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"Process For Preparation Of Phenolic Monoesters Of Hydroxymethyl Phenols"

Abstract: Disclosed herein is an improved and efficient process for preparation of fesoterodine and its pharmaceutically acceptable salt. Disclosed also herein is novel intermediate of formula (III). Also disclosed are metal salts of formula (XII) and preparation thereof-

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
11 May 2010
Publication Number
33/2012
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

INTAS PHARMACEUTICALS LIMITED
INTAS PHARMACEUTICALS LIMITED 2ND FLOOR, CHINUBHAI CENTRE, ASHRAM ROAD, AHMEDABAD 380009, GUJARAT, INDIA

Inventors

1. SANJAY JAGDISH DESAI
INTAS PHARMACEUTICALS LTD. PLOT 457/458, SARKHEJ-BAVLA HIGHWAY, MATODA-382210. TAL.:SANAND, AHMEDABAD. GUJARAT, INDIA.
2. KALPESH MAHENDRABHAI PATEL
INTAS PHARMACEUTICALS LTD. PLOT 457/458, SARKHEJ-BAVLA HIGHWAY, MATODA-382210. TAL.:SANAND, AHMEDABAD. GUJARAT, INDIA.
3. AAKASH MAHESHKUMAR SHAH
INTAS PHARMACEUTICALS LTD. PLOT 457/458, SARKHEJ-BAVLA HIGHWAY, MATODA-382210. TAL.:SANAND, AHMEDABAD. GUJARAT, INDIA.
4. RANJIT SHARDULBHAI PADA
INTAS PHARMACEUTICALS LTD. PLOT 457/458, SARKHEJ-BAVLA HIGHWAY, MATODA-382210. TAL.:SANAND, AHMEDABAD. GUJARAT, INDIA.
5. HITESH MANUBHAI MAKWANA
INTAS PHARMACEUTICALS LTD. PLOT 457/458, SARKHEJ-BAVLA HIGHWAY, MATODA-382210. TAL.:SANAND, AHMEDABAD. GUJARAT, INDIA.

Specification

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 Complete Specification [See Sections 10 and rule 13] Title: Process For Preparation Of Phenolic Monoesters Of Hydroxymethyl Phenols Applicant: (a) INTAS Pharmaceuticals Limited (b) Nationality: India (c) 2nd Floor, Chinubhai Centre, Ashram Road, Ahmedabad 380009 Gujarat, India FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of phenolic monoesters of 2-(3-diisopropylamino-1 -pbenylpropyl)-4-(hydroxymethyl)phenol specificaJJy fesoterodine or its fumarate salt which is a prodrug of tolterodine. The present invention also provides metal salts of (+)-5-HMT, R-(+)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxy methyl phenol an intermediate in the synthesis. BACKGROUND OF THE INVENTION In man, normal urinary bladder contractions are mediated, (inter alia), through cholinergic muscarinic receptor stimulation. Muscarinic receptors not only mediate normal bladder contractions, but may also mediate the main part of the contractions in the overactive bladder resulting in symptoms such as urinary frequency, urgency and urge urinary incontinence. U.S. Patent No. 6,713,464 disclosed a variety of phenolic monoesters derivatives, processes for their preparation, pharmaceutical compositions and method of use thereof. These compounds are anti-muscarinic agents with superior pharmacokinetic properties compared to existing drugs such as oxybutynin and tolterodine and useful in the treatment of urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions. Among them, Fesoterodine, chemically 2-[(lR)-3-[bis(l-methylethyl)amino]-l-phenylpropyl]-4-hydroxymethylphenylisoburyrate is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence. It has the formula (I) depicted below. A synthetic approach for the production of the Active Metabolite and monoesters of the phenolic hydroxy group of the Active Metabolite such as Fesoterodine has been described in US 6,713,464 which, is as follows: Fesoterodine is prepared by reaction of (±)-6-bromo-4-pheny]chroman-2-one with benzyl chloride in the presence of sodium iodide and anhydrous potassium carbonate in methanol and acetone to produce (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester as a light yellow oil. This product is reduced with lithiumaluminium hydride to produce (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-1-ol, which is then treated with p-toluenesulphonyl chloride in the presence of pyridine in djchloromethane to afford (±)-toluene-4-sulphonic acid 3-(2-bcnzyloxy-5-bromophenyl)-3-phenylpropyl ester. This product is then reacted with N, N-diisopropylamine in acetonitrile at reflux temperature for 97 hours to produce (±)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine as a brown and viscous syrup. This