FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
SUBSTITUTED [2-(4-DIPHENYLMETHYL PIPERAZIN-1 -YL)-ETHOXY] ACETIC ACID DERIVATIVES AND SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: : Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention provides substituted [2-(4-diphenylmethyl piperazin-1 -yl)-ethoxy] acetic acid derivatives and salts thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. DESCRIPTION

The invention provides substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivatives and salts thereof. The invention further provides a pharmaceutical composition comprising substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivatives and salts thereof.
Cetirizine of Formula I is chemically known as (±)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid, dihydrochloride. It is commercially available under the trade name ZYRTEC®. ZYRTEC® is indicated for the relief of symptoms associated with seasonal allergic rhinitis due to allergens such as ragweed, grass, tree pollens, dust mites, animal dander and molds.

U.S. Patent No. 4,525,358 discloses synthesis of cetirizine.
Several other processes are known in the art for preparation of cetirizine such as in U.S. Patent No. 6,046,332; European Patent No. 1,157,016; U.K. Patent Nos. 2,225,320; 2,225,321; PCT patent application Nos. WO 2004/103982 and WO 2007/066162.
U.S. Patent No. 5,419,898; U.S. Patent No. 5,698,558; U.S. Patent No. 6,171,618; U.S. Patent No. 6,384,038; U.S. Patent No. 6,413,970; U.S. Patent No. 6,432,961; U.S. Patent No. 6,537,573; U.S. Patent No. 7,014,867; U.S.


Patent No. 7,226,614 and U.S. Patent No. 6,790,849 discloses method of use of cetirizine or its salt.
The invention relates to novel substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivatives and salts thereof. The invention further provides processes for the preparation thereof and to pharmaceutical compositions containing them.
In one aspect of the invention there is provided substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivatives, compound of formula II,

wherein X is CI, F, Br, I or -CF3
R is H or-CH2-COOR1; wherein R1 is H, C1-C6 alkyl, or -N(R2)(R3); wherein R2 and R3 are independently selected from the group of-H and C1-C6 alkyl and salts thereof.
The specific compounds of invention include;
1) [2-[4-[(3-chlorophenyl) phenylmethyl]-piperazin-1-yl] ethoxy] acetic acid,
2) Methyl [2-[4-[(3-chlorophenyl) phenylmethyl]-piperazin-1-yl] ethoxy] acetate,
3) [2-[4-[(3-chlorophenyl) phenylmethyl]-piperazin-1-yl] ethoxy] acetamide,
4) [2-[4-[(3-chlorophenyl) phenylmethyl]-piperazin-1 -yl] ethoxy] N-methyl acetamide,
and salts thereof.


In this disclosure, C1-C6 alkyl refers to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and six carbon atoms by removal of a single hydrogen atom. The examples of C1-C6 alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl, and n-hexyl.
In this disclosure, the term "salts" refers to pharmaceutically acceptable acid and base addition salts. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, p-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine or ammonia.
In another aspect of the invention there is provided a pharmaceutical composition containing substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivative, compound of formula II in association with a pharmaceutically acceptable excipient, wherein the composition comprise a preparation such as


solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.
The non-limiting examples of solid composition include compressed tablets, pills, capsules, dispersible powders, granules, hard capsules and soft capsules. The non-limiting examples of liquid composition include emulsions, solutions, suspensions, syrups and elixirs. The non-limiting examples of injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
In yet another aspect of the invention there is provided cetirizine containing the compound of Formula II in the amount of 1% or less.
In yet another aspect of the invention there is provided a process for the preparation of substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivative, compound of Formula II, which includes the steps of:

FORMULA III FORMULA II
a) reacting substituted diphenyl piperazine derivative (Formula III) with alkylating agent in organic solvent to get substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivative (Formula-ll),
b) isolating compound of Formula II or salts from reaction mass thereof


The starting material i.e. compound of Formula III is prepared as per the methods known in the art such as U.S. patent No. 6,172,228.
The process involves reacting compound of Formula-Ill with alkylating agent in presence of base in organic solvent. The reaction mixture is heated to reflux to get alkylated product. Optionally, this alkylated product further treated with another alkylating agent. The reaction mass is cooled to room temperature and the compound of Formula-ll or salts is isolated from the reaction mass thereof.
The alkylating agent capable for synthesis of a hydroxyethyalated product suitable for use with the invention includes 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, ethane-1,2-diol or 2-tosylethanol and the like.
Another alkylating agent includes acetic acid derivatives of the compound of Formula-IV.

