FORM 2
THE PATENT ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
A PROCESS OF PRODUCING A PHARMACEUTICAL COMPOSITION COMPRISING ANTIHISTAMINE COMPOUND AND ITS DERTVATVES
M/S. CIPLA LIMITED, MUMBAI CENTRAL, MUMBAI-400 008, MAHARASHTRA India, an Indian Company incorporated under the Companies Act, 1956.
The following specification particularly describes and ascertains the nature of this invention, and
the manner in which it is to be performed.
-1-

This invention relates to a process of producing a pharmaceutical composition comprising antihistaminic compounds, and more particularly to derivatives of the antihistaminic compound cetirizine of formula (II) ([2-[4-[(4-chlorophenul)phenylmethyl]-l-piperaziny]ethoxy]acetic acid)
r^N


N N

O
-^V V

COOH

^^
(II)
Cetirizine is an antihistamine and is typically delivered in an orally acceptable dosage form. Its principal effects are mediated via selctive inhibition peripheral H receptors. Cetirizine is indicated for relief of symptoms associated with seasonal allergic rhinitis perennial allergic rhinitis and for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria.
Whilst cetirizine is a useful agent for treating these indications, it suffers from a number of side-effects, the most common of which is drowsiness. Less common, but significant, side-effects include fatigue, dry mouth, dizziness, headache and nausea. The most likely reason why cetirizine induces drowsiness is that it can cross the blood-brain barrier. However, derivatives of cetirizine wrhich incorporate more hydrophobic gourps to block blood-brain barrier transport can lead to an unacceptable loss in antihistamine potency.
(III)
-2-
For example, the antihistamine clocinizine of formula (III)(l-[(4- chlorophenyl)phenylmethyl]-4-(3-phenyl-2-propenyl)piperazine), shares the


(4-chlorophenyl)phenylmethyl piperazinyl part with cetirizine, but instead of the more hydrophilic carboxyl group it has a more hydrophobic phenyl group. However, clocinizin is markedly less active than cetirizine.
We have now found that it is possible to provide compounds which are more active antihistamines than cetirizine, but which are also more hydrophobic.
According to one aspect, the present invention provides an antihistaminic compound of formula

Wherein:
X is an aliphatic hydrocarbonylene linker; Y is a carbocyclic group, a heterocyclic group, a polycyclic hydrocarbonyl group, a heteropolycyclic group, a carbocyclic arenyl group, a heteropolycyclic arenyl group or theophylline; and
Y is optionally substituted with at least one substituent, the or each substituent being chosen from linear or branched C-C alkyl optionally substituted with one or more carbocyclic or heterocyclic groups, or a substituent defined herein up to C2ocycloalkyl optionally including one or more heteroatoms from 0, N and S, up to C20 bicycloalkyl optionally including one or more hetroatoms from 0, N and S up to C20 polycycloalkyl optionally includiong one or more heteroatoms from 0,N and S, linear or branched C20 Cyohaloalkyl, linear or branched C1-C10 perhaloalkyl, linear or branched C2-C10 perhaloalkenyl, linear or branched C2-C10 alkenyl linear or branched C2-C10 alkynyl, linear or branched C1C10 alkoxy, linear or branched C1-C10 alkylthio, linear or branched C1-C10 alkoxy (linear or branched C1-C10 alkyl), linear or branched C1-C20 alkoxycarbonyl, linear or branched C1-C10 hydroxyalkyl, linear or branched aminoalkyl, aryl, substituted aryl, naphthyl, substituted naphthyl phenyl, heteroaryl, halogen, nitrile, nitro, amino, linear or branched C1-C10 alkyl amino, linear or branched C1-C10 dialkyl amino, linear or branched C1-C20 alkoxycarbonyl, hydroxyl, formyl acetyl, carboxyl, carbonyl, amido, C1-C5 alkyl amido C1-C5 dialkylamido aroyl, benzoyl, arylamino, diarylamino, aryl C1-C10 alkyl amino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, indolino, piperazino, C1-C5 N-alkyl piperazino or N-aryl piperazino; and each cyclic substituent can in turn be substituted by one or more substituents as defined herein characterised in that the only bond rotation in the X linker is provided by an ethylene radical.
-3-