product is resolved to produce (R)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylproopyl] diisopropylamine which is then subjected to Grignard reaction with ethyl bromide and magnesium to produce (±)-4-benzyloxy-3-(-3-diisopropylamino-phenylpropyl)-benzoic acid hydrochloride, followed by esterification with methanol in the presence of sulphuric acid to produce (R)-4-benzy]oxy-3-(3-diisopropylamino-l-phenylpropyl)-benzoic acid methyl ester, this product is"reduced with lithiumaluminium hydride to produce (R)-[4-benzyloxy-3-(3-diisoprylamino-l-phenylpropyl)-phenyl]-methanol, which is then subjected to deprotection with Raney-Nickel to produce (R)-2-(3-diisopropylamino-I-pheny!propyI)-4-hydroxymethyJphenol followed by condensation with isobutyryl chloride to give fesoterodine. WO 94/11337 also describes a multi-stage process to synthesize the precursor to the Active Metabolite. US 6,809,214 discloses a process wherein compound of following formula is used for preparation of 3,3-diarylpropylamine derivative. US 6,858,650 discloses stable salts of 3,3-diphenyJpropylamine derivative, the process of '650 utilizes R-(-)-3-(3-diisopropylamino-phenylpropyl)-4-hydroxy-benzoic acid methyl ester in the preparation of fesoterodine. WO 2009/037569 discloses a process for preparation of fesoterodine. The process includes reaction of 4-phenylchromen of following formula: with benzyl chloride to give a compound of following formula which is further converted to fesoterodine (I) through multiple steps. These previously described methods for producing the Active Metabolite require numerous steps that result in complex purification procedures, time-delay, and enhanced possibility of human error, thereby prohibiting optimal efficiency and cost-effectiveness. Conversion of fesoterodine base into its fumarate salt is reported in US 6, 858, 650, WO 2007/140986 and US 2010/0152483. The problem associated with prior art process is long time is required for isolation of crystals still this purity level can not be considered satisfactory as compared to pharmacopeias requirement for this product. To overcome one or more insufficiencies of prior art processes the present invention provides a process for preparation of crystalline fesoterodine fumarate which is easy to handle on industrial scale and provides a product with high purity complying with the pharmacopial limits. OBJECTS OF THE INVENTION The main object of the invention to provide an improved process for the preparation of phenolic monoesters of 2-(3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyi)phenol, specifically fesoterodine or its fumarate salt A further object of the present invention is to provide cost effective process for the preparation of phenolic monoesters of 2-(3-diisopropy)amino-l-phenyIpropyl)-4-(hydroxymethyl) phenol. A further object of the present invention is to provide metal salts of (+)-5-HMT. Another object of the present invention is to provide a process for the preparation of crystalline fesoterodine fumarate. SUMMARY OF THE INVENTION The present invention relates to a novel process for the preparation of phenoJic " monoesters of 2-(3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenoJ by converting (±)6-halo-4-phenylchroman-2-one to (±)4-halo-2-(3-hydroxy-l-phenylpropyl)phenol. The two hydroxyl groups are protected and the protected compound is reacted with diisopropylamine to give (±)[3-(2-benzyloxy-5-halopheny!)-3-phenylpropyl]diisopropy!amine. The halo substituent on the benzene ring is converted to corresponding benzyl alcohol and then the protection is removed to give racemic 5-HMT. Racemic 5-HMT is converted R enantiomer and then it is esterified. In another aspect the present invention provides novel metal salts of formula (XII) and process for their preparation. In yet another aspect the process of present invention provides preparation of compound of formula (VI) by reacting compound of formula (V) with diisopropylamine in water or in polar aprotic solvent and metal iodide or in absence of solvent. In another aspect the present invention provides process to prepare compound of formula (VIII) by reduction of compound of formula (VII) in presence of borane