|Title of Invention||
"N-PIPERIDINO-5-(4-BROMOPHENYL)-1-(2,4-DICHLOROPHENYL)-4- ETHYLPYRAZOLE-3-CARBOXAMIDE OF FORMULA (I) AND COMPOSITION THEREOF"
|Abstract||The invention concerns N-piperidino-5-(4-bromophenyl)-1-(2,4dichlorophenyl)-4-ethylpyrazole-3-carboxamide, the salts and solvents thereof which are powerful antagonists of cannabinoid CB1? receptors. The method for preparing them consists in reacting a functional derivative of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid with 1-aminopiperidine with subsequent optional salification.|
|Full Text||PYRAZOLECARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates tc a novel pyrazole derivative, to its salts and to the solvates cne:: eor , to a process for their preparation and to pharmaceutical compositions containing them.
Patent applications EP-A-576 357, EP-A--553 546 and WO-97/19063 describe pyrazole derivatives with affinity for cannabinoid receptors. More particularly, patent appliction EP-A-656 354 describes N-piperidino-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxami.de, also known as SR 141 716, and the pharmaceutically acceptable salts thereof which have very good affinity for the central cannabinoid receptors.
Compounds similar to SR 141716 have been described in the literature, in particular N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, referred to hereinbelow as compound A, which is described by B.F. Thomas et al. in J. Pharm. Exp, Therap., 1998, 285, 285-292.
The effects of cannabinoids are due to an interaction with specific high-affinity receptors present at the central level (Devane et al., Mol. Pharrnacol . , 1988, 34, 605-613) and at the peripheral
level. (Nye *••::. ai,, Fharmaco 1 . and Exper imental Ther., 1985, 23-1, ..... ••••J--79L ; Kamnski et al . , 1992, Mel. Pharmaco ; . , •-.;, 736-M3 ; Munr: et al . , Nature, 1993,
,:-;:or. ists WIN ~:;-212-2 (J. Ph.arrr.ac: 1 . Exp. Ther., 19' ..:_-..•:, I 35/'-l 3n :) or C? 55,94.:- ( .. . Pharmaco!. Exp. :^8S, 2'}1, '; •.'•••i^-i 051) . The pharmacology of the CB: and CE; cannabinc 1.0 receptor subtypes is outlined in Pharmaco.!. Ther., 1997, 74, 12-130.
A ::cvei N-piper idino-3-pyrazolecarboxamide derivative has now been found which has very good affinity for the CB; subtype of cannabinoid receptors (CB: receptors) with long-lastinq action, which is
useful in the therapeutic fields in which cannabinoids
are known to be involved.
According to one of its aspects, the present
invention relates to N-piperidino-5-(4-bromophenyl)-
to its pharmaceutically acceptable salts and to the soivates thereof.
According to another of its aspects, the present invention relates to a process for preparing compound ( L
is treated with 1-aminopiperidine, in an organic solvent and in the presence of a base; and the compound thus obtained is optionally converted into one of its salts or one- of the soivates thereof.
The reaction is carried out in basic medium, for example;; in the presence of triethylamine in an inert solvent such as dichloromethane or t e t ra hydro f ur an.
Functional derivatives of the acid (II) which may be used are the acid chloride, the anhydride, a mixed anhydride, a C_-C,; alkyl ester in which the alkyl is straight or branched, an activated ester, for
example the p-nitrophenyl ester, or the suitably activated free acid, for example activated with N, N-dicyc lohexy Icarbodiimide or with benzotriazole-N- oxotr ;. s ( a irnechylamino) phosphoniurn (BOP) hexaf luor op; .osphate -
': MUS , by means of the process according to trie invent •,'.•:;.. it is possible to react the acid chloride or formula (II) obtained by reacting thionyl chloride with the acid of formula (II) in an inert solvent: such as benzene or toluene, or a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), an ether (for example tetrahydrofuran or dioxane), OL an amide (for example
N,N-dimethy1formamide) under an inert atmosphere, at a temperature of between 0°C and the reflux point of the solvent -
One variant of the procedure consists in preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as t r i e t hyLamin e.
