FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"A PROCESS FOR THE PREPARATION OF TAZAROTENE INTERMEDIATES AND USE THEREOF FOR THE PREPARATION OF TAZAROTENE"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
1

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to a process for the preparation of tazarotene. More specifically, the present invention relates to a process for the preparation of tazarotene.
2. Description of the Related Art
The present invention is directed towards a process for the preparation of Tazarotene
chemically known as ethyl 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinate having Formula I and intermediates thereof.
^C02Et

Formula I
Tazarotene is a member of the acetylenic class of retinoids and is a prodrug that is converted to its active drug form, known as AGN 190299, in most biological systems by rapid deesterificaion of the cognate carboxylic acid of tazarotene. AGN 190299 binds to all three members of the retinoic acid receptor (RAR) family: RARa, RARp, RARy. AGN 190299 shows relative selectivity for the RARp and RARy and may modify gene expression. Tazarotene is used in the treatment of psoriasis and is commercially available under the trade name Tazorac®. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 1621, monograph 9170.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is a process for the preparation of tazarotene. The process for the preparation of tazarotene comprises a Sonogashira coupling reaction between 4, 4-dimethyl-6-ethynylthiochroman with 6-chloronicotinonitrile in the presence of a base, e.g., triethylamine, a cuprous halide and a palladium catalyst to get 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinonitrile a novel intermediate.
In one aspect of the present invention 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinonitrile is hydrolyzed in presence of an aqueous alkaline solution such as sodium
2

hydroxide, potassium hydroxide, lithium hydroxide and mixtures thereof to get tazarotenic acid which is transformed into ethyl 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinate. Another aspect of the present invention 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinonitrile is hydrolyzed with alkali in presence of an organic solvents such as alcohols, ketones,ethers and mixture thereof to get 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinic acid which is transformed into ethyl 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinate.
Another aspect of the present invention 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinonitrile is hydrolyzed with alkali in presence of an aqueous organic solvents such as alcohols, ketones, ethers and mixture thereof to get 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinic acid which is transformed into ethyl 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinate.
In another aspect of the invention 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinonitrile is hydrolyzed using aqueous acidic solution such as to hydrochloric acid, sulfuric acid, methanesulfonic acid and mixture thereof obtain tazarotenic acid which is converted into ethyl 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinate. In another aspect of the invention 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinonitrile is hydrolyzed with acid in presence of an organic solvents such as alcohols, ketones,ethers and mixture thereof to obtain 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinic acid which is converted into ethyl 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinate.
Another aspect of the present invention 6-[2-(4, 4-dimethylthiochroman-6-yl)ethynyl] nicotinonitrile is hydrolyzed with acid in presence of an aqueous organic solvents such as alcohols, ketones,ethers and mixture thereof to get 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinic acid which is transformed into ethyl 6-[2-(4, 4-dimethylthiochroman-6-yl)-ethynyl] nicotinate.
3

In a preferred embodiment of the present invention, tazarotene is prepared according to Scheme: 1

