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WO1990012014A1 - Composes anti-viraux - Google Patents

Composes anti-viraux Download PDF

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Publication number
WO1990012014A1
WO1990012014A1 PCT/GB1990/000538 GB9000538W WO9012014A1 WO 1990012014 A1 WO1990012014 A1 WO 1990012014A1 GB 9000538 W GB9000538 W GB 9000538W WO 9012014 A1 WO9012014 A1 WO 9012014A1
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WO
WIPO (PCT)
Prior art keywords
compound
derivative
hydroxymethyl
virus
ring
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.)
Ceased
Application number
PCT/GB1990/000538
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English (en)
Inventor
Linda Fellows
Robert Nash
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Medical Research Council
Original Assignee
Medical Research Council
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Filing date
Publication date
Application filed by Medical Research Council filed Critical Medical Research Council
Publication of WO1990012014A1 publication Critical patent/WO1990012014A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • 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
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • This invention relates to chemical compounds with anti-viral activity; in particular to chemical compounds for use in inhibiting the Human Immunodeficiency Virus (HIV) , and therefore as potential therapeutic agents for treatment of Acquired Immune Deficiency Syndrome (AIDS) .
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immune Deficiency Syndrome
  • polyhydroxyalkaloids have been shown to have anti-viral activity at non-toxic concentrations. These include castanospermine (an indolizidine alkaloid; Tyms et al Lancet, 1025 1987), 1- deoxynojirimycin (DNJ, a piperidine alkaloid; Walker et al ⁇ Proc. Third Inter. Symposium, Washington June 1987) and 2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine (DMDP, a pyrrolidine alkaloid; Gruters et a ⁇ Nature 330 1987) Castanospermine and DNJ have also been shown to inhibit Moloney murine leukaemia virus (Sunkara et al B.B. Res. Comm.
  • a compound for use against a virus comprising a pyrrolizidine ring having more than two hydroxyl groups and at least one hydroxymethyl group.
  • the hydroxyl groups may or may not be attached directly to the ring; e.g>. they may be contained in one or more hydroxymethyl groups.
  • the virus may be the Human Immunodeficiency Virus (HIV) .
  • HIV Human Immunodeficiency Virus
  • the compounds are described, for convenience, as polyhydroxypyrrolizidines, to distinguish from many other pyrrolizidines which carry no more than two hydroxyl groups.
  • the compound may be an alexine derivative, or a stereoisomer or epimer thereof, or it may be a structural variant of these.
  • the compound may be produced by modification of naturally- occurring polyhydroxypyrrolizidines, or complete synthesis of unnatural compounds.
  • the compound may be one produced by modification of any of the active compounds defined hereinbefore for anti-viral use; for example, compounds in which one or more of the hydroxymethyl groups are replaced by -CH0H-CH 2 0H, glucoside derivatives in which a linking glucose moiety is either an alpha- or beta-D-glucopyranoside link via one hydroxyl group (either attached to a ring or as part of a hydroxymethyl group) ; first order derivatives such as those formed by a single chemical reaction; for example, alkylation of the ring nitrogen; analogues formed by the replacement of one or more elements by analogous elements; homologues differing from the above compounds by the insertion of a methylene, ethylene or similar groups which do not affect the central relationship of the functional groups; acylated derivatives, acetone derivatives and salts, such as hydrochloride salts, for example.
  • Fig. 1 shows examples of the probable configurations of polyhydroxyalkaloid structures related to pyrrolizidines; and Fig. 2 shows examples of other polyhydroxyalkaloids.
  • Tables 1 and 2 show the action of some of these compounds on mouse gut digestive glucosidase and against amyloglucosidase.
