Title of Invention

"NOVEL 4, 10ß-DIACETOXY-2A-BENZOYLOXY-5ß, 20-EPOXY-1-HYDROXY-9-OXO-19- NORCYCLOPROPA[G] TAX-11-EN-13A-YL (2R, 3 S)-TERT-BUTOXYCARBONYLAMINO-2- HYDROXY-3-PHENYLPROPIONATE DEHYDRATE COMPOUND"

Abstract Novel 4, 10B-diacetoxy-2a-benzoyloxy-5B, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g] tax-ll-en-13α-yl(2r, 3 s)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate compound
Full Text The present invention relates to a novel 4, 10ß-diacetoxy-2α-benzoyloxy-5ß, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g] tax-ll-en-13α-yl(2r, 3 s)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate compound
The present invention relates to 4,10(3-diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-l3a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate and to its preparation
F. Gueritte-Voegelein et al (Acta Cryst, (1990)
C46, 781-84) and Chemical Abstracts 113 (75), 1990, No. 142641K disclose the structure of N-tert-butoxycarbonyl-
l0-deacetyl-N-debenzoyl taxol, which is a synthetic taxol
precursor. This compound has hydroxy groups at the 7 and 10 positions of the taxoid structure and a methyl group at the 8-position.
4,l0ß-Diacetoxy-2α-benzoyloxy-50,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13cx-yl (2R,3S}-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate exhibits notable anticancer and antileukaemic properties. The bond between the 7 and 8 positions of the taxoid structure form a cyclopropyl ring. There is an acetoxy group at the 10-position.
4,10ß-Diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo~19-norcyclopropa[g]tax-11-en-13α-yl {2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate may be prepared by the process described in WO 94/13654.
It has now been found that 4,10ß-diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-axo-19-norcyclopropa[g]tax-1l-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate exhibits a stability which is markedly superior to that of the anhydrous product.
According to the invention, 4,10ß-diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-
norcyclopropa[g]tax-1l-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate exhibits notable anticancer and antileukaemic properties. The bond between the 7 and 8 positions of the taxoid structure form a cyclopropyl ring. There is an acetoxy group at the 10-position.
4, 108-Diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate may be prepared by the process described in WO 94/13654.
It has now been found that 4,10ß-diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13α-yl {2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate exhibits a stability which is markedly superior to that of the anhydrous product.
According to the invention, 4,10ß-diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-


norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-:outoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate can be obtained by crystallization of 4,10/3-diacetoxy-2a-benzoyloxy-5/3, 2O-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or the hydrate thereof or by recrystallization of the dihydrate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms or from a mixture of water and a ketone containing 3 or 4 carbon atoms, followed by either drying the product obtained under reduced pressure and by optionally maintaining the dried product at a relative humidity greater than or equal to 40 % or by direct drying at a relative humidity greater than or equal to 40 %.
In order to carry out the process according to the invention, it may be particularly advantageous
- to dissolve 4 , 10/3-diacetoxy-2a-benzoyloxy-5/3, 20-
epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13a-
yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-
phenylpropionate or its hydrate in an aliphatic alcohol
containing 1 to 3 carbon atoms or in a ketone
containing 3 to 4 carbon atoms,
- to treat the solution with water,
- to seed the solution with the dihydrate and then to
again treat with water,
- to separate the crystals obtained, then
- to dry them under reduced pressure and then

optionally to maintain them in an atmosphere with a relative humidity greater than or equal to 40 %, that is to say, by way of example for a relative humidity of 40 %, drying under a residual pressure of approximately 1.33 kPa for a temperature of 25°C and under a residual pressure of approximately 3.86 kPa for a temperature of 45°C,
- or to dry them directly in an atmosphere with a relative humidity greater than or equal to 40 %, that is to say, by way of example for a relative humidity of 40 %, drying under a residual pressure of approximately 1.33 kPa for a temperature of 25°C and under a residual pressure of approximately 3.86 kPa for a temperature of 45°C.
Generally, 4 ,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-l9-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate is dissolved in an excess of aliphatic alcohol, preferably ethanol, or in an excess of a ketone, preferably acetone. Preferably, the amount of alcohol or ketone is between 4 and 16 parts by volume with respect to the weight of 4,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate used.
Generally, the water is added such that the water/alcohol or water/ketone final volume ratio is between 1/3 and 3/1.