by mixing 4-chlorobenzhydryl piperazine ethyl chloride with DMF., of anhydrous potassium carbonate and potassium iodine, and azacyclonol;
heating the reaction mixture, followed by cooling and quenching the reaction mixture in ice under stirring for seperating out the solid by filtering and then drying.
Preferably the X linker is a C2-C10 aliphatic hydrocarbonyl linker such as C3, C5 or Cg but it is preferably an etylene or carboxyethlylene radical.
Without wishing to be bound by theory, we believe that the X linker between the piperazinyl part and the Y part requires a flexible carbon-carbon bond wherein the bond between each carbon atom and from each carbon atom is freely rotatable. We further believe that this flexibihty feature aids the interaction of the compunds according to the invention with the H1 receptor.
A process of producing antihistaminic compound derivative comprising sythesis of 4-chlorobenzhydrylpiperazine ethanol dihydrochloride by dissolving in methanol under stirring, adding sodium hydroxide under stirring and filtering to obtain sodium chloride and distilling off methanol completely, adding chloroform under stirring adding thionyl chloride and refluxing followed by filtering to seperating out the solid precipitate, adding acetonitrile and sodium carbonate, under stirring and refluxing and followed by filtering and distilling out acetonitrile under reduced pressure.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
According to another aspect of the present invention, a process of producing antihistaminic compound and its derivative comprising l-(4- chlorobenzhydryl)-4-ethyl-[2'[4"-(2-hydroxybenzhydryljpiperidine] piperazine (compound l)-hydrochloride 5% to 15% w/w, lactose IP 55% to 75% w/w, Starch IP 15% to 25% w/w, Magnesium stearate IP 1% to 2% w/w, Colloidal Silicon dioxide IP 0.5%to 1% w/s and Talc DP l%to 2% w/w and compressing the mixture forming tablet or encapsulating the sid mixture forming capsules.
-4-

According to a further aspect, the present invention provides a compound of the invention for use as a medicament.
The present invention also provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of antihistaminic conditions.
According to a further aspect of the present invention, there is provided the use of 4-chlorobenzhydrylpiperazine ethylchloride to make a compound according to the present invention..
According to a further aspect of the present invention, there is provided the use of 4-chlorobenzhydrylpiperazine to make a compound according to the present invention.
The compounds of the present invention can be formulated for administration to a patient in any convenient manner, for example for oral or parenteral routes of administration. We presently prefer an oral dosage tablet wherein a core containing the active ingredient is coated with an enteric coating. However, the composition may also be provided as a flavoured syrup to mask any unpleasant taste. An injectable formulation is one embodiment of a composition suitable for parenteral administration.
In order that the invention may be more fully understood, reference will be made to the following Examples, by way of illustration only. Example 1
Synthesis cf 4-chlorobenzhydrylpiperazine ethylchlcr'de. 4-chlorobenzlhydrylpiperazine ethylchloride is an intermediate for making many of the compounds of the present invention.
5

20g (0.04944 moles) of 4-chlorobenzhydrylpiperazine ethanol dihydrochloride was dissolved in a 100ml methanol in a 250ml three necked round bottom flask under stirring. To the clear solution 4g (0.1 moles) of sodium hydroxide was added and mixture was stirred for 30 minutes. Sodium chloride obtained was filtered and distilled off methanol completely. Chloroform (l00 ml) was added to the same flask stirred for 15 minutes. To the clear solution 40ml thionyl chloride was added and reaction mixture was refluxed for 5-6 hrs. Solid precipitated out was filtered.
The filtered solid was transferred to a 500ml round bottom flask containing 200ml acetonitrile and 5.2g (0.5 moles) of sodium carbonate, the mixture was stirred. The reaction mixture was refluxed for 2 hrs and filtered. Acetonitrile was distilled out under reduced pressure to obtain free base.
Yield : 15.53g(90%)
M.P : 196-198°C
TLC : Mobile phase : Benzene : MeOH (10:1) Rf: 0.8 Spectral Characteristics:
'HNMR(CDC13)

