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WO1992018520A1 - Nouveaux derives de la cytarabine, preparation et utilisation - Google Patents

Nouveaux derives de la cytarabine, preparation et utilisation Download PDF

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Publication number
WO1992018520A1
WO1992018520A1 PCT/EP1992/000712 EP9200712W WO9218520A1 WO 1992018520 A1 WO1992018520 A1 WO 1992018520A1 EP 9200712 W EP9200712 W EP 9200712W WO 9218520 A1 WO9218520 A1 WO 9218520A1
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WO
WIPO (PCT)
Prior art keywords
arac
formula
derivatives
radicals
branched
Prior art date
Application number
PCT/EP1992/000712
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German (de)
English (en)
Inventor
Michael Kluge
Herbert Schott
Original Assignee
Knoll Ag
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 Knoll Ag filed Critical Knoll Ag
Publication of WO1992018520A1 publication Critical patent/WO1992018520A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the present invention relates to new cytarabine derivatives, their preparation and their use in combating diseases.
  • N 4 -acyl-AraC is ineffective with AraC resistance.
  • AraC-resistant tumor cells would be taken up and enzymatically cleaved inside the active AraC 5'-monophosphate.
  • Prodrugs in which AraC or AraC-5'-monophosphate are present coupled to natural ester phospholipids and which were applied in the form of liposomes only partially met expectations.
  • a disadvantage of these prodrugs is that the natural lipid building blocks used to construct the prodrugs are enzymatically cleaved too quickly, so that these phospholipidAraC prodrugs are metabolized too quickly to inactive derivatives.
  • New cytarabine derivatives have now been found which are more effectively protected against enzymatic deamination and which are suitable for the therapy of AraC-resistant tumor cells.
  • the invention relates to cytarabine derivatives of the formula I.
  • R 1 is a hydrogen atom, a C 14 -C 24 -alkyl radical which may optionally contain 1 to 2 double bonds and can be branched, an aliphatic C 2 -C 24 -acyl radical which may optionally contain 1 or 2 double bonds and can be branched, or the Acyl residue of benzoic acid or anisic acid and
  • R 2 , R 3 which may be the same or different, hydrogen atoms, C 1 -C 24 -alkyl radicals, which may be 1 to
  • R 1 can be hydrogen atoms and R 1 ⁇ H when R 2 and R 3 are acyl radicals.
  • Suitable alkyl radicals for R 1 are in particular hexadecyl and octadecyl.
  • R 1 is an acyl radical, the following radicals are preferred:
  • Palmitoyl, oleoyl, behenoyl Palmitoyl, oleoyl, behenoyl.
  • R 2 and R 3 unbranched alkyl and acyl radicals having 1 to 20 carbon atoms are preferred.
  • the new cytarabine derivatives of the formula I can be prepared by a) preparing compounds of the formula II,
  • R 1 , R 2 and R 3 have the meaning given and R 4 represents a 2- or 4-chlorophenyl radical, splits off the chlorinated phenyl radical R 4 or b) a compound of the formula III
  • the chlorinated phenyl radical according to a) is cleaved particularly well if the compounds II are left to stand for 5 to 15 hours in an aqueous organic solvent at room temperature with tetrabutylammonium fluoride.
  • the oxidation of the compounds III is particularly successful at room temperature with iodine in organic aqueous solvents.
  • reaction products thus obtained can be purified by chromatography.
  • the compounds of the formula II used as starting material can be obtained by condensation of compounds of the formula IV
  • R 2 and R 3 have the meaning given, with a compound of the formula V (R 1 ⁇ H) in the presence of an acid chloride and subsequent oxidation in a known manner. If one or two of the radicals R 1 , R 2 and R 3 are to be hydrogen, acyl radicals must be exchanged for hydrogen in a corresponding acyl compound.
  • the compounds IV, V and VI are known or can be prepared by known processes (Chem. Pharm. Bull. 26, 981 (1978), Nucleic Acid Res. Symposium Series No. 18, 189 (1987)). Furthermore, the amphiphilic properties can surprisingly be varied within wide limits by the number, length, type and position of the respective substituents in the AraC derivatives according to the invention.