The acid of formula (II) can be prepared according to the reaction scheme described below, in which:
Li HMDS ;- lithium hexamethyldisilazi.de NBS -- N brc.mosuccinimide .
This process is characterized in that an alkyl ester, preferably the ethyl ester, of 5- !4 • -beomophenyl) - 1 -(2,4-dichlorophenyl)-4 -ethylpyrazole-3-carboxylie acid is prepared by cyo i i zat: ion o : an alkyl ester, preferably the ethyl ester, of 3 (4 • bromobenzoyl)-2-(2-(2,4-dichlorcphenyl)-hycr a zono }p
solvent suc?i as an alcohol, for example a C;-C
The reaction is carried out in a protic solvent, for example a Ci-C4 alcohol, preferably ethanol.
According to the invention, the alkyl ester, preferably the ethyl ester, of 4-bromobenzoyl-2-oxopentanoic acid is prepared by the action of LiHMDS and then of an alkyl ester, preferably the ethyl ester, of 2 - (1 -imidazoly1) -2-oxoacetic acid on b r o m o b i j t y i o p h e n o n e .
The reaction is carried out in an organic solvent: such as an aromatic solvent or an ether, preferably methyl tert-butyl ether. The first step of this reaction is carried out at low temperature, for example at a temperature between 0°C and -60°C, preferably at a temperature in the region of -20°C; the second :.-:. e;; is carried out at a temperature of between room temperature and -20°C, preferaDiy at room temperavure.
Thus, according to Scheme 2, the preparation of an a:_kyl ester of 5- (4-bromophenyl)-!•- (2, 4-dich i orophenyl) -4 -ethy Ipyrazole- 3 -carboxylic acid (VII) is carried out starting with 4-bromobenzoyl-2-oxopentanoic acid (VIII) by the action of a 2,4-dichlorophenylhydrazine salt, followed by cyclization.
Bromobutyrophenone is commercially available. The ethyl ester of 2-(1-imidazolyl)-
2-oxoacetic acid is described and prepared according to J. Org. Chem., 1981, 4J5 (1), 211-213.
The present invention also comprises a process for preparing an alkyl ester, preferably the ethyl ester, of 5-(4-bromophenyl)-
1 (2 ., 4-dichiorophenyl) -4--ethyIpyrazole- 3 -carboxylic acid, from 4-bromobenzoyl-2-oxopentanoic acid, by the action of a 2,4-dichlorophenylhydrazine salt, preferably the hydrochloride, in a protic solvent, for example a C-.-C^ alcohol, preferably ethanol . The
reaction is carried out at a temperature of between
room temperature and 80°C, preferably in relaxing
The compounds of fomula:
in which Alk represents a (C:-Ct) alkyl are novel and
form part of. the invention. Preferably, Alk represents
The compound of formula (I) obtained by the process according to the invention is isolated, in the
form of the free base or of a salt or solvate, according to the conventional techniques.
The pharmaceutically acceptable salts of the compound of formula (I) comprise the addition salts with acids, such as the hydrochloride, the hydrobromide, the sulphate, the hydrogen sulphate, the dihydrogen phosphate, the methanesulphonate, the methyl sulphate, t.he oxalate, the maleate, the fumarate, the
2-naphthaLenesulphonate, the glyconate, the gluconate, the citrate, the isethionate, the para-toluenesulphonate or the succinate.
The compound of formula (I) can be isolated in i:he form of one of its salts, for example the hydrochioride or the oxalate; in this case, the free base car. be prepared by neutralizing the said salt with an inorganic or organic base, such as sodium hydroxide or ammonium hydroxide, triethylamine or an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate, and converted into another salt such as the methanesulphonate, fumarate or 2 -naphthalenesulphonate.
When the compound of formula (I) is obtained in the form of the free base, the salification is carried out by treatment with the acid chosen in an organic solvent. By treating the free base, dissolved, for example, in an ether such as diethyl ether or in acetone, with a solution of the acid in the same solvent, the corresponding salt is obtained and is then isolated according to the conventional technicjues .