6

Chemical shift 6 Multiplicity Intensity Protons
2.5-3 m 10H c,d,e,f
3.7-3.9 t 2H a
4.2 s 1H g
7-7.5 m ;'9H aromatic
IR(KBr) cm'1 presence of-OH peak. Example 2
Synthesis of l(4-chlorobenzhydryl)-4-ethyl-[2'[4"-(2-hydroxy-benzhydryl]piperidine]piperazine

2g (0.005730 moles) of 4-chlorobenzhydryl piperazinc ethyl chloride was introduced into a 100ml three necked bottom flask containing 30ml dry DMF, 0.8292g (O.O0o moles) of anhydrous potassium carbonate and 0,()02g oi
7
potassium iodide. The reaction mixture was stirred for 30 minutes. To the same flask 1.52g (0.005730 moles) of azacyclonol was added. The reaction mixture was heated to 100°C for 16 hrs and then allowed to cool to 30°C. A solid separated out by quenching reaction mixture in a ice under stirring. The solid product so obtained was filtered and dried in oven at 60°C for 4 hrs. Yield : 2.8g (84.31%)
MP. : 130-134°C
TLC : Mobile Phase : Et.Ac : Benzene : Ammonia (5:2: 0.2) Rf: 0.6 Spectral characteristics:
'H NMR (CDC13)

Chemical shift d Multiplicity Intensity d Protons
1.4-1.8 m 5H a,b,c
2.2-3 m 16H d,e,f,g,h,i,j,k
3.4 bs IH m (D20 exchangeable)
4.3 s IH 1
7.1-7.7 m . 19H aromatic
IR(KBr)cm '
3435.5 (-O-II)
2900-3000 (-C-H sir.)
8
Example 3
Synthesis of l-4-chlorobenzhydryl)-4-ethyl-2"[2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one] piperazine

dCH2CH2^X[|/
0

H H3C^N

N— CHiCUi^^Y
0
',','< Compound - 2
4G (0.013 96) of 4-chlorobenzhydry1 piperazine was dissolved in 3 0ml DMF in a three necked 100ml round bottom flask equipped with condensor and thermometer pocket. To the clear solution 1.939g (0.014) of potassium carbonate, 3.134g (0.01396) of pyridopyrimidinone and catalytic amount of potassium iodide was added under stirring. The reaction mixture was refluxed for 10 hrs and then cooled to 25-30°C under stirring. A solid was precipitated out by pouring the reaction mixture in ice-cold water. The solid material obtained was filtered and washed with water thoroughly. The product was dried in oven at 50°C for 4 hrs.
Yield: 4.63g(70%)
M.P. : 85-90°c
TLC : Mobile Phase: Benzene: Methanol (5 : 0.2) Rf: 0.5 Spectral characteristics
'HNMR(CDC13)


b/N\d c\N-/ e h H
-CH2CH2-\-N^f g H

Chemical shift d Multiplicity Intensity Protons
2.2 m 4H. b,d
2.5 s 3H h
2.6-3.1 m 4H c,e
3.2-3.6 m 4H: i . f,g
4.1 s IH a
7-7.5 m \ 13H aromatic
IR(KBr)cm-1 1692 (C=0) 1098 (C-Clstr.) Example 4
Synthesis of (4-chlorobenzhydryl)-4-ethyl-[2'[4"-(p-chlorophenyl)-
4"-hydroxy]piperidine]piperazine
10


Compound! - 3
2g (0.005730 moles) of 4-chlorobenzhydryl piperazine ethylchloride was introduced in to 100ml three necked round bottom flask containing 1.5g (0.0178 moles) of sodium bicarbonate, 15ml toluene and 0.002g of potassium iodide under stirring. Stirring was continued for 30 minutes. 1.3g (0.005730) of 4-hydroxy-4-(p-chlorophenyl)-piperidine was added and the mixture was refluxed for 16 hrs. The reaction mixture was cooled to 30°C and filtered. Toluene was distilled out completely under vacuum. Water was added to the residue under stirring. Solid precipitated out was filtered and washed with water. The product was dried in oven at 50°C for 4 hrs.
Yield: 2.40g(80%)
M.P. : 96-100°C
TLC : Mobile Phase: Chloroform: Methanol (9 : 1) Rf: 0.5 Spectral characteristics:
1H NMR CDC13
11

