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Sommaire du brevet 2379544 

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Disponibilité de l'Abrégé et des Revendications

L'apparition de différences dans le texte et l'image des Revendications et de l'Abrégé dépend du moment auquel le document est publié. Les textes des Revendications et de l'Abrégé sont affichés :

  • lorsque la demande peut être examinée par le public;
  • lorsque le brevet est émis (délivrance).
(12) Demande de brevet: (11) CA 2379544
(54) Titre français: NOUVEAUX STILBENES A ACTIVITE DE DEGRADATION VASCULAIRE
(54) Titre anglais: NEW STILBENES WITH VASCULAR DAMAGING ACTIVITY
Statut: Réputée abandonnée et au-delà du délai pour le rétablissement - en attente de la réponse à l’avis de communication rejetée
Données bibliographiques
(51) Classification internationale des brevets (CIB):
  • C7C 43/23 (2006.01)
  • A61K 31/09 (2006.01)
  • A61P 35/00 (2006.01)
  • C7F 9/12 (2006.01)
(72) Inventeurs :
  • DAVIS, PETER DAVID (Royaume-Uni)
(73) Titulaires :
  • ANGIOGENE PHARMACEUTICALS LTD.
(71) Demandeurs :
  • ANGIOGENE PHARMACEUTICALS LTD. (Royaume-Uni)
(74) Agent: GOWLING WLG (CANADA) LLP
(74) Co-agent:
(45) Délivré:
(86) Date de dépôt PCT: 2000-08-09
(87) Mise à la disponibilité du public: 2001-02-22
Requête d'examen: 2005-07-18
Licence disponible: S.O.
Cédé au domaine public: S.O.
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Oui
(86) Numéro de la demande PCT: PCT/GB2000/003067
(87) Numéro de publication internationale PCT: GB2000003067
(85) Entrée nationale: 2002-02-11

(30) Données de priorité de la demande:
Numéro de la demande Pays / territoire Date
9918912.8 (Royaume-Uni) 1999-08-12

Abrégés

Abrégé français

L'invention concerne un nouveau groupe de cis-stilbènes représentés par la formule (1), ou un sel pharmaceutiquement acceptable de ceux-ci, ou un promédicament tel qu'un ester de phosphate. Dans cette formule, R?1¿, R?2¿, et R?3¿ représentent chacun indépendamment alkyle; R?4¿ représente alkyle, haloalkyle, alcényle, alcynyle, alkylthio, alkylsulphinyle, alkylsulphonyle ou halo; R?5¿ représente hydrogène, alcoxy, alkle, alkylthio, hydroxy ou halo. Ces composés possèdent une activité de dégradation vasculaire. et sont cependant potentiellement utiles pour traiter des maladies dans lesquelles le renversement de la néovascularisation peut présenter un bénéfice thérapeutique.


Abrégé anglais


A group of novel cis-stilbenes as disclosed of formula (1) wherein: R1, R2 and
R3 are each independently alkyl, R4 is alkyl, haloalkyl, alkenyl, alkynyl,
alkylthio, alkylsulphinyl, alkylsulphonyl or halo, R5 is hydrogen, alkoxy,
alkyl, alkylthio, hydroxy or halo, or a pharmaceutically acceptable salt
thereof or a prodrug such as a phosphate ester. These compounds have vascular
damaging activity and are therefore potentially of value in treatment of
diseases where reversal of neovascularisation may have therapeutic benefit.

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.


15
CLAIMS:
1. A cis-stilbene of formula
<IMG>
Wherein:
R1, R2 and R3 are each independently alkyl,
R4 is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulphinyl,
alkylsulphonyl or halo,
R5 is hydrogen, alkoxy, alkyl, alkylthio, hydroxy or halo,
or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
2. A cis-stilbene according to claim 1 wherein
R1, R2 and R3 are all methyl.
3. A cis-stilbene according to claim 2 wherein
R5 is hydrogen and R4 is alkyl or halo.
4. (Z-1-(3-hydroxy-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene.
5. A prodrug of a cis-stilbene which is an carboxylic ester, phosphate ester,
sulphate ester or carbonate of a cis-stilbene as claimed in any one of claims
1 to 3.
6. A prodrug of a cis-stilbene which is a phosphate ester of a cis-stilbene
according to claim 1.