The 4 ,10j8~diacetoxy-2a-benzoy loxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate which crystallizes is separated, preferably by filtration or centrifuging. The drying or the optional maintaining in an atmosphere with a relative humidity greater than or equal to 40 % is carried out under reduced pressure, generally of from 0.5 to 30 kPa, preferably about 5 kPa, at a temperature of from 10 to 70°C, preferably about 40°C.
The water activity isotherm of the product was studied. Thus, 4 , 10/3-diacetoxy-2a-benzoyloxy-5/3 , 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate samples, intentionally dehydrated by forced drying, were maintained in atmospheres of controlled relative humidity (RH) at 25°C. The water contents, determined by TGA, show that the products stabilize at contents in the region of 4 wt% (from 3 to 5 wt%) when the relative humidity is greater than or equal to 40 % (theoretical water content of 4.15 wt% for a dihydrate).

(Table Removed)
Water activity isotherm at 25°C
XD = X-ray diffraction

In order to use. the process according to the invention, it is possible to work directly on an ethanolic solution of 4 ,10(3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy~l-hydroxy-9-oxo-19-norcyclopropa[g] tax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained after deprotection in acid medium of 4 ,10j3-diacetoxy-2a-benzoyloxy-5|3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate.
The following examples illustrate the present invention.
EXAMPLE 1
2 g of crude 4, lO/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 20 cm3 of absolute ethanol are introduced into a three-necked flask. 20 cm3 of water are added over approximately 45 minutes to the stirred solution at 50°C and the suspension obtained is then cooled to a temperature in the region of 20°C. After filtration, the product is washed on the filter with 20 cm3 of an absolute ethanol/water (1/1 by volume) mixture and the product is then dried at 40°C under reduced pressure (5.3 kPa) . 1.64 g of 4,10/S-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-

butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, containing 3.8 wt% by TGA (Figure 5) of water (theoretical value of the water content of the dihydrate of 4.15 wt%), are obtained. The yield obtained is approximately 80 %. The XRPD (X-ray powder diagram) diagram represented by Figure 1 shows that the product thus obtained exhibits the characteristics of the dihydrate.
The X-ray powder diagram is obtained using a Philips PW 1700® device with a cobalt anti-cathode tube (A Kal = 1.7889 A), the sweeping being performed at an initial sweep angle of 5° 2-6, final sweep angle of 40° 2-6, with an increment of 0.02° 2-6, at a rate of 1 second per increment and using a silicon pastille.
Thermogravimetric analysis (TGA) is carried out using a Perkin-Elmer TGA 7® thermobalance at the initial temperature of 25°C and at the final temperature of 300°C with a temperature gradient of 10°C per minute.
EXAMPLE 2
515 g of crude 4,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate and 4 litres of absolute ethanol are introduced into a reactor purged with nitrogen. The suspension is heated at 35-40°C until dissolution is complete and the reactor is placed under

a reduced pressure of 8 kPa. Approximately 8 litres of solvent are distilled off at constant volume, the reactor being continuously supplied with ethanol (8 litres). After returning the reactor to atmospheric pressure, the solution is clarified by passing through a filter equipped with a 0.45 /Ltm filter cloth. After rinsing the filter with I litre of absolute ethanol, approximately 1.8 litres of water are added at 40°C over 1 hour to the whole of the solution. After initiating with 8 g of 4,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, the mixture is cooled at a temperature in the region of 20°C for 15 hours. The suspension is then heated to 40°C and then 1.66 litres of water are added over 4 hours. The mixture is cooled to a temperature in the region of 20°C and left stirring for 17 hours. The suspension is filtered on sintered glass 'and the filtered product is washed with 1.25 litres of an alcohol/water (50/50 by volume) mixture. The product is dried in an oven at 35°C at 5.3 kPa for 72 hours in the presence of a stock of water and then at 35°C at 2.7 kPa for 8 hours without a stock of water and again at 35°C at 5.3 kPa for 16 hours in the presence of a stock of water. 491 g of 4 ,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate

dihydrate containing 4.0 wt% of water (Karl Fischer) are thus obtained. The XRPD (X-ray powder diagram) diagram represented by Figure 2 shows that the product thus obtained exists in the form of a dihydrate (theoretical value of the water content of 4,10/3-diacetoxy-2a-benzoyloxy-5/3,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g] tax-ll-en-13a-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate of 4.15 wt%).
The X-ray powder diagram is obtained under the conditions described in Example 1.
EXAMPLE 3
2 g of crude 4,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa [g] tax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 20 cm3 of acetone are introduced into a three-necked round-bottomed flask. The solution obtained, which is stirred at a temperature in the region of 20°C, is treated with 20 cm3 of water over approximately 35 minutes. The suspension obtained is stirred for approximately 15 minutes. After filtration, the product is washed twice on the filter with 20 cm3 of an acetone/water (1/1 by volume) mixture and the product is then dried at 40°C under reduced pressure (5.3 kPa) . 1.28 g of 4,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-

3-phenylpropionate dihydrate are thus obtained. The yield obtained is approximately 75 %. The XRPD (X-ray powder diagram) diagram represented by Figure 3 shows that the product thus obtained exhibits the characteristics of the dihydrate.
The X-ray powder diagram is obtained under the conditions described in Example 1.
EXAMPLE 4
120 g of 4 , 10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate and 1.08 litres of ethyl acetate are introduced into a reactor purged with nitrogen. The suspension is stirred at a temperature in the region of 20°C and then a solution of 3.25 cm3 of 36 % hydrochloric acid in 17.6 cm3 of water is introduced. After maintaining for 3 hours 30 minutes, a solution of 3..5 g of sodium hydrogencarbonate in 350 cm3 of water is charged to the reactor and stirring is carried out for 15 minutes. After separation by settling and drawing off the aqueous phase, washing is carried out twice in succession with 350 cm3 of water. The organic phase is concentrated under reduced pressure at approximately 25°C until a residual volume of 350 cm3 is reached and then 350 cm3 of absolute ethanol are introduced. Distillation under reduced pressure is resumed at

approximately 30°C until the ethyl acetate has been exhaustively removed, while supplying with 1.5 litres of absolute ethanol. The solution is heated to 40°C and then 470 cm3 of water are added over 15 minutes. The solution is seeded with a suspension of 1 g of 4,10/3-diacetoxy-2a-benzoyloxy-5|3,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate in a mixture of 40 cm3 of water and 40 cm3 of absolute ethanol. After maintaining for 15 hours at approximately 40°C, 410 cm3 of water are added over 4-5 hours and the suspension is then cooled to 20°C. After filtration and washing the product on the filter, the product is dried for 15 hours under reduced pressure (2.7 kPa) at 25°C and then for 24 hours at 35°C. 102 g of 4 ,10/3-diacetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, containing 4.3 wt% of water (Karl Fischer), are thus obtained with a yield of approximately 93 %. The XRPD (X-ray powder diagram) diagram represented by Figure 4 shows that the product thus obtained exhibits the characteristics of the dihydrate.
The X-ray powder diagram is obtained under the conditions described in Example 1.











