FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION (See section 10)

2 7 MAR 2003

4-(DIARYLMETHVL)-l-PIPERAZINYL DERIVATIVES
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059. MAHARASHTRA,
INDIA
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

The present invention relates to compound of formula I, 4-(diarylmethyl)-l-piperazinyl derivatives with alkenyl moiety substituted at the 1-position of the piperazine unit.

Formula I
wherein X, Y, X' & Y' are selected from hydrogen, halogen, substituted or unsubstituted alkyl (linear, branched or cyclo), aryl, alkyloxy and haloalkyl group; R1, R2, R3 & R4 are selected from hydrogen, substituted or unsubstituted alkyl groups (linear, branched or cyclo), aryl, heteroaryl groups or aralkyl groups, heterocycles containing one or more of hetero atoms (viz., N, S, O), substituted or unsubstituted alkenyl or alkynyl groups of carbon 2 to 6, wherein the substituents R1 & R2 on the piperazinyl moiety are either syn or anti to each other and optionally R3 and R4 together with the carbons to which they are attached form a monocyclic saturated or aryl or substituted aryl or heteroaryl or substituted heteroaryl ring containing one or more hetero atoms selected from N, S and O with a ring size ranging from 3 to 6; with a proviso that when R3 & R4 together do not form part of a ring they may exist in either E or Z configuration; R5 is (CH2)n-0-CH2-CO-Z wherein n is 1 to 6; Z is selected from OH, OR, NRR',
N B N(OR)R',' N(R)-N(R)R' and wherein R & R' are selected from hydrogen,
substituted or unsubstituted alkyl groups (linear, branched or cyclo), aryl, heteroaryl
groups or aralkyl groups, heterocycles containing one or more of hetero atoms (viz., N, S,
O), substituted or unsubstituted alkenyl or alkynyl groups of carbon 2 to 6; and B is

selected from -(CH2-, wherein n is selected from 1 to 6 and -(CH2)x-D-(CH2)y wherein D is O, NR, S or SO2, x and y are independently selected from 1 to 6; and m is selected torn 1 to 6; and pharmaceutically acceptable salts thereof.
The R5 group in formula I represents an alkyloxy acetic acid and its derivatives, such as an ester, an amide, a hydroxamic acid or a hydrazide. These compounds include their non-toxic pharmaceutically acceptable acid addition salts and those derived from alkali metals, alkaline earth metals or amines including hydroxyalkyl and polyhydroxyalkyamines amines
The compound of the present invention is an antihistaminic compound useful in the treatment of histamine mediated diseases.
PRIOR ART
United States patent number 4525358 (Indian reference not available) discloses an antihistaminic compound cetirizine

which is used as an antiallergic, antihistaminic, bronchodilator or antispasmodic agent. It is useful in patients suffering from indications requiring the above mentioned effects. However, it is devoid of an olefinic side chain on the piperazine ring.
PCT publication WO 01/79188 discloses novel compounds of formula

N N-X—Y

which are more hydrophobic in nature than cetirizine as Y is substituted or unsubstituted carbocyclic, a heterocyclic, a polycyclic hydrocarbonyl, a heteropolycyclic, a carbocyclic arenyl, a heteropolycyclic arenyl or theophylline group.

for treating asthma, allergy and inflammatory disorders, wherein W or a substituent on the phenyl ring is a hydroxylamine.
European patent number 598123 discloses piperazine derivatives of formula

which are different from compound of formula I as they do not contain an olefinic side chain on the piperazine ring.
We have now found novel compounds that have high antihistaminic activity.
OBJECTS OF THE INVENTION:
The object of the present invention is to provide antihistaminic compound of formula I and pharmaceutically acceptable salts thereof.

SUMMARY OF INVENTION:
A compound of formula I

Formula I
wherein X, Y, X' & Y' are selected from hydrogen, halogen, substituted or unsubstituted alkyl (linear, branched or cyclo), aryl, alkyloxy and haloalkyl group; R1, R2, R3 & R4 are selected from hydrogen, substituted or unsubstituted alkyl groups (linear, branched or cyclo), aryl, heteroaryl groups or aralkyl groups, heterocycles containing one or more of hetero atoms (viz., N, S, O), substituted or unsubstituted alkenyl or alkynyl groups of carbon 2 to 6, wherein the substituents R1& R2 on the piperazinyl moiety are either syn or anti to each other and optionally R3 and R4 together with the carbons to which they are attached form a monocyclic saturated or aryl or substituted aryl or heteroaryl or substituted heteroaryl ring containing one or more hetero atoms selected from N, S and O with a ring size ranging from 3 to 6; with a proviso that when R3 & R4 together do not form part of a ring they may exist in either E or Z configuration; R5 is (CH2)n-0-CH2-CO-Z wherein n is 1 to 6; Z is selected from OH, OR, NRR',
N(OR)R', N(R)-N(R)R' and wherein R & R' are selected from hydrogen,
substituted or unsubstituted alkyl groups (linear, branched or cyclo), aryl, heteroaryl groups or aralkyl groups, heterocycles containing one or more of hetero atoms (viz., N, S, O), substituted or unsubstituted alkenyl or alkynyl groups of carbon 2 to 6; and B is selected from -(CH2)n- , wherein n is selected from 1 to 6 and -(CH2)x-D-(CH2)y wherein D is O, NR, S or SO2, x and y are independently selected from 1 to 6; and m is selected from 1 to 6; and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides compound of formula I

