|Title of Invention||
PROCESS FOR THE SYNTHESIS OF OPTICALLY ACTIVE ANTHRACYCLINES.
|Abstract||IT IS DESCRIBED A PROCESS FORTHE SYNTHESIS OF OPTIOCALLY ACTIVE ANTHRACYCLINES CHARACTERISED BY THE FACT THAT THE KEY INTERMEDIATE (R)2-ACETLY-2-HYDROXY-1,2,3,4-TETRAHYDRONAPHATALENE 5,8-DIALKOXY IS PREPARED FROM 5,8-DIALKOXY IS PREPARED FROM 5,8-DIALCOXY -3,4-DIHYDRONAPHTALENE BY ACYLATION ASYMMETRIC DIHYDROXYLATION, TRANSFORMATION INTO CHLOROACETATE , DEHYDROCHLORIDATION AND FINAL HYDROLYSIS.|
|Full Text||PROCESS FOR THE SYNTHESIS OF OPTICALLY ACTIVE ANTHRACYCLINES
Field of the invention
The present invention refers to a process for the synthesis of optically active
anthracyclines wherein the optically active key intermediate (R) 2-acetyl-2-
ihydroxy-1,2,3,4-tetrahydronaphthalene 5,8-dialkoxy of formula I.
wherein: R = C1-3 alkyl, preferably methyl.
is prepared starting from 5,8-dialkoxy-3,4-dihydronaphthalene by acvlation,
asymmetric dihydroxylation, transformation into chloroacetate dehydrochloridation
and final hydrolysis.
The invention refers also to the intermediates of formula V e VI:
Having an enantiomeric excess higher than 95%.
State of the art
As it is known the anthracyclines of formula VIII
Wherein: R1 = H, OH, OCH3; R2 = H, OH; R3 = X,Y o Z where
are compounds having a wide therapeutic use as anti-neoplastic drugs.
Known compounds of formula VIII having the above said properties are for
example Daunomicin (VIII, wherein: R1 = OCH3, R2 = H, R3 = X), la Doxorubicin
(VIII wherein: R1 = OCH3, R2 = OH, R3 = X), I"Hydrarubicin (VIII wherein: R1 = H,
R2 = H, R3 = X) e I"Epirubicin (VIII wherein: R1 = OCH3, R2 = OH, R3 = Y), or the
compounds described in EP721456, in particular the compound of formula VIII
wherein R1 = H, R2 = OH, R3 = Z, disaccharide anthracycline which is now under
The synthesis of anthracycline of formula VIII requires many steps and is normally
performed starting from an optically active tetraline of formula I which is reacted by
a Friedel-Craftsreaction with phthalic anhydride or its derivatives as phthaloyll
dichloride or phthaloyll chloride methylester and thereafter cyclised. The so
obtained tetracycle is protected in the 13-oxo position with ethylenglycol, is
brominated in position 7 and converted into a 7-OH derivative with known methods
(see Arcamone et al., Experientia, 1978,34,1255; Wong et al. Can. J. Chem.,
1971, 49, 2712; Swenton et al. , Tetrahedron, 1984,40, 4625). After deprotection
the anthracyclinone of formula VII (wherein R2 = H) is used as such or is converted
into a 14 acyloxy derivative (compound of formula VII wherein R2 = O-
acyl)according to known procedures. Thereafter the compounds of formula VII are
glycosidated with protected mono- or disaccharides as described in literature (see
Arcamone et al., Experientia, 1978,34, 1255; Terashima et al., Bull. Chem. Soc.
Jpn, 1986, 59, 423 ) and in EP.....6, by deprotection the anthracycline of formula
VIII are obtained.
In the above described process, or in other similar processes which include as
intermediate a tetraline, the key intermediate is the tetraline of formula I itself as
This AB synthon (Wong et al. Can. J. Chem, 1971, 49, 2712) allows the formation
of the corresponding optically active anthracyclinone of formula VII wherein R1 =
H, OH, OCH3 and R2 = H, OH, O-acyl wherein the acyl group is chosen among
formyl, acetyl, mono-, di- or trichloroacetyl, preferably acetyl.
As above said the compound is finally converted in the desired anthracycline.
The stereochemistry of position C-9 of the anthracyclinone is very important for the
biological activity of these compounds since only the compounds having (S)
configuration in C-9 show an antitumour activity.
