Title of Invention

"NEW PIPERAZINE DERIVATIVES AND THEIR USE AS SYNTHESIS INTERMEDIATES"

Abstract "AN ENANTIOMERICALLY PURE PIPERAZINE COMPOUND OF GENERAL FORMULA (I)" An enantiomerically pure piperazine compound of general formula (I) wherein Y represents p-toluenesulfonate (OSO2-C6H4-CH3) or perchlorate (OClO3).
Full Text The present invention relates to new plperaztne compound and to their use aa synthesis intermediates, especially for the preparation, of phaimaceutically active compounds.
Lerorotataiy {2-[4-[(4-chlorcphenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic
add, also known "by flic generic name of fevoceuilztae, has been proven useful as therapeutic agent for the treatment of allergic diseases. Said compound may be obtained from Its racemlc mixture by resolution of the enantiamers of cetfrizine [[2-{4-H4-chloroplicnyl)ptienyline(:hyl]- l-plperazlnyllethoxy]accilc add).
GB 2,225,321 describes a process for the preparation of cetirizme In the levorotatory form, dextrorotatory form or a mixture thereof comprising the hydrolysis of enantionieilcally pure or racemlc [2-[4-(4-chlrophenyl)phenylmethyl]-l-piperazmyllethoxyj-acetonltrile.
We have now found an atternattve, more simple process for preparing enanttomerfcaBy pure compounds, such as levocetWztoe, whereto a new enanttoinerlcalty pure totermediate Is used.
In a first aspect, the present invention relates to enantfornerically pure compounds of formula 0), in free form or in salt form,
(Formula Removed)
trihiereln
Y la hydroxy or a leasing group
and n Is 1, 2, 3, 4 or 5.