16
7. A prodrug according to claim 5 which is a dihydrogen phosphate ester.
8. (Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl dihydrogen
phosphate.
9. A composition for use in the treatment of neovascularisation which
composition contains an effective amount of a cis-stilbene according to any
one of
claims 1 to 4 or a prodrug thereof according to any one of claims 5 to 8.
10. Use in the preparation of a composition for the treatment of
neovascularisation
of a cis-stilbene as claimed in any one of claims 1 to 4 or a prodrug thereof
according
to any one of claims 5 to 8.

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.


CA 02379544 2002-02-11
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NEW STILBENES WITH VASCULAR DAMAGING ACTIVITY
Formation of new vasculature by angiogenesis is a key pathological feature of
several
diseases (J Folkman, New England Journal of Medicine 333, 1757-1763 (1995)).
For
example, for a solid tumour to grow it must develop its own blood supply upon
which
it depends critically for the provision of oxygen and nutrients; if this blood
supply is
mechanically shut off the tumour undergoes necrotic death. Neovascularisation
is also
a clinical feature of skin lesions in psoriasis, of the invasive pannus in the
joints of
to rheumatoid arthritis patients and of atherosclerotic plaques. Retinal
neovascularisation
is pathological in macular degeneration and in diabetic retinopathy. In all
these diseases
reversal of neovascularisation by damaging the newly-formed vascular
endothelium is
expected to have a beneficial therapeutic effect.
Compounds able to damage neovasculature have advantages in the treatment of
disease. For example, attacking tumour vasculature has several important
advantages
over a direct attack on the tumour. In particular the endothelial cells of
tumour
vasculature are more genetically stable than those of the tumour itself and
are therefore
less likely to become resistant to the damaging agent. Thus a major problem in
2o conventional anti-tumour chemotherapy, that of drug resistance, is
circumvented by
this approach. Furthermore, since the endothelial cells of the tumour
vasculature,
unlike the tumour cells themselves, are similar between different solid tumour
types,
vascular damaging agents are able to attack a wide range of tumour types.
A number of tubulin-binding agents including the stilbenes combretastatin Al,
combretastatin A4 (D. J. Chaplin et al.,British J. Cancer 27, S86-S88
(1996))and
combretastatin A4 phosphate (D.J. Chaplin et al., Anticancer Research 19, 189-
196,
(1999)) are known to selectively damage neovasculature of solid tumours in
animal
models. While there are reports of the activity of other analogues of
combretastatin
A4 in tubulin binding assays, in cytotoxicity assays and in tumour models
there have
been no reports of the vascular damaging activities of analogues. Since the
activity of

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tubulin-binding compounds against in vitro assays are poor predictors of
selective
vascular damaging activity and activity of such compounds in vivo can also be
mediated by direct antimitotic effects on the tumour itself, no prediction can
be made
of the selective vascular damaging activity of known or novel analogues of the
combretastatins from published reports. Thus compounds which have the
advantages
of a selective anti-vascular mechanism given above, rather than acting through
a direct
effect on the tumour tissue itself, are not apparent.
We have found a series of novel cis-stilbenes with vascular damaging activity.
These
to compounds specifically damage newly-formed vascular endothelium, especially
that
associated with solid tumours, without affecting the normal, established
vascular
endothelium of the host species. Such compounds are of use in the prophylaxis
and
treatment of cancers involving solid tumours and in other diseases where there
is
inappropriate formation of new vasculature such as diabetic retinopathy,
psoriasis,
15 rheumatoid arthritis, macular degeneration and the formation of
atherosclerotic
plaques.
Known vascular-damaging stilbenes, combretastatin Al, combretastatin A4 and
combretastatin A4 phosphate have a 4-methoxy group in the "B" ring. The
2o compounds of the invention lack a 4-methoxy group in the ring corresponding
to the
"B" ring of combretastatin A4. Several studies suggest that substituting
alternative
groups for the 4-methoxy group in the B-ring of combretastatin A4 would
considerably reduce biological activity:
25 In J. Med. Chem 1991, 34, 2579-2588, Cushman et al. state, regarding
analogues of
combretastatin A4: "the presence of a 4-methoxy group in the B-ring plays a
very
important role for this compound to be highly cytotoxic". Replacement of the 4-
methoxy group with chlorine, for example, gave compounds that were three to
four
orders of magnitude less potent against a panel of five different cell lines.

