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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Merimepodib; VX-497 selective IMPDH inhibitor and immunosuppressive agent


 

 

Merimepodib; VX-497; VX497; VX 497; MMP, VI21497; VI-21497; VI 21497.

198821-22-6

(S)-tetrahydrofuran-3-yl 3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate

N-[3-[3-[3-Methoxy-4-(5-oxazolyl)phenyl]ureido]benzyl]carbamic acid tetrahydrofuran-3(S)-yl ester

S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5-yl)phenyl)ureido)benzylcarbamate 

[(3S)-oxolan-3-yl] N-[[3-[[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]carbamoylamino]phenyl]methyl]carbamate

C23H24N4O6

Molecular Weight: 452.46

 Vertex Pharmaceuticals  innovator

selective IMPDH inhibitor and immunosuppressive agent

Merimepodib, an orally administered small molecule inhibitor of the enzyme inosine 5′-monophosphate dehydrogenase (IMPDH), has completed a phase II clinical trial at Vertex in combination with pegylated interferon and ribavirin for the treatment of hepatitis C viral (HCV).  

 Merimepodib, also known as VX-497,  is orally bioavailable IMPDH inhibitor, which inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. In vivo, oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.

IMPDH inhibition leads to a reduction in intracellular guanosine triphosphate (GTP), a cellular molecule required by viruses for replication. Reports indicate that IMPDH inhibitors may enhance the antiviral activity of ribavirin in vitro by depleting GTP and increasing the rate of incorporation of ribavirin into viral RNA, rendering the virus nonfunctional.

EP 0902782; US 5807876; US 6054472; WO 9740028

The oxidation of 3-methoxy-4-methylnitrobenzene (I) with CrO3, H2SO4 and AC2O in acetic acid gives the gem-diacetate (II), which is hydrolyzed with HCl in refluxing dioxane to yield 2-methoxy-4-nitrobenzaldehyde (III). Cyclization of (III) with tosylmethyl isocyanide and K2CO3 in refluxing methanol affords 3-methoxy-4-(5-oxazolyl)nitrobenzene (IV), which is reduced with H2 over Pd/C in ethyl acetate to provide the corresponding aniline (V). The activation of (V) with carbonyldiimidazole (CDI) in THF gives the carboxamide (VI), which is condensed with 3-(tert-butoxycarbonylaminomethyl)aniline (VII), obtained by reaction of 3-aminobenzylamine with Boc2O, and DMAP in refluxing THF to yield the urea (IX). Deprotection of (IX) with TFA in dichloromethane affords the free benzylamine (X), which is finally condensed with the 3-furyl ester of the succinimidyl-activated carbonate (XI) by means of TEA in dichloromethane/DMF.

…………………

http://www.google.com/patents/EP0902782A1?cl=en

Example 13

Figure imgf000072_0001

(168)

A suspension of 113 (from Example 5) (250mg, 5.76mmol) in CH2CI2 (lrtiL) was treated in a dropwise fashion at ambient temperature with several equivalents of trifluoroacetic acid and stirred for 90mm. The resulting solution was stripped m vacuo and tritrated with CH2CI2 and methanol. Pure product 168 was isolated by filtration in a yield of 258mg (99%) . The -H NMR was consistent with that of the desired product,

Figure imgf000072_0002

(120)

A suspension of 168 (250mg, 0.55mmol) in 21mL of CH2CI2/DMF (20:1 by volume) was treated with tπethyl amme (193μL, 1.38mmol) and stirred at ambient temperature until homogeneity was reached. The solution was cooled to 0 C, treated with (S) 3- tetrahydrofuranyl-N-oxysuccιnιmιdyl carbonate (635mg, 0.608mmol) and allowed to stir overnight with warming to ambient temperature. The mixture was poured into ethyl acetate (500mL), washed with NaHC0 (aq) ( 2x) , water (2x) , and brme(lx), dried over Na2S04 and stripped m vacuo . Pure product 120 was isolated by tπtration (30mL CH2C12, lOO L ether) in a yield of

212mg (85%) . The *H NMR was consistent with that of the desired product.