The compounds of formula (I) have very good in vitro affinity for the CBi cannabinoid receptors, under the experimental conditions described by Devane et al - , Mol. Pharmacol., 1988, 3.4, 605-613.
Thus, the compound according to the invention has very strong affinity for human CBi cannabinoid receptors (Ki = 5.4 riM) which compares favourably with
that of SF 141716 for the same receptors, determined under the same conditions (Ki = 34 nM),
'The compound according to the invention was also compared with N-piperidino-5-(4-bromophenyl)-1 - (2 , 4~u.ichi oropnenyl) - 4 -me thy Ipyrazole- 3 -carboxamide, (compound A). The affinity of this compound for human
C5. eanr.aoi.-iG. •; receptors, measured under the same
conditions, is reflected by a Ki value of 8 nM.
Moreover, the duration of occupation of the
CB: receptors present in the brain by the 3 compounds
below was compared:
- the compound of formula (I) according to the
- SR 141716,
- compound A.
The study was performed in vivo in mice,
after oral administration of each of the compounds at a dose of 10 mg/kg, according to the technique described in M. Rinaldi-Carmona et al., Life Sciences, 1995, 56, 1941-1947. The results obtained are collated in the table below
% of occupation of the receptors
Surprisingly, it is observed that the
compound of formula (I) according to the invention is the only compound which shows appreciable occupation (44%) 24 hours after its administration.
Moreover, the antagonist nature of the
compound of formula (I) was demonstrated by the results obtained in models of adenylate-cyclase inhibition as described in M. Rinaldi-Carmona et al., J. Pharmacol. Exp, Ther., 1996, 278, 871-878.
More particularly, the compound of the
present invention, in its native form or in the form of one of its pharmaceutically acceptable salts, is a powerful, and selective antagonist of the CBi cannabinoid receptors.
The antagonist nature of the compound according to the invention, as well as its good penet. rat: ion into the central nervous system, are confirmed by the results obtained in the model of
antagonism of the hypothermia induced with a cannabinoid receptor agonist. Thus, the compound of formula (I) according to the invention antagonizes the hypothermia induced with WIN 55212-2 in mice, with an oral ED-., or: G.3 ing/kg in the Lest described by Per twee R.G. et al . in Marijuana, E[4, Ed. Harvey, D.Y. Oxford .1RL -ress, 1965, 263-2 "7. In this test, the activity and the duration of action of 3 compounds were compared. Tne results obtained are collated in the table below:
Ant; agon ism of the hypothermia induced
It is found that the compound of the present invention has an EDt() which is comparable with those of the compounds of the prior art, but its duration of action is markedly longer.
Thus, whereas 24 hours after their
administration, SR 141716 and compound A are only
active at a dose of 10 mg/kg/p.o., the compound of formula (I) according to the invention is active 24 hours alter its administration, at a dose 10 times i ower (1 mq ' kg/p.o. ) .
The long-'asting action of the compound of formula (I/ according to the invention is particularly r.ot.ewor:;hy ani.: represents an important advantage for its use as a medicinal product.
The toxic;t/ or compounds (I) is compatible w 11 h t. he i r -1se as medicinal products.
According to another of its aspects, the present invention relates to the use of a compound of forrrmla (I), or one of the pharmaceutlcally acceptable salts or soLvates thereof, for the preparation of medicinal products intended for treating diseases involving the CBi cannabinoid receptors.
For example, and in a non-limiting manner, the compound of formula (I) is useful as a psychotropic medicinal product, in particular for the treatment of anxiety disorders, mood disorders, delirium disorders, psychotic disorders in general, for the treatment of schizophrenia and depression, as well as for the treatment of disorders associated with the use of psychotropic substances, in particular in the case of abuse of a substance and/or dependence on a substance, including alcohol dependency and nicotine dependency.
The compound of formula (I) according to the invention can be used as medicinal product for treating
neuropathies, migraine, stress, diseases of psychosomatic origin, epilepsy, locomotor disorders, in particular dyskinesias or Parkinson's disease.