containing reducing agents. In a further aspect the present invention provides a process for crystallisation of compound of formula (IX) by using solvent selected from alkanols, ketones, esters, aromatic hydrocarbons, halogenated solvents, nitrile, water or mixture thereof. In a further aspect the present invention provides improved method for isolation of intermediates of formula (VI) and (IX). In a further aspect the present invention provides a process for preparation of crystalline fesoterodine fumarate. DETAILED DESCRIPTION The following is (he detailed description of preferred process according to the invention for preparing phenolic monoesters of 2-(3-diisopropylamino-l-phenylpropyI)-4-(hydroxymethyl) phenol. According to one aspect of the invention there is provided a method for the preparation of phenolic monoesters of 2-(3-diisopropylamino-l-phenylpropyi)-4-(hydroxymethyl) phenol, specifically fesoterodine which comprises the following steps: The first step in the process according to the present invention comprises reduction of (±) 6-halo-4-phenylchroman-2-one with reducing agent. The starting material in the process of the present invention is (±)6-halo-4-phenylchroman-2-one having formula (II). One method for preparing bromo compound is described in Example 1 of the WO 2009/037569, and involves the reaction of cinnamic acid and 4-bromophenol in the presence of sulphuric acid. The reducing agent for step 1; can be selected from sodium borohydride, lithium borohydride or like. The reaction is carried out in presence of solvent. The solvent used for step I, can be selected from cyclic ether such as tetrahydrofuran. Although "X" in compound of formula (II) can be selected from any halo atom preferably 6-halo derivative i.e. (±) 6-bromo -4-phenylchroman-2-one is used for the purpose of present invention. The reaction can be carried out at higher temperature but preferably it is carried out at around ambient temperature. The reaction is carried out at 0-40 °C preferably at about 10-35 °C. The product of step 1 can be isolated by solvent extraction and pH adjustment. The solvents used for isolation of the product i.e. (±)4-bromo-2-(3-hydroxy-l-phenylpropyl)phenol (III) can be selected from any organic solvent preferably from a group comprising of ether like diisopropylether, aliphatic or aromatic hydrocarbon like hexane, cyclohexane, n-heptane, and mixture thereof. The second step involves protection of the hydroxy] group of the phenol by reacting (±) 4-bromo-2-(3-hydroxy-l-phenylpropyl)phenol with benzyl bromide or benzyl chloride in the presence of any base or acid scavenger and organic solvent to give (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanol. Preferably the base or the acid scavenger can be selected from any metal carbonate or hydroxide such as potassium carbonate, sodium carbonate, sodium hydroxide. The reaction can be carried out in any solvent but is preferably carried in presence of the solvent selected form the group comprising of ketone such as acetone, methyl isopropyl ketone, methyl-isobutyl ketone, methyl ethyl ketone or alkyl nitrile like acetonitrile. The product can be isolated from the reaction mixture by using organic solvent, such as ether, aliphatic or aromatic hydrocarbon or mixture thereof. In third step, (±)-3-(2-benzyloxy-5-bromophenyl)-3-pheny!propanol is converted to C±) toluene-4-sulphonic acid or any other corresponding sulphonic ester 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester by a process mentioned in US 6,713,464 Bl. In fourth step, (±) toluene-4-sulphonic acid 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester or any other corresponding sulphonic ester obtained in step III is reacted with diisoprqpylamine to give (±)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine (VI). The reaction can be carried in the absence of solvent, or using water as solvent or in the presence of aprotic solvents and metal iodide. The aprotic solvent can be selected from N, N-diisopropylamine, N,N-dimethylformamide. The alkali metal used in the process can be selected from potassium iodide or sodium iodide. The reaction can be carried out at temperature in range of 80-150 °C