 

Org Process Res Dev 2002,6(5),677

http://pubs.acs.org/doi/full/10.1021/op025546f

The desired intermediate 5-(2-methoxy-4-nitrophenyl)oxazole (IV) has been obtained as follows. The carbonylation of 2-methoxy-4-nitrophenyldiazonium tetrafluoroborate (I) by means of carbon monoxide catalyzed by Pd(OAc)2 and Tes-H in ethyl ether/acetonitrile gives 2-methoxy-4-nitrobenzaldehyde (II), which is cyclized with tosylmethyl isocyanate (III) by means of K2CO3 in refluxing methanol to afford the target intermediate 5-(2-methoxy-4-nitrophenyl)oxazole (IV) (see scheme no. 24362801a, intermediate (IV)).

Figure

 

 

…………

WO 2006122072

http://www.google.com/patents/WO2006122072A2?cl=en

Scheme 2:

Figure imgf000053_0001

-*0-C

2a

Figure imgf000053_0002
Figure imgf000054_0001

2d 2e

Figure imgf000054_0002

2f 2g

Figure imgf000054_0003

2e 2h

 Scheme 2A:

Figure imgf000055_0001

 

Figure imgf000055_0002

2d                                                                                                                                                        2e

 

Figure imgf000055_0003

2f                                                                                                                                                           2g

 

Figure imgf000055_0004

2e                                                                                                                                     2h

 

 Scheme 2A:

Figure imgf000055_0001
Figure imgf000055_0002

2d 2e

Figure imgf000055_0003

2f 2g

Figure imgf000055_0004

2e                                                                                                                                         2h

 Experimental Procedures :

Figure imgf000057_0001

2a toluene/H2O, 5O0C

Figure imgf000057_0002

 (S)-tetrahydrofuran-3-yl 3-nitrobenzylcarbamate (2c)

Added 13.84 g Na2CO3 to a 500 ml three neck round bottom flask equipped with a mechanical stirrer, addition funnel, and thermocouple. Then added 86 ml water and stirred until full dissolution at room temperature. 20 g 3-nitrobenzylamine HCl 2b was then added, followed by 154 ml toluene. The mixture was heated to 500C wherein a clear biphasic solution results. Added a 20% w/w solution of (S) -tetrahydrofuran-3-yl chloroformate, 2a (16 g) in toluene (80 ml) dropwise over 45 minutes wherein very little exotherm was noted. The reaction mixture was stirred for an additional 1 hour before the layers were separated at 500C. The mixture was concentrated to ~85 ml, cooled to 00C and stirred for 1 hour at 00C. Precipitated product was collected by filtration and dried for 18 hours at 53°C to give 26.64 g (94.4% yield, 99.90% a/a) of (S)- tetrahydrofuran-3-yl 3-nitrobenzylcarbamate (2c) as a white crystalline solid with consistent 1H NMR (500 MHz, dβ-DMSO) : 8.10 (m, 2H) ; 7.90 (m, IH) ; 7.70 (d, IH) ; 7.62 (t, IH) ; 5.10 (br, IH) ; 4.30 (d, 2H) ; 3.72 (m, 4H) ; 2.10 (m, IH) ; 1.87 (m,

IH) ppm.

£3- [ ( (S) -tetrahydro-furan-S-yloscycarbonylamino) – methyl] -phenyl}-carbamic acid phenyl ester (2e)

Figure imgf000058_0001

2c                                                                                                     2d

Figure imgf000058_0002

                                              2e

 Charged 15 g of (S) -tetrahydrofuran-3-yl 3- nitrobenzylcarbamate 2c in 120 ml EtOAc to a IL Parr bomb at room temperature under a blanket of N2. The agitator was started and the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped before adding 0.225 g of 5% Pd/C. The agitator was started, the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped. The vessel was pressurized with H2 to 2 bar, then the pressure was released. This procedure was repeated 3 times, then the vessel was pressurized with H2 to 6.75 bar. The agitator was started and the suspension stirred until complete conversion was evident by HPLC. The H2 pressure was released, the vessel re-pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times then, the agitator was stopped, the reaction mixture filtered through celite and the filter cake rinsed with 30 ml EtOAc to give crude (S) -tetrahydrofuran-3-yl 3-aminobenzylcarbamate 2d as a solution in EtOAc that was used as is immediately in the next step.

Dissolved 17.6 g of Na2SO4 in 105 ml water at 200C in a separate container. Charged the EtOAc solution of aniline 2d and the aqueous solution of Na2SO4 into a 250 ml glass jacketed vessel purged with N2. The agitator was started to blend the phases and the mixture heated to 500C. Phenyl chloroformate (7.72 ml) was added dropwise to the solution over 1 hour while maintaining the temperature at 500C. The reaction was monitored by HPLC for consumption of 2d and phenyl chloroformate. Once the reaction was complete the agitator was stopped, the phases separated and the agitator restarted. Added 60 ml water at 500C, stirred the contents for 30 minutes at 500C, then stopped the agitator, separated the layers and restarted the agitator.