CONFIRMATION COPY
Compounds of formula (I) include a centre of asymmetry indicated by the
asterisk.
The term "enantiomerically pure compounds", as used herein, refers to
compounds containing at least 90% of one enantiomer ((R) or (S)), preferably at least
98%, of the total amount of both enantiomers.
The term "leaving group", as used herein, has the same meaning to the skilled
man (Advanced Organic Chemistry: reactions, mechanisms and structure - Third
Edition by Jerry March, John Wiley and Sons Ed.; 1985 page 179) and represents a
group which is part of and attached to a substrate molecule ; in a reaction where the
substrate molecule undergoes a displacement reaction (with for example a
nucleophile), the leaving group is then displaced.
Preferred leaving groups are halogen, sulfonic esters such as OSO2-C6H4-CH3
(p-toluenesulfonate), OSO2-C6H4-Br (p-bromobenzenesulfonate), OSO2-C6H4-NO2 (pnitrobenzenesulfonate),
OSO2-CH3 (methanesulfonate), OSOz-CF3
(trifluoromethanesulfonate),OSO2-C4H9 (nonafluorobutanesulfonate), OSO2-CH2-CF3
(2,2,2-trifluoroethanesulfonate), OSO2-(CH2)n-NMe3+ (ammoniumalkanesulfonate),
OSO2-F (fluorosulfonate) and OC1O3 (perchlorate).
According to a preferred embodiment, n is 2.
According to another preferred embodiment, the compounds of formula (I) are
in the form of a (R)-enantiomer.
When in. formula (I) Y represents a leaving group, it is preferably halogen, more
preferably chlorine.
Compounds of formula (I) wherein Y is hydroxy or chlorine are preferred.
Compounds of formula (I) can be in free form or in salt form. In that case,
dihydrochloride and dihydrobromide salts are preferred. Most preferred are
dihydrochloride salts.
Compounds of formula (I) can be in the form of a solvate, which is included in
the scope of the present invention. Such solvates include for example hydrates,
alkoxide and the like.
Compounds of formula (I) are very stable and can be used as synthesis
intermediates.
Compounds of formula (I) may be obtained by resolution of the corresponding
racemic mixture which may be prepared as described in GB 2,225,320.
Enantiomerically pure compounds of formula (I) can be produced using industrial
chiral chromatographie separation by means of commercially available chiral
stationary phases. This separation can more particularly be performed using
chromatographie columns sold by DAICEL Company under the trademark
CHIRALPAK AD, CHIRALPAK AS and CHIRALPAK OD. Preferred are CHIRALPAK AD
columns. The process can be carried out using batch, MCC (Multi Column
Chromatography) or 8MB (Simulated Moving Bed) technologies.
The process Is particularly efficient when mobile phases (eluents) such as
alcohol, i.e. methanol, or mixtures of alcohols with alkanes are used. The preferred
alkanes are hexane, isohexane and heptane. More preferred is heptane. The preferred
alcohols are propanol, isopropanol, ethanol and methanol. More preferred alcohols are
ethanol and methanol. The preferred mixtures are: 5 % to 50 % of isopropanol in
hexane or in heptane, 5 % to 95 % of ethanol in hexane or in heptane, 1 % to 10 % of
methanol in isohexane, and 0 % to 10 % of methanol, ethanol or isopropanol in
acetonitrile.
Compounds of formula (I) may also be obtained by reaction of enantiomerically
pure l-[(4r-chlorophenyl)phenylmethyl]piperazine, obtainable by the method described
in GB 2,225,321, with a haloalkane.
In a second aspect, the present invention relates to the use of compounds of
general formula (I) as synthesis intermediates, especially for the preparation of
pharmaceutically active compounds.
According to a first embodiment, compounds of formula (I) are used for the
synthesis of enantiomerically pure cetirizine derivatives.
Hence, a further aspect of this invention is a process for the preparation of
compounds of general formula (II) as well as pharmaceutically acceptable salts thereof,
wherein
Z1 represents a group of formula -OR1 or -NR2R3, in which R1 represents
hydrogen, a hydrocarbon group or an alkali metal,
R2 and R3, each independently, represent hydrogen, a hydrocarbon group or -
NR2R3 represents a heterocycle containing up to 7 ring members,
comprising the reaction of a compound of formula (I) in the form of a (R)-enantiomer
and wherein Y is hydroxy, with a compound of formula (III)
(Figure Removed)
wherein W1 is a halogen and Z2 is as defined for Z1.
The term "hydrocarbon group", as used herein, is defined as including
rnonovalent radicals containing hydrogen and carbon atoms, such as straight,
branched and cyclic alkyls, alkenyls, alkynyls, aryls, alkylaryls and arylalkyls
containing 1-20 carbon atoms, preferably 1 to 4 carbon atoms for non-cyclic alkyl, 6
to 10 carbon atoms for aryl and 3 to 8 carbon atoms for cycloalkyl, as well as
combinations thereof.
The term "pharmaceutically acceptable salts", as used herein, refers to salts
prepared from pharmaceutically acceptable non-toxic acids.or bases including
inorganic acids and bases and organic acids and bases. Since the compounds of the
present invention are basic, salts may be prepared from pharmaceutically acceptable
non-toxic acids including inorganic and organic salts. Suitable pharmaceutically
acceptable acid addition salts for the compounds of the present invention include salts
of acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric,
gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,
mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric,
tartaric, p-toluenesulfonic acid and the like.
According to a preferred embodiment of the above mentioned process, Z1
represents a group of formula -OR1 wherein RHs hydrogen or a Cl-C4-alkyl, more
preferably R1 is hydrogen or methyl, most preferably R1 is hydrogen.
According to another preferred embodiment of the above mentioned process,
W1 is chlorine.
According to another preferred embodiment of the above mentioned process, Z2
represents a group of formula -OR1 wherein R1 is an alkali metal, more preferably R1 is
sodium.
The reaction of a compound of formula (I) with a compound of formula (III) is
generally carried out in the presence of a chemically inert solvent and in the presence
of a proton acceptor such as, for example, alkali metal hydrides, alkali metal
hydroxydes, alkali metal alkoxydes or alkali metals.
Any solvent, such as aliphatic and aromatic hydrocarbons, ethers, amides and
alcohols of low reactivity may be used. The preferred solvent is THF.
The reaction is generally carried out at a temperature of from 0°C to the reflux
temperature of the reaction mixture.
It was surprisingly found that no racemization occurs during that reaction.
According to a second embodiment, the compounds of formula (I) are used for
the synthesis of enantiomerically pure compounds of general formula (IV). Hence, the
present invention also relates to a process for the preparation of compounds of general
formula (TV), as well as pharmaceutically acceptable salts thereof,
wherein R4 is hydrogen or a group of formula -C(=O)Z3; Z3 represents a group of
formula -OR1' or-NR2'R3', in which R1'represents hydrogen, a hydrocarbon
group or an alkali metal, R2' and R3', each independently, represent hydrogen, a
hydrocarbon group or -NR2Tl31 represents a heterocycle containing up to 7 ring
members,
comprising the use of a compound of general formula (I) in the form of a (R)-
enantiomer as synthesis intermediate.
In the above mentioned process, n is preferably 2.
In the above mentioned process, R4 is preferably hydrogen or -C(=O)Z3 wherein
Z3 is -NH2 or -OR1' wherein R'1 is a C1-C4 alkyl, more preferably methyl. Most
preferably R4 is hydrogen or -CONHa.
According to a first variant of this process, compounds of formula (IV) are
prepared by (a) reaction of a compound of formula (V)
wherein P1 represents a hydroxy protecting group and P2 represents hydrogen or an
amine protecting group, with the proviso that P1 and P2 may be linked to form a single
protecting group when P2is not hydrogen,
with a compound of formula (I) wherein Y represents a leaving group especially with a
compound of formula CD wherein Y is halogen, most preferably Cl, and (b) a
deprotection step.
The term "protecting group", as used herein, refers to a substituent that is
commonly employed to block or protect one or more functionalities while carrying out
reactions with other functional groups on the compound. For example, an "amine
protecting group" is a substituent attached to an amino group that blocks or protects
the amino functionality in the compound. Suitable amine protecting groups include
for example optionally substituted groups of formula -C(=O)OR or -R wherein R
represents alkyl, aryl or a combination thereof. Similarly, a "hydroxy protecting group"
refers to a substituent of a hydroxy group that blocks or protects the hydroxy
functionality. Suitable hydroxy protecting groups include for example optionally
substituted groups of formula-C(=O)OR', -R', -C(=O)R', -C(=O)NR'R" or -CR'OR",
wherein R' and R" each independently represent alkyl, aryl or combinations thereof.
In case P1 and P2 are linked, the protecting group is preferably
dialkylmethylene, more preferably isopropylene (dimethylmethylene).
Preferably, the compound of formula (V) is
(Figure Removed)
Compounds of formula (V) may be prepared by reacting a compound of formula
(VI) wherein R5 is as defined for R4 and W2 is halogen with a compound of formula
(VII}, for example under Sonogashira or related conditions (ref. : Angew. Chem. Int. Ed.
2002, 41, 4176-4211).
(Figure Removed)
The reaction is generally carried out in the presence of organic or inorganic
proton acceptor such as triethylamine or di-isopropylamine, and solvent such as
ethylacetate, DMF, MTBE (methyl terbutyl ether), i-propylacetate, toluene, water or a
mixture thereof.
Compounds of formula (VII) can for example be obtained by reacting a
compound of formula (Vin) with the appropriate reagent to introduce the required
protecting groups P1 and P2.
Compounds of formula (VIIa) are preferably obtained by reacting a compound
of formula (VIE) with acetone, 2,2-dimethoxypropane or methoxypropane, in the
presence of acid, preferably sulfuiic acid.
The deprotection of the compound obtained from the reaction of compound (V)
with compound (I) can be carried out under acidic or basic conditions depending on
the nature of the protecting group.
According to a second variant of the process for the preparation of compounds
of general formula (TV) this process comprises the steps of:
(a) reacting a compound of formula (I) wherein Y is a leaving group, preferably
halogen, and more preferably Cl, with a compound of formula (VI) and
(b) reacting the compound thus obtained with a. compound of formula (VII), preferably
(VIIa), or (VIII).
(Figure Removed)

