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WO1990012014A1 - Anti-viral chemical compounds - Google Patents

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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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compound
derivative
hydroxymethyl
virus
ring
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PCT/GB1990/000538
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French (fr)
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Linda Fellows
Robert Nash
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Medical Research Council
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    • 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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  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

A compound for use against the HIV virus comprising a pyrrolizidine ring having more than two hydroxyl groups and at least one hydroxymethyl group or a derivative thereof. Some characteristic examples have structures (I), (II), (III), (IV).

Description

Anti-viral chemical compounds
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) .
Various naturally occuring 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. 1987) which, like HIV, is a retro-virus. All three compounds are reported to inhibit cytomegalovirus, a pathogen of AIDS patients which belongs to a different group of viruses, viz. it is a herpes virus (Taylor et al Antiviral. Res. lfJ 1988) and chemically modified forms of these compounds have been shown to have enhanced activity against HIV (Fleet et al Febs. Letts. 237 1988, Sunkara et al Abs. Proc. Complex Carb. Conf. San Antonio 1988). All three compounds have shown inhibition of glycosidases (Sasak et al Biochem. J. 232 1985, Saunier et al J. Biol. Chem. 257 1982, Elbein et al J. Biol. Chem. 259 1984, Scofield et al Life Sciences 3 1986).
According to the present invention there is provided a compound for use against a virus comprising a pyrrolizidine ring having more than two hydroxyl groups and at least one hydroxymethyl group.
Further according to the invention there is provided a method of treating a viral infection comprising administering a compound as defined in the preceding paragraph.
Further according to the invention there is provided a compound as defined in the two immediately proceding paragraphs for use in the manufacture of a medicament for the treatment^ of a viral infection.
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) .
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-CH20H, 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.
_
In the accompanying sheets of formulae:-
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.
The following abbreviations are used:-
NN9 : homonojirimycin (2,6-dideoxy-2,6-imino-D- glycero-L-guloheptitol CAST castanospermine (1,6,7,8-
(1) tetrahydroxyoctahydroindolizine) Fagomine 1,2,5,-trideoxy-1,5-imino-D-arabinohexitol CAST-2 3,8-diepialexine { (lR,2R,3S,7S,8R)-3-
(2) hydroxymethyl-1,2,7-trihydroxypyrrolizidine)
CAST-4 8-epialexine { (1R,2R,3R,7S,8R)-3-hydroxy-
(2) methyl-1,2,7,-trihydroxypyrrolizidine} NN10 2,6-dideoxy-5-0-( eta-D-glucopyranosyl)-2,6- imino-D-glycero-L-gulohepitol
DMJ deoxymannojirimycin (1,5-dideoxy-l,5-imino-D- mannitol)
DNJ deoxynojirimycin (1,5-dideoxy-l,5-imino-D- glucitol)
Alexine ( 1R, 2R, 3R, 7S , 8S ) -3-hydroxymethyl-l , 2 , 7-
(I) trihydroxypyrrolizidine DMDP 2R,5R-dihydroxymethyl-3R,4R- dihydroxypyrrolidine
Only four polyhydroxypyrrolizidines are known: alexine, diepialexine (CAST-2), CAST-3 and australine (CAST-4) and the structure of these are shown in 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.
Experimental Details and Results
The plant polyhydroxyalkaloids castanospermine (an indolizine), deoxynojirimycin (a piperidine) and DMDP (a pyrrolidine, see Fig. 2) have have been found to have selective anti-HIV effects in vitro at non-toxic concentrations. Similar action against cytomegalovirus, a common pathogen of AIDS patients has also been shown.
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) . In addition 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. In addition, 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) .
The structure of l,7a-diepialexine [(1S,2R,3R,7R,7aS)-3- hydroxymethyl-l,2,7-trihydroxypyrrolizidine] (7) was firmly established by X-ray crystallographic analysis of the hydrochlόride of l,7-isopropylidene-(lS,2R,3R,7R,7aS)-3- hydroxymethyl-l,2,7-trihydroxypyrrolizidine (8) .
The structure of 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.
The activity of all the naturally occurring alexines against glucosidase (disaccharidase) activity in the mouse (Table 1) and against fungal glucan 1,4-alpha-glucosidase (amyloglucosidase) (Table 2) has also been determined. Despite some activity against alpha-glucosidase (7_ and 9_) and trehalaεe these compounds appear to be weak inhibitors of mammalian digestive glycosidases compared to castanospermine. In contrast, all the compounds are strong inhibitors of the fungal glucan 1,4-alpha-glucosidase.