The reaction mixture was concentrated to 4 volumes, treated with isopropyl acetate (150 ml) , concentrated to 4 volumes, treated with isopropyl acetate (150 ml) , concentrated to 4 volumes, then cooled to 15-200C and stirred for 30 minutes. The slurry was filtered, then dried under house vacuum at 45°C until a constant weight to give 17.72 g (88% yield, 99.86% a/a) of {3- [ ( (S) -tetrahydro-furan-3- yloxycarbonylamino) -methyl] -phenyl} -carbamic acid phenyl ester 2e as a colorless crystalline solid with consistent 1H NMR (500 MHz, de-DMSO) : 10.20 (br, IH); 7.85 (br, IH); 7.40 (m, 4H); 7.25 (t, 2H); 7.20 (d, IH); 6.95 (m, IH); 6.75 (m, IH); 5.15 (m, IH); 4.15 (d, 2H); 3.75 (m, 2H); 3.70 (m, 2H); 2.10(m, IH) ; 1.90 (m, IH) ppm.

 {3- [ ( (S) -tβtrahydro-furan-3-yloxycarbonylamino) – methyl] -phenyl}-carbamic acid phenyl ester (2e)

Figure imgf000060_0001

2c

Figure imgf000060_0002

2e

A mixture of 2c (50 g, 1.00 equivalent), 5% Pd/C (0.75 g, 50% water, 0.75 wt %) and isopropyl acetate (400 ml, 8 volumes) was added to a hydrogenation vessel under nitrogen and heated to 60 0C. The vessel was pressurized with hydrogen (1.00 bar overpressure) and the mixture stirred at 60 0C. The reaction was complete within 3 hours. The pressure was released and the vessel purged with nitrogen. The mixture was filtered through a pad of Celite® and then the hydrogenation vessel and pad were rinsed with isopropyl acetate (100 ml, 2 volumes) . The solution of 2d in isopropyl acetate was then combined with a solution of sodium sulfate (29.3 g, 1.10 equivalents) in water (150 ml, 3 vol) and then the mixture was heated to 70 0C. Phenyl chloroformate (25.7 ml, 1.10 equivalents) was then added to the mixture while maintaining a temp, of 70 0C. The reaction was stirred for 30 min after the end of addition and then the stirring was stopped. The phases were allowed to separate and the aqueous phase was removed. Water (150 ml, 3 vol) was then added and the mixture stirred for an additional 30 min before the stirring was stopped. The phases were allowed to separate and the aqueous phase removed. The mixture was then distilled at atmospheric pressure to azeotropically remove water from the organic phase. Compound 2β precipitated from solution when all of the water was removed. Distillation continued until there were 4 volumes of solvent remaining. The mixture was cooled to 20 0C over 5 hours then filtered to isolate the solid. The reactor and filter cake were washed with isopropyl acetate (2 vol) then the cake was dried under vacuum at 50 0C to afford 61. Ig (91%) of 2e. [0112] 3-metho2£y-4-(oxazol-5-yl)benzenainine (2g)

Figure imgf000061_0001

2f 2g

Added 10 g of 5- (2-methoxy-4-nitrophenyl) oxazole 2f to a 500 ml 3-neck flask then added 1.0 g of Nuchar SA.20 charcoal. Next added 200 ml of isopropyl acetate, heated the reaction vessel to 400C under nitrogen, stirred for 2 hours at 400C then heated to 800C and hot filtered to remove the charcoal. The filtrate was concentrated to 1/2 volume on a rotary evaporator before adding the solution to a 500 ml Parr bomb containing 600 mg of 5% Pd/C (50% wet) . The suspension was purged with nitrogen for 20 minutes, then the system was sealed the agitator started. The mixture was heated to 400C while continuing the flow of nitrogen, then the bomb was pressurized to 40 psi with hydrogen. The pressure was released, then the vessel re-pressurized with Hydrogen to 40 psi and the process repeated 3 more times. Finally, 40 psi of hydrogen was maintained until intermediate pressure chromatography showed a complete conversion to 3-methoxy-4- (oxazol-5-yl)benzenamine 2g.

