Title of Invention

PROCESS FOR THE PREPARATION OF S-FLUOROMETHYL 6a, 9a-DIFLUORO -11B-HYDROXY-16a-METHYL-17a-PROPIONYLOXY -3-OXOANDROSTA-1,4-DIENE-17B-CARBOTHIOATE

Abstract

The present invention provides a convenient process for the preparation of S-fluoromethyl 6a, 9a-difluoro-11b-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1, 4-diene-17b-carbothioate, a compound of formula (1), comprising(a) treating 17b-[(N, N-dimethylcarbamoyl)thio]carbonyl-6a,9a-difluoro-11b-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1, 4-diene, a compound of formula (3) with alkali metal carbonate-alcohol system to obtain 6a, 9a-difluoro-11b-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1, 4-diene-17b-carbothioic acid, a compound of formula (4); (b) reacting the compound of formula (4) with bromofluoromethane to yield the compound of formula (1).The present invention also provides an improved process for preparation of c...

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) PROVISIONAL SPECIFICATION (See section 10) CONVENIENT SYNTHESIS OF S-FLUOROMETHYL 6oc,9a-DIFLUORO-llp-HYDROXY-16a-METHYL-17a-PROPIONYLOXY-3-OXOANDROSTA-l,4- DIENE-17p-CARBOTHIOATE 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 describes the nature of this invention. PROCESS FOR THE PREPARATION OF S-FLUOROMETHYL 6α, 9α- DIFLUORO-11β-HYDROXY-16α-METHYL-α -PROPIONYLOXY-3- OXO ANDROSTA-1, 4-DIENE- l7β -C ARBOTHIO ATE The present invention relates to the process for preparation of S-fluoromethyl 6α, α9-difluoro-11 β-hydroxy-16a-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate, a compound of formula 1. S-fluoromethyl 6α, 9α-difluoro-ll β-hydroxy-16 a-methyl-17a-propionyloxy-3-oxoandrosta-l,4-diene-17p-carbothioate, commonly known as fluticasone propionate (INN), is used as an anti-inflammatory and antipruritic agent. PRIOR ART United States Patent No. 4335121 (referred to herein as the '121 patent, Indian reference not available) discloses the compound of formula 1 and its preparation. It discloses the process of its preparation by treating a compound of formula 2 with dimethylthiocarbamoyl chloride to yield a compound of formula 3 , / —N 2 HO. HS '0 =0 0 F 5 which is decomposed by refluxing in diethylamine to the thioic acid of formula 4. The compound of formula 4 is then reacted with bromochloromethane in presence of sodium bicarbonate to give a chloromethyl ester of formula 5. The compound of formula 5, is converted to an iodomethyl ester by halogen exchange and subsequently treated with silver fluoride to yield the compound of formula 1. This process of preparation of the compound of formula 1 is very tedious, lengthy, and involves use of expensive and sensitive chemicals, viz. silver fluoride. This prior art teaches the use of ammonia, a primary amine or more preferably a secondary amine such as diethylamine or pyrrolidine for conversion of compound of formula 3 to compound of formula 4. However, the yield obtained with use of secondary amines such as diethyl amine is poor. PCT publication WO 01/62722 (Equivalent of which is US 2002/0133032A1, Indian reference not available) discloses the method of preparing the compound of formula 1 by reacting a compound of formula 2 with dimethylthiocarbamoyl chloride and molar equivalents of sodium iodide in 2-butanaone to get compound of formula 3. The compound of formula 3 is then reacted with a hydrolyzing agent such as sodium hydrosulfide to generate the sodium salt of formula 4, which can be alkylated in-situ with chlorofluoromethane to yield the compound of formula 1 or alternately can be acidified to obtain the compound of formula 4, which can be isolated and converted to compound of formula 1 by alkylation with chlorofluoromethane. This prior art publication teaches use of an alkoxide salt, a thioalkoxide salt or a hydrated sulphide salt for hydrolyzing the compound of formula 3 to obtain the corresponding thiocarboxylic acid, the compound of formula 4. The use of sodium hydrosulphide hydrate or sodium thiomethoxide as hydrolyzing agent for conversion of carboxylic acid to carbothioic acid 3 has been exemplified. However, sodium thiomethoxide is a corrosive and moisture sensitive reagent and use of sodium thiomethoxide would generate toxic methyl mercaptan during acidification and sodium hydrosulfide is unstable and converts to sodium thiosulfate and sodium carbonate upon storage. In the in-situ alkylation of sodium salt of compound of formula 4, the excess sodium hydrosulfide would react with the chlorofluoromethane generating highly toxic bis(fiuoromethyl)sulfide, which can pose severe