-02-19 Microbial Chem Res Found 新規４′−デメチル−４−エピポドフィロトキシン誘導体
US5066645A (en) * 1989-09-01 1991-11-19 Bristol-Myers Company Epipodophyllotoxin altroside derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9713776A2 *

Also Published As

Publication number Publication date
CN1202173A (zh) 1998-12-16
KR19990064166A (ko) 1999-07-26
NZ320323A (en) 1999-07-29
BR9610851A (pt) 1999-07-13
AU7304096A (en) 1997-04-30
CA2234484A1 (fr) 1997-04-17
FR2739857B1 (fr) 1998-01-02
WO1997013776A2 (fr) 1997-04-17
FR2739857A1 (fr) 1997-04-18
JP2000505053A (ja) 2000-04-25
MX9802933A (es) 1998-11-29
WO1997013776A3 (fr) 1997-06-05

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