Therefore also the tetraline intermediate of formula I must obviously possess the
same stereochemistry (i.e. an absolute configuration R).
The tetraline I is normally prepared. According to the literature, as a racernic
mixture starting from 2-acetyI-5,8-dimethoxy tetraline III by oxydrilation in position
C-2 with potassium t-butoxide/t-butanole in the presence of oxygen followed by
reduction "in situ" (Wong et al., Can. J. Chem., 1971, 49, 2712 ; Gardner et al.,
J.Org. Chem.1968, 33, 3294).
The compound III was prepared, with very low yields by reacting 5,8-dimethoxy-
3,4-dihydronaphthalene II with N-N-diphenylacetamide- POCI3 applying the
conditions of the Vilsmeier-Haack reaction followed by the reduction of the double
Several attempts of acylating compound II have been reported but all unsuccessful
(Rama Rao et al. Ind.J.Chem. 1985, 24B, 697).
Alternatively the compound III was prepared with a yield of about 50% in 4 steps
by reaction of 5,8-diacetoxy-3,4-dihydronaphthalene with acetyl chloride/AICl3 and
formation of a chloroacetyl derivative, followed by dehydrochloridation with LiCI,
hydrolysis and methylation "in situ" (Russell et al. J. Chem. Soc. Chem. Comm.
Another reaction path for obtaining the precursor III reported in literature includes
five steps starting from 5,8-dihydroxy-1,4-diidronphthalene with a total yield of
about 50% (Giles et al. S.Afr.J.Chem, 1990,43, 87).
The racemic tetraline I is thereafter converted into the pure enantiomeric
compound using the normal methods applied for the resolution of racemes through
diastereoisomeric Schiff bases on the acetyl lateral chain with (-)-1-
phenylethylamine (Arcamone et al. BP 02691/75, 1975). Alternatively the
enantiomeric pure compound was prepared by Kinetic resolution via a Sharpless
asymmetric epoxidation followed by oxidation of the obtained allyl alcohol obtained
by reducing 2-acetyl-5,8-dimethoxy-3,4dihydronaphthalene (Sharpless et al.
J.Am.Chem.Soc. 1981, 103. 6237). Another method for obtaining the optically
pure tetraline consists in the stereoselective reduction of the racemic mixture with
bakers" yeast to diastereoisomeric dioles mixtures followed by chromatographic
separation and re-oxidation (Terashima et al., Chem. Pharm. Bull. 1984, 32.
An asymmetric synthesis of the tetraline I starting from precursor III by
enantioselective dihydroxylation is described in M. Nakajima et al. Tetrahedron,
1993, 49, 10807, but the several steps and the final excess of tetraline I and
especially the use of osmium tetraoxide in stoichiometric quantities, instead of
catalytic, quantities and the use of expensive chiral amines (always in
stoichiometric quantities) quantities at a temperature of - 110°C, makes very
difficult the industrial use of this synthesis.
Other asymmetric synthesis of AB synthon using chiral compounds or compounds
comprising chiral derivatives of natural compounds are reported in literature but all
these synthesis are very complex and unsuitable for industrial application (Krohn,
Angew. Chem. Int. Ed. Engl., 1986, 25, 790).
Summary of the invention
The present invention describes a process for the preparation of anthracyclines of
formula VIII as above defined VIII wherein the optically active tetraline of formula I
as above defined is stereoselectively prepared starting from 5,8-dialkoxy-3,4-
dihydronaphthalene II which, contrary to the methods applying the resolution of
racemic mixture, which are difficult to perform, and give yields inferior to 30%,
shows the advantage of giving the key intermediate I in yields much higher than
those reported in literature and is easily industrially exploitable .
In particular, although the literature reported as fruitless, or non interesting
because of the low yields, the attempts of acylating compound II ( Rama Rao et al.
Ind.J.Chem.1985, 24B, 697, Russell et al. J. Chem. Soc. Chem. Comm. 1983,
994, Giles et al. S.Afr.J.Chem, 1990,43, 87), the 5,8-dialkoxy-3,4-
dihydronaphthalene (compound of formula II wherein R is a group C1-3 alkyl,
preferably methyl) can surprisingly be acylated in just one step in the presence of
an acyl chloride and aluminium trichloride forming the corresponding acyl
derivative III. Moreover this innovative application of the procedure of
enantioselective catalytic dihydroxylation of olefins (Sharpiess et al., Chem. Rev.