By performing the purification processes of the present invention, highly purified Tazarotene can be prepared with a degree of purity as determined by HPLC greater than about 98%, preferably greater than about 99% and most preferably greater than about 99.5% as compared to the crude product. Also, the content of free Tazarotene in the final product as determined by HPLC can be at a level of less than about 2%, preferably less than about 1% and more preferably less than about 0.5% as compared to the crude product. Moreover, the highly purified Tazarotene may be obtained substantially free of any unknown impurity, e.g., a content of less than about 0.1% of impurities. The crude Tazarotene for use herein can have purity as determined by HPLC which can ordinarily vary in the range of from about 92% to less than 98%.
Another aspect of the present invention is directed to a pharmaceutical composition containing at least the highly purified Tazarotene disclosed herein and at least one pharmaceutically acceptable excipient. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectabe solution, etc.
In one embodiment, the Tazarotene or pharmaceutically acceptable salt thereof disclosed herein for use in the pharmaceutical compositions of the present invention can have a D50 and D90 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. The particle sizes of the Tazarotene or pharmaceutically acceptable salt thereof prepared according to the present invention can be obtained by any milling, grinding micronizing or other particle size reduction method known in the art to bring the solid state tazaroteneor pharmaceutically acceptable salt thereof into any of the foregoing desired particle size range.
The dosage forms may contain the substantially pure Tazarotene disclosed herein or, alternatively, may contain the substantially pure Tazarotene as part of a composition. Whether administered in pure form or in a composition, the substantially pure Tazarotene may be in any form, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals in such dosage forms as oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracistemal,
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intravaginal, intraperitoneal, local (powders, ointments or drops), ophthalmic, transdermal, or sublingual forms or as a buccal or nasal spray. Oral dosage forms include, burt are not limited to, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs, tablets, capsules (including soft gel capsules), ovules, solutions, and the like which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. The highly purified form of Tazarotene disclosed herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the Tazarotene of the present invention is oral.
The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.
Tabletting compositions may have few or many components depending upon the tabletting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
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Capsule dosages will contain the solid composition within a capsule which may be coated
with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-
coated powder forms may have coatings comprising phthalic acid cellulose acetate,
hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate,
carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.
Example 1
Preparation of 6-(4, 4-Dimethylthiochroman-6-ylethynyl) nicotinonitrile.
In a 500 ml 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser charge dimethyl sulfoxide (150 ml), PdCl2 (0.180 gm), triphenyl phosphine (0.825 gm) and stir under nitrogen atmosphere for sometime. Raise the temperature to 130 - 150°C and maintain for 30-35 min. The reaction mixture was cooled to room temperature and added to mixture of 6-chloronicotinonitrile (3.5 gm), 4,4-dimethyl-6-ethynylthiochroman (4.5gm) in dimethyl sulfoxide (50 ml). The reaction mixture was stirred for 20 - 25 min followed by addition of cuprous iodide (0.325 gm) and triethylamine (10 gm). The temperature is slowly raised to 90 -100°C and maintained for 3 - 5 hours. After completion of reaction reaction mass is cooled to room temperature and filtered to remove insolubles. Ethyl acetate (75 ml) was added to the filtrate and the organic layer is quenched in water (200 ml). The ethyl acetate layer is separated, washed with water and concentrated to obtain 6-[2-(4,4-Dimethylthiochroman-6-yl)ethynyl]nicotinonitrile (1.5 gm).
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Example 2
Preparation of 6-[2-(4,4-Dimethylthiochroman-6-yl) ethynyl) nicotinic acid.
In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, ethanol (41.3 ml) and sodium hydroxide (5.22 g, 0.1305M) are added and heated to a temperature in the range of from about 80° C to about 90° C. The reaction mixture is stirred, and a solution of 6-(4, 4-dimethylthiochroman-6-ylethynyl) nicotinonitrile (3.0 gm, 0.01 M) is added dropwise in tetrahydrofuran (52.2 ml) under vigorous stirring. The reaction mixture is maintained at a temperature in the range of from about 80° C. to about 90° C. for about 2 hours. After completion of the reaction as determined by TLC, the solvents are distilled off; water is added followed by pH adjustement to neutral. The product is extracted with ether (15 mlx3). The ether layer is washed with brine (15 mlx3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get 6-(4, 4-Dimethylthiochroman-6-ylethynyl) nicotinic acid (2.0
gm)-
Example 3
Preparation of 6-[2-(4,4-Dimethylthiochroman-6-yl)ethynyl] nicotinic acid.