R3 Formula I
wherein X, Y, X' & Y' are selected from hydrogen, halogen, substituted or unsubstituted alkyl (linear, branched or cyclo), aryl, alkyloxy and haloalkyl group; R1, R2, R3 & R4 are selected from hydrogen substituted or unsubstituted alkyl groups (linear, branched or cyclo), aryl, heteroaryl groups or aralkyl groups, heterocycles containing one or more of hetero atoms (viz., N, S, O), substituted or unsubstituted alkenyl or alkynyl groups of carbon 2 to 6, wherein the substituents R1 & R2 on the piperazinyl moiety are either syn or anti to each other and optionally R3 and R4 together with the carbons to which they are attached form a monocyclic saturated or aryl or substituted aryl or heteroaryl or substituted heteroaryl ring containing one or more hetero atoms selected from N, S and O with a ring size ranging from 3 to 6; with a proviso that when R3 & R4 together do not form part of a ring they may exist in either EorZ configuration; R5 is (CH2)n-0-CH2-CO-Z wherein n is 1 to 6; Z is selected from OH, OR, NRR',
N B N(OR)R', N(R)-N(R)R' and wherein R & R' are selected from hydrogen,
substituted or unsubstituted alkyl groups (linear, branched or cyclo), aryl, heteroaryl
groups or aralkyl groups, heterocycles containing one or more of hetero atoms (viz., N, S,
O), substituted or unsubstituted alkenyl or alkynyl groups of carbon 2 to 6; and B is
selected from -(CH2)n- , wherein n is selected from 1 to 6 and -(CH2)x-D-(CH2)y
wherein D is O, NR, S or SO2, x and y are independently selected from 1 to 6; and m is
selected from 1 to 6; and pharmaceutically acceptable salts thereof.

The compound of the present invention wherein R3 and R4 together with the carbons to
which they are attached form a monocyclic saturated or aryl or substituted aryl or
heteroaryl or substituted heteroary ring containing one or more hetero atoms selected
from N, S and O with a ring size ranging from 3 to 6 is referred to herein as cornpound of
formula II ' ' .

formula II
The preferred compound of formula II is wherein the ring is a benzene ring

formula II
formula III

The compound of the present invention wherein R3 and R4 are in E configuration, is referred to herein as compound of formula III,

Preferably, compound of formula I wherein
X, Y, X' & Y' are selected from hydrogen, chloro and fluoro;
R1 and R2, are hydrogen;
R3 and R4 are hydrogen existing in the E or Z configuration or optionally ,R3 and R4
together with the carbons to which they are attached form a benzene ring; and
R5 is CH2-O-CH2-CO-Z wherein Z is selected from OH and OR wherein R may be
selected from methyl, ethyl and isopropyl; and m is 1.
Compounds of the present invention may be prepared using different routes. For instance, as illustrated in Schemes 1 to 4.
In process as illustrated in Scheme 1
compound of formula IV,
formula IV
Scheme 1



wherein X,Y,X', Y', R1 and R2 are as described above, is N-alkylated with compound of
formula V wherein L is a leaving group selected from halo, or an alkyl or arylsulfonate
group for e.g. methanesulfonate or p-toluenesulfonate and the like, to give compound of
formula VI,

which is then reacted with X1CH2COZ wherein Xi is halo group such as chloro to yield compound of formula I.
The starting material, compound of formula IV, may be prepared by known prior art such as Baltzly, R. et al, J. Org. Chem., 14, 775, 1949; Yung, D.K et al J. Pharm. Sci., 67(7), 1978.
In process as illustrated in Scheme 2, Scheme 2

IV

VIII

compound of formula I wherein R3 and R4 together form ring selected from cyclic, aryl or substituted aryl, heterocyclic aryl groups or substituted heterocyclic aryl groups containing one or more hetero atoms (viz., N, S, O) with a ring size ranging from 3 to 6, referred to herein as compound of formula II may be prepared by a process similar to that described above wherein compound of formula IV is N-alkylated with compound of formula VII wherein L is a leaving group selected from halo, or an alkyl or arylsulfonate group for e.g. methanesulfonate or p-toluenesulfonate and the like, to give compound of formula VIII,



formula VIII

which is then reacted with X1CH2COZ wherein X1 is halo group such as chloro to yield compound of formula I.