CA 02379544 2002-02-11
WO 01/12579 PCT/GB00/03067
3
In J. Med. Chem. 1998, 41, 3022-3032 Ohsumi et al. disclose anilino analogues
of
combretastatin A4 in which the replacement of the B-ring 4-methoxy group by
either a
methyl group or a chlorine atom gave a reduction in biological potency of 8.5-
fold and
13.5-fold respectively.
Similarly in Brit. J. Cancer 1995, 71, 705-711 Woods et al. disclose analogues
of
combretastatin with reduced potency. For example the 4-methyl compound shows
3.5
to 36-fold reduction in potency against four cell lines compared to the 4-
methoxy
compound.
It cannot be anticipated from the above studies that compounds in which the B-
ring 4-
methoxy group is replaced would retain anti-vascular activity. It is
particularly
unexpected that replacing the B-ring methoxy group of combretastatin A4 would
result
in a compound with similar potency as a vascular damaging agent.
Thus according to one aspect of the invention we provide a compound of formula
(1):
R5
R'O ~ ~ ~ ~ OH
Ra0 OR3 R4
(1)
Wherein:
R',RZ and R3 are each independently alkyl,
R4 is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulphinyl,
alkylsulphonyl or halo,
RS is hydrogen, alkoxy, alkyl, alkylthio, hydroxy or halo,
and the pharmaceutically acceptable salts, solvates, hydrates and prodrugs
thereof.

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As used herein the term "alkyl", alone or in combinations, means a straight or
branched-chain alkyl group containing from one to seven, preferably a maximum
of
four, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
t-butyl
and pentyl. Examples of alkoxy groups are methoxy, ethoxy, propoxy,
isopropoxy,
butoxy and t-butoxy.
The term "halogen" means fluorine, chlorine, bromine or iodine.
An alkenyl group may be for example an olefinic group containing from two to
seven
to carbon atoms for example methylene, ethylene, n-propylene, i-propylene, n-
butylene, i-
butylene, s-butylene and t-butylene. An alkynyl group may be for example an
ethynyl ,
propynyl or butynyl group.
Where one or more functional groups in compounds of formula (1) are
sufficiently
15 basic or acidic the formation of salts is possible. Suitable salts include
pharmaceutically
acceptable salts for example acid addition salts including hydrochlorides,
hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates,
arylsulphonates, acetates, benzoates, citrates, maleates, fumarates,
succinates, lactates
and tartrates, salts derived from inorganic bases including alkali metal salts
such as
2o sodium or potassium salts, alkaline earth metal salts such as magnesium or
calcium
salts, and salts derived from organic amines such as morpholine, piperidine or
dimethylamine salts.
Prodrugs of the invention are compounds which upon administration to a mammal
25 produce compounds of formula ( 1 ). Such prodrugs can be for example
converted
within the mammal by hydrolysis. Prodrugs are preferably ester derivatives of
the
phenolic hydroxy group contained in compounds of formula ( 1 ) such as, for
example,
phosphate esters, carboxylate esters, sulphate esters and carbonates.
30 Preferred compounds of the invention are those of formula 1 in which R', RZ
and R3
are all methyl, and prodrugs thereof

CA 02379544 2002-02-11
WO 01/12579 PCT/GB00/03067
Further preferred compounds of the invention are those of formula I in which
R', RZ
and R3 are all methyl and RS is hydrogen and prodrugs thereof
Still further preferred compounds of the invention are those of formula I in
which R',
RZ and R3 are all methyl, RS is hydrogen and R4 is alkyl or halo and prodrugs
thereof
Preferred prodrugs of the invention are phosphate esters. Particularly
preferred
prodrugs of the invention are dihydrogen phosphate esters.
to
Specifically preferred compounds of the invention are:
(~-I-(3-hydroxy-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene
15 (~-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl dihydrogen
phosphate
Compounds of the invention can be prepared by any process known to a person
skilled
in the art. Compounds of formulae ( 1 ) can be prepared by a number of
processes as
generally described hereinbelow and more specifically in the Examples
hereinafter. In
20 the general preparations described below it may be necessary to employ
protecting
groups which are then removed during the final stages of the synthesis. The
appropriate use of such protecting groups and processes for their removal will
be
readily apparent to those skilled in the art. In the following process
description, the
symbols R', Rz, R', R'~ and R5, when used in the formulae depicted are to be
25 understood to represent those groups described above in relation to formula
(1) unless
otherwise indicated
In one general example compounds of formula (1) can be prepared by Wittig
olefin
synthesis involving reaction of a phosphonium salt of formula (2) with a
strong base,
3o for example an alkyllithium such as n-butyllithium or t-butyllithium or a
metal hydride
such as sodium hydride in a solvent such as an ether solvent for example
diethyl ether

