Title of Invention

PROCESS FOR THE PREPARATION OF ARYLETHANOLAMINE DERIVATIVES HAVING AN ANTI-OBESITY AND ANTI-DIABETIC PROPERTIES

Abstract

"PROCESS FOR THE PREPARATION OF ARYLETHANOLAMINE DERIVATIVES HAVING AN ANTI-OBESITY AND ANTI-DIABETIC PROPERTIES" A process for the preparation of a compound of Formula (IA) or a pharmaceutically acceptable salt thereof: wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C1-6alkoxy, C1-6alkyl, hydroxymethyl, . trifluoromethyl, -NR6R6 and -NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl; R2 is hydrogen or C1 6alkyl; R3 is CO2R7 where R7 is hydrogen or C1-6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, or -CO2C1-6alkyl; and Y is N or CH comprising the step of preparing a diamide of Formula (II) or a pharmaceutically acceptable salt thereof: wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyramidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, Ci-ealkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHSO2R6, where each R6 is independently hydrogen or C1-4 alkyl; R2 is hydrogen or C1-6alkyl; R3 is CO2R7 where R7 is C1-6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, -CO2C1-6alkyl; and Y is N or CH.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10, Rule 13 ] PROCESS FOR THE PREPARATION OF ARYLETHANOLAMINE DERIVATIVES HAVING AN ANTI-OBESITY AND ANTI-DIABETIC PROPERTIES GLAXO GROUP LIMITED, a British company of Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex UB6 ONN, England, The following specification particularly describes the nature of the invention and the manner in which it is to be performed :- wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituent's selected from the group consisting of halogen, hydroxy, C,.6alkoxy, C,. 6alkyl, nitro, cyano, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHS02R6, where each R6 is independently hydrogen or C1-4alkyl; R2 is hydrogen or C1-6alky!; X is oxygen, NH, or NC1-4alkyl; R3 is cyano, tetrazol-5-yl, or C02R7 where R7 is hydrogen or C,.6alkyl; R4 and R5 are independently hydrogen, Chalkyl -C02H, -CO2C1-6alkyl, cyano, tetrazol-5-yl, halogen, trifluoromethyl, or C1-6alkoxy, or, when R7 and R5 are bonded to adjacent carbon atoms, R4 and R5 may, together with the carbon atoms to which they are bonded, form a fused 5 or 6 membered ring optionally containing one or two nitrogen, oxygen, or sulfur atoms; and Y is N or CH. Summary of the Invention Briefly, in one aspect, the present invention provides a process for the preparation of a compound of Formula (IA) or a pharmaceutically acceptable salt thereof: wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1- 6alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHS02R6, where each R6 is independently hydrogen or Chalky!; R2 is hydrogen or Chalky!; R3 is C02R7 where R7 is hydrogen or Chalky!; R4 and R5 are independently hydrogen, C1-6alkyl, -COzC1-6alkyl; and Y is N or CH comprising the. step of preparing 3 diamide of Formula (II) or a pharmaceutically acceptable salt thereof: wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-5alkoxy, C,. 6alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHS02R6, where each R6 is independently hydrogen or C1-4alkyl; R2 is hydrogen or Chalky!; R3 is C02R7 where R7 is C1.6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, -C02C1-6alkyl; and Yi s N or CH. In an alternative aspect, the invention provides a process for the preparation of a compound of Formula (IA): (IA) wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C,.6alkoxy, Ci-6alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHS02R6, where each R6 is independently hydrogen or d.4alkyl; R2 is hydrogen or Chalky!; R3 is C02R7 where R7 is hydrogen or Chalky!; R4 and R5 are independently hydrogen, d.6alkyl, -C02d.6alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof, comprising reduction of a compound of Formula (II): wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C^alkoxy, d- 6alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHS02R6, where each R6 is independently hydrogen or CV4alkyl; R2 is hydrogen or C,:6alkyl; R3 is C02R7 where R7 is C,.6alkyl; R4 and R5 are independently hydrogen, d-ealkyl, -C02Ci.6alkyl; and Y is N or CH, or a pharmaceutical^ acceptable salt thereof, and optionally the step of hydrolysis gJL the resulting ester group R7 in Formula (IA) to produce a compound of Formula (IA) wherein R7 is H. In another aspect, the present invention provides a compound of Formula (II), wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, d-ealkoxy, Chalky!, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHS02R6, where each R6 is independently hydrogen or C1.4alkyl; R2 is hydrogen or C1-6alkyl; R3 is C02R7 where R7 is C1-6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, -CO2C1.6alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof. Detailed Description of the Invention As used herein, the terms "alkyl" and "alkoxy" mean a straight or branched alkyl group or alkoxy group respectively, containing the indicated number of carbon atoms. For example, C,. 