We claim:
1. Novel 4, l0ß-diacetoxy-2a-benzoyloxy-5ß, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g] tax-ll-en-13α-yl(2r, 3 s)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate compound.
2 4, 10ß-diacetoxy-2a-benzoyloxy-5ß, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa [g] tax-ll-eh-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate aa claimed in claim 1, whenever prepared by a process comprising crystallising 4,l0ß-diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or the hydrate thereof from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms or from a mixture of water and a ketone containing 3 or 4 carbon atoms, and then either drying the product obtained under reduced pressure and then optionally maintaining the dried product under conditions of relative humidity greater than or equal to 40 %, or drying the product directly under conditions of relative humidity greater than or equal to 40 %
3. 4,10ß-Diacetoxy-2α-benzoyloxy~5ß, 20-epoxy^-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R, 3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as claimed in claim 2, wherein the water/alcohol or water/ketone ratio by volume is between 3/1 and 1/3.
4 4, l0ß-Diacetoxy-2ce-ben2oyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylproplonate as claimed in claim 2 or 3, wherein the alcohol is ethanol.
5 4,103-Diacetoxy-2a-benzoyloxy-5ß, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-

phenylpropionate as claimed in claim 2 or 3 wherein the ketone is acetone.
6. 4,l0ß-Diacetoxy-2α-benzoyloxy-5ß,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as claimed in any one of claims 2 to 5, wherein when conditions of relative humidity greater than or equal to 40 % are employed, the temperature is about 40°C and the pressure about 5 kPa and wherein the product stabilizes under these conditions at a water content of from 3 to 5 wt%.
7. 4,10ß-Diacetoxy-2α-benzoyloxy-5ß, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as claimed in claim 2, wherein the preparation is carried out directly from an ethanolic solution of 4, 10ß-diacetoxy-2α-benzoyloxy-5ß, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained by deprotection in acid medium of the ester 4,10ß-diacetoxy-2α-benzoyloxy-5ß,20--epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R, 4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate
8. 4,10ß-Diacetoxy-2α-benzoyloxy-5ß, 20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as defined in claim 2 substantially as described in the foregoing Examples.

Documents:

70-DEL-2000-Abstract-(12-05-2009).pdf

70-DEL-2000-Abstract-(24-02-2009).pdf

70-del-2000-abstract.pdf

70-DEL-2000-Claims-(12-05-2009).pdf

70-DEL-2000-Claims-(24-02-2009).pdf

70-del-2000-claims.pdf

70-DEL-2000-Correspondence-Others-(12-05-2009).pdf

70-DEL-2000-Correspondence-Others-(24-02-2009).pdf

70-del-2000-correspondence-others.pdf

70-DEL-2000-Description (Complete)-(12-05-2009).pdf

70-DEL-2000-Description (Complete)-(24-02-2009).pdf

70-del-2000-description (complete).pdf

70-DEL-2000-Drawings-(24-02-2009).pdf

70-del-2000-drawings.pdf

70-DEL-2000-Form-1-(12-05-2009).pdf

70-DEL-2000-Form-1-(24-02-2009).pdf

70-del-2000-form-1.pdf

70-del-2000-form-13.pdf

70-del-2000-form-18.pdf

70-DEL-2000-Form-2-(12-05-2009).pdf

70-DEL-2000-Form-2-(24-02-2009).pdf

70-del-2000-form-2.pdf

70-DEL-2000-Form-3-(24-02-2009).pdf

70-DEL-2000-Form-5-(24-02-2009).pdf

70-del-2000-form-5.pdf

70-del-2000-form-gpa.pdf

70-DEL-2000-GPA-(24-02-2009).pdf

70-DEL-2000-Petition-137-(24-02-2009).pdf

70-DEL-2000-Petition-138-(24-02-2009).pdf


Patent Number 234265
Indian Patent Application Number 70/DEL/2000
PG Journal Number 23/2009
Publication Date 05-Jun-2009
Grant Date 14-May-2009
Date of Filing 31-Jan-2000
Name of Patentee AVENTIS PHARMA S.A.
Applicant Address 20, AVENUE RAYMOND ARON, 92160 ANTONY, FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 JEAN-RENE AUTHELIN 51 RESIDENCE LES CENDRENNES, 91180 SAINT GERMAIN LES ARPAJON, FRANCE.
2 ERIC DIDIER 69 AVENUE DES GOBELINS, 75013 PARIS, FRANCE.
3 MICHEL LAVIGNE 4 ALLEE DES ACACIAS 91380 CHILLY MAZARIN, FRANCE.
PCT International Classification Number C07D 305/14
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 95 14841 1995-12-14 France