CA 02379544 2002-02-11
WO 01/12579 PCT/GB00/03067
or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example
toluene at
a temperature of between about -100°C to about 30°C followed by
treatment with an
aldehyde of formula (3) in which R6 is a protecting group, to give an
intermediate of
formula (4). The synthesis of compounds of formula (1) is then completed by
removal
of the group R6. Suitable protecting groups R6 include trialkylsilyl, for
example t-
butyldimethylsilyl, and allyl. Where R6 is a trialkylsilyl group it may be
removed, for
example, by treatment with a quaternary ammonium fluoride such as
tetrabutylammonium fluoride in an ether solvent such as tetrahydrofuran at a
temperature of about -30°C to about 40°C conveniently at or near
ambient
1o temperature. Where R~ is an allyl group it may be removed for example by
treatment
with a palladium(0) complex such as tetrakis(triphenylphosphine)Pd(0) in a
solvent
such as a chlorinated solvent, for example dichloromethane, at a temperature
of about -
40°C to about 40°C conveniently at or near ambient temperature,
in the presence of an
allyl scavenger such as morpholine.
Br Ph3 .
HO
_ Rs _ Rs _ Rs
R'O I \ ' ~ I OR R~ I \ ~ / OR6 ~ R'O I ~ \ I OH
R~ OR3 R~ R~ OR3 R' R~ OR'
(2) (3) (4) (t )
Aldehydes of formula (3) can be prepared by any process known to a person
skilled in
the art. In one general example an aldehyde of formula (3) can be prepared
from an
alcohol of formula (S) by oxidation with a suitable oxidising agent. Suitable
oxidising
2o agents include the Dess-Martin reagent and manganese dioxide. Alcohols of
formula
(5) can be prepared by application of standard methods of organic synthesis
including
the selective protection of phenols of formula (6). Where the protecting group
R6 is a
trialkylsilyl group, for example t-butyldimethylsilyl, alcohols of formula (5)
may be
prepared, for example, by treatment of a phenol of formula (6) with a strong
base, for
example an alkyllithium such as n-butyllithium or t-butyllithium or a metal
hydride such
as sodium hydride in a solvent such as an ether solvent for example diethyl
ether or
tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example
toluene at a

CA 02379544 2002-02-11
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7
temperature of between about -100°C to about 40°C followed by
treatment with tert-
butylchlorodimethylsilane.
Phenols of formula (6) are either known or may be prepared from known
compounds
using standard methods of organic synthesis.
HZOH H OH HO
RS z Rs RS
OH ~ I OR ~ I O
R~ R~ Rs
Compounds of formula ( 1 ) may also be prepared from other compounds of
formula
(I) by chemical modification. Examples of such chemical modifications that may
be
applied are standard alkylation, halogenation, oxidation and coupling
reactions. These
reactions may be used to add new substituents or to modify existing
substituents.
Prodrugs of compounds of formula ( 1 ) can be prepared by any process known to
a
person skilled in the art. Processes for the preparation of prodrugs of
compounds of
formula 1 include standard acylation, sulphation and phosphorylation
reactions. In
one general example dihydrogen phosphate esters of compounds of formula ( 1 )
can be
prepared by treatment of the corresponding di-t-butylphosphate esters with an
acid, for
example hydrochloric acid or trifluoroacetic acid, in a solvent such as a
chlorinated
2o solvent, for example dichloromethane, at a temperature of from about -
20°C to about
40°C, conveniently at room temperature.
Compounds according to the invention are able to destroy tumour vasculature
and
vasculature that has been newly formed while leaving unaf~'ected normal,
mature
vasculature. The ability of the compounds to act in this way may be determined
by the
tests described hereinafter.