preferably 90-110 °C. The product is isolated by extraction with solvent and pH adjustment of the organic layer. The solvent used for extraction can be selected from any suitable organic solvent. In the process of present invention the pH of organic layer is adjusted by using orthophosphoric acid. The reported processes generally use sulphuric acid for pH adjustment (acid-base purification) this results into sulphate salt of compound of formula (VI). The sulphate salt is difficult to remove as it does not separate in aqueous layer rather forms an oily layer which is difficult to isolate and also entraps many impurities. When orthophosphoric acid is used the resultant salt does not isolate as oil rather goes in aqueous layer and can be isolated easily by further processing and is obtained with high purity. The fifth step, of the process is to convert (±)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine to (±)-4-benzy]oxy-3-(3-diisopropylamino-l -phenylpropyl)-benzoic acid hydrochJoride by the process of US 6,713,464 Bl. In step VI, (±)4-Benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)-benzoic acid is converted by reduction to give {±)[4-Benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)-Phenyl]methanol. The reduction is performed by using borane containing reducing agents such BHvDMS (Boron Dimethylsulphide complex), BH3.THF (Boron THF). The process of present invention provides direct reduction of acidic group of compound of formula VII, whereas the process of US 6,713,464 discloses conversion of acid to ester by using methanol and sulphuric and then reduction of ester to alcohol. Thus the present invention avoids extra step and makes the overall process more feasible. The reduction can be carried out in presence of solvent selected from group comprising aromatic hydrocarbon like toluene, cyclic ether like tetra hydro furan or mixture thereof. The product can be isolated by using organic solvents selected from group comprising of alkanols, esters, hydrocarbon, ketone, halogenated solvents, water or mixture thereof; preferably solvent for isolation is selected from alcohol like isopropyl alcohol. In step VII, (±)[4-Benzyloxy-3-(3-diisopropylamino-l-phenylpropy])-Phenyl]-methanol is debenzylated by known methods to give racemic 5-HMT. Compound of formula (IX) is difficult to be crystallised as solid by following the reported procedure and is generally obtained as liquid or oil. The process of present invention uses solvents selected from group comprising of alcohols, ethers, ester, aliphatic or aromatic hydrocarbon, halogenated solvents, ketones, nitriles or water. Use of these solvents enables crystallisation of compound of formula (IX) thus easing the isolation process. Next step VIII relates to resolution of racemic compound of formula (IX). Resolution can be carried out by using a resolving agent like acetyl mandelic acid; in presence of any suitable organic solvent e.g. tetrahydrofuran. The process comprises reacting the racemic compound (IX) with acetyl mandelic acid to obtain salt of formula (X), treating the acetoxy mandelate salt of formula (X) with any suitable inorganic or organic base to liberate desired isomer i.e. (R)-(+)-2-(3-diisopropylamino-Iphenylpropyl)-4-hydroxy methyl phenol of formula (XI). The compound of formula (XI) can be isolated from reaction mixture by distilling off the reaction solvent and treating the residue with a suitable solvent such as ketone like acetone, alkane like hexane, heptanes or mixture thereof. According to another aspect of the invention there is provided metal salts of compound of formula (XII) and can in general be represented by following structural formula. Wherein M+ represents any metal ion such as Na+, K+ or Li+ The metal salts of formula (XII) can be used in the preparation of fesoterodine. Alternatively the product of formula (IX) i.e. racemic 5-HMT can also be converted to its metal salt. According to yet another aspect of the present invention there is provided a process for the preparation of the metal salts of formula (XII). For this the phenolic compound of formula (XI) is reacted with metal base such as sodium hydroxide, lithium hydroxide, potassium hydroxide or