When a compound of formula (VII) or (Vila) is used in this process, the process
usually contains a deprotection step, such as described here above.
The reaction step (a) of a compound of formula (I) with a compound of formula
(VI) generally gives rise to intermediates of formula (DQ
In this variant of the process, R5 is preferably H.
International patent application WO 00/58295 describes the synthesis of
compounds of formula (VIII). This patent application also describes 1,4 substituted
piperazines such as compounds of formula (IV) having lipoxygenase inhibition
properties as well as antihistaminergic properties. However, it does not include nor
suggest the use of enantiomerically pure compounds of formula (I) or the use of
compounds of formula (Va), (VIIa) or (IX) as synthesis intermediates for the
preparation of compounds of formula (IV).
The present invention therefore also relates to synthesis intermediates of
formulae (Va), (VIIa) and (IX).
The use of compounds of general formula (I) as synthesis intermediates permits
to produce piperazine derivatives of formula (H) and (IV) with high yield and purity,
using a short and simple route. Surprisingly, no racemization of the intermediate
compounds occurs under these harsh basic conditions.
The present invention will be better understood from the following examples
which only serve to illustrate the invention and therefore should not be taken to limit
the scope thereof. Those skilled in the art will appreciate that routine variations and
modifications of the following examples can be made without exceeding the spirit or
scope of the invention.
EXAMPLES
Example 1: Preparation of levocetirizine (compound 2a, (R)-enantiomer of compound of
formula II wherein n=2, Z1-OH)
1.1 Preparation of [2-f4-ff4-chlorophenyl)phenvlmethvll-l-piperazlnvnethanol
dihydrochloride fracernic mixture, compound la dihydrochlorlde):
50.1 g of sodium carbonate, 95.6 g of l-[(4-chlorophenyl)phenylmethyll-piperazine,
600 ml isopropanol, 45 g of 2-chloroethanol and 55 g of potassium iodide are refluxed
for 24 hours. After cooling to 20-25°C, salts are filtered and rinsed with isopropanol. A
isopropanol-HCl solution is dropwlse added to the mechanically stirred filtrate,
causing the precipitation of compound la dihydrochloride. The suspension is filtered
and the cake is dried under vacuum at 50°C. Thus, 108 g of compound la
dihydrochloride are obtained (Yield: 80 %; Purity: > 99,0 %, m.p.: 158°C).
1.2 Preparation of compound la (free form):
265 g of sodium carbonate and then 500g of compound la dihydrochloride are added
to a stirred mixture of toluene (2,51) and water (2,51). The reaction mixture is heated to
reflux. After cooling to 25°C, the toluene layer Is separated and concentrated under
reduced pressure to dryness to leave compound la free base as a liquid (385 g; Yield:
95%).
1.3 Preparation of compound Ib (compound of formula I In free form wherein n=2,
Y=OH. (Kl-enantiomer):
The chromatographic separation of the enantiomers of compound la such as obtained
in 1.2 is performed using 8 columns of 4.8 x 11.3 cm for 1 kg of chiral stationary
phase CfflRALPAK AD (DAICEL) with methanol as the eluent.
The chromatographlc parameters are:
k'l (capacity factor of the R - enantiomer) = 0.525
k'2 (capacity factor of the S - enantiomer) = 1.111
Alpha (selectivity factor) = 2.118
Resolution = 2.164
Temperature = 23°C
Purity of (R)-enantiomer is 99.5 %; ee = 99 %
1.4 Preparation of compound Ib dlhydrochloride:
lOOg of compound Ib in free form is dissolved in 500ml of Isopropanol by stirring. In
another vessel, excess HC1 gas is bubbled through a solution of isopropanol (500ml).
The two solutions are mixed at 20-25°C with a mechanical agitator, which causes the
precipitation of compound Ib dihydrochloride. The suspension is filtered and the cake
dried under vacuum at 50°C to yield 98g (80% yield; >99.0 % purity) of compound Ib
dihydrochloride.
1.5 Preparation of compound 2a dmydrochloride:
To a stirred solution of compound Ib dihydrochloride (80 g) in THF (800 ml) at room
temperature is dropwise added a mixture of potassium tert butoxlde (77,8 g) in THF
(300ml) then sodium chloroacetate (34,6 g) is added in one portion.
The reaction is heated to reflux overnight, then cooled to room temperature and finally