1994, 94, 2483) to give the insature acyl derivative allows to obtain the optically
active diol IV in a good yield. The compound is thereafter converted into the
corresponding 1-chloro-2-acetyl-derivative by Sharpiess procedure (Sharpiess et
al, Tetrahedron, 1992, 48, 10515) and dehalogenated following known methods,
for example by catalytic hydrogenation or in the presence of tin and a radical
precursor or can be directly dehydroxylated by catalytic reduction. The final
hydrolysis of the ester group allows the formation of compound I in good yields
and high optical purity.
Detailed description of the invention
In Schema I it is reported a process for obtaining the tetraline of formula I wherein
R = CH3. In this case the starting product is the 5,8-dimethoxy-3,4-
dihydronaphthalene II, obtained by known methods starting from butadiene and p-
quinone (Fieser et al., J.Am.Chem.Soc, 1948, 70, 3151).
In spite of the fact that in literature the attempts of acylating the compound II were
reported as fruitless or non interesting because of the low yields, the 5,8-
dimethoxy-3,4-dihydronaphthalene II is treated with acetyl chloride in the
presence of an excess of aluminium trichloride, preferably 5-9 moles of
aluminium trichloride for one mole of acyl chloride, at the temperature of -35° ÷
25°C, preferably at 0°C. After the usual work-up and crystallisation with ethyl
acetate, the product, 2-acetyl-5.8-dimethoxy-3,4-dihydronaphthalene is obtained
in yields higher than 70%.
Compound III is stereoselectively converted to diol IV by a Sharpless asymmetric
dihydroxylation which is described in literature for other olefin substrates
(Sharpless et al., Chem. Rev. 1994, 94, 2483). The reactive used in this step is
AD-mix a (catalogue Aldrich, reactive 39275-8, see also J. Org. Chem. 1992, 57,
2768) with a further addition of the osmium salt (K2OsO2(OH)4) and
The osmium salt is always in catalytic quantity vis-a-vis the substrate. The reaction
is performed at low temperature,-4 e +20°C, preferably at 0°C, the yield is 70%,
with an enantiomeric excess higher than 95%.
The optically active diol IV is converted into a chloroacetate V through the
formation "in situ" of a cycle intermediate using trimethylortoacetate in the
presence of an acid catalyst followed by treatment with trimethylsilyl chloride
according to a method already described in literature for different dioles (Sharpless
et al. Tetrahedron, 1992, 48,10515).
This step gives yields higher then 80%.
The reduction of the chloroacetate to acetate VI can be performed photochemical
or by thermic treatment in the presence of tributyltinhydride and radical precursors
as AIBN or BPO or by catalytic hydrogenation.
The yields are higher then 80%.
The acetate can be obtained directly by catalytic reduction of diol IV.
The hydrolysis of the acetate can be performed with ionic exchange resins in
quantitative yield. Alternatively the known methods for the hydrolysis of the
acetates, as the treatment with sodium methoxide or sodium hydroxide.
What reported in Scheme I can be easily applied to the synthesis of all the
compounds of formula I, using the corresponding starting products.
The tetraline I which is an object of the present invention is therefore obtained in
only 4-5 steps with a total yield much higher than the one reported for the known
Moreover, the reaction conditions as described make it possible the industrial
scale up of the process. The subsequent steps of the process through the
anthracyclinone to the final anthracycline are performed as described in literature.
The process according to the invention will be better understood in the light of the
hereinafter reported Example which refers to the Scheme 1 i.e. to the preparation
of the tetraline of formula I wherein R = CH3.
Synthesis of III
To a suspension of aluminium trichloride (449 g) in dichloromethane (2 I) in
nitrogen current, acetyl chloride (380 ml) is added drop by drop at 0°C. After 30
min. stirring at 0°C, to the so obtained solution a solution of 5,8-dimthoxy-3,4-
dihydronaphthalene II (80 g) in dichloromethane (2,5 I) is slowly added drop by
drop. After 30 min stirring at 0°C the mixture was hydrolysed with ice. After
separation of the organic phase and washing with HCI 1N (3 x 6 I), H2O (3 x 41)
and brine (2 x 4 I), the solvent was evaporated u.v. at 40°C giving a yellow solid
residue (98 g). By crystallisation from refluxing ethyl acetate 71 g of the desired
compound III where obtained.