In process as illustrated in Scheme 3,
Scheme 3


o

IV

XI

in

compound of formula I wherein R3 and R4 are hydrogen and in E or Z configuration, may be prepared by N-alkylating compound of formula IV with compound of formula IX,



formula IX

wherein P maybe H or any protecting group such as acetate to give compound of formula X, which is reduced to give compound of formula XI. Compound of formula XI is then reacted, after removing the protecting group wherever required, \vith X1CH2COZ wherein X1 is halo group such as chloro to yield compound of formula I.

formula XI
In process as illustrated in Scheme 4,
Scheme 4

iv xv '"
compound of formula I wherein R3 and R4 are in E configuration may be prepared by N-alkylating compound of formula IV with compound of formula XII to give compound of formula XIII which is then reduced to yield compound of formula XTV.

formula XII

R3
formula XIII


Compound of formula XIV is treated with X1CH2COZ wherein X1 is halo group such as chloro to yield compound of formula I.

R3 formula XIV
Another aspect of the present invention relates to formulation of compound of formula I in suitable form, which can be administered to the patient. ,
Compounds of the present invention can be provided as a pharmaceutical composition for use in the treatment of histamine mediated diseases. The composition comprises compound of formula I and pharmaceutically acceptable ingredients.
Such compositions may" be prepared by admixing compound of formula I and pharmaceutically acceptable ingredients. Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual, transdermal or opthalmic administration.
The compositions may be in the form of tablets, capsules, powders, granules, nasal spray, aerosols, lozenges, ointments, creams, transdermal patches, reconstitutable powders, or liquid preparations, such as oral or sterile solutions or suspensions.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets and capsules and may
contain conventional excipients such as binding agents, for example syrupy acacia,
gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for .example"lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example
magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium
starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting
agents such as sodium lauryl sulpToate.
The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting known to those skilled in this art. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non¬aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the, concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be

dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local" anaesthetic, a preservative and buffering agent can be dissolved in the vehicle: To enhance the stability, the composition can be frozen after filling into the vial and-the .water removed under vacuum.
For ophthalmic administration, sterile solution or suspension can be prepared. Ophthalmic solution can be prepared by dissolving the compound in water for injection along with suitable preservative, chelating agent, osmogen, viscosity enhancing agent, 'antioxidant and buffering agent. Solution is aseptically filtered and filled into suitable vials or bottles of suitable material. Similarly suspension can be prepared by aseptically dispersing the sterile compound in a sterile aqueous vehicle containing suitable preservative, chelating agent, osmogen, suspending agent, anti-oxidant and buffering agent. Preservative-free unit doses can also be prepared in similar way for solution as well as suspension and aseptically filled into unit dose containers.
Compositions may contain from 0.1 % to 99.0% by v/eight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
Composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
The compound of formula I on being formulated is useful for various histamine mediated diseases. IC50 was determined for the compounds prepared by the present invention.

EXAMPLES
Example 1
4-{4-[Bis-(4-nuorophenyl)methyl]piperazin-l-yI}-(Z)-but-2-en-l-ol, (VIa, X=X;=4-F;
Y=Y'=R1=R2=R3=R4=H; m=n=l):
A solution containing l-[bis-(4-fluorophenyl)methyl]piperazine (140g, 0.485mol), toluene (700ml), 4-chloro-2-butene-l-ol (67.25g, 0.631), and diisopropylethylamine (125.8g, 0.971mol) is stirred at 47-49° C for 5hrs. Water (350ml) is added to the reaction mixture, the organic layer separated and the aqueous layer extracted with dichloromethane (2x200ml). The combined organic layer is washed with water (200ml), and concentrated to obtain crude product which is purified by flash column chromatography on silica gel using dichloromethane-methanol (9.6:0.4) as mobile phase to obtain pure product.
H-NMR (CDC13, rppm): 2.15-2.80 (m, 8H), 3.01 (d, J=4.90Hz, 2H), 4.13 (d, J=3.96Hz, 2H), 4.20 (s, 1H), 5.55-5.75 (m, 1H), 5.75-6.00 (m, 1H), 6.96 (t, J=8.14Hz,'4H), 7.20-7.40 (m, 4H).
Example 2
(R,S)-4-{4-[(4-chlorophenyl)phenyImethyl]piperazin-l-yl}-(Z)-but-2-en-l-oI, [VIb(R,S), X=C1; X'=Y=Y'=R1=R2=R3=R4=H; m=n=l]:
(R,S)-l-[(4-chlorophenyl)phenylmethy!]piperazine 8.0g (mol) is converted to (R,S)-4-{4-[(4-chlorophenyl)phenylmethyl]piperazin-l-yl}-(Z)-but-2-en-l-ol in a manner similar to example 1. Crude product is obtained as a syrupy mass, which is purified by flash column chromatography on silica gel using toluene-methanol (9:1) as mobile phase to obtain pure product.
'H-NMR (CDC13, Tppm): 2.10-2.90 (m, 8H), 3.01 (d, J=5.75Hz, 2H), 4.13 (d, J=-5.25Hz, 2H), 4.19 (s, 1H), 5.50-5.75 (m,.lH), 5.75-6.00 (m, 1H), 7.00-7.40 (m, 9H).