like. Solvent used for the reaction can be selected from any suitable organic solvent such as alcohol like methanol, isopropanol or ethanol; ketones like acetone, methyl ethyl ketone, methyl isopropyl ketone or methyl isobutyl ketone or mixture thereof. The reaction is carried out under heating preferably at a temperature in the range of 25-85 °C. The metal salt of formula (XII) can be isolated from the reaction mixture by distilling off the reaction solvent followed by addition of solvent to the residue. The product of formula (XII) can be isolated from residue by adding solvent selected from aromatic hydrocarbon like toluene, halogenated solvent like dichloromethane, ether like tetrahydrofuran, diisopropyl ether, petroleum ether, alkane like cyclohexane. The solid thus obtained can be separated by filtration or similar technique and dried. (+)-5-HMT or its metal salt is esterified to give phenolic monoesters of 2-(3-diisopropyJamino-1-phenylpropyl)-4-(hydroxymethyl) phenol. According to the present invention the esterification can be done by the Following methods: 1) Esterification of (+)-5-HMT in an organic solvent and in the absence of base 2) Esterification of (+)-5-HMT in an organic acid like isobuiyric acid in the presence of coupling reagents like N,N-dicyclohexylcarbodiimide (DCC) or 1-hydroxybenzotriazole in an organic solvent. 3) Esterification of metal salts of (+)-5-HMT in presence of an organic solvent The final step of the process is conversion of phenolic monoesters of 2-(3- diisopropylamino-1 -phenylpropyl)-4-(hydroxymethyl)phenol, specifically fesoterodine to its fumarate salt. According to the present invention, fesoterodine fumarate is prepared by reacting fesoterodine base with fumaric acid in presence of 2-butanone and using anti solvent selected from ether, alkane, aromatic hydrocarbons or mixtures thereof. The fesoterodine fumarate can be further recrystllised using the same solvent system used for the preparation of salt. The characteristic features of product obtained as per the above method matches with product obtained as per e.g. 6 of US 6, 858, 650 and with Form I as disclosed in US 2010/0152483. For reference the comparative data is provided in tables given below. Table 1: 2 theta values of product obtained as per US 6, 858, 650, process of present disclosure and of US203 0/0152483 Folio US6858 wing 650 B1 Following US2010/152483 A1 Process of present disclosure 2 Theta Value Intensity 2 Theta Value Intensity 2 Theta Value Intensity 4.4 3.7 4.5 1.95 4.4 2.7 8.79 14.2 8.94 8.22 8.78 9.9 10.37 87.8 10.55 23.71 10.37 91.3 11.52 47.6 11.63 13.72 11.52 52.2 11.8 58.2 11.93 19.95 11.82 50.2 12.85 37 12.83 43.2 13.2 20.7 13.01 17.71 13.19 15.9 14.86 9.8 13.31 17.9 14,89 8.5 15.1 7.7 15.09 2.95 15.09 8.3 15.29 2.2 15.89 11 15.9 10.5 16.21 18.8 16.2 21.8 16.54 19.2 16.42 10.37 16.55 25.1 17.64 67.9 17.74 61.68 17.61 55.8 17.97 33.4 18.1 23.67 17.95 21.3 18.81 56.4 18.96 85.2 18.96 100 19.32 27.8 19.14 27.82 19.31 31.6 19.59 9.37 19.98 36.8 20.06 24.45 19.99 38.4 20.16 30.05 20.79 56.4 20.98 16.27 20.79 74.1 22.07 100 22.2 100 22.06 82.5 22.82 16.8 23.05 36.1 23.06 37.7 23.33 6.7 23.25 15.13 23.33 7.J 23.75 9 23.82 8.1 24.09 13.1 24.05 17 24.16 8.76 24.1 17.7 24.92 21.2 25.07 7.36 24.93 21.3 25.3 5.9 25.53 9.3 25.55 10.3 25.89 32.4 25.86 37 26.12 23.08 26.17 3.3 27.01 7 27.02 8 27.46 5.4 27.74 10.1 27.73 14.6 28.06 14.2 28.2 20.4 28.34 21.45 28.2 22.2 29.17 3.3 29.14 3.2 29.44 3.04 30.46 3.7 30.46 4.1 30.78 5.5 31.07 2.27 30.77 6.5 31.22 2 31.64 6.2 31.96 2.21 31.65 7.4 32.51 12.5 32.66 12.4 32.51 13.9 32.81 3.9 33.3 1.5 34.98 2.1 35.73 2.5 35.83 2.37 35.75 2.7 36.28 5.2 36.46 2 36.26 6 36.93 3.9 37.01 2.72 36.92 3.6 37.35 2.1 38.44 1.5 38.65 2.3 38.68 2.2 39.02 3.4 39.23 3.5 39.2 3.9 40.07 2.1 40.12 1.9 40.59 2.8 40.59 3.3 41.47 1.9 41.46 2.1 42.34 1.8 42.29 2 44.83 1.7 45.05 2.3 45.05 2.4 45.3 2 45.33 2.2 Table 2: DSC values of product obtained as per US 6,858, 650, process of present disclosure and of US2010/0152483 Sr.No Reference DSC Value Solvents used 1 Following US 6, 858, 650 105.7 to 111.55 2-butanone & cyclohexane 2 Following US2010/0152483 A1 105.95 to 109 As disclosed therein 3 Process of present disclosure 