Chemical shift d Multiplicity Intensity Protons
1.5-2 m 4H a,b
2.2-3 m 16H c,d,e,f,g,h,i,j
4 bs 1H 1
4.2-4.3 s 1H k
7-7.6 m 13H aromatic
IR (KBr)cm-1 3407 (O-H) 2948 (C-H str.) 1089 (C-Cl str.) Example 5
Synthesis of l-(4-chlorobenzhydryl)-4-(3-phenyl-3-propanone)-piperazine



N NU+CI

12

Compound - 4

2g (0.0068) of 4-chlorobenzhydryl piperazine was dissolved in 15ml toluene in a 50ml three necked round bottom flask equipped with thermometer pocket and condensor. To the clear solution 1.126g (0.0068) of 3-chloropropiophenone, 1.2g (0.0086) of potassium carbonate and catalytic amount of potassium iodide was added under stirring. The reaction mixture was refluxed for 4 hrs. and filtered to remove inorganic material. The toluene was distilled out under vacuum to obtain oily residue. The solid was separated out by addition of hexane to the oily material under stirring. The solid product was filtered and dried in oven at 50°C for 2 hrs.
Yield: 2.45g(84%)
M.P. : 105-108°C
TLC : Mobile Phase : Benzene : MeOH (1.0 : 0.8) Rf: 0.42 Spectral characteristics:
1HNMR(CDC13)
K ) f d K !?
ci

Chemical shift 6 Multiplicity Intensity Protons
2.1-2.8 m 12H a,b,c,d,e,f
3.9-4.0 s 1H g
6.7-7.2 m 14H aromatic
IR(KBr)cm-1
2913-3000 (C-H sir.)
13

1681 (C=0)
1089 (C-Clstr.) Example 6
Synthesis of 1 -(4-chlorobenzhydryl)-piperazine-4-ethyl-2'[4"(2,3, 4-trimethoxy benzyl)]piperazine


OMe
CH2CH2C1

+

/ HN N
\ /

OMe

OMe

K2C03

OMe
CH2CH2N N

OMe

OMe

Compound 5
2g (0.005770 moles) of 4-chlorobenzhydryl piperazine ethyl chloride and 1.9426g (0.005730 moles) of trimetazidine were added in a 100ml three necked round bottom flask containing 20ml dry DMF, 1.575g (0.01 14 moles) of potassium carbonate and 0.00lg of potassium iodide. The reaction mixture was heated to 100-1 10°C for 8 hrs and then allowed to cool to 30°C. It was
14

then added to a beaker containing ice water under stirring. The product was
extracted with chloroform (2x1.5ml) and chloroform layer was washed with
water. The washed chloroform layer was dried over an sodium sulfate and the
chloroform was evaporated completely. Etheral hydrochloride was added to
the residue and the pH was adjusted to 2 under stirring precipitating a solid.
The solid was filtered and dried in a vacuum at 60°C.
Yield : 2.8g(75%)
M.P. : 234-236°C
TLC : Mobile Phase : Ethyl acetate Rf: 0.42
Spectral characteristics:
1H NMR(DMSOd6) CI

CH2CH2N N^Q^o^
OMe OMe
o n
f g w ,K

Chemical shift d Multiplicity Intensity Protons
2.2-2.8 m 20H b,c,d,e,f,g,h,i,j,k
3.9 s 9H m,n,o
4-4.2 m 3H a,l
7.1-7.3 m 11H aromatic

IR(KBr)cm -1
2960-3000 (C-H sir. )1099 (C-O-C str.)