EXPERIMENT 1
Isolation
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 (NH4 +) by elution with aq. NH4OH. Three unidentified compounds were eluted after castanospermine ( _) . One was crystallized and shown by comparison of -^H and 13 CNMR data to be australine ( 3_) , [data for authentic australine being supplied by Dr R.J. Molyneux]. The others, l,7a-diepialexine (7_) (130 g) and 7,7a-diepialexine ( 9_) (200 mg) , were concentrated to oils and also converted to the corresponding hydrochlorides. Alkaloid peaks from the ion exchange column were analysed by gas chromatography of the pertrimethylsilyl derivatives on a 3% OVl column (1.5m x 4mm) at 170 degrees (isothermal) Nash, R.J. et al, 1986 J. Chromatog. 366,431. The retention times of the tri ethylsilylated derivatives, relative to that of 4_, were: 1_, 0.62; 9_, 0.62; 2_, 0.67; _2, 0.73; 1 , 0.78.
X-Ray crystal structure analysis.
The structure of the hydrochloride of 1,7-0-isopropylidene- 1,7a-diepialexine[ (IS,2R,3R,7R,7aS)-1,7-0-isopropylidene-3- hydroxymethyl-l,2,7-trihydroxypyrrolizidine] (8>) was established by single crystal X-ray analysis. The salt was recrystallized from Me2CO-H2θ.
Unfortunately, the crystals of 7,7a-diepialexine hydrochloride were not suitable for X-ray crystallographic analysis and the assignment of the relative configurations has been made on the basis of equilibrium NOE experiments on peracetylated 9 evidence for the stereochemistry of the substituents on the fully substituted five-membered ring was provided by observations of NOE's between substituents in a cis-1,3 relationship.
Enzyme assays.
The reagents and conditions for the assay of enzyme inhibition of mouse gut digestive glucosidase (Table 1) have been reported elsewhere (Scofield, A.M. et al (1986) Life Sci. 39, 645). Glucan 1,4-alpha-glucosidase (amyloglucosidase) [EC 3.1.2.3] from Aspergillus niger [Sigma, Poole] was assayed (Table 2) using amylose from potato [Sigma, Poole]; the reaction mixture containing amylose (0.13%), inhibitor and enzyme in 50mM maleate buffer, pH 6, was incubated for 15 min at 37 degrees. 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.
EXPERIMENT 2
Anti-HIV activity
Cell line: JM. Virus: GBB strain of HIV.
Protocol:-
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. After 3 days incubation at 37 degrees C, numbers of syncytia were scored in quadruple using an Olympus CK2 inverted microscope. At the same time, the supernatant culture fluid was sampled and clarified by centrifugation (2,000 rpm/5 minutes). The level of P24 antigen was determined by the Abbot core antigen ELISA test after treatment with 0.5% Triton X-100 and progeny virus infectivity was measured in culture medium by "back" titration in the respective T-cell line after ten fold dilution. End-points were determined by numbers of "countable" syncytia after 48 hours incubation. Dose- response curves were plotted against log10 drug concentration and the 50% effective dose (ED5Q) computed for both tests after linear regression analysis.
RESULTS
Compound , Concentration Syn.cytia Mean %
(Nos)
Virus Control 65, 90, 105 90 100 87, 110, 82
Castanospermine l.OmM 1, 0 0.5 0.5
0.5mM 4, 1 2.5 2.7
0.25mM 2 , 0 1.0 1.1
Alexine l.OmM 76, 80 78 87
0.5mM 99, 90 94.5 >100
CAST-2 l.OmM 97, 86 91.5 >100
0.5mM 95, 103 99 >100
CAST-3 l.OmM 7, 2 4.5 5
0.5mM 36, 35 35.5 40
0.25mM 54, 73 63.5 71
CAST-4 l.OmM 101, 111 106 >100
0.5mM 101, 112 106.5 >100
6-epi- castanospermine l.OmM 39, 62 50.5 56
0.5mM 90, 87 88.5 98
0.25mM 90, 77 83.5 93
% = % of virus control.
(Nos) = Number of syncytia aggregates.
NN9 and NN10 were inactive, TABLE 1
Action of naturally occurring alexines on mouse gut digestive glucosidase (disaccharidase) activy compared with that of castanospermine
p-Nitrophenyl p-Nitrσphenyl
Inhibitor alpha-D-glucopyranoside B-D-glucopyran
l,7a-Diepialexine ( 7 ) 9.5 x 10 -5 NI 7,7a-Diepialexine (9) 1.6 x 10"5 2.3 X 10"4 Alexine (JL) NI NI 3,7a-Diepialexine (2) NI NI 7a-Epialexine (3) NI 3.3 X 10 -4 Castanospermine (4) 2.8 X 10 1.7 X 10-5
Inhibitor Trehalose
l,7a-Diepialexine (7) NI
7,7a-Diepialexine (9) 1.0 X 10 -4
Alexine (1) 5.9 X 10
3,7a-Diepialexine (2) NI
7a-Epialexine (3) NI
Castanospermine (4) 9.8 X 10 -6
Concentration (M) of alkaloid giving 50% inhibition, NI=less than 50% inhibition at 3.3 x 10~4M.
TABLE 2
Action of naturally occurring alexines on glucan 1,4-alpha- glucosidase-catalysed hydrlolysis of potato amylose compared with that of castanospermine.
Concn. (M) of alkaloid
Inhibitor giving 50% inhibition
l,7a-Diepialexine (7) 1.5 x 10"
.-7
7,7a-Diepialexine (9.) 1.3 x 10
Alexine (1) 1.1 x 10-5
3,7a-Diepialexine (2) 2.1 x 10-6
7a-Epialexine (3) 1.5 x 10-6
Castanospermine (4) 1.5 x 10"
Modifications and improvements may be added without departing from the scope of the invention.