6alkyl means a straight or branched alkyl containing at least 1 and at most 6 carbon atoms As used herein, the term "aryl" means monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl. Preferably, R1 is phenoxymethyl or phenyl optionally substituted by one, two or three substituents selected from halogen, hydroxy, C^alkoxy, d.6alkyl, hydroxymethyl and trifluoromethyl. More preferably, R1 is phenoxymethyl or phenyl substituted by a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group, which atom or group is preferably located in the meta position. Most preferably R1 is phenyl substituted by a chlorine atom located in the meta position. Preferably, R2 is hydrogen or methyl. Most preferably R2 is hydrogen. Preferably, R3 is bonded to the carbon atom meta to the bonded phenyl ring. In a compound of Formula (IA), R3 is preferably C02H. In a compound of Formula (II), R3 is preferably C02CH3. Preferably, at least one of R4 and R5 is hydrogen. Most preferably, both R4 and R5 are hydrogen. Preferably Y is CH. Particularly preferred compounds, or compounds of the processes, of the invention include those in which each variable is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable is selected from the more preferred or most preferred groups for each variable. Reagents for the transformation of a compound of Formula (II) to a compound of Formula (I) include any suitable reagent for the reduction of amide carbonyl bonds, e.g. borane-ether, borane-sulfide, borane-amine complexes and also conditions which form borane in situ (for example, sodium borohydride and iodine or sulfuric acid). Suitable solvents include hydrocarbons, e.g. toluene or ethers, e.g. tetrahydrofuran. The reaction may be conveniently carried out on a solid substrate, such as a bead or standard substrate used in solid-phase synthesis. For example, a compound of Formula (II) may be attached to the solid substrate through the group R3, i.e. -C02-solid substrate. In order to form a compound of Formula (IA) wherein R7 is hydrogen, the step of reductiojLOf-acompound,pf.Formula (II) should be followed by hydrolysis of the resulting ester group R7. A compound of Formula (II) may be prepared by reaction of a compound of Formula (III) with a compound of Formula (IV) using any suitable method for teaming an amide link, e.g. suitable coupling agents include diimides, e.g. diisopropylcarbodiimide, dtfydohexylcarbodiimide, or carbonyl diimidazole, hydroxytriazoles and equivalents, or chloroformates, whilst suitable solvents include esters, e.g. ethyl acetate, ethers, halogenated solvents, N-methylpyrroiidinone, acetonitrile or trifluorobenzene. As a further aspect of the present invention, there is provided a compound of Formula (IV), wherein R2 is hydrogen or Chalky!; R3 is C02R7 where R7 is d-ealkyl; R4 and R5 are independently hydrogen, C1-6alkyl. -CO2C1-6 alkyl; and Y is N or CH, or a pharmaceutical^ acceptable salt thereof. Compounds of Formula ("0 are commercially available or may be prepared by standard methods, for example, as described in the examples herein. Compounds of Formula (IV) may be prepared from compounds of Formula (V) using any suitable method for forming an amide link. For example, a compound of Formula (V) may be treated with a compound of Formula (VIII) using standard coupling procedures, e.g. diimide coupling agents, e.g. diisopropylcarbodiimide, dicyclohexylcarbodiimide or carrjonyl diimidazole with a suitable glycine compound, e.g. N-Boc-glycine, in a suitable solvent such as esters, e.g. ethyl acetate, ethers, or hydrocarbons. P2 is a standard protecting group for a riitrogen, for example butoxy carbonyl. Compounds of Formula (V) may be prepared by reaction of a compound of Formula 'Vh 5237), where Z is halogen or triflate, using a suitable boronic acid coupling conditions, e.g. palladium on carbon and sodium carbonate or Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium (0)), followed by reduction of the nitro group using standard methods, e.g. under hydrogen using a suitable catalyst, such as palladium on carbon, in a suitable solvent such as an alcohol, tetrahydrofuran, DME, ethyl acetate, toluene, iso-octane, cyclohexane or water or mixtures thereof, optionally at elevated temperature. Compounds of Formula^ may also be conveniently prepared using a two step one-pot reaction starting from reaction of a compound of Formula (VI) with a compound of Formula (VII) under conditions described above, i.e. in the presence of a palladium on carbon catalyst, followed by reduction of the nitro group under hydrogen, using the reagents described above. Compounds of Formula (V) may also be prepared by reaction of a compound of Formula (VII) with a compound of Formula (IX) using standard boronic acid coupling methods described above. Examples The invention is further illustrated by the following intermediates and examples. All temperatures are in degrees centigrade. Mass spectra (Ms) were obtained using electrospray (positive or negative ion) analysis. Methvl 3'-amino[1.1 '-biphenvl]-3-carboxvlate Method 1 A mixture of 3-nitrobenzeneboronic acid (20g), methyl 3-bromobenzoate (27g), sodium carbonate (14g) and 10% palladium on carbon (50% wet paste, 1g) in methanol (120ml) was heated under reflux for 2 hours. The mixture was taken off reflux, diluted with iso-propyl acetate (240ml) and cooled to room temperature. The mixture is stirred under an atmosphere of hydrogen until uptake ceases, water (80ml) is