The compound of formula (I) according to the invention •>•.:'! also be used as a medicinal product in the treatment of memory disorders, cognitive disorders, in pa i :.. ou'...-.; r LH the treatment of senile dementia and Alzheimer's disease, as well as in the treatment, of attention disorders or vigilance disorders. Furthermore, the compound of formula (I) may be useful as a neuroprotective agent, in the treatment of n e u r o d e u e n e r. a t i v e diseases.
The compound of formula (I) according to the invention can be used as a medicinal product in the treatment of appetite disorders, cravings (for sugars, carbohydrates, drugs, alcohol or any appetizing substance) arid/or eating disorders, in particular as an anorexigenic agent or for the treatment of obesity or bulimia, as well as for the treatment of type II diabetes or non-insulin-dependent diabetes. Furthermore, the compound of formula (I) according to the invention can be used as a medicinal product in the treatment of gastrointestinal disorders, diarrheic disorders, ulcers, vomiting, urinary and bladder disorders, cardiovascular disorders, fertility disorders, inflammatory phenomena, infectious diseases and as
According to the present invention, the
compound of formula (I) is most particularly useful for treating psychotic disorders, in particular schizophrenia; for treating appetite disorders and obesity, for creating for memory and cognitive disorders; for treating alcohol dependency or nicotine ..-.ependency. i.e. for withdrawal from alcohol and for •,vi thdrawal from tobacco.
According to one of its aspects, the present: invention relates to the use of a compound of formula (I), its pharmaceutlcally acceptable salts and the solvates thereof for the treatment of the disorders and diseases indicated above.
According to another of its aspects, the present invention also relates to the use of the compounds of formula (I), in their native form or in radiolabelled form, as a pharmacological tool in man or animals, for detecting and labelling the CBX receptors.
The compound according to the invention is generally administered as a dosage unit.
The said dosage units are preferably
formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.,
Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a
NMR: 1.05 ppm: t: 3H; 1.30 ppm: t: 3H; 2.60 ppm: q: 2H; 4.30 ppm: q: 2H; 7.15 ppm: d: 2H; 7.50-7.75 ppm: m: 5H.
~i - ( 4 - Bi'ornophery/l) -1 • i2 , 4 -dl chloropheny 1 ) -
4-ethyInyra^ole-3-carboxylic acid (II).
:.b q of the ester obtained in Preparation 1
are placed in 54 ml of MeOH and a solution containing 1.08 g ! KOH in 6.85' ml or water is added. The reaction medium is re fluxed for 3 hours and then concentrated under vacuum. The residue is taken up in ice-cold water., acidified to pH = 1 with 1 N HCl and then extracted with DCM. 3.3 g of the expected compound are obtained, m.p. -- 218°C.
NMR: l.LO ppm: t: 3H; 2.70 ppm: q: 2H; 7.25 ppm: d: 2H; 7.60-7.85 ppm: rn: 5H.
Ethyl 3 (4- bromobenzovl)-2-oxopentanoate
A solution of 247 g of 4-bromobutyrophenone in 1500 ml of MTBE is added to a solution of 210 g of LiHMDS in 2500 ml of MTBE, while keeping the temperature at -20°C. After stirring for 3 hours at this temperature, 210 g of ethyl 2-(1-imidazolyl)-2-oxoacetate in 1000 ml of MTBE are added over 1 hour, at 10°C, and the mixture is left stirring for 18 hours at room temperature. The lithium salt formed is iiltered off and then suspended in 800 ml of MTBE.
800 ml of 6 N hydrochloric acid are added to the suspension. After separation of the phases by settling, the ether pnase is washed 4 times with 1000 ml of water and then concentrated under reduced pressure. The expected compound is isolated (263 g). From the NMR analysis, ir is a mixture containing 8% of the 4 -bromobuty • opher.one smarting material . NMR: 0.86 porn: t: 3H; 1.10 ppm: t: 3H; 1.83 ppm: mt : 2H; 4.1L> pp;n: q: 2H; 5.19 ppm: t: 1H; 7.70 ppm: d: 2H; 7.98 ppm: a: 2H .
