WO1995018816A1 - Nouveaux produits d'addition nucleoside-lipide, preparation et utilisation pharmaceutique - Google Patents

Nouveaux produits d'addition nucleoside-lipide, preparation et utilisation pharmaceutique Download PDF

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Publication number
WO1995018816A1
WO1995018816A1 PCT/DE1995/000041 DE9500041W WO9518816A1 WO 1995018816 A1 WO1995018816 A1 WO 1995018816A1 DE 9500041 W DE9500041 W DE 9500041W WO 9518816 A1 WO9518816 A1 WO 9518816A1
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WO
WIPO (PCT)
Prior art keywords
formula
cytidine
residue
thymidine
adenosine
Prior art date
Application number
PCT/DE1995/000041
Other languages
German (de)
English (en)
Inventor
Hans Brachwitz
Peter Langen
Iduna Fichtner
Wolfgang E. Berdel
Matthias Baeseler
Uwe Lachmann
Karin Dressler
Yvonne Thomas
Original Assignee
Max-Delbrück-Centrum für Molekulare Medizin
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 Max-Delbrück-Centrum für Molekulare Medizin filed Critical Max-Delbrück-Centrum für Molekulare Medizin
Priority to EP95905541A priority Critical patent/EP0738274A1/fr
Publication of WO1995018816A1 publication Critical patent/WO1995018816A1/fr