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The compounds according to the invention are thus of particular use in the
prophylaxis
and treatment of cancers involving solid tumours and in the prophylaxis and
treatment
of diseases where inappropriate angiogenesis occurs such as diabetic
retinopathy,
psoriasis, rheumatoid arthritis, atherosclerosis and macular degeneration.
The compounds of the invention may be administered as a sole therapy or in
combination with other treatments. Thus the invention includes compositions
for the
treatment of neovascularisation which compositions contain an effective amount
of a
cis-stilbene or prodrugs thereof as hereinbefore defined. The invention also
includes
l0 the use in the preparation of a composition for the treatment of
neovascularisation of a
cis-stilbene or prodrugs therof as hereinbefore defined. For the treatment of
solid
tumours compounds of the invention may be administered in combination with
radiotherapy or in combination with other anti-tumour substances for example
those
selected from mitotic inhibitors, for example vinblastine, vincristine,
vinorelbine,
15 paclitaxel and docetaxel; platinum derivatives for example cisplatin and
carboplatin;
alkylating agents, for example melphalan, chlorambucil, busulphan, ifosfamide
and
cyclophosphamide; antimetabolites, for example methotrexate, 5-fluorouracil,
cytosine
arabinoside, gemcitabine and hydroxyurea; antitumour antibiotics for example
bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C,
2o dactinomycin and mithramycin ; enzymes, for example aspariginase;
topoisomerase
inhibitors for example etoposide,teniposide, topotecan and irinotecan;
thymidylate
synthase inhibitors for example raltitrexed; biological response modifiers for
example
interferon; antibodies for example edrecolomab and trastuzumab; anti-hormones
for
example tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene,
anastrozole,
25 letrazole, vorazole ,exemestane, flutamide, nilutamide and bicalutamide;
anti-growth
factor compounds for example EGFr tyrosine kinase inhibitors VEGFr kinase
inhibitors and PDGFr tyrosine kinase inhibitors; and anti-angiogenesis agents
such as
angiostatin, endostatin and thalidomide. Such combination treatment may
involve
simultaneous or seduential application of the individual components of the
treatment.

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9
For the prophylaxis and treatment of disease the compounds according to the
invention
may be administered as pharmaceutical compositions selected with regard to the
intended route of administration and standard pharmaceutical practice. Such
pharmaceutical compositions may take a form suitable for oral, buccal, nasal,
topical,
rectal or parenteral administration and may be prepared in a conventional
manner
using conventional excipients. For example for oral administration the
pharmaceutical
compositions may take the form of tablets or capsules. For nasal
administration or
administration by inhalation the compounds may be conveniently delivered as a
powder
or in solution. Topical administration may be as an ointment or cream and
rectal
to administration may be as a suppository. For parenteral injection (including
intravenous,
subcutaneous, intramuscular, intravascular or infusion) the composition may
take the
form of, for example, a sterile solution, suspension or emulsion.
The dose of a compound of the invention reduired for the prophylaxis or
treatment of a
particular condition will vary depending on the compound chosen, the route of
administration, the form and severity of the condition and whether the
compound is to
be administered alone or in combination with another drug. Thus the precise
dose will
be determined by the administering physician but in general daily dosages may
be in the
range 0.001 to I OOm.~~,/kg preferably 0.1 to IOmg/kg.
BIOLOGICAL ACTIVITY
The following test was used to demonstrate the activity of compounds according
to the
invention.
Activity against tumour vasculature measured by fluorescent dye.
The following experiment further demonstrates the ability of the compounds to
damage tumour vasculature.
Tumour functional vascular volume in CaNT tumour-bearing mice was measured
using
3o the fluorescent dye Hoechst 33342 according to the method of Smith et al
(Brit J
Cancer 57, 247-253, 1988). At least three animals were used in control and
treated

CA 02379544 2002-02-11
WO 01/12579 PCT/GB00/03067
groups. The fluorescent dye was dissolved in saline at 6.25 mg/ml and injected
intravenously at 10 mg/kg 24 hours after intraperitoneal drug treatment. One
minute
later, animals were killed and tumours excised and frozen; 10 ~m sections were
cut at
3 different levels and observed under UV illumination using an Olympus
microscope
5 equipped with epifluorescence. Blood vessels were identified by their
fluorescent
outlines and vascular volume was quantified using a point scoring system based
on that
described by Chalkley, (J Natl Cancer Inst, 4, 47-53, 1943). All estimates
were based
on counting a minimum of 100 fields from sections cut at the 3 different
levels.
Examples of the activity of compounds of the invention in this test are given
in the
to table:
Compound of ExampleDose (mg/kg) % Reduction in Functional
Vascular Volume
1 50 88
3 50 27
S 50 20
The following non-limiting Examples illustrate the invention:
EXAMPLE 1
(~-1-(3-hydroxy-4-meth~phenyl)-2-(3,4,5-trimethoxyphenyl)ethene
A solution of 1-(3-tort-butyldimethylsilyloxy-4-methylphenyl)-2-(3,4,5-
trimethoxyphenyl)ethene (491mg) in anhydrous tetrahydrofuran (lOml) at room
temperature was treated slowly with a 1.1M solution of tetrabutylammonium
fluoride
in tetrahydrofuran (1.1m1). After 30 minutes crushed ice (5m1) and
diethylether (30m1)