health hazards. Although isolation of thioic acid of formula 4 can be performed (by treatment with an acid) to overcome the problem caused by excess sodium hydrosulfide, the sulfur will also precipitate in the acidification step, whose removal would be very difficult. Some other shortcomings of this prior art method include (i) the time taken for the completion of alkylation reaction with chlorofluoromethane is very long, requiring about 26 hours, (ii) the amount of chlorofluoromethane required is in large molar excess, with almost 7.5 molar equivalents being used, and (iii) chlorofluoromethane being a gas would create handling difficulties. Gordon H. Phillipps et al, Journal of Medicinal Chemistry 37, 3717-3729 (1994), disclose the method of preparing the compound of formula 1 by treating a compound of formula 6 with carbonyldiimidazole under nitrogen, followed by a reaction with hydrogen sulfide to give the thioic acid of formula 7, which is isolated and treated with propionyl chloride to give the compound of formula 4. This compound is then alkylated with bromofluoromethane under nitrogen to yield the compound of formula 1 in 69.3% yield. This reference does not mention the preparation of compound of formula 1 directly from the compound of formula 3. 4 In the process of the present invention an alkali metal carbonate is used as a hydrolyzing agent for conversion of a compound of formula 3 to a compound of formula 4 in contrast to prior art use of an alkoxide, a thioalkoxide or hydrated sulphide salt (as in WO 01/62722) or use of amines such as diethyl amine as in the ' 121 patent for this reaction. OBJECT OF THE INVENTION The object of the present invention is to provide a facile, efficient and economic process for the preparation of S-fluoromethyl 6α, 9α-difluoro-llβ-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate. In particular, the process of the present invention provides a simple and economical process wherein an alkali metal carbonate is used for conversion of a compound of formula 3 to a compound of formula 4. Use of alkali metal carbonate provides improved yield of compound of formula 4. SUMMARY OF INVENTION We have found a facile, efficient and economic process for the preparation of S- fluoromethyl 6α, 9α-difluoro-11 β-hydroxy-16a-methyl-17α-propionyloxy-3- oxoandrosta-l,4-diene-17β-carbothioate (compound of formula 1) that provides an improved yield of the compound, using reagents that are easy to handle, utilizing a low reaction time and using the reagents in lesser molar amounts. The present invention provides a process for the preparation of S-fluoromethyl 6α, 9α-difluoro-11 β-hydroxy-16α-methyl-l 7α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate, a compound of formula 1, comprising (a) reacting the compound of formula 3 with an alkali metal carbonate in an alkanol solvent to obtain the compound of formula 4; (b) reacting the compound of formula 4 with bromofluoromethane to yield the compound of formula 1; 5 ./~-F > 3 HS. / o 4 DETAILED DESCRIPTION OF THE INVENTION In the process of the present invention the compound of formula 3 is converted to a compound of formula 4 by reacting with an hydrolyzing agent, which is an alkali metal carbonate to generate the alkali metal salt of compound of formula 4, viz., a compound of formula 4a, wherein M is the metal ion corresponding to the alkali metal carbonate used, such as K, Na or Li. The compound of formula 4a can be neutralized in-situ by treatment with an acid to obtain the compound of formula 4. The compound of formula 4 is then reacted with bromofluoromethane to obtain the compound of formula 1. It is also possible to convert the compound of formula 3 to the compound of formula 1 directly i.e. without isolating the compound of formula 4 by avoiding the reaction of compound of formula 4a with the acid, and directly reacting the compound of formula 4a generated in-situ with bromofluoromethane to obtain the compound of formula 1 (See Scheme 1). 