Ethyl 5 (4-bromophenyl)-1-(2,4-dichlorophenyl)-
4 --ethylpyra'zole- 3 -carboxylate
A) Ethy1 3 - (4-bromobenzoyl)-2 -(2-(2 , 4-dichlorophenyl)-
A suspension of 155 g of
2,4-dichlorophenylhydrazine hydrochloride in 1200 ml of
ethanol is prepared and 263 g of the compound of Preparation 3 in 1000 ml of ethanol are added at room temperature.
A small portion of the intermediate formed can be isolated by filtration and characterized. NMR: 0.92 ppm: t: 3H; 1.04 ppm: t: 3H; 1.89 ppm: mt: 2H; 4.16 ppm: q: 2H; 4.76 ppm: t: 1H; 7.42 ppm: mt: 2H; 7.60 ppm: s: 1H; 7.75 ppm: d: 2H; 7.93 ppm: d: 2H; 12.31 ppm: :- : 1H.
E ) E t hy 1 5 ( 4 - b r omoph eny 1) - 1 - (2, 4-dichlo r oph eny 1 ) -4 -ethylpyra::ole- 3 -carboxylate
'"he suspension obtained is refluxed for 4 hours; and then left stirring for 18 hours at room t einpera : _i e . The product formed is filtered off and then dr,.ed under vacuum at 50°C to give the expected
NMP : 1 . ••:•"' ppm: t: 3H; 1.28 ppm : t: 3H; 2.58 ppm : q: 2H; 4.-: per;: q; 2H; 7.16 ppm: d: 2H; 7.53 ppm: dc : 1H; 7.59 ppir, : c: : 2H; 7.73 ppm: d + small d: 2H.
EXAMPLE IN -• Piper idino- 5- ( 4 -bromophenyl ) -
1 - ( 2 , 4 -dich 1 orophenyl ) ~4-ethylpyrazole-3 -carboxamide
A) 5 - ( 4 -Bromophenyl ) -1- (2 , 4-dichlorophenyl ) -
4 -ethyl pyrazo le-.3 -carboxylic acid chloride
] . 2 q of the acid obtained in the above step are placed in suspension in 32 ml of toluene, 1.6 ml of thionyl chloride are added and the mixture is then refluxed for 3 hours. The reaction medium is concentrated under vacuum and then taken up in toluene.
The operation is repeated several times. 3.3 g of the
expected compound are obtained.
B) N-Piper idino -5- ( 4 -bromophenyl ) -1- (2, 4-dichloro-
phenyl ) -4 -ethy lpyrazole-3-carboxamide
A solution of 0.23 ml of N-aminopiperidine
and 0 . 2 •"> ml of tr lethylamine in 20 ml of DCM is
prepared, under nitrogen, and is cooled to a
r.empera-.ure- of between 0°C and 5°C. 0.8 g of the acid
chloride obtained in the above step in 20 ml of DCM is added. After leaving overnight at RT, the resulting mixture is poured onto ice-cold water and the phases are separated by settling. The organic phase is extracted with DCM and the:: washed with water, with 5% Na-:CO- solution and with saturated NaCl solution. The resulting solution is evaporated to cryness and the residue is then chromatographed on silica, eluting with a toluene/EtOAc mixture (80/2C; v/v). 0.52 g of the expected compound is obtained, rr.. p. = 113°C. NMR: 1.05 ppin: t: 3H; 1.25-1.65 ppm: m: 6H; 2.65 ppm: q: 2H; 2.80 ppm: m: 4H; 7.15 ppm: d: 2H; 7.50-7.80 ppm: m: 5H; 9.10 ppm: S: 1H.
N-Piperidino- 5 - ( 4-brornophenyl) -1- ( 2 , 4-dichlorophenyl) -
4-ethylpyrazole-3-carboxylic acid chloride
A mixture containing 97 g of thionyl chloride and 118 g of the compound of Preparation 4 in 1200 ml of toluene is prepared and is heated gradually to reflux and is then maintained at reflux for 3 hours. The reaction medium is concentrated.