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Classifications

    • 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
    • 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
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • New nucleoside-lipid adducts their production and their pharmaceutical use
  • the invention relates to new nucleoside-lipid adducts of the general formula I including all enantiomeric forms and all pharmaceutically usable salts of these compounds.
  • the invention further relates to processes for the preparation of the compounds I and their pharmaceutical use.
  • the field of application of the invention is thus the chemical and pharmaceutical industries.
  • CDP-DAG cytidine phosphate diacylglycerols
  • the aim of the invention was now to synthesize new cytostatically active nucleoside-lipid adducts which are introduced into the cell in analogy to the naturally occurring CDP-DAG and which, owing to their structure, have a high level of biostability and therefore a longer residence time in the organism and / or inhibit the proliferation of tumor cells by blocking natural pathways of degradation or synthesis of metabolically modified cleavage product and which are therefore suitable for pharmaceutical use.
  • the invention relates to new nucleoside-lipid adducts of the general formula I
  • R is a straight-chain or branched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted by halogen, hydroxy, alkoxy or cyano-substituted hydrocarbon radical with 1-22 carbon atoms means or
  • A is saturated or mono- or polyunsaturated, unsubstituted or mono- or polysubstituted by halogen, hydroxy, alkoxy or cyano (C5-C30) alkoxy or alkenoxy,
  • B has one of the meanings given for A or denotes hydrogen, hydroxyl, halogen, cyano, acyloxy (C2-C22) or a group of the general formula 0- (CH2) ⁇ -CF3, where x is 0-3.
  • Nk is a nucleoside, preferably cytidine, 2'-deoxycytidine, thymidine, adenosine and ara-cytidine residue, d) n is 0 or 1 and m is 1 or 2.
  • Another variant of the method consists in the implementation of an activated lipid phosphate or phosphonate component, e.g. B. in the form of an amidate with the corresponding nucleoside monophosphate.
  • nucleoside diphosphate with an alkylphosphoamidate or alkylphosphonoamidate
  • nucleoside monophosphate with an alkyldiphosphoamidate or alkylphosphonophosphoamidate.
  • the compounds of general formula I and their salts are biologically active and have a pronounced antitumor activity, which u. a. on human immoralized breast epithelial cells H 184 A 1 and on human breast tumor cells (Matu) in vitro.
  • the selectivity of the antiproliferative effect is shown by a significantly lower inhibition of growth of bone marrow cells in vitro by the compounds according to the invention.
  • Tab. 1 shows the inhibition of cell growth of human breast epithelial cells H 184 1 and human breast tumor cells of selected compounds of the general formula I: Tab. 1 IC 50 - selected (50% inhibition of cell growth in ⁇ M) selected substances of formula I.
  • Cyt cytidine residue
  • Thy thymidine residue
  • Ad adenosine residue
  • ara-cyt ara-cytidine residue
  • the compounds of general formula I and their salts can be used as cytostatic agents, preferably in a 3-5% mixture with pharmaceutically customary carriers and additives. ⁇
  • the further purification was carried out on a CM-52 cellulose column (50 g). It was washed with CHCI3 / CH3OH 8: 2 until no phosphate was detectable in the 1 50 ml fractions, which were concentrated to about 4 ml. Then the CH3OH content was increased to 50% and the clean substance was eluted. The eluate was evaporated to dryness and crystallized with acetone. 513 mg of clean substance were obtained in the form of the disodium salt.
  • octadecylphosphonate 500 mg (1.5 mmol) of octadecylphosphonate were mixed with 1.2 g (1.72 mmol) of cytidine-5'-monophosphomorpholidate (as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt) in 40 ml of dry pyridine at 38 ° C Stirring implemented in 4 days.
  • the mixture was worked up and purified on a CM-52 cellulose column (25 g) in accordance with Example 1. 200 mg of pure substance were obtained in the form of the disodium salt.
  • Example 1 799.2 mg (1, 15 mmol) of cytidine-5'-monophosphomorpholidate (as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt) with 364 mg (1 mmol) of 3-hexadecyloxypropylphosphonic acid at 35 ° C implemented.
  • the batch was worked up as described in Example 1. 1 87.5 mg of pure substance were obtained in the form of the disodium salt (dihydrate).
  • Example 1 793.2 mg (1, 15 mmol) of cytidine-5-monophosphomorpholidate (as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt) with 400 mg (1 mmol)
  • Example 8 from cytidine-5'-diphosphomorpholidate (as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt with 1.5 mol water) and hexadecylphosphoric acid at 35-50 ° C.
  • the substance is obtained as a disodium salt (dihydrate).
  • CM-52 cellulose column used. 131 mg of product were obtained in the form of the disodium salt.
  • Example 10 322.4 mg (1.0 mmol) of hexadecyl phosphate with 770.3 mg (1.5 mmol) of 2'-deoxycytidine-5'-monophosphomorpholidate (as 4-morpholine-N, N'- dicyclohexylcarboxamidinsalz with 1, 5 mol water) implemented.
  • Example 1 According to the instructions in Example 1, 200 mg (0.65 mmol) of hexadecylphosphonate with 514 mg (0.75 mmol) of thymidine-5'-monophosphomorpholidate (as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt with 1.5 mol of water) ) implemented.
  • the substance was purified as described in Example 14. With 60 mg of substance applied, 14 mg of pure substance were obtained in the form of the disodium salt.
  • Thymidine 5 (2-chloro-3-hexadecyloxypropyl-1-phosphono) phosphate
  • Example 1 According to Example 1, 288.4 mg (0.7 mmol) of 2-chloro-3-hexadecyloxypropyl-1-phosphate with 548 mg (0.8 mmol) of thymidine-5'-monophosphomorpholidate (as 4-
  • Nk adenosine residue
  • the pyridine was distilled off and the product was taken up in 1.5 ml of water, 30 ml of CH3OH and 25 ml of CHCl3 and adjusted to pH 4 with 1 N formic acid.
  • the upper phase was extracted twice with chloroform.
  • the organic phases were combined, dried, brought to pH 9 with methanolic NH3 and evaporated to dryness. 178 mg were obtained.
  • the substance obtained was purified by means of HPLC on an RP1 8 column; it is obtained as the free acid with 2.5 mol of water.
  • Nk adenosine residue
  • Example 20 300 mg (0.98 mmol) of hexadecylphosphonate with 798.7 mg (1.13 mmol) of adenosine-5'-monophosphomorpholidate (as 4-morpholine-N, N'-dicyclo- hexylcarboxamidine salt reacted with 1.5 mol water). 340 mg of crude product were obtained. The substance was isolated and purified as described in Example 20.
  • Example 1 200 mg (0.5 mmol) of 2-chloro-3-hexadecyloxypropyl-1-phosphonic acid 409.2 mg (0.58 mmol) of adenosine-5'-monophosphomorpholidate (as 4-morpholine-N, N'- dicyclohexylcarboxamidinsalz with 1, 5 mol water) implemented. The mixture was worked up and the end product was purified as indicated in Example 1. 94 mg of pure substance were obtained in the form of the disodium salt.
  • adenosine-5'-monophosphomorpholidate as 4-morpholine-N, N'- dicyclohexylcarboxamidinsalz with 1, 5 mol water
  • Example 20 300 mg (1.3 mol) of dodecyl phosphate with 91 9.57 mg (1.3 mmol) of adenosine 5'-monophosphomorpholidate (as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt with 1.5 mol Water) implemented. 290 mg of crude product were obtained. The reaction mixture was worked up and the substance was purified as indicated in Example 20.
  • Example 20 300 mg (0.92 mmol) of hexadecyl phosphate were reacted with 750 mg (1.07 mmol) of adenosine-5'-monophosphomorpholidate (as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt with 1.5 mol of water) . There were 1 60 mg of crude product receive. The reaction mixture was worked up and the substance was purified as described in Example 20.
  • adenosine-5'-monophosphomorpholidate as 4-morpholine-N, N'-dicyclohexylcarboxamidine salt with 1.5 mol of water
  • Example 1 223 mg (0.54 mmol) of 2-chloro-3-hexadecyloxypropyl-1-phosphate with 438.8 mg (0.62 mmol) of adenosine 5'-monophosphomorpholidate (as 4-morpholine-N, N ' -dicyclohexylcarboxamidinsalz with 1, 5 mol water) implemented.
  • the mixture was worked up and the end product was purified on a CM-52 cellulose column as shown in Example 1.
  • 123 mg of pure substance were obtained in the form of the disodium salt.
  • Nk ara-cytidine residue
  • Nk ara-cytidine residue
  • Example 26 310 mg (0.97 mmol) of hexadecyl phosphate were reacted with 758 mg (1.1 mmol) of ara-cytidine monophosphomorpholidate at room temperature. The reaction mixture was worked up and the product was isolated as shown in Example 26 using a CM-52 column. 100 mg of pure substance were obtained in the form of the disodium salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne de nouveaux produits d'addition nucléoside-lipide de formule générale (I), y compris toutes les formes énantiomériques ainsi que tous les sels de ces composés utilisables en pharmacie. Le domaine d'application est l'industrie chimique et l'industrie pharmaceutique. La préparation de ces composés (I) avec un groupement diphosphate ou phosphonophosphate s'effectue par condensation de nucléoside-5'-monoamidophosphates avec les phosphates ou les phosphonates lipidiques correspondants ou par condensation des lipidoamidophosphates ou des lipidoamidophosphonates avec les 5'-nucléosidemonophosphates correspondants. Les composés (I), qui contiennent un groupement triphosphate ou phosphonodiphosphate, sont obtenus par condensation d'un nucléosideamidodiphosphate avec un alkylphosphate ou un alkylphosphonate ou par réaction d'un amidophosphate ou d'un amidophosphonate lipidiques avec un 5'-nucléosidediphosphate ou par condensation d'un phosphate ou d'un phosphonophosphate lipidiques avec un 5'-nucléosidemonoamidophosphate ou par réaction d'un amidodiphosphate ou d'un amidophosphonophosphate lipidiques avec un 5'-nucléosidemonophosphate. Les composés de formule (I) ont une action cytostatique.
PCT/DE1995/000041 1994-01-07 1995-01-04 Nouveaux produits d'addition nucleoside-lipide, preparation et utilisation pharmaceutique WO1995018816A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP95905541A EP0738274A1 (fr) 1994-01-07 1995-01-04 Nouveaux produits d'addition nucleoside-lipide, preparation et utilisation pharmaceutique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4400310.2 1994-01-07
DE19944400310 DE4400310A1 (de) 1994-01-07 1994-01-07 Neue Nukleosid-Lipid-Addukte, ihre Herstellung und ihre pharmazeutische Verwendung