  • Alexine 1R, 2R, 3R, 7S , 8S ) -3-hydroxymethyl-l , 2 , 7-
  • CAST-2 diepialexine
  • CAST-3 australine
  • Fig. 1 The activity of all four compounds against HIV has been compared and one, a pyrrolizidine alkaloid coded CAST-3, has been shown to be especially active in inhibiting the spread of the AIDS virus in cultured human lymphocytes at a concentration which is not toxic to the cells. It may therefore be of use in the clinical management of HIV infection.
  • the plant polyhydroxyalkaloids castanospermine an indolizine
  • deoxynojirimycin a piperidine
  • DMDP a pyrrolidine
  • CAST-2, CAST-3 and CAST-4 Three novel polyhydroxyalkaloids, all pyrrolizidines coded CAST-2, CAST-3 and CAST-4 (see Fig. 1) have been isolated from seed of Castanosper um australe (Leguminosae) .
  • CAST-2, CAST-3 and CAST-4 Two previously known but incompletely studied compounds, 6-epicastanospermine (an indolizidine) from C. australe and alexine (a pyrrolizidine) from Alexa species, have been re-isolated in order to compare their anti-HIV action with that of castanospermine.
  • certain other novel alkaloids, (NN9 and NN10, two piperidines) with known glycosidase-inhibitory properties were also tested against HIV.
  • CAST-2,-3 and -4 have been found to be epi ers of alexine.
  • the structure of CAST-2 is known but the stereochemistry of CAST-4 is still to be confirmed.
  • the likely structures are shown in (Fig. 1) .
  • CAST-3 has tentatively been assigned by spectroscopic techniques as 7,7a-diepialexine t(1R,2R,3R,7R,7aR)-3-hydroxymethyl-l,2,7- trihydroxyprrolizidine] (9) or its enantiomer 1,2,3- triepialexine [(IS,2S,3S,7S,7aS)-3-hydroxymethyl-l,2,7- trihydroxypyrrolizidine] (10) (Nash et al Phytochemistry, Vol. 29, No. 1, pp. 111-114, 1990).
  • CAST-3 has anti-HIV activity iir vitro at non-toxic concentration, whereas CAST-2 and CAST-4 have none.
  • the potency of CAST-3 is less than that of castanospermine. Nevertheless this is the first report of HIV inhibition by a pyrrolizidine and its activity may be enhanceable by acylation, in a manner analogous to recent modifications of deoxynojirimycin and castanospermine.
  • Ground freeze-dried seed 200g of Castanospermum australe A. Cunn. (Queensland Herbarium voucher no. BRI AQ 426819- M.P. HEGARTY) was extracted with 75% aq. EtOH(2x41) and the combined extracts concentrated under vacuum.
  • the alkaloids were purified by ion-exchange chromatography on Amberlite CG 120 (NH 4 + ) by elution with aq. NH 4 OH. Three unidentified compounds were eluted after castanospermine ( _) .
  • the reaction was stopped by immersion in a boiling water bath for 5 min, followed by incubation for 1 hr at 37 degrees with a tris-glucose oxidase reagent (Dahlqvist, A. (1968) Anal. Biochem. 22, 99) in which the colour reagent was 2,2 -azino-bis(3-ethylbenzthiazoline 6-sulphonic acid).
  • the assay was terminated by addition of 5M aq. HC1 and the absorbance read at 420nm.
  • Cell line JM.
  • Virus GBB strain of HIV.
  • Virus stock of the GB8 strain prepared from cell-free medium of acutely infected JM cells was diluted in growth medium (RPMI 1640, 10% fetal calf serum) containing different concentrations of test compound. After 15 minutes at room temperature, cells were added and virus absorption carried out at this temperature for 2 hours to provide a multiplicity of infection (MOI) of 0.001 syncytial-forming units per cell. Infected cells were pelleted, washed three times in phosphate buffered saline, resuspended in fresh growth medium containing test compounds at appropriate concentrations and distributed into 24 well tissue culture plates.
  • MOI multiplicity of infection
  • % % of virus control.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé utilisable contre le virus HIV comprenant un anneau pyrrolixidine ayant plus de deux groupes hydroxyle et au moins un groupe hydroxyméthyle ou un dérivé de celui-ci. Des exemples typiques ont les structures suivantes (I), (II), (II), (IV).
PCT/GB1990/000538 1989-04-08 1990-04-09 Composes anti-viraux Ceased WO1990012014A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898907951A GB8907951D0 (en) 1989-04-08 1989-04-08 Anti-viral chemical compounds
GB8907951.1 1989-04-08