Yield 73 %.
1H NMR (CDCI3): 2.44 (s, 3H, H10); 2.53 (m, 2H, H6); 2.80 (m, 2H, H5); 3.30, 3.84
(2s, 6H, OCH3); 6.75 (dd, 2H, H2 + H3); 7.81 (m, 1H, H8);
13C NMR (CDCI3): 19-9, 20.5 (C5, C6); 25.3 (C10); 55.9, 56.1 (OCH3); 108.5, 113.2
(C2, C3); 122.6, 127.2 (C4a, C8a); 131.5 (C8); 137.2 (C7); 150.4, 151.0 (C1, C4);
TLC: r.f. 0.80 (Petrol ether/Ethyl acetate = 80/20).
HPLC: r.t. = 8.9 min (Conditions: Lichrospher 100 RP 18 (5µm, 250 x 4 mm)
CH3CN / H2O + 0.1 % TFA = 60 / 40; 1 ml/min; X = 214 nm; 20 µJ of a solution 1
Synthesis of IV
To a solution of AD mix-? (600 g) and K2OsO2(OH)4 (1 g) in water (2 I) t-butanole
(2.15 I), methansulphonammide (40.7 g), sodium bicarbonate (109 g) are added.
The mixture was stirred up to complete solution of the solid components, cooled
down at 0°C, added with 4-acetyl-3,4-dihydronaphthalene (100 g) and vigorously
stirred for 96 h.
After complete reaction of the precursor, checked by TLC (Petrol ether/ethyl
acetate = 80/20), 630 g of sodium bisulphite are added in portions and, after 1 h
stirring, 4 I of AcOEt are added and the phases are separated.
The organic phase was washed with NaOH 1N (1 x 2 I), H2O (1x2 1) and
evaporated under vacuum.
The obtained solid was solved in 750 ml CH2CI2 and the solution was extracted
with H2SO4 3 % saturated with K2SO4 (4 x 200 ml), NaHCO3 s.s. (1 x 300 ml)
and H2O (1 x 300 ml).
The organic phase, dried on anhydrous MgSO4, was evaporated under vacuum
leaving a solid residue.
The product was crystallised from AcOEt / cyclohexane = 1/1, filtered and dried
78.7 g of a crystalline solid were obtained. Yield: 70.5%
1H NMR (CDCI3): 1.87 (m, 2H, H6); 2.38 (s, 3H, H10); 2.79 (m, 2H, H5); 3.78, 3.84
(2s, 6H, OCH3); 3.81 (m, 1H, H8); 4.87 (d, 1H, OH8); 5.29 (s, 1H, OH7); 6.71 (s,
2H, H2 + H3).
13C NMR (CDCI3): 19.1 (C10); 25.8 (C5); 28.7 (C6); 55.7, 55.7 (OCH3); 68.5 (C8);
78.7 (C7); 108.0, 108.8 (C2, C3); 125.8, 127.1 (C4a, C8a); 151.1, 152.3 (C1, C4);
TLC: r.f. 0.25 (Petrol ether/Ethyl acetate = 80/20)
HPLC: r.t. = 4.1 min (Conditions: Lichrospher 100 RP 18 (5µm) 250 x 4 mm
CH3CN / H2O + 0.1 % TFA = 50 / 50; 1 ml/min; X = 214 nm; 20 µl of a solution 2.8
e.e. = 98 % determined by chiral HPLC (Conditions: Chiralcel OD 250 X 4.6 mm;
n-hexane / EtOH = 90 /10; 1 ml/min; X = 214 nm; 20 µl of a solution 1.3 mg / 10
m. p. = 141-143°C.
[?]D25=-21.9° (c= 1.0, CHCl3)
Synthesis of V
To a solution of diol (77 g) in CH2CI2 (600 ml), under nitrogen,
trimethylortoacetate (59.3 ml) and piridiniumtoluene-4-sulphonate (2 g) are added.
The solution is stirred at room temperature for 24 H. The solvent is evaporated
under vacuum leaving a solid residue.
The solid was solubilised CH2CI2 (600 ml) and added, under nitrogen, with
trimethylsiiyl chloride (65 ml). The reaction mixture is stirred at room temperature
for 1 h and, after evaporation of the solvent under vacuum, was treated with
cyclohexane (400 ml) under vigorous stirring for 3 h.