B) N-Piperid.ino- 5 - ( 4-bromophenyl) -1- (2, 4-dichloro-
The acid chloride formed is taken up in
380 ml of methylcyclohexane and 2.8 g of triethylamine
in 218 ml of THF are introduced. The mixture is kept at
A solution c: ~: Q g of N-aminopiperidine and 28 g of tr i-ethy lamine in 34 ml of methylcyclohexane is prepared and cooled to 10°C, and the mixture containing the acid chloride is added slowly. After stirring for 2 hours at 10°C, the product formed is filtered off, taken up in 2000 ml of DCM and washed twice with 2000 ml of water. The product is recrystallized from 4500 ml of methylcyclohexane and then filtered off and dried. 125 g of the expected compound are obtained.
L. N-Pipendino-5- (4-bromophenyl) -
--(2 ,4-dichioiophenyl) - 4-ethylpyrazole-3-carboxamide, of torrriu 1 a -
its pharmaceutically acceptable salts and the solvates thereof,
2. Process for preparing N-piperidino-5- (4-brornophenyl) -1- (2 , 4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide, its salts and the solvates thereof, characterized in that a functional derivative of 5-(4-bromophenyl)-1-(2, 4-dichlorophenyl)-4-ethylpyrazole--3-carboxylic acid, of formula:is tieaved with 1-aminopiperidine, in an organic solvent: and in the presence of a base; and the compound thus obrained is optionally converted into one of its salts or one of the solvates thereof.
3. Process according to Claim 2, for preparing an alkyl ester of 5-(4-bromophenyl)-1 -(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid by cyclization of an alkyl ester of 3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)-hydrazono)pentanoic acid (IX).
4, Process according to Claim 3, for
preparing an alkyl ester of 3~(4-bromobenzoyl)-
2-(2-(2 , 4-dichlorophenyl)hydrazono)pentanoic acid by the action of a 2,4-dichlorophenylhydrazine salt on an alkyl ester of 4-bromobenzoyl-2-oxopentanoic acid (VIII).
5, Process according to Claim 4, for
preparing an alkyl ester of 4-bromobenzoyl-
2 -oxopentanoic acid by the action of LiHMDS and then an
alkyl ester of 2-(1-imidazolyl)-2-oxoacetic acid on bromobutyrophenone.
6. Process according to Claim 2, for preparing an alkyl ester of 5-(4-bromophenyl)-1- ( 2 , 4-dich.l o.vopheny.1} -4 -ethylpyrazole- 3 -carboxyl ic acid from 4-bromobenzoyl-2-oxopentanoic acid by the action of a 2 , 4 - dichiorophenyIhydrazine salt, followed by eye11za 11on.
7 Compound of formula:
in which Alk represents a (C:-C6) alkyl. 8 Compound of formula
in which Alk represents a (C.-C6)alkyl.
9. Pharmaceutical composition containing,
as active principle, a compound according to Claim I.
10. Pharmaceutical composition according to
Claim 9, containing from 0.1 to 1000 mg of active
principle, in unit dosage form, in which the active principle is mixed with at least one pharmaceutical excipieat.
11. Use of a compound according to Claim 1
for the preparation of medicinal products intended for
treating diseases involving the CBj cannabinoid
12. Use of a compound according to Claim 11
for the treatment of psychotic disorders, for the
treatment of appetite disorders and obesity, for the
treatment oi: memory and cognitive disorders; for the
treatment of: alcohol dependency and for withdrawal from
ethylpyrazole-3-carboxamide of formula substantially as hereinbefore
described with reference to the foregoing examples.
14 Process for preparing N-Piperidino-5-[4-bromophenyl]-l-[2,4-
dichlorophenyl]-4-ethylpyrazole~3-carboxamide of formula substantially
as hereinbefore described with reference to the foregoing examples.
15 Compounds of formula substantially as hereinbefore described
with reference to the foregoing examples.
16 Pharmaceutical composition substantially as hereinbefore
described with reference to the foregoing examples.
|Indian Patent Application Number||20/DEL/2004|
|PG Journal Number||25/2008|
|Date of Filing||06-Jan-2004|
|Name of Patentee||SANOFI-SYNTHELABO|
|Applicant Address||174, AVENUE DE FRANCE F-75013 PARIS, FRANCE.|
|PCT International Classification Number||A61K 31/00|
|PCT International Application Number||N/A|
|PCT International Filing date|