6 / s*w /—o —► HCV /\J / ° / ° cr ^-^ F F 4a Scheme 1 The term "alkali metal carbonate", as used herein, refers to potassium carbonate, sodium carbonate, cesium carbonate and the like. The term "acid", as used herein, refers to reagents capable of donating protons during the course of the reaction. Examples of acids include mineral acids such as HC1, HBr, HI, sulfuric acid, phosphoric acid and the like; organic acids such as acetic, formic, trifluoroacetic acid and the like; and sulfonic acids such as para-toluenesulfonic acid and the like. Further in the process of the present invention for alkylating the compound of formula 4, bromofluoromethane, a liquid, which is easier to handle is used, as compared to chlorofluoromethane, a gas, which is used in the prior art process of WO 01/62722. The process of the present invention also utilizes lesser molar amounts of bromofluoromethane, as compared to the large molar amounts of chlorofluoromethane required in the prior art process. Also, the alkylation with bromofluoromethane requires shorter reaction time. 7 According to the process of the present invention, in step 'a' of the process, the reaction of compound of formula 3 is carried out with an alkali metal carbonate in an alkanol solvent to obtain the compound of formula 4. Examples of alkali metal carbonate that can be used include sodium carbonate, potassium carbonate, cesium carbonate and the like. The most preferred hydrolyzing agent is potassium carbonate. In a preferred embodiment of the process of the present invention, the compound of formula 3 is treated with potassium carbonate in methanol at ambient temperature for about 3 hour to about 10 hours. The reaction mixture is worked up by addition of water, followed by washing with an organic solvent such as toluene. The separated aqueous layer is acidified with an acid such as HC1 acid to pH of about 1.5 to about 2 and the precipitated product is isolated. In step 'b' of the process of the present invention, the compound of formula 4 is alkylated with bromofluoromethane The mole ratio of bromofluoromethane to the compound of formula 4 may be in the range of about 1:1 to about 5:1. Preferably, the mole ratio of bromofluoromethane to the compound of formula 4, used in the process of the present invention, is 3:1. In a preferred embodiment of the process of the present invention, the compound of formula 3 is treated with potassium carbonate in methanol at ambient temperature for about 3 hour to about 10 hour. The reaction mixture is worked up by addition of water, followed by washing with an organic solvent such as toluene. The separated aqueous layer is acidified with an acid such as HC1 acid to pH of about 1.5 to about 2 and the precipitated product is isolated to obtain a compound of formula 4. The compound of formula 4 is reacted with bromofluoromethane in presence of potassium carbonate in acetone at about 0°C to about -5°C for a period of about 3 hours to about 10 hours. The reaction is quenched by addition of water and the precipitated product is isolated to obtain a compound of the formula 1. 8 It is also possible to prepare the compound of formula 1 by the process of the present invention wherein the compound of formula 3 is reacted with an alkali metal carbonate to obtain the compound of formula 4a which is not treated with an acid but is converted to compound of formula 1 directly by reaction with bromofluoromethane. The compound of formula 1 may be purified by treatment with a solvent system comprising one or more organic solvents selected from alcohols, esters, ethers, ketones, amides, nitriles, aliphatic or aromatic hydrocarbons and mixtures thereof. The ratio of the organic solvent to the compound of formula 1 is in the range of about 1:1 to about 50:1 The compound of formula 3 can be prepared, for example, by reacting 6 α, 9α-difluoro-lip-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)-androsta-l,4-dien-17-β-carboxylic acid, a compound of formula 2, with N,N-dimethylthiocarbamoyl chloride in an inert aprotic solvent in the presence of an iodide catalyst and a base. In the prior art process of WO 01/62722 the compound of formula 2 is reacted with N,N-dimethylthiocarbamoyl chloride in 2-butanone and sequentially treated with triethylamine, sodium iodide and water. However, the reaction mixture becomes unstirrable slurry after addition of sodium iodide and water. Whereas, in the process of the present invention it was observed that when the compound of formula 2 is reacted with N,N-dimethylthiocarbamoyl chloride in tetrahydrofuran and sequentially treated with triethylamine and catalytic tetrabutyl ammonium iodide the reaction mixture remains clear. The base selected may be inorganic or organic. Examples of inorganic bases that may be used in the present invention include hydrides, hydroxides, carbonates, or fluorides of alkali or alkaline earth metals. The organic base may be selected from secondary or tertiary amines and quaternary ammonium bases which may be cyclic or acyclic, Preferably, the organic base is selected from hindered acyclic or cyclic tertiary amines and quaternary ammonium bases. In a preferred embodiment, an organic base is used. Particularly preferred organic base is triethylamine. 