WO1981002164A1 - Composes cycliques a sept chainons utilise en tant qu'inhibiteurs de cytidine deaminase - Google Patents

Composes cycliques a sept chainons utilise en tant qu'inhibiteurs de cytidine deaminase Download PDF

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Publication number
WO1981002164A1
WO1981002164A1 PCT/US1981/000127 US8100127W WO8102164A1 WO 1981002164 A1 WO1981002164 A1 WO 1981002164A1 US 8100127 W US8100127 W US 8100127W WO 8102164 A1 WO8102164 A1 WO 8102164A1
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WIPO (PCT)
Prior art keywords
compound
mmol
cytidine deaminase
solution
nmr
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PCT/US1981/000127
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English (en)
Inventor
P Liu
V Marquez
J Driscoll
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Us Commerce
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Publication of WO1981002164A1 publication Critical patent/WO1981002164A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • 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
    • 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
    • C07H19/052—Imidazole radicals

Definitions

  • This invention is directed to seven-member heterocyclic nucleosides and component aglycones used to inhibit the deamination enzyme responsible for inactivating arabinosylcytosine (ara-C).
  • Preferred nucleosides containing an active seven-member ring are as follows :
  • R H , benzoyl , paranitrobenzoyl
  • PROTECTION OF AMINOPYRIMIDINE NUCLEOSIDES Enzymes which deaminate natural aminopurine and aminopyrimidine nucleosides can also convert active drugs into inactive compounds in the human body.
  • the purine nucleoside arabinosyladenine (ara-A) shows little activity against standard animal tumors which are used as models for human cancer, This is because the enzyme adenosine deaminase converts the amino group of the drug rapidly to a hydroxyl group producing an inactive compound.
  • Arabinosylcytosine is a pyrimidine nucleoside with excellent human anticancer properties in leukemias. Ara-C is degraded by cytidine deaminase to inactive arabinosyluracil. A potent inhibitor of cytidine deaminase will make ara-C an even more useful drug.
  • the invention described herein describes a new class of very potent inhibitors of cytidine deaminase.
  • K m values for these two enzymes and their respective substrates differ only by about an order of magnitude depending on the enzyme source, coformycin and its 2'-deoxy analogue are far more potent in inhibiting adenosine deaminase than THU is in inhibiting cytidine deaminase.
  • the purine deaminase inhibitors (K i 10 - 1 1 to 10 -12 M) are roughly 10 4 to 10 5 times more tightly bound to its enzyme than THU is to cytidine deaminase (K i ca. 10 -7 M).
  • nucleosides of the type 3-7 involved first the synthesis of the seven-member ring heterocycle and second, its condensation with an appropriate sugar derivative. Methods were devised for the synthesis of the required heterocycles and their corresponding nucleosides which successfully afforded the desired compounds. In general, for the ribosides containing an acyl protecting functionality, formation of the ⁇ - anomer is exclusive or predominant. This fact is probably due to the participation of the 2'-acyl function during the condensation reaction (Watanabe et al, J. Carbohydr., Nucleosides, Nucleotides,
  • cytidine deaminase catalyzes the displacement of ammonia by water through an addition-elimination mechanism analogous to that proposed for adenosine deaminase.
  • 2'-deoxycoformycin the verypotent adenosine deaminase inhibitor
  • 6b designed as a coformycin analogue in the pyrimidine series
  • 6b is the most potent known inhibitor of cytidine deaminase (ten times more potent than THU) tends to support the idea of an intrinsic mechanistic similarity between these two important deaminases.
  • the K i value for tetrahydro-2-oxopyrimidine riboside, the six-member ring aglycone analogue of 3b is 4 x 10 -6 M forthe mouse kidney enzyme.
  • 3b is more than ten times more tightly bound to the enzyme (see Table 1) reflecting a potency increase of more than an order of magnitude in going from a six- to a seven-member ring aglycone. Placement of a hydroxyl group in the seven-member ring with the correct stereochemistry at carbon -5 (6b versus 3b) is responsible for another order of magnitude increase in binding to the enzyme.
  • the precursor keto compound 5b behaved as a poor inhibitor of the enzyme.
  • the enzymatic assay proves to be a useful tool for assigning the ⁇ -configuration to the inhibitors prepared in the ribofuranosyl series.
  • the enzyme's selectivity for the ⁇ -anomers constitutes additional proof for the ⁇ -configuration assigned to these nucleosides. Only ⁇ -cytidine, the natural substrate, is deaminated. ⁇ -cytidine, with the opposite configuration, was neither a substrate nor an inhibitor. This indicates that only nucleosides with the ⁇ -configuration fit into the enzyme's receptor site.
  • the benzene layer was dried (MgSO 4 ) and reduced to dryness to leave a clear oil; IR (neat) 1740 cm -1 , NMR (CDCl 3 ) ⁇ 2.30 (A 2 B 2 multiplet, 4), 2.60 (s,2), 3.65 (s,6), and 3.95 (s,4).
  • the oily ketal was immediately hydrolyzed under reflux for 1.5 h in a solution of 4.4 g of 86% KOH in 50 ml of 95% ethanol. After cooling, the slight precipitate formed was dissolved by adding a small amount of water.
  • Heterocycle (1c) (Example 3) (0.642 g, 5 mmol) was suspended in 25 ml of dry acetonitrile and treated with excess of bis- (trimethylsilyl) -trifluoroacetamide (BSTFA, 20 ml) and stirred at room temperature for 2 h. The solvent and excess reagent were removed in vacuo under careful anhydrous conditions. The residual persylylated heterocycle was dissolved in dry benzene (10 ml) and added immediately to a refluxing mixture of 1.8 g each of HgO and HgBr in 60 ml of benzene.
  • BSTFA bis- (trimethylsilyl) -trifluoroacetamide
  • 2, 3, 5-tribenzoyl-D-ribofuranosyl bromide prepared from 3.16 g (6.26 mmol) of 2,3,5- tribenzoyl- ⁇ -D-ribofuranosyl acetate, according to Stevens et al, J. Org. Chem., 33:1806 (1968), was added as a benzene solution in 20 ml of. solvent. The refluxing continued for 16 h. After cooling, the catalyrt was removed by filtration and the benzene solution was extracted twice with concentrated NaHCO 3 . solution. The organic extract was dried (MgSO 4 ) and reduced to dryness to yield a foamy residue.
  • this isomer of compound 5a (Example 11) was obtained along with 5a when the persylylated (1c; Example 3) was refluxed with the mercury catalysts for about ten minutes prior to the addition of the bromosugar. Under these conditions, 8a was the major component of the mixture and it appeared on TLC with an Rf value of 0.18. Separation was accomplished by a similar procedure as above affording the pure isomer in 37.5% as a thick syrup.
  • a solution of 0.4 g of the high Rf isomer (6a) in a few ml of chloroform was added to 50 ml of a saturated methanolic ammonia solution and kept in a pressure bottle at room temperature for 20 h.
  • the solution was reduced to dryness and extracted with CHCl 3 and water.
  • the aqueous layer was washed several times with CHCl 3 and then it was treated with charcoal, filtered and lyophilized.
  • the lyophilized material (0.160 g, 87%) was recrystallized from a mixture of MeOH-CHCl 3 -Et 2 O to give white needles, mp 110-112°; IR (KBr), 3250 and 1600 cm -1 , NMR (CD 3 OD) ⁇ 5.4 (multiplet, 6Hz wide,1,H' 1); [ ⁇ ] D 25 -115° (C 0.1, H 2 0) .
  • Mouse kidney cytidine deaminase was isolated and partially purified from mouse kidney acetone powder obtained from Sigma Chemical Co., Lt. Louis, Missiouri 63178. The powder was extracted with pH 8.0 phosphate butter (0.05 M) and the extract filtered through a
  • Cytidine deaminase from human liver was isolated by the procedure Of Wentworth et al, Biochemistry, 14:5099 (1975).