concentrated to dryness. The solid residues are dissolved in water (500 ml); the
solution is acidified with concentrated HC1 to pH=4,8, and then extracted twice with
dichloromethane (250ml). After evaporation of the dichloromethane, the residue is
taken up in acetone (400ml). To this solution heated at 55°C is added a solution of
HC1 (10 g) in acetone (100ml). After 30 minutes the reaction is cooled to 0°C and
maintained at 0°C overnight. The precipitate is filtered, washed with acetone and dried
under vacuum at 50 °C, providing 37 g of compound 2a dihydrochloride.
Purity : > 96 % ee
Example 2: Preparation of compound 4a (compound of general formula IV wherein
n=2, R4=-CONH2)
2.1 Preparation of compound VIII:
Reaction between commercially available 3-butyn-l-ol and methanesulfonyl chloride is
performed in presence of triethylamine at 0-10 °C, under vigorous stirring. As soon as
the reaction Is complete, hydrochloric salts of triethylamine are filtered off and washed
with toluene. The collected organic phases are washed successively with aqueous
NaHCO3 solution, aqueous HC1 solution, and finally with demineralized water. The
organic phase is then evaporated under vacuum to give crude 3-butyn-l-yl
methanesulfonate ester as an. oil (approx. 90 % yield).
Reaction between 3-butyn-l-yl methanesulfonate ester and an excess of
hydroxylamine is carried out in aqueous solution In presence of methyl alcohol. When
the reaction is complete, methyl alcohol is evaporated under vacuum. The solution is
washed with toluene. The aqueous phase is then washed with ethyl acetate to extract
N-(3-butyn-l-yl) hydroxylamine. The organic phases containing N-(3-butyn-l-yl)
hydroxylamine are collected in order to be concentrated and then directly used into
the next step.
EtOAc solution of N-(3-butyn-l-yl) hydroxylamine obtained from the previous step is
directly used in the next step. Into the solution are added potassium cyanate
previously dissolved in demineralized water. The mixture is cooled down to 0 °C, and
under vigorous stirring, HC1 (37% aqueous solution) is slowly added. The reaction
medium is then heated to 20 °C and after decantation, the two phases are separated.
Sodium chloride is added to the aqueous phase under stirring to saturation and the
aqueous phase is washed with EtOAc. All the EtOAc phases are collected and
evaporated under vacuum to dryness to give crude N-(3-butyn-l-yl) N-hydroxyurea
(compound VIII).
2.2 Preparation of compound Vila:
Crude compound VIII is dissolved in a mixture of acetone and 2,2-dimethoxypropane.
Sulfuric acid is slowly added and the reaction mixture is heated at reflux. As soon as
the reaction is complete, the mixture is cooled down, potassium carbonate is added
and the mixture is stirred overnight and then filtered. The filter cake is washed with
acetone. The combined organic phases are evaporated under vacuum. The evaporation
is stopped when condensation is no longer observed. Water and acetone are added
and the medium is maintained at 40 °C for a while. The mixture is then cooled down
to 0 °C and stirred at that temperature. Compound VIIa crystallizes as a white solid
and is filtered. After filtration, the cake is washed with water and toluene. The solid is
then dried under vacuum to give compound VIIa (58 % yield, > 98 area % purity by
HPLC).
2.3 Preparation of compound Vb (compound of formula V wherein R4=-COOCH3
and P1P2=isopropylene):
The reactor is flushed with N2 prior to charging material. 5-iodosalicylate methyl ester,
compound Vila, PdfPPHsJaCk, Cul, EtOAc, water, triethylamine and tetra butyl
ammonium bromide are vigorously stirred, The solid compound Vb is filtered, washed
with water, and then dried to give a white to off-white powder (77% yield, > 98%
purity).
2.4 Preparation of compound Va:
Ammonolysis of compound Vb to give compound Va is carried out under pressure in
rnethanol, isopropanol, tert-amyl alcohol or other pentyl alcohol at a temperature
between 25 °C and 40 °C. As soon as the reaction is complete, the excess of ammonia
is removed and the reaction mixture is slightly concentrated in order to initiate the
precipitation of the product. The suspension is then cooled down to 0 °C to complete
the precipitation of compound Va. After filtration of crude product, the cake is washed
with cooled alcohol.