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11
were added and the aqueous phase extracted with diethylether (5 portions of
Sml).
The combined extracts were washed with water (3 portions of l Oml) and brine (
l Oml),
dried (MgS04) and concentrated under reduced pressure to give a solid.
Recrystallisation from ethyl acetate/hexane gave the title compound (208mg) as
a
white solid m.p. 123-125°C. nmr: SH (SOOMHz, d6-DMSO) 2.07 (s, 3H),
3.57 (s,
6H), 3.62 (s, 3H), 6.40 (d, J = l2Hz, 1H), 6.46 (d, J = 12 Hz, 1H), 6.56 (s,
2H), 6.61
(dd, J = 8Hz, 2Hz, 1H), 6.76 (d, J= l.7Hz, 1H), 6.98 (d, J = 8Hz, 1H), 9.21 (s
1H).
The 1-(3-tort-butyldimethylsilyloxy-4-methylphenyl)-2-(3,4,5-
trimethoxyphenyl)ethene
to used as starting material in the above preparation was prepared as follows:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (848mg) in
dry
tetrahydrofuran (50m!) at -78°C was treated dropwise with n-
butyllithium (0.9m1 of a
1.8M solution in hexane) and the mixture allowed to warm to -40°C and
stir for 1h.
The mixture was recooled to -78°C and a solution of 3-tert-
butyldimethylsilyloxy-4-
methylbenzaldehyde (390mg) in tetrahydrofuran (40m1) added slowly. After a
further
2h the mixture was allowed to warm to room temperature before being poured
into ice
water (20m1). The aqueous phase was extracted with diethylether (5 portions of
20m1)
and the combined extracts were washed with water (3 portions of 20m1) and
brine (2
portions of 20m1), dried (MgS04) and concentrated under reduced pressure to
give an
oil. Purification by chromatography on silica gel, eluting with petroleum
ether / ethyl
acetate (90:10) gave 1-(3-tort-butyldimethylsilyloxy-4-methylphenyl)-2-(3,4,5-
trimethoxyphenyl)ethene (456mg) as a red oil.
The 3-tort-butyldimethylsilyloxy-4-methylbenzaldehyde used as starting
material in the
above preparation was prepared as follows:
A solution of Dess-Martin periodinane (187mg) in dichloromethane (4m1) was
treated
slowly with a solution of 3-tort-butyldimethylsilyloxy-4-methylbenzyl alcohol
(100mg)
in dichloromethane (4m1) and the mixture stirred for 1 h at room temperature.
Diethylether ( l Oml) was added followed by aqueous sodium thiosulphate
solution
(lOml) and the mixture stirred for 15 minutes. The aqueous phase was extracted
with
diethylether (5 portions of 20m1) and the combined extracts were washed with
aqueous

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12
sodium thiosulphate solution (3 portions of lOml), water (3 portions of lOml)
and
brine (2 portions of IOmI), dried (MgS04) and concentrated under reduced
pressure to
give a yellow solid. Purification by chromatography on silica gel, eluting
with
petroleum ether / diethyl ether (50:50) gave 3-tert-butyldimethylsilyloxy-4-
methylbenzaldehyde (85mg).
The 3-tert-butyldimethylsilyloxy-4-methylbenzyl alcohol used as starting
material in the
above preparation was prepared as follows:
A solution of 3-hydroxy-4-methylbenzyl alcohol (275mg) in dry tetrahydrofuran
to (lSml) at -78°C was treated slowly with n-butyllithium (1.2m1 of a
1.8M solution in
hexane) and the mixture stirred for I Sminutes before being allowed to warm to
room
temperature and stir for a further 30minutes. A solution of tert-
butylchlorodimethylsilane (287mg) in tertrahydrofuran ( I Oml) was added and
the
mixture stirred for 16h. Water (20m1) was added and the mixture extracted with
diethylether (5 portions of 20m1) and the combined extracts were washed with
water (2
portions of I Oml) and brine (20m1), dried (MgS04) and concentrated under
reduced
pressure. Purification by chromatography on silica gel, eluting with petroleum
ether /
diethyl ether (50:50) gave 3-tort-butyldimethylsilyloxy-4-methylbenzyl alcohol
(390mg).
EXAMPLE 2
~Z)-2-methyl-5-[2-~3.4,5-trimethoxyphenyl)ethen~]phenyl dihydro~en phosphate
Trifluoroacetic acid (0.22mL, 2.95mmol) was added dropwise to a stirred
solution of
(~-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl di-tertbutyl phosphate
(401mg, 0.82mmo1) and dichloromethane (l6mL). The mixture was stirred at room
temperature overnight. Solvent was removed in vacuo, and the residue
azeotroped
four times with toluene. The colourless oil was triturated with ether to give
the title
compound as a white solid (181mg, 58%) m.p. 109-113°C. nmr: 8H (SOOMHz,
d6-
3o DMSO) 2.39 (s, 3H), 3.81 (s, 6H), 3.87 (s, 3H), 6.69 (d, J=l2Hz, 1H), 6.74
(d,