  • the a ⁇ hiphilen AraC derivatives are thus soluble in aqueous buffer systems and / or dispersible in the form of liposomes.
  • liposome formation can be achieved without and / or with other lipid components. All known liposome imaging methods can be used for liposome formation, such as, for example, ultrasound, gel chromatography, detergent dialysis.
  • the lipophilic residues introduced in each case also decisively influence the size and stability of the liposomes which are formed from the respective amphiphilic AraC derivatives.
  • the cytostatic effect of AraC can also be decisively optimized.
  • the new compounds can even be used against malignant diseases of the hematopoietic cells, in particular against acute leukaemias and chronic myeloid leukemia in the blast episode.
  • the cytostatic effect of the amphiphilic AraC derivatives can surprisingly be used in so-called immunoliposomes for the targeted destruction of certain tumor cells.
  • the amphiphilic AraC derivatives are dispersed together with other lipid components in the form of liposomes in physiological buffer systems.
  • Monoclonal antibodies are immobilized on functional groups of the liposome membrane.
  • the immunoliposomes thus obtained are preferably taken up in vitro by the tumor cells which express the antigen corresponding to the antibody. The result of this cell targeting is the selective destruction of the respective target tumor cell in a mixture of different cells.
  • DBA / 2 mice were injected with L1210 tumor cells intravenously, simulating leukemia. On days 3 and 7 after the tumor cell injection, different doses of the test substance or solvent were administered to the tumor-bearing animals.
  • the new compounds showed a better activity than AraC.
  • the new compounds are said to be in a dosage of about
  • the residue obtained according to a) was mixed with 200 ml of a 0.2 M iodine solution (tetrahydrofuran / pyridine / water, 90/5/5, V / V / V) and left for 40 min at room temperature.
  • a 0.2 M iodine solution tetrahydrofuran / pyridine / water, 90/5/5, V / V / V
  • reaction mixture was shaken with a mixture of 500 ml of chloroform and 500 ml of 2% aqueous NaHSO 3 solution.
  • the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to the syrup.
  • the syrup was taken up with about 80 ml of chloroform and fractionated on a silica gel column in a chloroform / methanol gradient.
  • the fractions of the desired product which left the column with chloroform / methanol (9/1, v / v) were combined, concentrated to dryness and then from methanol
  • Example 1 was repeated, but with D-1,2-di-O-palmitoyl-glycero-3-hydrogenphosphonate as the starting material. 4.4 g of product were obtained.
  • Example 3
  • Example 3 was repeated, but with D-1,2-di-0-palmitoyl-glycero-3- (2-chlorophenyl) phosphate as the starting material.
  • the yield was 5.9 g.
  • the condensation product obtained according to a) was kept closed with an excess of methanolic ammonia for about 24 hours at room temperature.
  • the solvent was then removed in vacuo and the residue was fractionated on a silica gel column in a chloroform / methanol gradient. Fractions that the contained desired product were concentrated.
  • the residue which was crystallized from acetone / water, gave a white powder which had an R F value of 0.19 in the chloroform / methanol system (1/1, v / v).
  • Chloroform-methanol (1/1, v / v); each 100 mg soy phosphatidylcholine, 10 mg cholesterol, 1 mg ⁇ -tocopherol, 7 mg
  • 0.6 ml of this lipid stock solution was transferred in a test tube by blowing with air into a lipid film, which was then dried in vacuo for about 1 h at 50 ° C.
  • the lipid film was mixed with 3 ml of 10 mM PBS (0.9% NaCl and 10 mM NaH 2 PO 4 , pH 7.3) and sonicated at 40 watts for 30 min with the aid of a microtip of a disintegrator. An opalescent liposome dispersion was formed, which was used for the following reaction.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Saccharide Compounds (AREA)