Example 3
4-{4-BenzhydryIpiperazin-l-yI}-(Z)-but-2-en-l-ol, (VIc, X=X'=Y=Y'=H;
R1=R2=R3=R4=H; m=n=l):
A solution containing 1-benzhydrylpiperazine (3g, 0.0119mol), toluene (20ml), 4-chloro-2-butene-l-ol (1.65g, 0.0155mol), diisopropylethylamme (3.81g, 0.0295mol), and DMF (3ml) is stirred at 55-60° C for 5hrs. The reaction mass is quenched with water (20ml), organic layer separated and the aqueous layer extracted with dichloromethane (2x20ml). The organic extract is washed with water (10ml), and concentrated to obtain crude product, which is purified by flash column chromatography on silica gel using dichloromethane-methanol (9.3:0.7) as mobile phase to obtain pure product.
'H-NMR (CDC13, Tppm): 2.10-2.80 (m, 8H), 3.01 (d, J=5.52Hz, 2H), 4.13 (dd, J,=5.19Hz, J2=0.68Hz, 2H), 4.21 (s, 1H), 5.50-5.75 (m, 1H), 5.75-6..00 (m, 1H), 7.00-7.50 (m, 10H).
Example 4
4-{4-[Bis-(2,4-difluorophenyl)methyI]piperazin-l-yl}-(Z)-but-2-en-l-ol, (VId,
X=X'=Y=Y'=F; R1=R2=R3=R4=H; m=n=l):
l-[Bis-(2,4-difluorophenyl)methyl]piperazine (20.0g, 0.0617mol) is converted to 4-{4-[bis-(2,4-difluorophenyl)methyl]piperazin-l-yl}-(Z)-but-2-en-l-ol in a manner similar to example 1. Crude product is obtained as a syrupy mass, which is purified by flash column chromatography on silica gel using toluene-methanol (9:1) as mobile phase to obtain pure product.
'H-NMR (CDCI3, Tppm): 2.20-2.85 (m, 8H), 3.02 (dd, J1=6.00Hz, J2=0.74Hz, 2H), 4.14 (dd, J,=5.31Hz, J2=0.98Hz, 2H), 4.94 (s, 1H), 5.50-5.75 (m, 1H), 5.75-6.00 (m, 1H), 6.55-7.00 (m, 4H), 7.30-7.60 (m, 2H).

Example 5
4-{4-{Bis-(4-chlorophenyl)methyl]piperazin-l-yl}-(Z)-but-2-en-l-oI, (VIe, X=X'=CI;
Y=Y'=R1=R2=R3=R4=H; m=n=l):
1-[Bis-(4-chlorophenyl)methyl] piperazine (5.044g, mol) is converted to 4-{4-[bis-(4-chlorophenyl)methyl]piperazin-l-yl}-(Z)-but-2-en-l-ol in a manner similar to example 1. The crude product obtained is purified by flash column chromatography on silica gel using toluene-methanol (9:1) as mobile phase to obtain pure product.
'H-NMR (CDC13, rppm): 2.10-2.80 (m, 8H), 3.01 (d, J=5.87Hz, 2H), 4.13 (dd,
J,=5.26Hz, J2=0.88, 2H), 4.18 (s, IH), 5.50-5.75 (m, IK), 5.75-6.00 (m, IH), 7.00-7.40
(m,8H). ... • '
Example 6
{2={4-[Bis-(4-fluofophenyl)methyl]piperazin-l-yl-niethyl}phenyl}methanol (Villa, X=X'=F; Y=Y'=R1=R2=H; m=n=l, A=benzene ring):
l-[Bis-(4-chloroph"enyl)methyl] piperazine (5.0g, 0.0173mol) is converted to {2-{4-[bis-
(4-fluorophenyl)methyl]piperazin-l-ylmethyl}phenyl}methanol using 2-
(chloromethyl)benzyl alcohol, in a manner similar to example 1. The crude product obtained as brownish yellow syrup is purified by flash column chromatography on silica gel using toluene-methanol (9.2:0.8) as mobile phase to obtain pure product.
'H-NMR (CDGI3, Tppm): 2.00-2.80 (m, 8H), 3.6 (s, 2H), 4.18 (s, 1H), 4.57 (s, 2H), 6.70-7.03 (m, 4H),7.05-7.40 (m, 8H).
Example 7
{2-{4-[(4-chlorophenyI)phenylmethyl]piperazin-l-ylmethyI}phenyI}methanol, (VIIIB;X=C1; X'=Y=Y'=R1=R2=H; m=n=l, A=benzene ring):
l-[Bis-(4-chlorophenyl)methyl] piperazine (4.0g, 0.0140mol) is converted to {2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-l-ylmethyl}phenyl}methanol in a manner similar to example 1. The crude product obtained is purified by flash column chromatography on