Claims

1. A compound for use against a virus comprising a pyrrolizidine ring having more than two hydroxyl groups and at least one hydroxymethyl group, in which one or more of the hydroxymethyl groups may or may not be replaced by -CHOH-CH2OH,or a glucoside derivative thereof in which a linking glucose moiety is either an alpha- or beta-D- glucopyranoεide link via one hydroxyl group (either attached to a ring or as part of a hydroxymethyl group); or a first order derivative thereof; or an analogue thereof formed by the replacement of one or more elements by analogous elements; or a homologue thereof differing therefrom by the insertion of a group which does not affect the central relationship of the functional groups; or an acylated derivative thereof; or an acetone derivative; or a salt thereof.
2. A method of treating a viral infection comprising administering a compound as defined in Claim 1.
3. A compound as defined in Claim 1, for use in the manufacture of a medicament for the treatment of a viral infection.
4. A compound as defined in Claim 1, wherein at least one of said hydroxyl groups is attached directly to the ring.
5. A compound as defined in Claim 1, wherein at least one of said hydroxyl groups is not attached directly to the ring.
6. A compound as defined in Claim 5, wherein at least one of said hydroxyl groups is contained in a hydroxymethyl grou
7. A compound as claimed in any one of the preceding Claims, wherein the virus is Human Immunodeficiency Virus (H
8. A compound as claimed in any one of the preceding Claims, wherein the compound is a polyhydroxypyrrolizidine.
9. A compound as claimed in Claim 8, wherein the compound is an alexine derivative.
10. A compound as claimed in Claim 9, wherein the compound i a stereoisomer or epimer of the alexine derivative.
11. A compound as claimed in Claim 9 or Claim 10, wherein th compound is a structural variant of the alexine derivative or a stereoisomer or epimer thereof.
12. A compound as claimed in any one of Claims 8, 9 or 10, wherein the compound is produced by modification of a naturally-occurring polyhydroxypyrrolizidine.
I*
13. A compound as claimed in any one of Claims 1 to 11, wherein the compound is produced by complete synthesis from unnatural compounds.
PCT/GB1990/000538 1989-04-08 1990-04-09 Anti-viral chemical compounds WO1990012014A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0538194A1 (en) * 1991-10-17 1993-04-21 Ciba-Geigy Ag Bicyclic nucleosides, oligonucleotides, their method of preparation and intermediates therein

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 (3)

* Cited by examiner, † Cited by third party
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EP0538194A1 (en) * 1991-10-17 1993-04-21 Ciba-Geigy Ag Bicyclic nucleosides, oligonucleotides, their method of preparation and intermediates therein
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

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