Publications (1)

Publication Number Publication Date
WO1990012014A1 true WO1990012014A1 (fr) 1990-10-18

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Application Number Title Priority Date Filing Date
PCT/GB1990/000538 Ceased WO1990012014A1 (fr) 1989-04-08 1990-04-09 Composes anti-viraux

Country Status (2)

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GB (1) GB8907951D0 (fr)
WO (1) WO1990012014A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0538194A1 (fr) * 1991-10-17 1993-04-21 Ciba-Geigy Ag Nucléosides et oligonucléosides bicycliques, leur procédé de préparation et leurs intermédiaires
CN118356450A (zh) * 2024-04-24 2024-07-19 黄山徽药饮片有限公司 一种基于贡菊提取液的护眼液配方及其工艺

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Journal of Natural Products, Volume 51, No. 6, November/December 1988, (Columbus, Ohio, US), R.J. MOLYNEUX et al.: "Australine, A Novel Pyrrolizidine Alkaloid Glucosidase Inhibitor from Castanospermum Australe", pages 1198-1206, see page 1198, lines 26-35; page 1203, lines 33-36 *
Tetrahedron Letters, Volume 29, No. 20, May 1988, Pergamon Press, (Oxford, GB), R.J. NASH et al.: "Isolation from Alexa Leiopetala and X-Ray Crystal Structure of Alexine, (1R,2R,3R,7S,8S)-3-Hydroxymethyl-1,2,7-Trihydroxy-Pyrrolizidine ((2R,3R,4R,5S,6S)-2-Hydroxymethyl-1-Azabicyclo(3.3.0) Octan-3,4,6- Triol), a unique Pyrrolizidine Alkaloid", pages 2487-2490, see page 2487, lines 1-6 *
Tetrahedron Letters, Volume 29, No. 42, October 1988, Pergamon Press, (Oxford, GB), G.W.J FLEET et al.: "Synthesis from D-Glucose of Alexine ((1R,2R,3R,7S,8S)-3-Hydroxymethyl-1,2,7-Trihydroxy-Pyrrolizidine), 3-Epialexine and 7- Epialexine", pages 5441-5444, see page 5441, lines 1-9 *
Tetrahedron Letters, Volume 30, No. 42, October 1989, Pergamon Press, (Oxford, GB), C.M. HARRIS et al.: "I-Epiaustraline, a new Pyrrolizidine alkaloid from Castanospermum Australe", pages 5685-5688, see page 5685, lines 12-14; page 5686, lines 8-11 *
Tetrahedron Letters, Volume 44, No. 18, September 1988, Pergamon Press, (Oxford, GB), R.J. NASH et al.: "Isolation from Castanospermum Australe and X-Ray Crystal Structure of 3,8-Diepialexine, (1R,2R,3S,7S,8R)-3-Hydroxymethyl-1,2,7-Trihydroxypyrrolizidine ((2S,3R,4R,5S,6R)-2-Hydroxymethyl-1-Azabicyclo(3.3.0)Octan-3,4,6-Triol)", pages 5959-5964, see page 5959, lines 1-6 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0538194A1 (fr) * 1991-10-17 1993-04-21 Ciba-Geigy Ag Nucléosides et oligonucléosides bicycliques, leur procédé de préparation et leurs intermédiaires
US5319080A (en) * 1991-10-17 1994-06-07 Ciba-Geigy Corporation Bicyclic nucleosides, oligonucleotides, process for their preparation and intermediates
US5393878A (en) * 1991-10-17 1995-02-28 Ciba-Geigy Corporation Bicyclic nucleosides, oligonucleotides, process for their preparation and intermediates
CN118356450A (zh) * 2024-04-24 2024-07-19 黄山徽药饮片有限公司 一种基于贡菊提取液的护眼液配方及其工艺

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