Abstract

On décrit de nouveaux dérivés de la cytarabine de formule (I) dans laquelle R1, R2 et R3 ont la notation indiquée dans la description, ainsi que leur préparation. Les composés sont utilisables pour le traitement de maladies.
PCT/EP1992/000712 1991-04-10 1992-03-31 Nouveaux derives de la cytarabine, preparation et utilisation WO1992018520A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19914111730 DE4111730A1 (de) 1991-04-10 1991-04-10 Neue cytarabin-derivate, ihre herstellung und verwendung
DEP4111730.1 1991-04-10

Publications (1)

Publication Number Publication Date
WO1992018520A1 true WO1992018520A1 (fr) 1992-10-29

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PCT/EP1992/000712 WO1992018520A1 (fr) 1991-04-10 1992-03-31 Nouveaux derives de la cytarabine, preparation et utilisation

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WO (1) WO1992018520A1 (fr)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001362A1 (fr) * 1993-07-01 1995-01-12 Boehringer Mannheim Gmbh Liponucleotides de desoxynucleosides, leur fabrication et leur utilisation comme medicaments antiviraux
WO1995032984A1 (fr) * 1994-05-28 1995-12-07 Boehringer Mannheim Gmbh Nouveaux esters lipidiques de monophosphates de nucleosides et leur utilisation comme medicaments immunosuppresseurs
FR2781229A1 (fr) * 1998-07-17 2000-01-21 Univ Nice Sophia Antipolis Nouveaux composes analogues des nucleotides, leurs procedes de preparation et leurs applications
US6620796B1 (en) 1999-11-08 2003-09-16 Micrologix Biotech Inc. Combinatorial library synthesis and pharmaceutically active compounds produced thereby
WO2004096233A3 (fr) * 2003-04-25 2005-06-16 Gilead Sciences Inc Analogues d'un phosphonate nucleosidique
US7256179B2 (en) 2001-05-16 2007-08-14 Migenix, Inc. Nucleic acid-based compounds and methods of use thereof
US7273716B2 (en) 2003-04-25 2007-09-25 Gilead Sciences, Inc. Methods and compositions for identifying therapeutic compounds with GS-7340 ester hydrolase
US7300924B2 (en) 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
US7407965B2 (en) 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7417055B2 (en) 2003-04-25 2008-08-26 Gilead Sciences, Inc. Kinase inhibitory phosphonate analogs
US7427624B2 (en) 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
US7427636B2 (en) 2003-04-25 2008-09-23 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
US7429565B2 (en) 2003-04-25 2008-09-30 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7432272B2 (en) 2003-12-22 2008-10-07 Gilead Sciences, Inc. Antiviral analogs
US7432261B2 (en) 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
US7432273B2 (en) 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
US7452901B2 (en) 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
US7462608B2 (en) 2002-04-26 2008-12-09 Gilead Sciences, Inc. Non nucleoside reverse transcriptase inhibitors
US7470724B2 (en) 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
US7638528B2 (en) 1999-10-28 2009-12-29 Wake Forest University School Of Medicine Compositions and methods for targeting cancer cells
US7645747B2 (en) 2003-04-25 2010-01-12 Gilead Sciences, Inc. Therapeutic phosphonate compounds
US8951986B2 (en) 2008-07-08 2015-02-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US9413712B2 (en) 2000-04-03 2016-08-09 Neustar Ip Intelligence, Inc. Method and system to associate a geographic location information with a network address using a combination of automated and manual processes
US9457035B2 (en) 2004-07-27 2016-10-04 Gilead Sciences, Inc. Antiviral compounds
US10851125B2 (en) 2017-08-01 2020-12-01 Gilead Sciences, Inc. Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563257A (en) * 1990-08-20 1996-10-08 Boehringer Mannheim Gmbh Phospholipid derivatives of nucleosides

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3543346A1 (de) * 1984-12-07 1986-06-12 Boryung Pharmaceutical Co., Ltd., Seoul Neue nucleosidderivate und verfahren zu ihrer herstellung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3543346A1 (de) * 1984-12-07 1986-06-12 Boryung Pharmaceutical Co., Ltd., Seoul Neue nucleosidderivate und verfahren zu ihrer herstellung