15

Example 7
Synthesis of l-(p-chlorobenzhydryl)4-ethyl-2'-[l,3-dimethyl xanthine]-piperazine



NCH2CH2C1
H3C^

+

Compound-6
2g (0.0047 moles) of 4-chlorobenzhydryl piperazine ethylchloride dihydrochloride was added to a 100ml three necked bottom flask containing 30ml DMF, 2.7g (0.01950) moles of potassium carbonate and 0.00lg of potassium iodide. The reaction mixture was stirred for 30 minutes. To the same flask 0.853g (0.0047 moles) of theophylline was added. The reaction mixture was heated to 100-110°C for 16 hrs and then allowed to cool to 30°C. A solid was precipitated by quenching the reaction mixture in icy water under stirring. The solid product obtained was filtered and dried in oven at 50°C for 4 hrs.
Yield : 2.03g(87%)
M.P. : 98-100°C
TLC : Mobile Phase : Ethvl acetate Rf: 0.5
16

Spectral characteristics: 1H.NMR(CC14)

CI' 'H NMR CCI4

CH3 I 0
( ) c e

Chemical shift d Multiplicity Intensity Protons
2.2-2.8 m 10H b,c,d,e,f
3.3 s 3H i.
3.4 s 3H J
4-4.2 m 3H a,g
7-7.5 m 10H aromatic,h
IR (KBr) cm-1
2960 (C-H str.)
1653 (C=O str.)
Example 8 Biological Activity Testing
Antihistaminics are evaluated in vitro by Magnus procedure (see Ghosh, M N and Schild, H O, Fundamentals of Experimental Pharmacology, 63, 1971; Schmidt, L and Seeger E, Arzneim. Forsch (Drug Research), 6, 22, 1956) in which the minimum amount of drug is measured which relaxes hislamin'c-induccd spasm in an isolated strip of guinea pig's small intestine
17

immersed in Tyrode solution. The isolated ileum of guinea pig is the mos sensitive and accurate test object for the assay of histamine. A piece o: terminal ileum was suspended in an isolated bath in Tyrode solution containing 0.6mg/ml atropine sulphate. This eliminates or reduces contractile responses due to cholinergic agents, causes relaxation of the guinea pig ileum producing a fixed base line and reduces or eliminates spontaneous contractile activity in the guinea pig ileum. The bath was kept at 35°C, and kept oxygenated with a continuous supply of oxygen or air. A frontal writing lever magnified 10 times and with tension of 1 g was used for recording the contractions.
Contraction of the guinea pig ileum to histamine was observed for 30 seconds; relaxation during rinsing or washing of the bath with 2 or 3 changes of Tyrode solution was also almost complete in 1.5 minutes. Hence contractions for exactly 30 seconds were regularly obtained at intervals of 1.5 minutes. The tissue preparation gave good response to histamine in various concentration range (lug-l00mg). The results were analysed using the 'Latin Square' technique to provide a standard curve of histamine response, and the mean contraction of the responses for each dose of histamine was calculated. For quantitative estimation of IC50 value of the synthesized compounds, the one single standard dose of histamine was repeated until the fixed standard length of contraction of histamine response was obtained. The mean length of contraction of standard histamine was evaluated as the 100% std. response, and this was used to determine the IC50 and IC100 for the antihistamine (antagonist) to be tested. Antagonists were added to the Tyrode solution simultaneously with the standard dose of histamine and the contraction response was determined. The tissue was washed with fresh Tyrode solution before addition of a different antagonist concentration.
18

Comparative compounds



0
Cetirizine

/ N N
\ /

0

OH

Clocinizine

Comparative compound 1

l-(4-chlorobenzhydryl)-4-(3-phenyl-3-propanol)-piperazine


— N
Comparative compound 2
CI

l-(4-chlorobenzhydryl)-4-methyl(2-cyanobiphenyl)-piperazine
19

Comparative compound 3

l-(4-chlorobenzhydryl)-4-(2(2',4'-dichIorobenzene)eliian-z-one


Comparative compound 4

1-(4-chlorobenzhydryl)-4-(2(2,,4,-difluorobenzene)ethan-2-one)piperazine
The results of the Magnus procedure experiment for each of compounds 1 to 6 and the comparative compounds 1 to 6 and the comparative compounds cetirizine, clocinizine and comparative compounds 1 to 4 are shown in Table 1 below.
20