9 The iodide catalyst may be an iodide salt selected from alkali metal iodides, alkaline earth metal iodides and quaternary ammonium iodides, the preferred catalyst being quaternary ammonium iodides, most preferably tetrabutylammonium iodide. The mole ratio of the catalyst to 6α, 9α-difluoro-lip-hydroxy-16 α-methyl-3-oxo-17α-(propionyloxy)androsta-l,4-dien-17β-carboxylic acid, the compound of formula 2 that may be used in the process of the present invention lies in the range of about 0.01:1 to about 0.5:1, preferably 0.1:1. The reaction of a compound of formula 2 with N,N-dimethylthiocarbamoyl chloride may be carried out in an inert aprotic solvent such as aliphatic or aromatic hydrocarbons, ethers, esters, nitriles and amides, or mixtures thereof. In preferred embodiments of the present invention ethers are used as the solvents. The ethers that are used are, cyclic or acyclic such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl ether and the like, and mixtures thereof; more preferably tetrahydrofuran is used as the solvent. The reaction of a compound of formula 2 with N,N-dimethylthiocarbamoyl chloride may be carried out at temperature ranging from -10° C to 100° C, preferably from about 0° C to 25°C. Preferably the compound of formula 3 is prepared by treating the compound of formula 2 with N,N-dimethylthiocarbamoyl chloride in tetrahydrofuran, in the presence of triethylamine and tetrabutyl ammonium iodide at room temperature, followed by cooling to 10 -15°C. The reaction mixture is warmed to ambient temperature and stirred for 2-8 hours, preferably for 4 hours. At the end of the reaction, the reaction mixture is treated sequentially with a polar aprotic solvent and water. This polar aprotic solvent may be selected from dimethylformamide, dimethylacetamide and dimethyl sulfoxide and the like; the preferred solvent being dimethylacetamide. The mixture is then cooled to 0° C, stirred and the compound of formula 3 is isolated. 10 The compound of formula 2, 6α,9α-difluoro-llβ-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-l,4-diene-17β-carboxylic acid, may be prepared in conventional manner e.g. by oxidation of 6α,9α-difluoro-llβ,17α-dihydroxy-16α-methyl-3,20-dione-21-hydroxy-androsta-l,4-diene i.e. flumethasone, followed by reaction with propionyl chloride or propionyl anhydride. The oxidation reaction may be carried out with a suitable oxidizing agent such as periodic acid. Given below is the schematic representation of a preferred process by which a compound of the formula 2 may be prepared. The present invention is further defined by the following: A] A process for the preparation of S-fluoromethyl 6α, 9α-difluoro-11 β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-l,4-diene-17β-carbothioate, a compound of formula 1, comprising (a) reacting the compound of formula 3 with an alkali metal carbonate in an alkanol solvent to obtain the compound of formula 4; (b) reacting the compound of formula 4 with bromofluoromethane to yield the 11 compound of formula 1; HS. H0 V^X ^-/'' '°^ 4 B] The process as defined in 'A' above, wherein the alkali metal carbonate is potrassium carbonate. C] The process as defined in 'A' above, wherein the alkanol is methanol. D] The process as defined in 'A' above, wherein the mole ratio of bromofluoromethane to the compound of formula 4 is 3:1. E] The process as defined in 'A' above, wherein the compound of formula 3 is prepared by reacting 6α, 9α-difluoro-lip-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy) androsta-l,4-dien-17β-carboxylic acid, a compound of formula 2, with N,N- dimethylthiocarbamoyl chloride in an inert aprotic solvent in the presence of an iodide catalyst and a base. F] The process as defined in 'E' above, wherein the inert aprotic solvent is an ether. G] The process as defined in 'F' above, wherein the ether solvent is tetrahydrofuran. H] The process as defined in 'E' above, wherein the iodide catalyst is tetrabutylammonium iodide. I] The process as defined in 'H' above, wherein the mole ratio of the catalyst to the compound of formula 2 is 0.1:1. 12 J] The process as defined in 'E' above, wherein the base is an organic base. K] The process as defined in 'J' above, wherein the organic base is triethylamine. The invention is illustrated but not restricted by the description in the following examples. 