CA 02379544 2002-02-11
WO 01/12579 PCT/GB00/03067
13
J=l2Hz, 1H), 6.78 (s, 2H), 7.07 (d, J=8Hz, 1H), 7.28 (d, J=8Hz, 1H), 7.49 (s,
1H),
9.0 (bs, 2H).
(~-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl di-tertbutyl phosphate
was
prepared as follows:
Di-tert-butylphosphoramidite (498mg, 2.OOmmo1) in dichloromethane ( 1 mL) was
added to a solution of (~-1-(3-hydroxy-4-methylphenyl)-2-(3,4,5-
trimethoxyphenyl)ethene (300mg, I.OOmmol), 1H-tetrazole (182mg, 2.60mmo1) in
dichloromethane (3mL) under nitrogen. After 2h, magnesium monoperoxyphthalate
to hexahydrate ( 1.248, 2.OOmmol) was added in portions. After stirring for a
further 2h,
the reaction mixture was partitioned between ethyl acetate and water; the
aqueous
phase was extracted (ethyl acetate x2); the combined organic extracts were
washed
(water x2, brine x1); dried (MgSO~) and concentrated in vacz~o. Flash
chromatography, eluting with 33% ethyl acetate/hexane, gave (~-2-methyl-5-[2-
(3,4,5-trimethoxyphenyl)ethenyl]phenyl di-tertbutyl phosphate as a yellow oil
(401mg,
82%).
EXAMPLE 3
(~-1-(4-fluoro-3-hvdroxyphenyl)-X3,4.5-trimethoxyphenyl)ethene
This compound was isolated directly from the Wittig reaction between 3,4,5-
trimethoxybenzyltriphenylphosphonium bromide and 3-teat-butyldimethylsilyloxy-
4-
fluorobenzaldehyde (340mg) performed in an analogous manner to that of Example
1.
There was obtained the title compound (80mg) as a colourless oil. nmr:
(300MHz, d6-
DMSO) 3.59 (s, 6H), 3.63 (s, 3H), 6.46 (d, J=l2Hz, 1H), 6.48 (d, J=l2Hz, 1H),
6.54
(s, 2H), 6.68 (m, 1H), 6.90 (dd, J=8.8, 2.lHz, 1H), 7.06 (dd, J=11.4, 8.4Hz,
1H), 9.80
(s, 1H).
The following compounds were prepared in an analogous manner to that of
Example
1:

CA 02379544 2002-02-11
WO 01/12579 PCT/GB00/03067
14
EXAMPLE 4
~,Z~-1-(4-chloro-3-hyd roxyphenyl)-X3,4, 5-trimethoxyphenyl)ethene
From (~-1-(3-tort-butyldimethylsilyloxy-4-chlorophenyl)-2-(3,4,5-
trimethoxyphenyl)ethene (240mg) there was obtained the title compound (121mg)
as a
colourless oil. nmr: (300MHz, d6-DMSO) 3.59 (s, 6H), 3.63 (s, 3H), 6.49 (m,
2H),
6.54 (s, 2H), 6.71 (dd, J=8.2, 0.9Hz, 1H), 6.93 (d, J=0.9Hz, 1H), 7.25 (d,
J=8.2Hz,
1H), 10.11 (bs, 1H).m/e 320 (M+).
l0
EXAMPLE 5
(~-1-(4-ethyl-3-h d~yphenyl)-X3.4,5-trimethoxYphenyl)ethene
From (~-1-(3-tort-butyldimethylsilyloxy-4-ethylphenyl)-2-(3,4,5-
trimethoxyphenyl)ethene (926mg) there was obtained the title compound (208mg)
as a
white solid m.p. 105-107°C, nmr: 8H (300MHz, CDC13) 1.02 (t, J=7.6Hz,
3H), 2.6 (q,
J=7.5Hz, 2H) 3.7 (s, 6H), 3.8 (s, 3H), 4.6 (bs, 1H), 6.4 (d, J = l2Hz, 1H),
6.5 (d, J =
12 Hz, 1 H), 6. 5 (s, 2H), 6. 7 (s, l H), 6. 8 (d, J= 7.6Hz, 1 H), 7.0 (d, J =
7. 6Hz, 1 H).
2o

Dessin représentatif
Une figure unique qui représente un dessin illustrant l'invention.
États administratifs

2024-08-01 : Dans le cadre de la transition vers les Brevets de nouvelle génération (BNG), la base de données sur les brevets canadiens (BDBC) contient désormais un Historique d'événement plus détaillé, qui reproduit le Journal des événements de notre nouvelle solution interne.