Abstract

Nucleosidea heterocycliques a sept chainons utilises pour inhiber l'enzyme de deamination responsable de la desactivation de l'arabinosylcytosine (ara-C). Les nucleosides preferes contenant un aglycone a sept chainons sont les suivants: (FORMULE) R = H, benzoyl, para-nitrobenzoyl X = H, OR A = R, mono-, di- et tri-phosphates (PO3E2, P2O6E3, P3O9E4) E = H, Na. Les aglycones preferes sont les suivants: (FORMULE) 1a: X = OCH2CH2O; 1b: X = SCH2CH2S; 1c: X= O; 1d: X = H, OH; 1e: X = 2H; Les composants actifs utilises contre les pyrimidines deaminases extraites de tissus de mammiferes (reins de rats et foies humains) ont presente des avantages optimaux en comparaison avec la tetrahydro uridine (THU).
PCT/US1981/000127 1980-01-28 1981-01-28 Composes cycliques a sept chainons utilise en tant qu'inhibiteurs de cytidine deaminase WO1981002164A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US115900 1980-01-28
US06/115,900 US4275057A (en) 1980-01-28 1980-01-28 Seven-membered ring compounds as inhibitors of cytidine deaminase

Publications (1)

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WO1981002164A1 true WO1981002164A1 (fr) 1981-08-06