In order to get a high purity material (> 99.0 %), compound Va is then recrystalllzed in
isopropanol.
2.5 Preparation of compound Ic (compound of formula I dihydrochloride salt or
free base wherein n=2 and Y=C1. (Rl-enantiomer):
82 g of compound Ib prepared as described in Example 1, 11 of toluene, 45 g of
thionyl chloride and 5 g of dimethyl formamide are successively added to a vessel. The
mixture is stirred at reflux for 48 hours then cooled to room temperature. It is then
filtered, washed with toluene and then dried under vacuum at 50°C to give the
compound Ic dihydrochloride salt (Yield>90%). 50g of the filtered solid is stirred in a
mixture of toluene and water and sodium carbonate (25 g) is added. The toluene layer
is separated and evaporated to dryness, leaving compound Ic free base as a thick
liquid (Purity: > 99% ).
2.6 Preparation of compound 4a:
A mixture of compound Va, compound Ic free base and KaCOa are stirred in
isopropanol or in pentyl alcohol at a temperature between 30 °C and 40 °C. The
reaction mixture is cooled down to room temperature and filtered. The filter cake is
washed with isopropanol or pentyl alcohol.
The deprotectiori step is carried out at room temperature, in a mixture of HOAc, H2SO4
and water. As soon as the reaction is complete, the solvent is evaporated. The residual
oil is dissolved in EtOAc and the solution is washed with saturated aqueous NaHCOa
solution. The EtOAc layer is then washed twice with saturated NaCl aqueous solution.
The solution is concentrated (half of the EtOAc is evaporated) using a hot water bath.
The solution is stirred and allowed to cool to room temperature, and then cooled down
to 0 °C. The solid is filtered, washed with EtOAc and dried to give compound 4a as a
white to off-white solid (70 % yield, > 99 % purity).
Purity : > 96 % ee.
2.7 Preparation of compound 4a fumarate salt:
100 g of compound 4a and 21 g of fumaric acid are dissolved in a mixture of ethyl
acetate and ethanol at reflux. The solution is allowed to cool to 5 °C and stirred during
12 hours. The precipitate is filtered and dried under vacuum to give 102 g of
compound 4a fumarate salt (Yield: 84 %). The salt formation is also efficiently carried
out in solvents such as ethanol, THF, mixtures of ethyl acetate/ethanol,
THF/methanol or THF/ethanol.
Example 3: Preparation of compound 4b (compound of formula IV wherein n=2 and
R4=H)
3. 1 Preparation of compound 9a oxalate (compound of formula IX wherein n=2,
R5=H and W2=I):
To a suspension of compound 1c dihydrochloride salt (102. 9g) prepared as described
in Example 2, in toluene (820ml) and water (360ml) is added iodophenol (59.01g),
potassium carbonate (118.0g) and potassium iodide (4.05g ) then the mixture is
heated to 95°C for 24 hours, then cooled and transferred to a separating funnel. The
aqueous layer is removed and the organic layer transferred to a 2L round bottomed
flask. A solution of oxalic acid (24.15g) in ethyl acetate (340ml) is added affording a
white precipitate. The precipitate is collected by suction filtration and washed with
ethyl acetate to afford compound 9a oxalate as an off-white powder (149.56g,
quantitative yield).
3.2 Preparation of compound 4b in free form:
To a mixture of compound 9a oxalate (100g) in toluene-THF (1:1, 1000ml) and water
(300ml) is added diisopropylamine (79ml), PdCl2(PPh3)2 (1128mg) and Cul (459mg),
then compound VIII such as prepared in Example 2 (26. 8g). After 24 hours at room
temperature, the two layers are separated and to the organic layer is added activated
charcoal (50g) and the mixture is stirred overnight. The contents are filtered through a
short pad of celite and the pad is washed with THF. The combined organic nitrates are
then concentrated in vacuo at 45°C to give an amorphous solid (quantitative yield).
3.3 Preparation of compound 4b malate salt:
Compound 4b in free form is dissolved with L-malic acid (23. 7g) in hot ethyl acetate
(1L). The solution is allowed to cool to 10°C and stirred overnight. The precipitate is
filtered and then washed with EtOAc and finally dried under vacuum to give 87g (81%
yield) of an off-white. powder which is pure by TLC, HPLC and !H NMR. The salt
formation is also efficiently carried out in common solvents such as ethanol, THF and
mixtures of ethyl acetate/ethanol or THF/methanol or THF/ ethanol.