105.22 to 109.73.17 2-butanone & Diisopropyl ether Table 3: IR frequencies of product obtained as per US 6,858, 650, process of present disclosure and of US2010/0152483 Following US6858650B1 Following US2010/0152483 Process of present disclosure Wave length { 1/cm) Wavelength ( 1/cm) Wave length ( 1/cm) 3481 3473 3473 3412 1757 3373 1700 3348 J558 3331 1234 1757 1213 1755 1701 1176 1691 1544 1156 1680 1629 1127 1581 .1232 1097 1226 1213 1018 1215 1176 982 1176 1157 907 1128 1126 794 1095 1097 703 1020 1064 983 1037 910 1020 794 981 746 939 702 908 792 748 702 The following examples are illustrative of the invention but not limitative of the scope thereof Examples:- Example 1: Preparation of (±)-4-bromo-2-(3-hydroxy-l-phenylpropyl) phenol (III) 6-bromo-4-phenyIchroman-2-one (900g) and tetrahydrofuran (10.8 litres) were taken into a reaction flask. All tha contents were cooled to 0-5°C. This was followed by addition of sodium borohydride (14200 g), after completion of addition the temperature of reaction mixture was raised to 25-35c'C. The reaction mass was stirred at the same till completion of reaction. Reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to 0-5°C, to this water (1.8 litre) was added and the solvent was distilled off. Again the reaction mass was cooled to 5-15°C followed by addition of water (5.4 litre); the pH of resultant mixture was adjusted to 1-2 by using hydrochloric acid. The reaction mixture was stirred for 30 minutes at 25 to 30°C, followed by addition of ethyl acetate 5.4 lit, the layers were separated, and organic layer was washed with sodium chloride solution, followed by distillation of solvent. To the residue thus obtained 0.5 volume of toluene was added and distilled off, followed by second addition of toluene (4.5 lit) to the residue, the reaction mixture thus obtained was heated to 50-55°C and then cooled to 25-30°C and stirred at the same for about 40 minutes. The reaction mixture was further cooled to 0-10°C and maintained at the same for 60-65 minutes; the solid thus separated was filtered and dried to obtain 8750 g. of title compound. Purity 98.2% Mass -LC-MS 306.83 (M - H); NMR (400 MHz, DMSO-d6) δ 2.15 (q, 2, OCH2CH2), 3.35 (m, 2, OCH2CH2), 4.45 (t, 1. CHCH2), 4.52 (s, 1, OH), 6.76 (d, 1, H-Ar), 7.13-7.39

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1 1486-MUM-2010-ABSTRACT(11-5-2011).pdf 2018-08-10
1 1486-MUM-2010-FROM 5(11-5-2011).pdf 2018-08-10
2 1486-MUM-2010-CLAIMS(11-5-2011).pdf 2018-08-10
2 1486-MUM-2010-FROM 3(11-5-2011).pdf 2018-08-10
3 1486-mum-2010-from 2(11-5-2011).pdf 2018-08-10
3 1486-MUM-2010-CORRESPONDENCE(11-5-2011).pdf 2018-08-10
4 1486-MUM-2010-FROM 1(11-5-2011).pdf 2018-08-10
4 1486-MUM-2010-CORRESPONDENCE(16-5-2011).pdf 2018-08-10
5 1486-mum-2010-form 3.pdf 2018-08-10
5 1486-MUM-2010-CORRESPONDENCE(18-5-2011).pdf 2018-08-10
6 1486-MUM-2010-FORM 3(16-5-2011).pdf 2018-08-10
6 1486-mum-2010-correspondence.pdf 2018-08-10
7 1486-MUM-2010-FORM 26(18-5-2011).pdf 2018-08-10
7 1486-MUM-2010-DESCRIPTION(COMPLETE)-(11-5-2011).pdf 2018-08-10
8 1486-mum-2010-form 2.pdf 2018-08-10
8 1486-mum-2010-description(provisional).pdf 2018-08-10
9 1486-mum-2010-form 1.pdf 2018-08-10
9 1486-mum-2010-form 2(title page).pdf 2018-08-10
10 1486-MUM-2010-FORM 2(TITLE PAGE)-(11-5-2011).pdf 2018-08-10
11 1486-mum-2010-form 1.pdf 2018-08-10
11 1486-mum-2010-form 2(title page).pdf 2018-08-10
12 1486-mum-2010-description(provisional).pdf 2018-08-10
12 1486-mum-2010-form 2.pdf 2018-08-10
13 1486-MUM-2010-DESCRIPTION(COMPLETE)-(11-5-2011).pdf 2018-08-10
13 1486-MUM-2010-FORM 26(18-5-2011).pdf 2018-08-10
14 1486-mum-2010-correspondence.pdf 2018-08-10
14 1486-MUM-2010-FORM 3(16-5-2011).pdf 2018-08-10
15 1486-MUM-2010-CORRESPONDENCE(18-5-2011).pdf 2018-08-10
15 1486-mum-2010-form 3.pdf 2018-08-10
16 1486-MUM-2010-CORRESPONDENCE(16-5-2011).pdf 2018-08-10
16 1486-MUM-2010-FROM 1(11-5-2011).pdf 2018-08-10
17 1486-MUM-2010-CORRESPONDENCE(11-5-2011).pdf 2018-08-10
17 1486-mum-2010-from 2(11-5-2011).pdf 2018-08-10
18 1486-MUM-2010-CLAIMS(11-5-2011).pdf 2018-08-10
18 1486-MUM-2010-FROM 3(11-5-2011).pdf 2018-08-10
19 1486-MUM-2010-FROM 5(11-5-2011).pdf 2018-08-10
19 1486-MUM-2010-ABSTRACT(11-5-2011).pdf 2018-08-10