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US (1) US4275057A (fr)
EP (2) EP0034424A3 (fr)
JP (1) JPS57500023A (fr)
WO (1) WO1981002164A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1513402A1 (fr) * 2002-05-30 2005-03-16 Albert Einstein College Of Medicine Of Yeshiva University Inhibiteurs ameliores d'adp-ribosyl transferases, cyclases, et hydrolases
US8951987B2 (en) 2007-10-16 2015-02-10 Otsuka Pharmaceuticals Co., Ltd. Certain compounds, compositions and methods
US9040501B2 (en) 2009-04-06 2015-05-26 Otsuka Pharmaceutical Co., Ltd. Compositions and methods for treating cancer

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5736531A (en) * 1987-10-28 1998-04-07 Pro-Neuron, Inc. Compositions of chemotherapeutic agent or antiviral agent with acylated pyrimidine nucleosides
EP1370139A4 (fr) * 2001-01-04 2010-09-22 Einstein Coll Med Inhibiteurs des adp-ribosyl transferases, cyclases, et hydrolases, et utilisations de ceux-ci
FR2875231B1 (fr) * 2004-09-15 2006-12-01 Centre Nat Rech Scient Cnrse Nouveaux derives de 1,3,5-triazepine-2,4-diones, leur procede de preparation et les compositions pharmaceutiques les contenant
ES2628609T3 (es) * 2009-04-06 2017-08-03 Otsuka Pharmaceutical Co., Ltd. Combinación de fármacos antineoplásicos a base de citidina con inhibidor de citidina deaminasa y uso del mismo en el tratamiento de cáncer
EP2416780B1 (fr) * 2009-04-06 2017-03-08 Otsuka Pharmaceutical Co., Ltd. Association de décitabine et d'un inhibiteur de la cytidine désaminase et utilisation de cette association dans le traitement du cancer
AR076262A1 (es) * 2009-04-06 2011-06-01 Eisai Inc Derivados heterociclicos de diazepin-2-ona, composiciones farmaceuticas y sus usos en el tratamiento del cancer
CN114990176A (zh) * 2022-05-26 2022-09-02 宁夏华吉生物有限公司 一种生产尿嘧啶核苷的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3462416A (en) * 1967-01-30 1969-08-19 Upjohn Co Hydrogenated pyrimidine nucleosides and nucleotides
US4163839A (en) * 1977-12-09 1979-08-07 Zaidan Hojin Biselbutsu Kagaku Kenkyu Kai Isocoformycin and a process for the production thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3462416A (en) * 1967-01-30 1969-08-19 Upjohn Co Hydrogenated pyrimidine nucleosides and nucleotides
US4163839A (en) * 1977-12-09 1979-08-07 Zaidan Hojin Biselbutsu Kagaku Kenkyu Kai Isocoformycin and a process for the production thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Volume 72, No. 17, issued 1970 (Columbus, Ohio, U.S.A.), Kunieda et al:, "Preparation and photochemistry of 5,6-cyclopropyluridines and of bicyclic isomers of thymines", pages 442-443, the Abstract No. 72:90805e; & J. Amer. Chem. Soc., 1969, 91, 7751-2 *
Chemical Abstracts, Volume 86, No. 15, issued 1977 (Columbus, Ohio, U.S.A.), Thieller et al:, "Unconventional nucleotide analogs. XV. Novel base - modified nucleosides", page 547, the Abstract No. 86: 106948f; & Heterocycles, 1976, 5, 19-24 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1513402A1 (fr) * 2002-05-30 2005-03-16 Albert Einstein College Of Medicine Of Yeshiva University Inhibiteurs ameliores d'adp-ribosyl transferases, cyclases, et hydrolases
EP1513402A4 (fr) * 2002-05-30 2009-10-28 Einstein Coll Med Inhibiteurs ameliores d'adp-ribosyl transferases, cyclases, et hydrolases
US8951987B2 (en) 2007-10-16 2015-02-10 Otsuka Pharmaceuticals Co., Ltd. Certain compounds, compositions and methods
US9567363B2 (en) 2007-10-16 2017-02-14 Otsuka Pharmaceutical Co., Ltd. Certain compounds, compositions and methods
US9040501B2 (en) 2009-04-06 2015-05-26 Otsuka Pharmaceutical Co., Ltd. Compositions and methods for treating cancer

Also Published As

Publication number Publication date
US4275057A (en) 1981-06-23
EP0034424A2 (fr) 1981-08-26
EP0065324A1 (fr) 1982-11-24
EP0034424A3 (fr) 1981-11-18
JPS57500023A (fr) 1982-01-07

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