added and the suspension is filtered. The filtrate is separated and the organic phase is washed with brine. The organic solution is concentrated by distillation to a low volume, treated with cyclohexane and filtered to give the title compound as a beige solid (24.5g), Mass spec. M+H = 228 (electrospray). Method 2 A mixture of 3-aminophenylboronic acid hemisulfate (0.5g), methyl 3-bromobenzoate (0.61 g), sodium carbonate (0.57g) and 10% palladium on carbon (50% wet paste, 30mg) in methanol (5.4ml) was heated under reflux for 14 hours. The mixture was taken off reflux, diluted with ethyl acetate (20ml) and filtered through a Ceiite pad, rinsing through with ethyl acetate. The filtrate was washed with water (10ml) and saturated brine (10ml). The organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound as a dark oil, which slowly solidifies (0.58g). Methyl 3'-aminon ,V-biphenyiV3-carboxylate hydrochloride A mixture of 3-nitrobenzeneboronic acid (20g), methyl 3-bromobenzoate (27g), sodium carbonate (14g) and 10% palladium on carbon (50% wet paste, 1g) in methanol (120ml) was heated under reflux for 2 hours. The mixture was taken off reflux, diluted with iso-propyl acetate (240ml) and cooled to room temperature. The mixture is stirred under an atmosphere of hydrogen until uptake ceases, water (80ml) is added and the suspension is filtered. The filtrate is separated and the organic phase is washed with brine. The organic solution is concentrated by distillation and treated with anhydrous hydrochloric acid (prepared from acetyl chloride (19ml) and isopropanol (82ml)) to give the title compound as a white solid (29.5g). Methvl 3'T(aminoacetvi)amino][1.1 '-biphenylj-3-carboxylate hydrochloride Method 1 A mixture ot methyl S'-aminoll.V-biphenyll-S-carboxylate (A.Og), N-tert-butoxycarbonylglycine (3.24g) and dicyclocarbodiimide (3.81g) in ethyl acetate (48ml) was stirred at room temperature for 1 hour, cooled to 5°C and filtered. The solid was washed with ethyl acetate (8ml) and the combined organic layers were washed with aqueous sodium bicarbonate and then water. The organic solution is treated with concentrated hydrochloric acid (3.5ml), stirred overnight and the mixture is filtered to give the title compound as a white solid (4.4g). 'H NMR (400MHz, DMSO) 5 ppm : 3.84(s broad); 3.90(s); 7.45(ddd); 7.49(dd); 7.66(dd); 7.68(ddd); 7.93(ddd); 7.98(ddd); 8.00(dd); 8.17(dd); 8.32(broad peak); 10.97(s). Method 2 A mixture of 3-nitrobenzeneboronic acid (20g), methyl 3-bromobenzoate (27g), sodium carbonate (14g) and 10% palladium on carbon (50% wet paste, 1g) in methanol (120ml) was heated under reflux for 2 hours. The mixture was taken off reflux, and diluted with iso-propyl acetate (240ml) and cooled to room temperature. The mixture is stirred under an atmosphere of hydrogen until uptake ceases, water (80ml) is added and the suspension is filtered. The filtrate is separated and the organic phase is washed with brine. The organic solution is concentrated by distillation to a low volume, cooled to room temperature and then treated sequentially with N-tert-butoxycarbonylglycine (21 g) and 1,3-diisopropylcarbodiimide (19ml) at less than 30°C. The mixture is stirred for 1 hour, filtered and the solid is washed with further iso-propyl acetate. The combined filtrates are washed with 2M aqueous sodium carbonate and then water. The organic solution is treated with concentrated hydrochloric acid (35ml), stirred overnight and the mixture is filtered to give the title compound as a white solid (33g). Methvl 3'-f ({f(2$)-2-(3-chlorophenvl)-2-hvdroxvethanovl]amino)acety|)amino1[1.1 '-biphenvll-3-carboxvlate A suspension of methyl 3'-[(aminoacetyl)amino][1,1'-biphenyl]-3-carboxylate hydrochloride (50g) in ethyl acetate (350ml) is treated with 1M aqueous sodium carbonate (250ml) at room temperature. The lower aqueous phase is discarded, 1 -hydroxybenzotriazole hydrate (10g) and then dicyclohexylcarbodiimide (30.6g) is added to the organic phase and the mixture is cooled to approximately 10°C. This mixture is treated with a solution of (R)-3-chioromandelic acid (5.8g) in ethyl acetate (40ml) over approximately 1 hour. The mixture is stirred for several hours and filtered. The filtrate is washed with 6%w/w aqueous sodium bicarbonate and water, and the organic phase is concentrated to low volume. Isopropanol is added and the organic solution is further concentrated to low volume. The organic solution is warmed to 70°C, treated with water, cooled to room temperature and the mixture is filtered to give the title product (60g). Mass spec. M+H = 453/455 (electrospray). Methyl 3'-r(2-{{(2R)-2-(3-chlorophenyl)-2-hydroxvethyllamino\ethvUaminol[1.1 '-biphenvH-3-carboxvlate hydrochloride Method 1 A solution of methyl 3'-[({[(2S)-2-(3-chlorophenyl)-2-hydroxyethanoyl]amino} acetyl)amino][1,r-biphenyl]-3-carboxylate (10g) in tetrahydrofuran (40ml) is heated to 40-60°C and treated with a solution of 1M borane-tetrahydrofuran complex in tetrahydrofuran (51ml) over 15-60 minutes. The mixture is heated at this temperature for approximately 2 hours, then treated with further of 1M borane-tetrahydrofuran complex in tetrahydrofuran (6.7ml). After approximated hours further, 1M borane-tetrahydrofuran complex in tetrahydrofuran (4.4ml) is added. The reaction is stirred overnight at this temperature, and then methanol (13ml) is added. A solution of anhydrous hydrogen chloride (prepared from acetyl chloride (4.7ml) and methanol (50ml) is added to the mixture, and the resulting suspension is concentrated to low volume, diluted with ethyl acetate, cooled to 0-5°C and filtered to give the title mmnound as a white solid (8.2g). Method 2 A suspension of methyl 3'-[({[(2S)-2-(3-chlorophenyl)-2-hydroxyethanoyl] amino} acetyl)amino][1,1'-biphenyl]-3-carboxylate (10g) in toluene (44ml) is heated to 100°C and treated with a solution of borane-dimethylsulfide complex (4.9ml) over 60-120 minutes. The mixture is heated for a further 1-4h, cooled and treated with ethanol (44ml). Concentrated hydrochloric acid (5.6ml) is added, the suspension is stirred for 2-20 hours and filtered to give the title compound as a white solid (6.6g). Mass spec. M+H = 425/427 (electrospray). 3'-[(2-{[(2R>-2-(3-chlorophenyl)-2-hvdroxvethyl]amino}ethvhamino1f 1.1 '-biphenyll-3-carboxylic acid hydrochloride A suspension of methyl 3'-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino][1,1'- biphenyl]-3-carboxylate hydrochloride (10g) and methanol (67ml) at 40-50°C is treated with 1.5N aqueous sodium hydroxide (60ml) and held at this temperature for at least 1 hour. This solution is added to a solution of concentrated hydrochloric acid (10ml) in water (20ml) and methanol (33ml) at 50°C. The resulting suspension is cooled to room temperature and filtered to give the title compound (8g). Mass spec. M+H = 411/413 (electrospray). 1H NMR (400MHz, DMSO) 5 ppm: 3.06(dd); 3.17(f); 3.25(dd); 3.52(t); 5.07(d); 6.10(broad peak); 6.36(broad peak); 6.70(dd); 6.89 (d); 6.92(s); 7.23(dd); 7.38(m, broad); 7.47(s); 7.57(dd); 7.86(d); 7.92(d); 8.14(s); 9.03(broad peak); 9.41(1 broad peak); 13.04(broad peak). WE CLAIM: 1. A process for the preparation of a compound of Formula (IA): wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl,-NR6R6, and-NHS02R6, where each R6 is independently hydrogen or C1-4 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is CO2R7 where R7 is hydrogen or C1-6 alkyl; R4 and R5 are independently hydrogen, C1-6 alkyl,-CO2C1-6 alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof, comprising reduction of a compound of Formula (II); using a suitable reagent selected from the list consisting of borane-ether, borane-sulfide, borane- amine complexes or conditions which form borane in situ: wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6 alkoxy, C1-6 alkyl, hydroxymethyl, trifiuorornethyl,-NR6R6, and-NHS02R6, where each R6 is independently hydrogen or C1 -4 alkyl; R2 is hydrogen or C1-6alkyl; R3 is CO2R7 where R7 is C1-6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, or-CO2C1-6 alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof, and optionally the step of hydrolysis of the resulting ester group R7 in Formula (IA), to produce a compound of Formula (IA) wherein R7 is H. 2. The process as claimed in claim 1, wherein R1 represents phenyoxymethyl or phenyl optionally substituted by one, two or three substituents selected from halogen, hydroxy, C1-6 alkoxy, C1-6alkyl, hydroxymethyl and trifluoromethyl. 3. The process as claimed in claim 2 wherein R1 represents phenoxymethyl or phenyl substituted by a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group. 4. The process as claimed in any one of claims 1-3 wherein R2 is hydrogen or methyl. 5. A process as claimed in any one of claims 1-4, wherein at least one of R4 and R5 is hydrogen. 6. The process as claimed in any one of claims 1-5 wherein said compound of Formula (IA) is selected from the group consisting of: (R)-5- [3- [ [2- [ [2- (3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino] phenyl]-3-pyridinecarboxylic acid; 3-[[2R-[[2-(3-chlorophenyl)-2R-hydroxyethyl]amino]propyl]amino]-[ 1,1'-biphenyl]-2, 4-dicarboxylic acid; . (R)-3'-[[2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl]amino-[ 1,1 '-biphenyl]-3-carboxylic acid; (R)-3'-[[2-[(2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino-[l,l'-biphenyl]-2-methyl-5-carboxylic acid; (R)-3'-[[2-[(2-(3-chlo^ophenyl)-2-hydroxyethyl]amino]ethyl]amino-[l,l'-biphenyl]-3- carboxylic acid; and pharmaceutically acceptable salts thereof. 7. A compound of Formula (II) or a pharmaceutically acceptable salt thereof utilized in the process as claimed in claim 1: wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl,-NR6R6, and-NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl; R2 is hydrogen or C1-5alkyl; R3 is-CO2C1-6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, or-CO2C1-6alkyl; and Y is N or CH. 8. A process for the preparation of a compound of Formula (II) utilized in the process of claim 1 comprising reaction of a compound of Formula (III) with a compound of Formula (IV) to form an amide linkage, e.g. coupling agents include diimides. 9. A compound of Formula (IV) or a pharmaceutical acceptable salt thereof utilized in the process of claim 8: wherein: R2 is hydrogen or C1-6alkyl; R3 is-CO2C1-6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, or -CO2C1-6alkyl; and Y is N or CH. Dated this 8th day of May,2002. (DEEPAK KUMAR) OF REMFRY & SAGAR ATTORNEYS FOR THE APPLICANTS