Veuillez noter que les événements débutant par « Inactive : » se réfèrent à des événements qui ne sont plus utilisés dans notre nouvelle solution interne.

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , Historique d'événement , Taxes périodiques et Historique des paiements devraient être consultées.

Historique d'événement

Description Date
Inactive : CIB expirée 2017-01-01
Demande non rétablie avant l'échéance 2006-08-09
Le délai pour l'annulation est expiré 2006-08-09
Inactive : CIB de MCD 2006-03-12
Lettre envoyée 2005-08-12
Réputée abandonnée - omission de répondre à un avis sur les taxes pour le maintien en état 2005-08-09
Requête d'examen reçue 2005-07-18
Toutes les exigences pour l'examen - jugée conforme 2005-07-18
Exigences pour une requête d'examen - jugée conforme 2005-07-18
Lettre envoyée 2003-04-24
Inactive : Transfert individuel 2003-02-20
Inactive : Page couverture publiée 2002-08-08
Inactive : Lettre de courtoisie - Preuve 2002-08-06
Inactive : Notice - Entrée phase nat. - Pas de RE 2002-07-31
Demande reçue - PCT 2002-05-06
Exigences pour l'entrée dans la phase nationale - jugée conforme 2002-02-11
Exigences pour l'entrée dans la phase nationale - jugée conforme 2002-02-11
Demande publiée (accessible au public) 2001-02-22

Historique d'abandonnement

Date d'abandonnement Raison Date de rétablissement
2005-08-09

Taxes périodiques

Le dernier paiement a été reçu le 2004-07-19

Avis : Si le paiement en totalité n'a pas été reçu au plus tard à la date indiquée, une taxe supplémentaire peut être imposée, soit une des taxes suivantes :

  • taxe de rétablissement ;
  • taxe pour paiement en souffrance ; ou
  • taxe additionnelle pour le renversement d'une péremption réputée.

Les taxes sur les brevets sont ajustées au 1er janvier de chaque année. Les montants ci-dessus sont les montants actuels s'ils sont reçus au plus tard le 31 décembre de l'année en cours.
Veuillez vous référer à la page web des taxes sur les brevets de l'OPIC pour voir tous les montants actuels des taxes.

Historique des taxes

Type de taxes Anniversaire Échéance Date payée
Taxe nationale de base - générale 2002-02-11
TM (demande, 2e anniv.) - générale 02 2002-08-09 2002-07-22
Enregistrement d'un document 2003-02-20
TM (demande, 3e anniv.) - générale 03 2003-08-11 2003-07-25
TM (demande, 4e anniv.) - générale 04 2004-08-09 2004-07-19
Requête d'examen - générale 2005-07-18
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
ANGIOGENE PHARMACEUTICALS LTD.
Titulaires antérieures au dossier
PETER DAVID DAVIS
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
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Description du
Document 
Date
(yyyy-mm-dd) 
Nombre de pages   Taille de l'image (Ko) 
Dessin représentatif 2002-08-06 1 3
Page couverture 2002-08-07 1 33
Abrégé 2002-02-10 1 54
Revendications 2002-02-10 2 34
Description 2002-02-10 14 569
Rappel de taxe de maintien due 2002-07-30 1 114
Avis d'entree dans la phase nationale 2002-07-30 1 208
Demande de preuve ou de transfert manquant 2003-02-11 1 102
Courtoisie - Certificat d'enregistrement (document(s) connexe(s)) 2003-04-23 1 107
Rappel - requête d'examen 2005-04-11 1 117
Accusé de réception de la requête d'examen 2005-08-11 1 177
Courtoisie - Lettre d'abandon (taxe de maintien en état) 2005-10-03 1 176
PCT 2002-02-10 4 134
PCT 2002-02-11 4 189
Correspondance 2002-07-30 1 24
PCT 2002-02-11 4 172
Taxes 2003-07-24 1 28
Taxes 2002-07-21 1 47
Taxes 2004-07-18 1 33