silica gel using toluene-methanol (9.2:0.8) as mobile phase to obtain pure product as a white foamy solid.
'H-NMR (CDCI3, Tppm): 2.00-2.80 (m, 8H), 3.60 (s, 2H), 4.16 (s, 1H), 4.56 (s, 2H), 6.86 (br, exchangeable by D2O), 6.95-7.40 (m, 13H).
Example 8
4-{4-[Bis-(4-fluorophenyl)methyl]piperazin-l-yl}but-2-yn-l-ol (Xa, X=X'=-F;
Y=Y'=R1=R2=H; m=l):
Method A: Using 4-chloro-2-butyne-l-ol
To a solution containing l-[bis-(4-fluorophenyl)methyl]piperazine (300g, 1.040mol), tetrahydrofuran (1800ml) and diisopropylethylamine (242. Ig, 1.873mol) is added dropwise 4-chloro-2-butyne-l-ol (130.5g, 1.248mol) during lhr at 10-15° C. After stirring at 10-15° C for 1.5hr the temperature is gradually raised to 25-30° C and stirred for further 7hr. Thereafter, a solution of citric acid (437.3g, 2.08mol) in water (500ml) is added and the mixture is concentrated under reduced pressure at below 60° C to remove most of the solvent. The resulting aqueous mass is washed with toluene (2x400ml), basified to pH=9-10 and the product extracted into dichloromethane (2x400ml). The dichloromethane layer is washed with water (300ml) and degassed to obtain crude product, which is purified by flash column chromatography on silica gel using toluene-methanol (9:1) as mobile phase.,
'H-NMR (CDCI3, rppm): 1.84 (br, 1H, D20 exchangeable), 2.20-2.80 (m, 8H), 3.31 (t, J=1.84Hz, 2H), 4.21 (s, 1H), 4.29 (t, J=1.80Hz, 2H), 6.80-7.05 (m, 4H), 7.10-7.50 (m, 4H).
MethodB: Using 2-butyne.-l,4-diol
A solution of methanesulfonyl chloride (48.69g, 0.425mol) and tetrahydrofuran (100ml) is added dropwise to a stirred solution of 2-butyne-l,4-diol (lOOg, 1.162mol) and diisopropylethylamine (62.45g, 0.483mol) in tetrahydrofuran (400ml) during 2hr at 0-

5°C. After 1hr stirring at 0-5°C for 1hr the temperature is raised to 25-30°C and stirred for further 1hr. The reaction mixture is then cooled to 10-15°C, and to it is added diisopropylethylamine (99.34g, 0.769mo1), followed by l-[bis-(4-fluQrophenyl)methyl]piperazine (110.8lg, 0.384mol) in portions during 30min. The reaction mass is stirred at 10-15°C for Ihr and then at 25-30°C for furthers 8hrs. Toluene (500ml) is added to it and the contents washed with water (2x400ml). Thereafter, a solution of citric acid (161.52g, 0.769mol) in water (500ml) is added and the mixture is concentrated under reduced pressure at below 60° C to remove most of the solvent. The resulting aqueous mass is washed with hexane (2x250ml), basified to pH=9-10 and the product extracted into ethyl acetate (2x300ml). The ethyl acetate layer is washed with water (200ml) and degassed to obtain crude product which is purified by flash column chromatography on silica gel using toluene-methanol (9.3:0.7) as mobile phase to obtain pure product.
Example 9
(R,S)4-{4-[(4-CbIor6phenyl)phenylmethyl]piperazin-l-yl}but-2-yo-l-ol (by method
A in Example 10), (Xb, X=C1; X'=Y=Y'=R1=R2=H; m=l):
A solution containing (R,S)-l-[(4-chlorophenyl)phenylmethyl]piperazine (lOg, 0.0349mol), toluene (50ml), 4-chloro-2-butyne-l-ol (4.74g, 0.0453mol), and diisopropylethylamine (9.02g, 0.0698mol) is stirred at 45-50° C for 6hrs. The reaction mixture is quenched with water (20ml). The organic layer is separated and the aqueous layer extracted with dichloromethane (2x30ml). The organic layers is washed with water (20ml) and concentrated to obtain crude product as a syrupy mass,
which is purified by flash column chromatography on silica gel using dichloromethane-methanol (9.6:0.4) as mobile phase to obtain pure product.
'H-NMR (CDC13, Ippm): 1.88 (br, 1H), 2.20-2.75 (m, 8H), 3.31 (t, J=1.72Hz, 2H), 4.20 (s,1H), 4.29 (t, J=1.63Hz, 2H), 7.05-7.50 (m, 9H).

