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WO1996032403A2 - Nouveaux derives cytosine et cytidine - Google Patents

Nouveaux derives cytosine et cytidine Download PDF

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Publication number
WO1996032403A2
WO1996032403A2 PCT/EP1996/001595 EP9601595W WO9632403A2 WO 1996032403 A2 WO1996032403 A2 WO 1996032403A2 EP 9601595 W EP9601595 W EP 9601595W WO 9632403 A2 WO9632403 A2 WO 9632403A2
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimidin
tetrahydro
pyrrolo
hydrogen
fluorine
Prior art date
Application number
PCT/EP1996/001595
Other languages
German (de)
English (en)
Other versions
WO1996032403A3 (fr
Inventor
Helmut VORBRÜGGEN
Konrad Krolikiewicz
Michael Schirner
Martin Schneider
Herbert Wiesinger
Original Assignee
Schering Aktiengesellschaft
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 Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU54000/96A priority Critical patent/AU5400096A/en
Publication of WO1996032403A2 publication Critical patent/WO1996032403A2/fr
Publication of WO1996032403A3 publication Critical patent/WO1996032403A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • C07H19/14—Pyrrolo-pyrimidine radicals

Definitions

  • the invention relates to cytosine and cytidine derivatives, their production and use in medicaments.
  • cytidines in particular aracytidine and other cytosine derivatives as cytostatics or virus therapeutics, is impaired by their rapid deactivation by cytidine deaminases, the corresponding inactive uridines or uracil derivatives being formed from the biologically potent cytidines or cytosine derivatives as described by GW Camiener et al., Biochem. Pharmacol. 14, 1405 (1965), 16, 1681 (1967) and W. Kreis et al., Helv. Chim. Acta 61, 1011 (1978). It is therefore of great therapeutic interest to synthesize cytidines or cytosine derivatives which are not substrates of the cytidine deaminase and which have a longer duration of action in vivo.
  • Ansa-cytosine and Ansa-cytidine derivatives which have a dimethylene grouping between the C 5 carbon atom and the N 4 nitrogen atom, are biologically potent molecules which are not substrates of the cytidine Are deaminase and therefore do not have the disadvantages mentioned above of the cytosine and cytidine derivatives which already belong to the prior art.
  • the invention relates to cytosine and cytidine derivatives of the general formula 1,
  • R is hydrogen, C ⁇ O, COR 6 with R 6 in the meaning of C 1 -C 17 alkyl and phenyl, or COOR 7 with R 7 in the meaning of C 1 -C 4 alkyl or benzyl
  • R ' is hydrogen or the groups
  • R 2 is hydrogen, fluorine, CH 3 or CN
  • R 3 is hydrogen, fluorine, hydroxy or -OCH 3 ,
  • R 4 is hydrogen, fluorine, hydroxy, N 3 or NH 2 ,
  • R 5 is hydrogen or PO (OH) 2 ,
  • R 2 , R 3 together CH 2 ,
  • R 3 , R 4 together form a double bond and their salts.
  • the compounds of general formula 1 can be represented, for example, as follows:
  • the Ansacytidin 11 can by the usual methods, for. B. by reaction of 11 with 2-acetoxyisobutyric acid chloride (JG Moffatt et al .; J. Org. Chem. 39, 2182 (1974)) or 2-acetoxybenzoyl chloride (JJ Fox et al .; Synthesis 533 (1976)) at 24 ° C in acetonitrile or by heating with diphenyl carbonate in the presence of sodium bicarbonate (CB Reese et al., J. Chem. Soc, Perlon Trans.
  • the 3'-azido derivative 29 can be hydrogenated to the 3'-amino derivative.
  • Reaction of ketone 22 with NaCN / NaHCO 3 in Et 2 O / H 2 O leads to cyanohydrin 34.
  • the invention relates to the process for the preparation of the compounds of the formula 1
  • R 13 is hydrogen, an SiR 14 R 15 R 16 radical in which R 14 , R 15 , R 16 are identical or different and are phenyl or C 1 -C 4 alkyl, or is tert-butyloxycarbonyl, with a urea derivative or an isourea derivative such as 16
  • Hydroxyl groups are converted into the 5'-phosphate and, if appropriate, protective groups are split off or the salts are formed.
  • Alkali salts such as sodium and potassium salts and ammonium salts are suitable as salts of the 5'-phosphates.
  • the customary groups can be used as hydroxyl protective groups.
  • Alkyl is to be understood as meaning straight-chain and branched alkyls, in particular C 1-4 alkyls and C 15 and C 16 alkylene radicals.
  • nucleosides of formula 1 with free 5'-hydroxyl groups can be prepared using known methods (M. Yoshikawa, T. Kato and T. Takenishi, Bull. Chem. Soc. Jap. 42, 3505 (1969) and T. Sowa and S Ouchi, Bull. Chem. Soc. Jap. 48, 2084 (1975)) can easily be converted into the corresponding 5'-phosphates and their salts.
  • the listed new ansacytidines of general formula 1 as well as their 5'-phosphates and salts are particularly characterized by long-lasting in vitro and in vivo effects in various mouse leukemia models, in particular in mouse L1210 leukemia, HL 60 cell culture and in various viral diseases out.
  • Compound 21 in particular and the corresponding phosphoramidates of 21 are particularly suitable for the formation of stable triplex DNA (cf. 5-methyl-2'-deoxycytidine: GC Best and PB Dervan. J. Amer. Chem. Soc. 117, 1187 (1995)).
  • a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains.
  • suitable pharmaceutical, organic or inorganic inert carrier materials such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains.
  • the Pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the silyl compound was treated with 18.64 g (36.97 mmol) of 1-O-acetyl-2,3,5-tri-O-benzoyl- ⁇ -D-ribofuranose 9 under nitrogen in 200 ml of abs. Dissolved 1,2-dichloroethane, then 8 ml (44 mmol) of trimethylsilyl triflate in 75 ml of 1,2-dichloroethane were added dropwise with stirring at 24 ° within 30 min and the reaction mixture was left at 24 ° for 72 h.
  • 1,2-dichloroethane and added 3.86 g (10 mmol) of 3,5-di-O-toluolyl-2-deoxy- ⁇ -D-ribofuranosyl chloride and then at +5 ° 1.99 ml (11 mmol) of trimethylsiltriflate 40 ml abs. 1,2-dichloroethane for 30 min. with stirring. After a further 15 min at +7 °, the mixture was stirred for about 4 h at +21 ° and the reaction mixture was kept in the refrigerator for 18 h at +4 °. When working up with 120 ml of ice-cold NaHCO 3 solution, some red-brown substance precipitated out and an emulsion formed.
  • the mother liquor mainly contained the ⁇ -anomer 20 and was therefore inoculated with crystalline ⁇ -anomer in a little acetone, with further crystalline ⁇ -anomer 20 Mp 148 - 150 °.
  • the aqueous phase extracted twice with 50 ml of MBE and 75 ml of CH 2 CI. After evaporation of the aqueous phase, the residue was dissolved in 10 ml of water, mixed with 0.2 g of activated carbon and filtered off