Table 1: Results of Magnus procedure experiments

CompNo. Dose % inhibition molar cone, [cj Log |[c] ED50 /ig/ml PA2 = -logEDso logP
1 0.5 6.25% 8.6281x10-' -6.06408
l 12.5% 1.7256xl0"6 -5.7630 2.0561 5.45 7.658
2 31.25% 3.4513xl06 -5.4620
4 100% 6.9025x10-* -5.1609 -
2 1 0.0% 2.1075x10^ -5.6762
2 37.5% 4.2150x10^ -5.3752
4 62.5% 8.4300x10^ -5.0741 2.6608 5.25 5.083
8 75.0% 1.6860xl0-5 -4.7731
10 100% 2.1075x10s -4.6762
3 0.11 6.0% 2.0985xl0"7 -6.6780
0.22 9.0% 4.1970X10"7 -6.3770 , / s
0.44 15.1% 8.3940xl9-7 -6.0760 j
0.88 15.1% 1.6788X10"6 -5.7750
1.1 21.2% 2.0984X10"6 -5.6781
2,2 24.2% 4.1970x10^ -5.3770 11.7351 4.65 6.524
4.4 27.2% 8.3940x10^ -5.0760
6.6 30.3% 1.2591X10"5 -4.8999
8.8 39.3% 1.6788xl05 -4.7750
11.0 48.4% 2.0985xl0'5 -4.6780
16.5 60.6% 3.1477X105 -4.5020
22 87.8% 4.1970x10s -4.3770
27.5 96.96% 5.2462x10s -4.2801
28 100% 5.3416x10s -4.2723
4 10 30% 20346xl0'5 -4.6915
20 50% 4 0692xl0"'1 -4.3904
30 70% 6 1037x10 s -4.2144 19.566 4.4 6.31X
21
35 90% 7.1210x10 s -4.1474
37.5 100% 7.6298xl05 -4.1174
5 10 4% 1.5349x10-* -4.8139
20 4% 3.0698X105 -4.5129
40 20% 6.1397xl0'5 -4.2153 46.1226 4.15 6.15
50 92% 7.6746xl0"5 -4.1873
55 100% 8.4420xlO-5 -4.1483
6 10 14.2% 2.0304xlO-5 -4.6924
20 43.0% 4.0609xl0"5 -4.3913
30 72.0% 6.0913xlO"5 -4.2153 21.9999 4.35 4.418
32 86.0% 6.4975x10s -4.1873
35 100% 7.1066xl0"5 -4.1483
Std. 10, 0.0% 2.16x10s -4.6655
Cetirizine 20 22.85% 4.33x10s 4.3635
30 84.28% 6.50x10s -4.1870
.35 85.7% 7.58x10s -4.1203
40 92.85% 8.66x10s 4.0624 25.95 4.25 2.221
50 95.71% 1.083x10-" -3.9653
60 97.14% 1.3x10^ -3.8860 •
70 98.57% 1.51x10^ -3.8210
75 100% 1.62x10^ -3.7904
Std. 20 10.52% 4.0527x10"5 -4.3923
Clocinizine 40 15.7% 8.1054xl0'5 -4.0912
80 15.7% 1.6211x10^ -3.7902
160 21.0% 3.242x10-" -3 4892
200 26.3% 4.0527x10-" -3.3923 439.8323 3.05 6.851
300 31.5% 6.0790x10^ -3.2162
400 42.1% 8.1053x10^ -3.0912
500 63.15% 1.01317xl0-3 -2.9943
600 78.9% 1.2158x10"" -2.9151
700 84.2% 1.4184x10-' | -2.8482
800 94.7% 1.6211x10' -2.7901
22

840 100% 1.7021x103 -2.7690
ComparativeCompound1 10 0% 2.0263x10' -4.6933
20 18.42% 4.0526x10s -4.3922 31.1377 4.2 5.398
40 57.89% 8.1033xl0"5 -4.0912
50 100% 1.0137x10" -3.9943
ComparativeCompound 3^g of histamine was not inhibited by even 250^g of comparative compound 2 7.8622
ComparativeCompound 40/ig of histamine was not inhibited by even 500//g of comparative compound 3 7.223
ComparativeCompound 40/zg of histamine was not inhibited by even 500//g of comparative compound 4 6.4684
In the above table, the % inhibition values were determined from kaymograph. The log[C] vs % inhibition was plotted to get ED50 values for the compounds 1-11. Further, -logED50 was calculated to obtain PA2 values.
23