Example 10
(R,S)4-{4-[(4-fluorophenyI)phenyImethyI]piperazin-l-yl}but-2-vn-l-ol (by method
B in Example 10), (Xc, X=F; X'=Y=Y'=R1=R2=H; m=l):
A solution of methanesulfonyl chloride (1.86g, 16.27mmol) and retrahydrpfuran (5ml) is added dropwise to a stirred solution of 2-butyne-l,4-diol (3.82g, 44.3mmol) and diisopropylethylamine (6.30g, 48.8mmol) in tetrahydrofuran (20ml) during 30min at 0-5°C. After lhr stirring the temperature is raised to 25-30pC and stirred for further lhr. The resulting mixture containing mesylate of 2-butyne-l,4-diol is added dropwise to a stirred solution of (R,S)-l-[(4-fluorophenyl)phenylmethyl]piperazine (4.0g, 14.79mol) in tetrahydrofuran (25ml) during lhr at 5-10°C. The reaction mass is stirred at 5-10°C for lhr and then at 25-30° C for further 5hrs. Thereafter, citric acid (3.2g, 0.0l523mol) is added and the mixture is concentrated under reduced pressure at below 60° C to remove most of the solvent. Water (50ml) is charged to the residual mass and the resulting aqueous layer washed with hexane (2x30ml), basified to pH=9-10 and the product extracted into dichloromethane (3x30ml). The dichloromethane layer is washed with water (25ml) and degassed to obtain crude product as a sticky solid, which is. purified by flash column chromatography on silica gel using dichloromethane-methanol (9.2:0.8) as mobile phase to obtain pure product as a thick syrupy mass.
'H-NMR (CDC13, [ppm): 1.87 (b), 2.25-2.70 (m, 8H), 3.30 (t, J=1.83Hz, 2H), 4.21 (s, 1H), 4.29 (t, J=1.78Hz, 2H), 6.85-7.02 (m, 2H), 7.13-7.42 (m, 7H).
Example 11
4-{4-[Bis-(4-nuorophenyl)methyl]piperazin-l-yl}-(E)-but-2-en-l-ol, (XlVa, X-X'=4-
F. Y=Y'=R1=R2=R3=R4=H; m=n=l):
To a stirred solution of methyl 4-{4-[bis-(4-fluorophenyl)methyl]piperazin-l-yl}-(E)-but-2-enoate (3'80'g, 0.984mol) in tetrahydrofuran (1900ml) at -10 to 0° C is added dropwise DIBALH (560 g, 3.938mol, as 20% solution in toluene) during about 2-3 hrs. After completion of addition, the reaction mass is stirred for further 1.0 hrs at 0 to 10° C and then quenched by sequential addition of ethyl acetate (400ml) and water (800ml). After

vigorous stirring for 2 hrs the mass is filtered. The organic layer is separated"from, the:

filtrate, washed with water (1500ml) and concentrated to get crude product The crude product is taken in toluene (2000ml), extracted into 10% acetic acid (2O0Qml), the aqueous extract basified to pH 9-10 with 20% aqueous sodium hydroxide and the product extracted into dichloromethane (3x 1,500ml). The dichloromethane layer is washed with water (800ml), and concentrated to get a syrupy mass which is purified by flash column chromatography on silica gel using toluene-methanol (9:1) as mobile phase.
'H-NMR (CDCI3, rppm): 1.70 (br, D20 exchangeable), 2.20-2.70 (m, 8H), 3.00 (d, J=5.38Hz, 2H), 4.12 (d, J=4.40Hz, 2H), 4.21 (s, 1H), 5.65-5.90 (m, 2H), 6.85-7.05 (m, 4H), 7.28-7.40 (m. 4H).
Example 12
4.-{4.{Bis-(4-fluorophenyl)methyl]pip&razin-l-yl}-(E)-but-2-en-l-ol (XIa, X=X'=4-F;
Y=Y'=R1=R2=H; m=l):
To a stirred solution of 4-{4-[bis-(4-fluorophenyl)methyl]piperazin-l-yl}but-2-yn-l-ol (135g, 0.379mol) in tetrahydrofurah (4300ml) at 5-10° C is added lithium aluminum hydride (43.1 g, 1.136mol) in portions during 3-4 hrs. The reaction mixture is stirred for further 5-6 hrs. and then quenched by addition of ethyl acetate (135ml), followed by water (100 ml) at 5-10° C. The resulting mixture is filtered, the organic layer separated from the filtrate, and concentrated to get crude product, which is purified by flash column chromatography on silica gel using toluene-methanol (9:1) as mobile phase to obtain pure product.
'H-NMR (CDCI3, Tppm): 1.77 (br, D20 exchangeable), 2.20-2.70 (m, 8H), 3.00 (d, J-4.91Hz, 2H), 4.11 (d, J=3.71Hz, 2H), 4.21 (s, 1H), 5.55-5.90 (m, 2H), 6.80-7.05 (m, 4H), 7.10-7.50 (m,4H).