We Claim:
1. An enantiomerically pure piperazine compound of general formula (I)
(Formula Removed)
wherein
Y represents p-toluenesulfonate (OSO2-C6H4-CH3) or perchlorate (OClO3).

Documents:

3098-DELNP-2005-Abstract (8-1-2008).pdf

3098-DELNP-2005-Abstract-(05-03-2008).pdf

3098-DELNP-2005-Abstract-(10-07-2008).pdf

3098-DELNP-2005-Abstract-(24-11-2008).pdf

3098-DELNP-2005-Abstract-(27-01-2009).pdf

3098-DELNP-2005-Abstract-05-05-2008.pdf

3098-delnp-2005-abstract.pdf

3098-DELNP-2005-Claims (8-1-2008).pdf

3098-DELNP-2005-Claims-(05-03-2008).pdf

3098-DELNP-2005-Claims-(10-07-2008).pdf

3098-DELNP-2005-Claims-(24-11-2008).pdf

3098-DELNP-2005-Claims-(27-01-2009).pdf

3098-DELNP-2005-Claims-05-05-2008.pdf

3098-delnp-2005-claims.pdf

3098-delnp-2005-complete specification (granted).pdf

3098-DELNP-2005-Correspondence-Others (8-1-2008).pdf

3098-DELNP-2005-Correspondence-Others-(05-03-2008).pdf

3098-DELNP-2005-Correspondence-Others-(10-07-2008).pdf

3098-DELNP-2005-Correspondence-Others-(24-11-2008).pdf

3098-DELNP-2005-Correspondence-Others-(31-10-2008).pdf

3098-DELNP-2005-Correspondence-Others-05-05-2008.pdf

3098-delnp-2005-correspondence-others.pdf

3098-DELNP-2005-Description (Complete) (8-1-2008).pdf

3098-DELNP-2005-Description (Complete)-(05-03-2008).pdf

3098-DELNP-2005-Description (Complete)-(24-11-2008).pdf

3098-DELNP-2005-Description (Complete)-(27-01-2009).pdf

3098-DELNP-2005-Description (Complete)-05-05-2008.pdf

3098-DELNP-2005-Description (Complete)-10-07-2008.pdf

3098-delnp-2005-description (complete).pdf

3098-DELNP-2005-Form-1 (8-1-2008).pdf

3098-DELNP-2005-Form-1-(05-03-2008).pdf

3098-DELNP-2005-Form-1-(10-07-2008).pdf

3098-DELNP-2005-Form-1-(18-03-2009).pdf

3098-DELNP-2005-Form-1-05-05-2008.pdf

3098-delnp-2005-form-1.pdf

3098-delnp-2005-form-18.pdf

3098-DELNP-2005-Form-2 (8-1-2008).pdf

3098-DELNP-2005-Form-2-(05-03-2008).pdf

3098-delnp-2005-form-2.pdf

3098-DELNP-2005-Form-3 (8-1-2008).pdf

3098-DELNP-2005-Form-3-(24-11-2008).pdf

3098-delnp-2005-form-3.pdf

3098-delnp-2005-form-5.pdf

3098-DELNP-2005-GPA (8-1-2008).pdf

3098-delnp-2005-gpa.pdf

3098-delnp-2005-pct-210.pdf

3098-delnp-2005-pct-304.pdf

3098-DELNP-2005-Petition-137 (8-1-2008).pdf

3098-DELNP-2005-Petition-138 (8-1-2008).pdf


Patent Number 233120
Indian Patent Application Number 3098/DELNP/2005
PG Journal Number 13/2009
Publication Date 27-Mar-2009
Grant Date 26-Mar-2009
Date of Filing 12-Jul-2005
Name of Patentee UCB FARCHIM SA.
Applicant Address Z.I. PLANCHY, CHEMIN DE CROIX BLANCHE, 10, C.P. 411, CH-1630 BULLE, SWITZERLAND.
Inventors:
# Inventor's Name Inventor's Address
1 CELAL ATES COURS D'ORVAL 8, B-1348 LOUVAIN-LA-NEUVE, BELGIUM.
2 EMILE CAVOY ALLEE DE MORFAYT 42, B-6120 HAM-SUR-HEURE, BELGIUM.
3 DIDIER BOUVY AVENUE VAN DE WALLE 50, B-1340 OTTIGNIES, BELGIUM.
PCT International Classification Number C07D
PCT International Application Number PCT/EP2004/000399
PCT International Filing date 2004-01-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03001565.5 2003-01-23 EPO