13 EXAMPLE Example 1: Preparation of 6α,9α-difluoro-lip,17α-dihydroxy-16α-methyl-3-oxoandrosta-l,4-diene-17β-carboxylic acid A solution of periodic acid (83g, 0.365 mole) in water (200ml) is prepared by heating to 50-55° C and cooling to 30-35° C. This solution is added dropwise to a stirred suspension of flumethasone (l00g, 0.244 mole) in tetrahydrofuran (400ml) at 0-5° C. After completion of addition the mixture is stirred for further 2 hrs. at 0-5° C and thereafter quenched by addition of water (600ml) while maintaining temperature at 5-15 ° C, then cooled to 0-5° C and filtered. The product 6a,9a-difluoro-lip,17ot-dihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-17p-carboxylic acid is washed with water (-2.0 ltr), and dried at 45-50° C. Yield 92.0g (95.3%, purity 99.55%). Example 2: Preparation of 6α,9α-difluoro-11β-hydroxy-16oc-methyl-3-oxo-17α-(propionyloxy)-androsta-l,4-diene-17β-carboxylic acid, a compound of formula 2 To suspension of 6α,9α-difluoro-lip,17α-dihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-17p-carboxylic acid (80g, 0.202mole) in acetone (400ml) at 10-15° C is added sequentially triethylamine (85ml, 0.606mole) and propionic anhydride (78ml, 0.606mole). After stirring for 4 hrs. at 25-30° C, dimethylamine (42ml, 0.404mole) is added dropwise at 10-15° C and then stirred at ambient temperature for 1 hr. Thereafter the reaction mixture is acidified to pH 1.0 -1.5 at 0-5° C. The precipitated product is filtered, washed with water, and dried at 4-45° C, until water content is below 5%. Yield 90g on dry basis (98.6%, purity >99.5%) Example 3: Preparation of 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-α-propionyloxy-3-oxoandrosta-l,4-diene, a compound of formula 3 14 A solution of 6α, 9α-difluoro-lip-hydroxy-16α-methyl-3-oxo-17α- (propionyloxy)androsta-l,4-diene-17β-carboxylic acid, (50.0 g, 110 mmol) and N,N- dimethylthiocarbamoyl chloride (27.4 g, 222 mmol) in tetrahydrofuran (250 ml) at room temperature is cooled to 10 to 15°C. It is sequentially treated with triethylamine (24.9 g, 244 mmol) and tetrabutylammonium iodide (4.1 g, 11 mmol) at 10-15° C. The reaction mixture is warmed to ambient temperature, stirred for 4 hrs and then treated sequentially with dimethylacetamide (150 ml) and water (1.0 lit). The resultant mixture is cooled to 0° C, stirred for 2 hours, and the product is filtered. The solid obtained is washed with water (230 ml) and dried at 55° C for 4.0 hours to provide 57.0 g (96.0% yield, purity >98.5%) of 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-lip-hydroxy-16a- methyl-17α-propionyloxy-3-oxoandrosta-l,4-diene. Example 4: Preparation of 6α,9α-difluoro-lip-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-l,4-diene-17β-carbothioic acid, a compound of formula 4 A suspension of 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-l 1(3-hydroxy- 16α-methyl-17α-propionyloxy-3-oxoandrosta-l,4-diene (20 g, 0.037 mol.) and potassium carbonate (10.23 g, 0.074 mol.) in methanol (100 ml) is stirred at ambient temperature for 5 hrs under a blanket of nitrogen. Thereafter, water (100 ml) is added to the reaction mixture and the resultant clear solution is extracted with toluene (60 ml). The aqueous layer containing the product is charcoalized (2 g charcoal) at ambient temperature and then acidified with 2N HC1 until pH is 1.5 to 2.0. The precipitated product is filtered, washed with water, and dried at 50-60° C to obtain 6α,9α-difluoro-lip-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta -l,4-diene-17β-carbothioic acid (5) (yield 17.3 g, moisture content 3.3%, 96.33% on dry basis). Example 5: Preparation of S-fluoromethyl 6 α,9 α-difluoro-lip-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-l,4-diene-17β-carbothioate, compound of formula 1 15 A stirred mixture of 6α,9α-difluoro-lip-hydroxy-16a-methyl-17α-propionyloxy-3-oxo-androsta-l,4-diene-17β-carbothioic acid (5) (4 g, 0.0085 mol)) and anhydrous potassium carbonate (0.82 g, 0.0059 mol.) in acetone (20ml) under a blanket of nitrogen is cooled to 0 to -5°C and bromofluoromethane (1.05g, 0.009 mol.) is added. The mixture is then stirred at 0 to -5°C for further 5 hrs and then quenched with water (20 ml). The precipitated product is filtered, washed with water (8 ml), and dried to obtain crude product (yield: 3.625 g, moisture content 0.36%, 84. 8%, purity 98.11%) Example 6: Purification of compound of formula 1 The crude fluticasone obtained as above is dissolved in 68 ml 1-butanol at 117-120°C to get a clear solution (which may be optionally charcoalized and filtered hot), and then gradually cooled to ambient temperature for crystallization. The crystallized product is filtered, washed with 1-butanol (4ml). Dried at 55-60°C to obtain pure fluticasone propionate (Yield 3.0 g, purity 99.24%) 16