The solid was filtered and dried under vacuum.
98.1 g of the desired product were obtained (quantitative yield).
1H NMR (CDCI3): 1.96 (s, 3H, H10); 1.97 - 3.15 (m, 4H, H5 + H6); 2.43 (s, 3H, H12);
3.81, 3.87 (2s, 6H, OCH3); 5.35 (d, 1H, H8); 6.76 (dd, 2H, H2 + H3);
13C NMR (CDCI3): 19.6 (C11); 20.2, 20.5 (C5, C6); 26.3 (C12); 52.9 (C8); 55.6, 56.0
(OCH3); 82.9 (C7); 108.3, 110.1 (C2, C3); 123.2, 125.4 (C4a. C8a); 150.7, 151.6 (C1,
C4); 169.6 (C11); 204.2 (C9).
TLC : r.f. = 0.55 (Petrol ether / AcOEt = 75 / 25)
m.p. = 128-138°C.
[?]D25=-16.2° (c =1-0, CH2CI2).
Synthesis of VI
To a solution of chloacetate (97.3 g) in toluene (2 I) AIBN (1.5 g) and tributyl-
tinhydrure (225 ml) were added in nitrogen current. The mixture was stirred under
the light of a 200 Watt wolfram lamp for 24 h and thereafter extracted with water
(500 ml). The organic phase is separated, dried and evaporated under vacuum.
The residue is treated with cyclohexane (500 ml) under stirring, filtered and dried
under vacuum at 40°C.
67.8 g of the desired product are obtained in the form of a white solid.
Yield : 80.3 %.
1H NMR (CDCI3): 1.95, 2.50 (2m, 2H, H6); 2.05 (1.3H, H10); 2.22 (1.3H, H12); 2.40,
2.90 (2m, 2H, H5); 3.00 (dd, 2H, H8); 3.77, 3.80 (2s, 6H, OCH3); 6.66 (m, 2H, H2 +
13C NMR (CDCl3): 19.5, 21.0 (C5, C6); 24.0 (C10); 26.7 (C12); 30.2 (C8); 55.6, 55.5
(OCH3); 83.6 (C7); 107.0, 107.2 (C2, C3); 122.7, 125.1 (C4a, C8a);150.9, 151.4 (C1,
C4); 170.5 (C11); 206.5 (C9).
TLC : r.f. = 0.28 (Toluene/Ethylacetate = 95/5)
HPLC: r.t. = 7.4 min (Conditions: Lichrospher 100 RP 18 (5µm) 250 x 4 mm,
CH3CN / H2O + 0.1 % TFA = 60 / 40; 1 ml/min; ? - 214 nm; 20 µL of a solution 1.2
[?]D25: -46.3° (c = 1.0, CHCl3).
Synthesis of I
To a solution of acetate (66 g) in methanol (5 I) the Amberlite IRA-400 resin (OH)
(183 ml) previously activated by treatment with NaOH 30% (8 x 400 ml) and
washed with water (5 x 400 ml) and methanol (4 x 400 ml) was added. The
reaction mixture is stirred for a night at room temperature. After removal of the
resin by filtration and evaporation of the solvent under vacuum a solid residue was
obtained which after crystallisation from cyclohexane/ethylacetate, filtration and
drying gave 51.85 g of desired product.
Yield: 92 % .
1H NMR (CDCI3): 1.89 (m, 2H, H6); 2.33 (s, 3H, H10); 2.91 (m, 4H, H5 + H8); 3.65
(s, 1H, OH); 3.77, 3.80 (2s, 6H, OCH3); 6.66 (s, 2H, H2 + H3).
13C NMR (CDCI3): 19.2 (C5); 23.9 (C10); 29.7, 32.4 (C6, C8); 55.5, 55.6 (OCH3);
76.4 (C7); 107.0, 107.4 (C2, C3); 122.7, 125.5 (C4a, C8a); 151.1, 151.6 (C1, C4);
TLC: r.f. = 0.27 (Petrol ether/Ethylacetate = 80/20
HPLC : r.t. = 5.9 min (Conditions: Lichrospher 100 RP 18 (5µm) 250 x 4 mm,
CH3CN / H2O + 0.1 % TFA = 50 / 50; 1 ml/min; ? = 214 nm; 20 µl of a solution 2.5
e.e = > 99% determined by chiral HPLC (Conditions: Chiralcel OD 250 X 4.6 mm;
n-hexane I EtOH = 90 /10; 1 mi/min; X = 214 nm; 20 µl of a solution 1.35 mg /10
m.p. : 126-129°C.