Example 13
{R,S}4-{4-[(4-chloropheny0pheny!methy!]piperazin-l-yl}-(E)-but-2-en-l-ol, (Xlb, X=C1;X'=Y=Y'=Rl=R2=H;m=l):
{R,S)-4-{4-[(4-chlorophenyl)phenylmethyl]piperazin-l-yl}but-2-yn-1-ol (3.5g,mol) is converted to (R,S)-4-{4-[(4-chlorophenyl)phenylmethyl]piperazin-l-yl}-(E)-but-2"en-l-ol in a manner similar to example 14. Crude product is obtained as a syrupy mass, which is purified by flash column chromatography on silica gel using toluene-methanol (9:1) as mobile phase to obtain pure product.
'H-NMR (CDCb, Tppm): 2.20-2.65 (m, 8H), 3.00 (d, J=4.83Hz, 2H), 4.11 (d, J=3.52Hz, 2H), 4.20 (s, 1H), 5.60-5.90 (m, 2H), 7.00-7.50 (m, 9H).
Example 14
(R,S)-4-{4-J(4-fluorophenyl)phenylmethyl]piperazin-l-yl}-(E)-but-2-en-l-ol (XIc, X=F; X'=Y=Y'=R1=R2=H; m=l):
(R, S)A- {4- [(4-fluorophenyl)phenylmethyl]piperazin-1 -yl} but-2-yn-1 -ol . (2.13 g,
0.0063mol) is converted to (R,S)-4-{4-[(4-fluorophenyl)phenylmethyl]piperazin-l-yl}-(E)-but-2-en-l-ol in a manner similar to example 14. Crude product obtained is obtained as a syrupy mass which is purified by flash column chromatography on silica gel using dichloromethane-methanol (9.3:0.7) as mobile phase to obtain pure product.
'H-NMR (CDCI3, Fppm): 1.71 (br, exchangeable by D20), 2.10-2.70 (ra, 8H), 3.00 (d, J-5.23Hz, 2H), 4.11 (d, J=4.20Hz, 2H), 4.22 (s, 2H), 5.65-5.90 (m, 2H), 6.85-7.02 (m, 2H), 7.10-7.45 (m,7H).
Example 15
Methyl 4-{4-[Bis-(4-fluorophenyl)methyl]piperazin-l-yl}-(E)-but-2-enoate, (XIHa,
X=X'=4-F; R=CH3; Y=Y'=R1=R2=R3=R4=H; m=n=l):
A solution of methyl-4-bromocrotonate (46.56g, 0.260mol) in toluene (50ml) is added dropwise to a mixture containing l-[bis-(4-fluorophenyl)methyl]piperazine (50g, 0.173mol), diisopropylethylamine (49.30g, 0.38 lmol) in toluene (250ml) at 25-30° C

during 30 minutes. After stirring for 8hrs, the reaction mass is washed successively with water (2x150ml), 0.2N hydrochloric acid (3x 150ml), and water (150ml). To the organic layer at 5-10° C is added 3N hydrochloric acid (200mi), stirred and the aqueous layer containing product is separated. It is then washed with toluene (200ml), basified to pH = 9-10 with 20% sodium hydroxide solution and the product extracted into ethyl acetate (2x150ml). The organic layer is washed once with water (100ml), concentrated and degassed. The residue is triturated with hexane (150ml) and the solid filtered. The product is further purified by recrystallization from cyclohexane.
'H-NMR (CDC13, Tppm): 1.63 (br, 1H, D20 exchangeable), 2.20-2.65 (m, 8H), 3.13 (d, J=5.00Hz, 2H), 3.72 (s, 3H), 4.22 (s, 1H), 5.88-6.03 (m, 1H), 6.80-7.05 (m, 5H), 7.20-7.40 (m, 4H).
Example 16
Methyl 4-{4-[(4-chIorophenyI)phenylmethyI]piperazin-l-yI)-(E)-but-2-enoate,
(XIHb, X=C1; X'=Y=Y'=R1=R2=R3=R4=H; m=n=l):
A solution containing (7?,$-l-[(4-chlorophenyl)phenylmethyl]piperazine (5g, 0.0174mol), DMF (30ml), methyl-4-bromocrotonate (4.7g, 0.0263mol), and diisopropylethylamine (6.75g, 0.0522mol) is stirred at 27-30° C for 6hrs. The reaction is quenched with water (40ml) and the product extracted into dichloromethane (3x30ml). The organic layer is washed with water (2x30ml) and concentrated to obtain crude product which is purified by flash column chromatography on silica gel using ethyl acetate-hexane (6.5:3.5) as mobile phase to obtain pure product.
rH-NMR (CDCI3, Tppm): 2.20-2.65 (m, 8H), 3.14 (dd, J1=6.20Hz, J2=1.39Hz, 2H), 3.72 (s,-3H) 4:20 (s, 1H), 5.85-6.05 (m,lH), 6.8-7.05 (m, 1H), 7.05-7.50 (m, 9H).
Example 17
{4-{4-(Bis-(4-fluorophenyl)methyl]-piperazin-l-yl}-(Z)-but-2-enyloxy} acetic acid
dihydrochloride, (la):

We claim:
1. A compound of formula I

Formula I

wherein X, Y, X' & Y' are selected from hydrogen, halogen, substituted or unsubstituted alkyl (linear, branched or cyclo), aryl, alkyloxy and haloalkyl group; Rb R2, R3 & R4 are selected from hydrogen, substituted or unsubstituted alkyl groups (linear, branched or cyclo), aryl, heteroaryl groups or aralkyl groups, heterocycles containing one or more of hetero atoms (viz., N, S, O), substituted or unsubstituted alkenyl or alkynyl groups of carbon 2 to 6, wherein the substituents R1 & R2 on the piperazinyl moiety are either syn or anti to each other and optionally R3 and R4 together with the carbons to which they are attached form a monocyclic saturated or aryl or substituted aryl or heteroaryl or substituted heteroaryl ring containing one or more hetero atoms selected from N, S and O with a ring size ranging from 3 to 6; with a proviso that when R3 & R4 together do not form part of a ring they may exist in either E or Z configuration; R5 is (CH2)n-O-CH2-C0-Z wherein n is lto6;Z is selected from OH, OR,
N B NRR', N(OR)R;, N(R)-N(R)R' and wherein R & R' are selected
from hydrogen, substituted or unsubstituted alkyl groups (linear, branched
or cyclo), aryl, heteroaryl groups or aralkyl groups, heterocycles
containing one or more of hetero atoms (viz., N, S, O), substituted or