In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3 ml) and sulfuric acid (5.22 g, 0.0533 M) are added and heated to a temperature in the range of from about 50° C to about 75 ° C. The reaction mixture is stirred, and 6-(4,4-dimethylthiochroman-6-ylethynyl) nicotinonitrile (3.0 gm, 0.01 M) is added slowly under vigorous stirring. The reaction mixture is maintained at a temperature in the range of from about 50° C. to about 75° C. for about 2 hours. After completion of the reaction as determined by TLC, pH of the reaction mass is adjusted to and extracted with ether (15 mlx3). The ether layer is washed with brine (15 mix3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get 6-(4, 4-Dimethylthiochroman-6-ylethynyl) nicotinic acid (2.2 gm).
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Example 4
Preparation of 6-[2-(4, 4-Dimethylthiochroman-6-yl) ethynyl] nicotinic acid ethyl ester
In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, 6-(4, 4-dimethylthiochroman-6-ylethynyl) nicotinic acid (3.0 gm, 0.01 M)3 ml) is dissolved in ethanol (50 ml) and concentrated sulfuric acid (l.0gm) is added and heated to reflux. After completion of the reaction as determined by TLC, the solvents are distilled off; water is added followed by pH adjustement to neutral. The product is extracted with ethyl acetate (25 mlx3). The ethyl acetate layer is washed with brine (15 mlX3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get 6-(4, 4-Dimethylthiochroman-6-ylethynyl) nicotinic acid ethyl ester (1.0 gm).
Example 5
Preparation of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-l-al
In a 500 ml 4-necked round bottom flask fitted with a mechanical stirrer and a reflux condenser, 6-acetyl-4,4-dimethylthio-chroman (22 g) and dimethylformamide (38 ml) are added at a temperature in the range of from about 35° C. to about 95° C. under stirring. The reaction mixture is then cooled to a temperature in the range of from about -5° C. to about 0° C. Phosphorus oxychloride (17.2 g) is added to the reaction mixture dropwise over about 30 minutes. Following the addition of the phosphorous oxychloride, the reaction mixture is maintained at a temperature in the range of from about 10° C. to about 15° C. for about 8 hours to about 10 hours. After completion of the reaction as determined by TLC, the reaction mixture is added to cold water (100 ml) at a temperature of from about 0° C. to about 5° C. containing sodium acetate (25 g). The aqueous layer is extracted with dichloromethane (200 mlX3). The organic layer is washed with demineralized water (100 ml*3) until it becomes neutral. The dichloromethane layer is concentrated on a rotavapor bath at a temperature in the range of from about 25° C. to about 30° C. under plant vacuum until no more drops are observed. The resulting residual oil is purified by flash chromatography with petroleum ether and ethyl acetate (9:1 mixture) resulting in a pale yellow oil, weighing about 22 g, yield of about 82%, purity of about
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98% (HPLC). The IR (neat) shows the following stretching 2900 cm'1 (C—H str), 2750 cm"1 (C—H str), 1690 cm"1 (—C=0 str), 1620 cm"1 (—C=C-str), 760 cm"1 (—C=C—CI str). The 1H-NMR (CDCI3) using TMS as internal standard shows the following signals at 8 1.35 (6H,s) 1.92-1.98 (2H,m), 3.02-3.08 (2H,m), 5.5 (lH,s), 7.13 (lH,d 8.6 Hz), 7.58 (lH,dd,J 8.6 Hz, 2H), 7.99 (lH,d,J 2 Hz), 8.9 (s,lH). The CI mass shows m/z 266 (M+).
Example 6
Preparation of 4,4-Dimethyl-6-ethynylthiochroman
In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3 ml) and sodium hydroxide (5.22 g, 0.1305M) are added and heated to a temperature in the range of from about 80° C. to about 90° C. The reaction mixture is stirred, and a solution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-l-al (3.0 gm, 0.0113 M) is added dropwise in 1,4-dioxane (52.2 ml) under vigorous stirring. The reaction mixture is maintained at a temperature in the range of from about 80° C. to about 90° C. for about 2 hours. After completion of the reaction as determined by TLC, the solvents are distilled off and the product is extracted with ether (15 mlx3). The ether layer is washed with brine (15 ml*3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get an oily residue. The resulting crude oil is distilled under high vacuum and the vapors are collected at a temperature of about 126° C./0.2 mm as the main product. The main fraction appears as red viscous oil, which upon standing crystallized. Net wt of about 2.00 g, yield of about 87.68%; m.p. in the range of from about 69° C. to about 72° C, purity of about 98% (HPLC). The IR (neat) shows the following absorptions: 3200 cm'1 (C—H-str), 2950 cm"1 (—C=C—H str), 2100 cm"1 (—C=C—). The 1H-NMR (CDCI3), TMS as internal standard shows the following signals 8 1.35 (6H,s), 1.92-1.98 (2H,m), 3.02-3.08 (3H,m), 7.13 (lH,d 8.6 Hz), 7.58 (lH,dd,J 8.6 Hz,2 Hz), 7.99 (lH,d,J 2 Hz). The CI/MS shows m/z 202 (M+).
Example 7
Preparation of phenyl-3-methylbut-2-enyl sulfide
In a 5 L 4-neck round bottom flask, methanol (1400 ml) and thiophenol (200 g) were added under stirring at a temperature ranging from about 25° C. to about 35° C. Sodium hydroxide
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(powder LR grade) (73.60 g) and methanol (100 ml) were added under stirring. The reaction mixture was left under a nitrogen atmosphere and stirred at room temperature (about 25° C. to about 30° C.) for an hour. l-bromo-3-methyl-2-butene (274 gm) was added to the reaction mixture and it was observed that the temperature rose to about 40° C. The reaction mixture was heated to reflux and maintained for about 12 hours. After completion of the reaction as determined by HPLC, the methanol was distilled out from reaction mixture under vacuum at a temperature below 60° C. Ethylene dichloride (1500 ml) and water (1000 ml) were added to the residue. The organic layer was separated and washed with a 5% sodium hydroxide (600 ml) solution and then water (3><600 ml) until the pH was about 7. The organic layer was then washed with a brine solution (700 ml). The ethylene dichloride was distilled out until the moisture content was less than 0.1%.