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WO1995018816A1 true WO1995018816A1 (fr) 1995-07-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005090370A1 (fr) * 2004-02-05 2005-09-29 The Regents Of The University Of California Agents pharmacologiquement actifs contenant des phosphonates esterifies, et leurs procedes d'utilisation
WO2020041051A1 (fr) * 2018-08-20 2020-02-27 Cure Biopharma Inc. Promédicaments de gemcitabine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4291024A (en) * 1978-04-10 1981-09-22 Turcotte Joseph G Cytotoxic liponucleotide analogs
GB2168350A (en) * 1984-12-07 1986-06-18 Boryung Pharm Nucleoside derivatives
EP0355016A1 (fr) * 1988-08-17 1990-02-21 Clarion Pharmaceuticals, Inc. Procédé pour la préparation de cytidine 5'-diphosphate-alkanols et -glycérols
JPH0283393A (ja) * 1988-09-19 1990-03-23 Kyowa Hakko Kogyo Co Ltd ５−フルオロウラシル誘導体
DD279249A1 (de) * 1989-01-01 1990-05-30 Akad Wissenschaften Ddr Verfahren zur herstellung von 2',3'-didesoxythymidin-5'-diphosphat-1,2-di-o-alkylglycerolen und deren salzen

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4291024A (en) * 1978-04-10 1981-09-22 Turcotte Joseph G Cytotoxic liponucleotide analogs
GB2168350A (en) * 1984-12-07 1986-06-18 Boryung Pharm Nucleoside derivatives
EP0355016A1 (fr) * 1988-08-17 1990-02-21 Clarion Pharmaceuticals, Inc. Procédé pour la préparation de cytidine 5'-diphosphate-alkanols et -glycérols
JPH0283393A (ja) * 1988-09-19 1990-03-23 Kyowa Hakko Kogyo Co Ltd ５−フルオロウラシル誘導体
DD279249A1 (de) * 1989-01-01 1990-05-30 Akad Wissenschaften Ddr Verfahren zur herstellung von 2',3'-didesoxythymidin-5'-diphosphat-1,2-di-o-alkylglycerolen und deren salzen

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 9018, 23 March 1990 Derwent World Patents Index; Class B03, AN 90-135705 *
EKCSTEIN F. ET AL: "Synthesis of guanosine 5'-di- and -triphosphate derivatives with modified terminal phosphates. Effect on ribosome-elongation factor G-dependent reactions", BIOCHEMISTRY, vol. 14, no. 23, 1975, EASTON, PA US, pages 5225 - 5232 *
LANGEN P. ET AL: "Cytostatic Effects of Various Alkyl Phospholipid Analogues on Different Cells in vitro", ANTICANCER RESEARCH, vol. 12, no. 6B, November 1992 (1992-11-01), pages 2109 - 2112 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005090370A1 (fr) * 2004-02-05 2005-09-29 The Regents Of The University Of California Agents pharmacologiquement actifs contenant des phosphonates esterifies, et leurs procedes d'utilisation
WO2020041051A1 (fr) * 2018-08-20 2020-02-27 Cure Biopharma Inc. Promédicaments de gemcitabine

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DE4400310A1 (de) 1995-07-13
EP0738274A1 (fr) 1996-10-23

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