As will be seen by comparing the ED50 and PA2 (log ED50) values, compounds 1 to 4 are potent H,-receptor antagonist by reference to the known antihistamine cetirizine and clocinizine, whilst compounds 5 and 6 show a moderate, but significant, increase in potency. Comparative compound 1 has a similar activity to cetirizine, but it is more lipophilic.
The calculated Log P of the synthesized and tested compounds between 5-7.7 was found optimum for good H,-receptor antagonist activity. Hence logP, a parameter for lipophilicity, shows that lipophilicity has an important role for eliciting the biological response of these compounds. LogP by its nature governs the pharmacokinetic profile of the compounds. The more lipophilic a compound the less likely it is to cross the blood-brain barrier. Compounds 1 to 6 and comparative compound 1 are therefore less likely to cause drowsiness.
Furthermore, a comparison of the activity of clocinizine and comparative compound 1 with compounds 1 to 6 shows that an important feature of the present invention is that the linker X in formula (I) should be ethylene or a radical including a carbon-carbon bond which is free to rotate. A substituted propylene radical X linker (compare compound 4 and comparative compound 1) including two freely rotatable carbon-carbon bonds results in a less antihistaminically active molecule,
Example 9
Oral dosage tablet containing lOmg of l-(4-chlorobenzhydryl)-4-ethyl-[2'[4"-(2-hydroxybenzhydryl]piperidine] piperazine (compound 1)-hydrochloride.
24
L.UVU iiiiii i-vaivsvi lauivi vuniaiiio V^WIIIJ
INGREDIENTS QTY/TAB
(mg)
Compound 1 hydrochloride 10.0
Lactose IP 80.0
Starch IP 25.20
Magnesium stearate IP 2.0
Colloidal Silicon dioxide IP 1.0
Talc IP 1.8
120.0
The above formulation includes standard fillers and glidants well known to those of skill in the art. The skilled person will be able to scale-up production to batch size using the above amounts as a guide or with routine experimentation. The processes for dry mixing of the ingredients for tablet compression or for encapsulation into capsules are also well known and will not be discussed further herein.
Tablets so formed may be coated with suitable water soluble or water insoluble polymers or polymers which have pH dependent solubility, as desired.
25

We Claim:
1. A process of producing pharmaceutical composition comprising l-(4- chlorobenzhydryl)-4-ethyl-[2'[4"-(2-hydroxybenzhydryl]piperidine] piperazine (compound l)-hydrochloride 5% to 15% w/w, lactose IP 55% to 75% w/w, Starch IP 15% to 25% w/w, Magnesium stearate IP 1% to 2% w/w, Colloidal Silicon dioxide IP 0.5% to 1% w/s and Talc IP 1% to 2% w/w and compressing the mixture forming tablet or encapsulating the said mixture forming capsules.
2. A process of producing pharmaceutical composition as claimed in claim 1 wherein fillers and/or glidants are added into the mixture obtained in claim 1.
3. A process of producing pharmaceutical composition as claimed in claim 1 or 2 wherein the said tablets are coated with suitable water soluble or water insoluble polymers having pH dependent solubility.
4. A process as of producing pharmaceutical composition substantially as herein described and illustrated in example 9.
Dated this 12th Day of May, 2003.
-26-

ABSTRACT
A process of producing pharmaceutical composition comprising l-(4- chlorobenzhydryl)-4-ethyl-[2'[4"-(2-hydroxybenzhydryl]piperidine] piperazine (compound l)-hydrochloride 5% to 15% w/w, lactose IP 55% to 75% w/w, Starch IP 15% to 25% w/w, Magnesium stearate IP 1% to 2% w/w, Colloidal Silicon dioxide IP 0.5% to 1% w/s and Talc IP 1% to 2% w/w and compressing the mixture forming tablet or encapsulating the sid mixture forming capsules.

Dated this 12m Day of May, 2003.

-1-