Example 8
Preparation of 4,4-dimethylthiochroman
In a 5 L 4-neck round bottom flask, ethylene dichloride (1500 ml) was added to the phenyl-3-methylbut-2-enyl sulfide from the previous step. Phosphorous pentoxide (200 gm) was added to the reaction mixture at a temperature ranging from about 25° C. to about 35° C. under stirring. Ortho phosphoric acid (174 ml) was added carefully under nitrogen. The reaction mixture was heated to reflux, a temperature of about 80° C. to about 90° C. and maintained at that temperature for about 12 hours. After completion of the reaction as determined by HPLC, the reaction mass was cooled to a temperature ranging from about 25° C. to about 35° C. and water (2000 ml) was slowly added to the reaction mass. The organic layer was separated, and the aqueous layer was extracted with EDC (2 Lx2). The organic layers were combined and washed with saturated sodium bicarbonate solution (2 Lx2) and water (1.5 Lx2) until the pH was about 7. This was followed by a washing with a brine solution (1.5 L). The EDC layer was distilled out under reduced pressure below a temperature of about 70° C. until the moisture content was less than 0.1%. EDC (2 L) was added to the residue and taken for the next step without further purification.
Example 9
Preparation of 4, 4-dimethyl-6-acetylthiochroman
In a 5 L 4-neck round bottom flask, EDC (2 L) was added to the 4,4-dimethylthiochroman from
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the previous step. The contents were stirred and cooled to a temperature of about -10° C. Aluminum chloride (252 g) was slowly added to the reaction mixture. Acetyl chloride (152.7 g) was added at a temperature ranging from about -10° C. to about -5° C. over about 1.5 hours. After the addition, the reaction mixture was maintained at a temperature ranging from about -5° C. to about 0° C. for about 2 hours. The reaction was monitored by TLC. [If the reaction is incomplete as determined by TLC, bring the reaction mixture to a temperature ranging from about 25° C. to about 35° C. under stirring for about 4 hours.] The reaction mixture was quenched with ice (4.87 kg) and hydrochloric acid (1.63 L), and the reaction mass was stirred for about 30 minutes. EDC (2.5 L) was added to the reaction mass. The layers were separated. The aqueous layer was extracted with MDC (2x2 L). The organic layers were combined and washed with 5% sodium bicarbonate solution (2x2 L) and water (2x2 L) until the pH is about 7. This was followed by a washing with brine (1.5 L). The EDC and MDC layer were distilled out under reduced pressure until the moisture content was less than about 0.1%.
Example 10
Preparation of 6-[2-(4, 4-Dimethylthiochroman-6-yl) ethynyl] nicotinonic acid N oxide.
In a 500 ml 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser charge dimethyl sulfoxide (150 ml), PdCb (0.180 gm), triphenyl phosphine (0.825 gm) and stir under nitrogen atmosphere for sometime. Raise the temperature to 130 - 150°C and maintain for 30-35 min. The reaction mixture was cooled to room temperature and added to mixture of 6-chloronicotinonic acid N oxide (3.5 gm), 4, 4-dimethyl-6-ethynylthiochroman (4.5gm) in dimethyl sulfoxide (50 ml). The reaction mixture was stirred for 20-25 min followed by addition of cuprous iodide (0.325 gm) and triethylamine (10 gm). The temperature is slowly raised to 90 - 100°C and maintained for 3 - 5 hours. After completion of reaction reaction mass is cooled to room temperature and filtered to remove insolubles. Ethyl acetate (75 ml) was added to the filtrate and the organic layer is quenched in water (200 ml). The ethyl acetate layer is separated, washed with water and concentrated to obtain 6-(4,4-Dimethylthiochroman-6-ylethynyl)nicotinonic acid N oxide (1.5 gm).
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It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Dated this Seventh (7th ) day of April, 2006

(Signed)
NITIN SHARAD CHANDRA PRADHAN VICE PRESIDENT GLENMARK PHARMACEUTICALS LIMITED
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FORM 3
THE PATENT ACT, 1970
STATEMENT AND UNDERTAKING UNDER SECTION 8
(See Rule 12) We, Glenmark Pharmaceuticals Limited, an Indian company incorporated under section25 of the Companies Act, 1956, having its registered office at Glenmark Pharmaceuticals Limited,Glenmark House, HDO - Corporate Bldg, Wing -A, B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099 hereby declare:
(i) that we have not made any application for the same /substantially the same invention outside India
(ii) that the rights in the applications) have been assigned to :
Glenmark Pharmaceuticals Limited,
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
(iii) that we undertake that up to the date of grant of the patent by the controller, we would keep him informed in writing the details regarding corresponding applications for patents filed outside India within three months from the date of filing such application.
Dated this Seventh (7th) day of April, 2006

(Signed).
O.^Z-
NITIN SHARAD CHANDRA PRADHAN
VICE PRESIDENT
GLENMARK PHARMACEUTICALS LIMITED

To
The Controller of Patents
The patent office Branch, Mumbai