Wherein,
R5 is C1-C6 alkyl, or -N(R2)(R3); wherein R2 and R3 are independently selected from the group of -H and C1-C6 alkyl.
Wherein R6 is good leaving group.
The non-limiting examples of organic solvents include solvents such as hexane, benzene, toluene, xylene, dimethoxyethane (DME), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), 1,4-dioxane, N,N-dimethylacetamide and the like.
The base includes organic bases such as primary, secondary and tertiary amines, substituted amines including diethylamine, N-ethylpiperidine,


isopropylamine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine or ammonia; or inorganic bases such as sodium hydroxide or potassium hydroxide and the like.
The compound of Formula II can also be prepared by coupling first both alkylating agent together followed by its reaction with compound of Formula III.
The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example
Example 1: Preparation of 2-[4-((3-chlorophenyl)-(phenyl)-methyl)-piperazin-1-yl]ethanol:
2-chloroethanol (0.67 g,) and triethylamine (1.12 g) are added to the solution of 1-[(3-chlorophenyl)(phenyl)-methyl]-piperazine (2.5 g) in toluene (40 ml). The reaction mixture was heated to reflux for 4 h. The reaction mass was cooled to room temperature and to this reaction mass again added 2-chloroethanol (0.67 g,) and triethylamine (1.12 g). The reaction mass was heated to reflux for ten hours. After completion of reaction, the reaction mass was cooled to room temperature and quenched with distilled water (100 ml). The organic layer was separated and the aqueous layer was again extracted with toluene (50 ml). The combined organic layer was washed with distilled water, brine and dried over Na2SO4. After removing the solvent, the crude material obtained was purified by column chromatography by using chloroform and methanol (95:5) as the eluant. Yield: 1.7 g
1H NMR (400 MHz, DMSO): 5 7.43 (1H, s). 7.34-7.41 (3H, m), 7.24-7.34 (3H, m), 7.14-7.24 (2H, m), 4.32 (1H, bs), 4.28 (1H, s), 3.43 (2H,m), 2.41 (4H, m), 2.34 (2H, m), 2.27 (4H, m).


1H NMR (400 MHz, DMSO/D20): 5 7.31-7.46 (4H, m), 7.20-7.31 (3H, m),7.08-7.20 (2H ,m ), 4.20 (1H, s ), 3.40-3.50 (2H, m), 2.05-2.40 (10H,m). Mass:(m/e): 331.2 (M+1).
Example 2: Preparation of [2-[4-[(3-chlorophenyl)-phenylmethyl]- piperazin-1-yl] ethoxy] acetic acid dihydrochloride
Sodium monochloroacetate (0.65 g) and powdered potassium hydroxide (0.6 g) were added in the solution of 2-[4-((3-chlorophenyl)(phenyl)-methyl)-piperazin-1-yl]ethanol (1.7 g) in N.N-dimethylformamide (30 ml) at 10 °C. The reaction mixture was stirred at 10 °C for 30 minutes and again sodium monochloroacetate (0.65 g) and powdered potassium hydroxide (0.6 g) were added to the reaction mixture. The reaction mixture was stirred at the same temperature for another 30 minutes and then brought to room temperature and stirred for four hours. After completion of the reaction, the reaction mixture was quenched with distilled water (100 ml). The pH of reaction mass was adjusted to 4.2 using 6 N hydrochloric acid and the aqueous layer was extracted with dichloromethane (100 ml). The organic layer was washed with distilled water, brine, dried over anhydrous Na2S04. After removing solvent, the crude material obtained was dissolved in acetone (10 ml) and converted in to its hydrochloric salt using aqueous hydrochloric acid solution (pH=1).
Then product obtained was filtered and dried to get the title compound. Yield: 0.55 g HPLC Purity: 97.46%
1H NMR (400 MHz, CD3OD): 5 7.67 (1H, s), 7.55-7.65 (3H, m), 7.29-7.45 (5H, m), 4.96 (1H, bs), 4.18 (2H, s), 3.89 (2H, t, J= 4.8 Hz), 3.66 (4H,bs), 3.46 (2H, t, J=4.8Hz), 3.12 (4H, bs).
Mass:(m/e): 389.1 (M+1).