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

Abstract

L'invention concerne des dérivés cytosine et cytidine de la formule générale (1), ainsi que leur production et leur utilisation dans des produits pharmaceutiques
PCT/EP1996/001595 1995-04-12 1996-04-12 Nouveaux derives cytosine et cytidine WO1996032403A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54000/96A AU5400096A (en) 1995-04-12 1996-04-12 Novel cytosine and cytidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19514523.2 1995-04-12
DE1995114523 DE19514523A1 (de) 1995-04-12 1995-04-12 Neue Cytosin- und Cytidinderivate

Publications (2)

Publication Number Publication Date
WO1996032403A2 true WO1996032403A2 (fr) 1996-10-17
WO1996032403A3 WO1996032403A3 (fr) 1996-11-28

Family

ID=7759937

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/001595 WO1996032403A2 (fr) 1995-04-12 1996-04-12 Nouveaux derives cytosine et cytidine

Country Status (3)

Country Link
AU (1) AU5400096A (fr)
DE (1) DE19514523A1 (fr)
WO (1) WO1996032403A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601820B2 (en) 2004-07-21 2009-10-13 Pharmasset, Inc. Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8580765B2 (en) 2007-03-30 2013-11-12 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8629263B2 (en) 2009-05-20 2014-01-14 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US10039779B2 (en) 2013-01-31 2018-08-07 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
US10287311B2 (en) 2003-05-30 2019-05-14 Gilead Pharmasset Llc Modified fluorinated nucleoside analogues
US10456414B2 (en) 2011-09-16 2019-10-29 Gilead Pharmasset Llc Methods for treating HCV
US10577359B2 (en) 2004-09-14 2020-03-03 Gilead Pharmasset Llc Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3042910B1 (fr) 2010-11-30 2019-01-09 Gilead Pharmasset LLC 2'-spiro-nucléosides pour le traitement de l'hépatite c

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62255499A (ja) * 1986-04-28 1987-11-07 Teijin Ltd 螢光性ヌクレオシド又はヌクレオチド
US5204466A (en) * 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287311B2 (en) 2003-05-30 2019-05-14 Gilead Pharmasset Llc Modified fluorinated nucleoside analogues
US7601820B2 (en) 2004-07-21 2009-10-13 Pharmasset, Inc. Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
US10577359B2 (en) 2004-09-14 2020-03-03 Gilead Pharmasset Llc Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
US8906880B2 (en) 2007-03-30 2014-12-09 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US12121529B2 (en) 2007-03-30 2024-10-22 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
US8580765B2 (en) 2007-03-30 2013-11-12 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US11642361B2 (en) 2007-03-30 2023-05-09 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
US10183037B2 (en) 2007-03-30 2019-01-22 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US9585906B2 (en) 2007-03-30 2017-03-07 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US9085573B2 (en) 2007-03-30 2015-07-21 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8735372B2 (en) 2007-03-30 2014-05-27 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8957045B2 (en) 2008-12-23 2015-02-17 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8629263B2 (en) 2009-05-20 2014-01-14 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8633309B2 (en) 2009-05-20 2014-01-21 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9284342B2 (en) 2009-05-20 2016-03-15 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8735569B2 (en) 2009-05-20 2014-05-27 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9637512B2 (en) 2009-05-20 2017-05-02 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8642756B2 (en) 2009-05-20 2014-02-04 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9206217B2 (en) 2009-05-20 2015-12-08 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
US10456414B2 (en) 2011-09-16 2019-10-29 Gilead Pharmasset Llc Methods for treating HCV
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US10039779B2 (en) 2013-01-31 2018-08-07 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
US11707479B2 (en) 2013-08-27 2023-07-25 Gilead Sciences, Inc. Combination formulation of two antiviral compounds

Also Published As

Publication number Publication date
DE19514523A1 (de) 1996-10-17
AU5400096A (en) 1996-10-30
WO1996032403A3 (fr) 1996-11-28

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