unsubstituted alkenyl or alkynyl groups of carbon 2 to 6; and B is selected from -(CH2)n-, wherein n is selected from 1 to 6 and -(CH2)x-D-(CH2)y wherein D is O, NR, S or SO2, x and y are independently selected from I to 6; and m is selected from 1 to 6; and pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim 1 wherein
X, Y, X' & Y' are selected from hydrogen, chloro and fluoro;
Ri and R2, are hydrogen;
R3 and R4 are hydrogen existing in the EorZ configuration or optionally when
they are in Z-configuration R3 and R4 together with the carbons to which they are
attached form a benzene ring; and
R5 is CH2-0-CH2-CO-Z wherem Z is selected from OH and OR wherein R may
be selected from methyl, ethyl and isopropyl;
and m is 1.
3. A compound as claimed in claim 1 wherein the compound is {4-{4-[Bis-(4-fluorophenyl)methyl]-piperazin-l-yl}-(Z)-but-2-enyloxy} acetic acid or its pharmaceutically acceptable salt.
4. A compound as claimed in claim 1 wherein the compound is {4-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-l-yl]-(Z)-but-2-enyloxy} acetic acid or its pharmaceutically acceptable salt.
5. A compound as claimed in claim 1 wherem the compound is [4-(4-Benzhydrylpiperazin-l-yl)-(Z)-but-2-enyloxy]acetic acid or its pharmaceutically acceptable salt.
6. A compound as claimed in claim 1 wherein the compound is {4-{4-[Bis-(2,4-difluorophenyl)methyl]-piperazin-l-yl}-(Z)-but-2-enyloxy} acetic acid or its pharmaceutically acceptable salt.
7. A compound as claimed in claim 1 wherein the compound is {4-[4-[Bis-(4-chlorophenyl)methyl]-piperazin-l-yl]-(Z)-but-2-enyloxy}acetic acid or its pharmaceutically acceptable salt.
8. A compound as claimed in claim 1 wherein the compound is {4-{4-[Bis-(4-
fluorophenyl)methyl]-piperazin-l-yl}-(Z)-but-2-enyloxy} acetic acid methyl ester or its pharmaceutically acceptable salt.

9. A compound as claimed in claim 1 wherein the compound is {4-{4-[Bis-(4-fluorophenyl)methyl]-piperazin-l-yl}-(Z)-but-2-enyloxy} acetic acid ethyl ester or its pharmaceutically acceptable salt.
10. A compound as claimed in claim 1 wherein the compound is {4-{4-[Bis-(4-fluorophenyl)methyl]-piperazin-l-yl}-(Z)-but-2-enyloxy} acetic acid isopropyl ester or its pharmaceutically acceptable salt.
11. A compound as claimed in claim 1 wherein the compound is {4-[4-[(4-chlorophenyl)phenyJrnethy]]piperazin-1 -yl]-(Z)-but-2-enyloxy} acetic acid isopropyl ester or its pharmaceutically acceptable salt.
12. A compound as claimed in claim 1 wherein the compound is {4-[4-[(4-chlorophenyl)phenylmethyl]pipera2in-l -yl]-(Z)-but-2-enyloxy}acetic acid methyl ester or its pharmaceutically acceptable salt.
13. A compound as claimed in claim 1 wherein the compound is {4-[4-[(4-chlorophenyl)phenylmethyl]piperazin-l-yl]-(Z)-but-2-enyloxy}acetic acid ethyl ester or its pharmaceutically acceptable salt.
14. A compound as claimed in claim 1 wherein the compound is {2-{4-[Bis-(4-fluorophenyl)rnethyi]piperaXin-l-ylmethyl}benzyloxy} acetic acid • or its pharmaceutically acceptable salt.
15. A compound as claimed in claim 1 wherein the compound is {2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-l-ylmetbyl}benzyl-oxy}acetic acid or its pharmaceutically acceptable salt.
16. A compound as claimed in claim 1 wherein the compound is {4-[4-[Bis-(4-fluorophenyl)methyl]piperizin-l-yl]-(E)-but-2-enyloxy} acetic acid or its pharmaceutically acceptable salt.
17. A compound as claimed in claim 1 wherein the compound is {4-[4-[(4-Chlorophenyl)phenylmethyl]piperizin-l-yl]-(E)-but-2-enyloxy} acetic acid or its pharmaceutically acceptable salt.
18. A compound as claimed in claim 1 wherein the compound is {4-[4-[(4-Fluorophenyl)phenylmethyl]piperazin-l-yl]-(E)-but-2-enyloxy} acetic acid or its pharmaceutically acceptable salt.

19. A compound of formula I as claimed in any of claims 1 to 18 substantially as herein described and illustrated by examples 1 to 32.



Dated this 27th day of March, 2003.