[?]D25 = -46.2° (c = 1.0, CHCl3)
Process for the preparation of anthracycline of formula VIIl:
wherein R1 = H, OH, OCH3; R2 = H5 OH; R3 = X, Y or Z where:
comprising the formation of the intermediate of formula (l):
wherein: R = C1-3, alkyl
characterised in that said intermediate of formula (I) is prepared starting from a 5-
dialkoxy-3,4-dihydronaphthaiene of formula (H):
wherein R = C1-3 alkyl
according to the following steps:
a) the 5,8-dialkoxy-3,4-dihydronaphthalene of formula (II), is acylated in a single
step with acetyl chloride in the presence of an excess of AlCl3 at a
temperature comprised between -35° and 25° C , forming the corresponding
acyl derivative (III)
wherein R = C1-3 alkyl;
b) the acyl derivative (III) is enantioselectively hydroxylated by a Sharpless
asymmetric dihydroxylation, to form the diol (IV):
wherein R = C1-3 alkyl;
c) the diol (IV) is converted into the acetate (VI)
by direct catalytic reduction or, alternatively, through the chloroacetate (V):
by reaction with trimethylortoacetate in the presence of an acid catalyst followed by
treatment with trimethylsilylchloride and subsequent reduction according to known
d) the acetate (VI) is hydrolyzed to the tetralin of formula (I).
2. Process as claimed in claim 1 wherein the tetralin of formula (I) is converted,
according to known procedures, into the anthracyclinone of formula (VII),
wherein R1 = H, OH, OCH3, R2 = H, OH, O-acyl, wherein acyl is chosen between
formyl, acetyl, mono- or di-chloroacetyl
and this is finally converted into the anthracycline of formula (VIII) as claimed in
claim 1 according to known procedures.
3. Process as claimed in claim 2 wherein R = methyl and R2 = O-acetyl.
4. Process as claimed in claim 1 wherein the acylation is performed at 0° C.
5. Process as claimed in claiml wherein the enantioselective dihydroxylation
according to step (b) is performed using catalytic quantities of osmium using the
reactive AD-mix a with a addition of art osmium salt and methanesulphone-amide.
6. Process as claimed in claim 5 wherein the osmium salt used is K2OSO2 (OH)4.
7. Process as claimed in claim 6 wherein the reaction is performed at -4- +20°C.
8. Process as claimed in claim 7 wherein the reaction is performed at 0°C.
9. Process as claimed in claims 1-8 wherein the anthracyclmes of formula
(VIII) are: daunomicin (VIII, wherein R1 = OCH3, R2 = H1 R3 = X), doxorubicin
(VIII wherein: R1 = OCH3, R2 - OH, R3 = X), l"idarubicin (VIII wherein R1 = H, R2
= H, R3 = X) l"epirubicin (VIII, wherein: R1 = OCH3, R2 = OH, R3 = Y), or a
tetracycline of formula VIII wherein: R1 - H, R2 = OH, R3 = Z, where X, Y, and Z
are as claimed in claim 1.
10. Optically active compound of formula V
It is described a process for the synthesis of optically active anthracyclines characterised by the fact that the key intermediate
(R)2-acetyl-2-hydroxy-1,2,3,4-tetrahydronaphtalene 5,8-dialkoxy is prepared from 5,8-dialcoxy-3,4-dihydronaphtalene
by acylation asymmetric dihydroxylation, transformation into chloroacetate, dehydrochloridation and final hydrolysis.
|Indian Patent Application Number||604/KOLNP/2003|
|PG Journal Number||04/2008|
|Date of Filing||13-May-2003|
|Name of Patentee||MENARINI RICERCHE S.P.A,.|
|Applicant Address||VIA TITO SPERI, 10,1-00040 POMEZIA ITALY|
|PCT International Classification Number||C07H 15/252|
|PCT International Application Number||PCT/EP01/13217|
|PCT International Filing date||2001-11-15|