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Band 116, Nr. 13, erschienen 30. MÛrz 1992 (30.03.92) (Columbus, Ohio, USA), CH. Mc GUIGAN et al. "Trans- -esterification reaction yield novel masked phosphate derivatives of the anticancer agent araC" *
CHEMICAL ABSTRACTS, Band 116, Nr. 9, erschienen 02. MÛrz 1992 (02.03.92) (Columbus, Ohio, USA), CH. LE BEC et al. "Synthesis of lipophilic phosphate triester derivatives of 5-fluorouridine and arabinocytidine as anticancer prodrugs", *
CHEMICAL ABSTRACTS, Band 96, Nr. 7, 15 Februar 1982 (15.02.82) (Columbus, Ohio, USA), A. ROSOWSKY et al. "Lipophilic 5'-alkyl phos- phate esters of 1-Beta-D-ara- binofuranosylcytosine and its N4-acyl and 2,2'-anhydro-3'- -0-acyl derivatives as potential prodrugs", *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001362A1 (fr) * 1993-07-01 1995-01-12 Boehringer Mannheim Gmbh Liponucleotides de desoxynucleosides, leur fabrication et leur utilisation comme medicaments antiviraux
WO1995032984A1 (fr) * 1994-05-28 1995-12-07 Boehringer Mannheim Gmbh Nouveaux esters lipidiques de monophosphates de nucleosides et leur utilisation comme medicaments immunosuppresseurs
FR2781229A1 (fr) * 1998-07-17 2000-01-21 Univ Nice Sophia Antipolis Nouveaux composes analogues des nucleotides, leurs procedes de preparation et leurs applications
US7638528B2 (en) 1999-10-28 2009-12-29 Wake Forest University School Of Medicine Compositions and methods for targeting cancer cells
US6620796B1 (en) 1999-11-08 2003-09-16 Micrologix Biotech Inc. Combinatorial library synthesis and pharmaceutically active compounds produced thereby
US9413712B2 (en) 2000-04-03 2016-08-09 Neustar Ip Intelligence, Inc. Method and system to associate a geographic location information with a network address using a combination of automated and manual processes
US7256179B2 (en) 2001-05-16 2007-08-14 Migenix, Inc. Nucleic acid-based compounds and methods of use thereof
US7709449B2 (en) 2001-05-16 2010-05-04 Migenix, Inc. Nucleic acid-based compounds and methods of use thereof
US7649015B2 (en) 2002-04-26 2010-01-19 Gilead Sciences, Inc. Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds
US7462608B2 (en) 2002-04-26 2008-12-09 Gilead Sciences, Inc. Non nucleoside reverse transcriptase inhibitors
US7432261B2 (en) 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
US8871785B2 (en) 2003-04-25 2014-10-28 Gilead Sciences, Inc. Antiviral phosphonate analogs
WO2004096233A3 (fr) * 2003-04-25 2005-06-16 Gilead Sciences Inc Analogues d'un phosphonate nucleosidique
US7427636B2 (en) 2003-04-25 2008-09-23 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
US7429565B2 (en) 2003-04-25 2008-09-30 Gilead Sciences, Inc. Antiviral phosphonate analogs
US9139604B2 (en) 2003-04-25 2015-09-22 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7407965B2 (en) 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7273716B2 (en) 2003-04-25 2007-09-25 Gilead Sciences, Inc. Methods and compositions for identifying therapeutic compounds with GS-7340 ester hydrolase
US7452901B2 (en) 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
US7300924B2 (en) 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
US7470724B2 (en) 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
US8022083B2 (en) 2003-04-25 2011-09-20 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7645747B2 (en) 2003-04-25 2010-01-12 Gilead Sciences, Inc. Therapeutic phosphonate compounds
US7417055B2 (en) 2003-04-25 2008-08-26 Gilead Sciences, Inc. Kinase inhibitory phosphonate analogs
US7273717B2 (en) 2003-10-24 2007-09-25 Gilead Sciences, Inc. Methods and compositions for identifying therapeutic compounds with GS-9005 ester hydrolase B
US7273715B2 (en) 2003-10-24 2007-09-25 Gilead Sciences, Inc. Methods and compositions for identifying therapeutic compounds with GS-9005 ester hydrolase A
US7432273B2 (en) 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
US7427624B2 (en) 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
US7432272B2 (en) 2003-12-22 2008-10-07 Gilead Sciences, Inc. Antiviral analogs
US9457035B2 (en) 2004-07-27 2016-10-04 Gilead Sciences, Inc. Antiviral compounds
US9579332B2 (en) 2004-07-27 2017-02-28 Gilead Sciences, Inc. Phosphonate analogs of HIV inhibitor compounds
US8951986B2 (en) 2008-07-08 2015-02-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US9381206B2 (en) 2008-07-08 2016-07-05 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US9783568B2 (en) 2008-07-08 2017-10-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US10851125B2 (en) 2017-08-01 2020-12-01 Gilead Sciences, Inc. Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate

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Publication number Publication date
DE4111730A1 (de) 1992-10-15

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