Documents:

in-pct-2002-00582-mum-abstract(1-10-2007).pdf

in-pct-2002-00582-mum-abstract(18-01-2007).doc

in-pct-2002-00582-mum-cancelled pages(18-01-2007).pdf

in-pct-2002-00582-mum-claims(granted)-(18-01-2007).doc

in-pct-2002-00582-mum-claims(granted)-(18-01-2007).pdf

in-pct-2002-00582-mum-correspondence(18-10-2007).pdf

in-pct-2002-00582-mum-correspondence(ipo)-(08-10-2007).pdf

in-pct-2002-00582-mum-form 1a(01-10-2007).pdf

in-pct-2002-00582-mum-form 2(granted)-(18-01-2007).doc

in-pct-2002-00582-mum-form 2(granted)-(18-01-2007).pdf

in-pct-2002-00582-mum-form 3(01-10-2007).pdf

in-pct-2002-00582-mum-form 3(08-05-2002).pdf

in-pct-2002-00582-mum-form 5(08-05-2002).pdf

in-pct-2002-00582-mum-form-pct-ipea-409(08-05-2002).pdf

in-pct-2002-00582-mum-form-pct-isa-210(08-05-2002).pdf

in-pct-2002-00582-mum-petition under rule 137(01-10-2007).pdf

in-pct-2002-00582-mum-petition under rule 138(01-10-2007).pdf

in-pct-2002-00582-mum-power of authority(01-10-2007).pdf