Documents:

387-mum-2003-claims(granted)-(4-1-2008).doc

387-mum-2003-claims(granted)-(4-1-2008).pdf

387-mum-2003-correspondance-received-ver-080503.pdf

387-mum-2003-correspondance-received-ver-101103.pdf

387-mum-2003-correspondance-received-ver-110304.pdf

387-mum-2003-correspondance-received-ver-110403.pdf

387-mum-2003-correspondance-received-ver-170106.pdf

387-mum-2003-correspondance-received-ver-170406.pdf

387-mum-2003-correspondance-received-ver-280105.pdf

387-mum-2003-correspondance-send-ver-230403.pdf

387-mum-2003-correspondance-send.pdf

387-mum-2003-correspondence(1-4-2008).pdf

387-MUM-2003-CORRESPONDENCE(11-5-2010).pdf

387-mum-2003-correspondence(ipo)-(18-3-2008).pdf

387-mum-2003-description (provisional).pdf

387-mum-2003-form 1(17-4-2003).pdf

387-MUM-2003-FORM 15(11-5-2010).pdf

387-mum-2003-form 18(17-4-2006).pdf

387-mum-2003-form 2(granted)-(4-1-2008).pdf

387-mum-2003-form 3(10-11-2003).pdf

387-mum-2003-form 5(10-11-2003).pdf

387-mum-2003-form 5(4-1-2008).pdf

387-mum-2003-form pct-ipea-210.pdf

387-mum-2003-form pct-ipea-409.pdf

387-mum-2003-form pct-ipea-416.pdf

387-mum-2003-form-1.pdf

387-mum-2003-form-18.pdf

387-mum-2003-form-2-(granted)-(4-1-2008).doc

387-mum-2003-form-2.doc

387-mum-2003-form-2.pdf

387-mum-2003-form-3.pdf

387-mum-2003-form-5.pdf

387-mum-2003-form-pct-ipea-409(17-4-2003).pdf

387-mum-2003-form-pct-isa-210(4-1-2008).pdf

387-mum-2003-granted.pdf