We claim:
1. [2-(4-diphenylmethyl)-piperazin-1-yl)-ethoxy] acetic acid derivatives and salts thereof,

Wherein, X is CI, F, Br, I or-CF3
R is H or-CH2-COOR1; wherein RT is H, C1-C6 alkyl, or-N(R2)(R3); wherein R2 and R3 are independently selected from the group of-H and C1-C6alkyl. C1-C6alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl, and n-hexyl.
2. The compound of claim 1, wherein specific compounds of invention include;
a) [2-[4-[(3-chlorophenyl)-phenylmethyl]-piperazin-1-yl] ethoxy] acetic acid,
b) Methyl [2-[4-[(3-chlorophenyl)-phenylmethyl]-piperazin-1-yl] ethoxy] acetate,
c) [2-[4-[(3-chlorophenyl)-phenylmethyl]-piperazin-1-yl] ethoxy] acetamide,
d) [2-[4-[(3-chlorophenyl)-phenylmethyl]-piperazin-1-yl] ethoxy] N-methyl acetamide,
and salts thereof.
3. A process for the preparation of compound of Formula II, which comprises of:
a) reacting substituted diphenyl piperazine derivative (Formula III) with alkylating agent in organic solvent and base to get substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivative (Formula-ll),



FORMULA III FORMULA II
b) isolating compound of Formula II or salts from reaction mass thereof.
4. The process of claim 3, wherein alkylating agent includes 2-chloroacetic acid
or its derivatives (Formula-IV) and salts thereof.

Wherein,
R5 is C1-C6 alkyl, or -N(R2)(R3); wherein R2 and R3 are independently selected from the group of -H and C1-C6 alkyl.
Wherein R6 is good leaving group.
The good leaving group comprises from the group of CI, Br, I or tosyl and the like.
5. The process of claim 3, wherein organic solvent selected from the group of
hexane, benzene, toluene, xylene, dimethoxyethane, tetrahydrofuran,
dimethylsulfoxide, N.N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide
and the like,
5. The process of claim 3, wherein base selected from the group of wherein primary, secondary and tertiary amines, substituted amines including diethylamine, N-ethylpiperidine, isopropylamine, morpholine, N-ethyl morpholine,


piperazine, piperidine, triethylamine, trimethylamine or ammonia; or inorganic bases such as sodium hydroxide or potassium hydroxide and the like.
8. The pharmaceutical composition, containing compound of Formula II in
association with a pharmaceutically acceptable excipient and/ or carrier.
9. The pharmaceutical composition of claim 8, wherein the composition comprise
a formulations which includes solid compositions, liquid compositions or other
compositions for oral administration or as injections, liniments or suppositories for
parenteral administration.
10. A cetirizine hydrochloride containing the compound of Formula II in the
amount of 1 % or less.



Abstract
The invention provides substituted [2-(4-diphenylmethyl piperazin-1-yl)-ethoxy] acetic acid derivatives and salts thereof. The invention further provides a pharmaceutical composition comprising substituted [2-(4-diphenylmethyl)-piperazin-1-yl)-ethoxy] acetic acid derivatives and salts thereof.