Nitrogen was passed through the reaction, the mixture was cooled to room temperature, filtered through CeIite, rinsed with 20 ml of isopropyl acetate, then the filtrate volume reduced to 1/3 volume on a rotary evaporator under reduced pressure at 47°C. The mixture was cooled to room temperature, charged with 100 ml n-Heptane, the filtrate volume reduced to 1/3 on a rotary evaporator under reduced pressure at 47°C and this process was repeated one more time. The mixture was cooled to room temperature, filtered and dried at 45°C in a house vacuum oven to give 7.91 g of 3-methoxy-4- (oxazol-5- yl)benzenamine 2g (91% yield, 99.7% a/a) as a yellow solid with consistent 1H NMR (500 MHz, d6-DMSO) : 8.20 (s, IH); -7.32

(d, IH); 7.15 (s, IH); 6.31 (s, IH); 6.25 (d, IH); 5.50 (s, 2H) ; 3.80 (s, 3H) ppm.

[0114] 3-methoxy-4- (oxazol-5-yl) benzenamine (2g)

Figure imgf000062_0001

[0115] Compound 2f (50 g, 1.0 eq. , Nippon Soda) and 1% Pt, 2% V on C (2.78 g, 64% wet, 2.0 wt % on a dry basis, Degussa Type CF1082) were charged to a hydrogenation vessel under nitrogen. Ethyl acetate (500 ml, 10 vol) was added and the mixture was heated to 60 0C. The vessel was pressurized with hydrogen (1.00 bar overpressure) and the mixture was stirred at 60 0C. The reaction was complete within 3 hours. The pressure was released and nitrogen was bubbled through the reaction mixture. The reaction mixture was filtered through Celite® and washed with EtOAc (100 ml, 2 vol) . The solvent level was reduced to 4 vol by distillation at reduced pressure and toluene (500 ml, 10 vol) was charged into the vessel. The solvent level was reduced to 4 vol by distillation at reduced pressure and a second portion of toluene (500 ml, 10 vol) was charged into the vessel. The solvent level was reduced to 5 vol under reduced pressure then the mixture was heated to 90 0C at atmospheric pressure to dissolve any solids. The solution was then cooled slowly to 20 0C to induce crystallization. The resulting yellow solid was filtered and washed with toluene (100 ml, 2 vol) to give compound 2g which was dried in a vacuum oven at 50 0C with a nitrogen bleed until a constant weight of 39.4 g (91%) was achieved.

[0116] (S)-tβtrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oκazol- 5-yl)phenyl)ureido)benzylcarbamatβ (2h)

Figure imgf000063_0001

 Added 15 g of {3- [ ( (S) -tetrahydro-furan-3- yloxycarbonylamino) -methyl] -phenyl} -carbamic acid phenyl ester 2e and 8.58 g of 3-methoxy-4- (oxazol-5-yl)benzenamine 2g into a 500 ml 3-necked flask and then purged the system with nitrogen before adding 225 ml of ethyl acetate. Next added 5.43 g of diisopropylethylamine over 1 minute, then heated at reflux for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stired for an additional 1 hour. Precipitated solid was filtered, washed with 45 ml of EtOAc 2 times, then dried at 58°C for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude (S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5- yl) phenyl) ureido)benzylcarbamate 2h (90.4% yield, 98.46% a/a) as a white crystalline solid.

Crude 2h was recrystallized in a 500 ml 3-neck flask by the following procedure. 15 g of 2h was dissolved in 84 ml of NMP and stirred for 10 minutes at 200C. The mixture was heated to 48°C, then MeOH (67.5 ml) was added dropwise over 20 minutes using a syringe pump and the mixture seeded with 0.15 g of crude 2h. The mixture was stirred at 480C for 10 minutes, during which time a thin slurry results. Additional MeOH (88.5 ml) was added dropwise using a syringe pump over 90 minutes at 48°C. After completed addition, the reactor was cooled to 00C over 5 hours and further stirred at 00C for 1 hour. The suspension was filtered, washed 2 times with MeOH (150 ml each) wherein each wash was stirred for 1 hour at ambient temperature and then pressed dry using nitrogen. The solid was dried at 500C in a house vacuum oven for 5 hours to give 11.7 g of

S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5-yl)phenyl)ureido)benzylcarbamate 2h (78% recovery, 99.93% a/a) as a white crystalline solid with consistent

 1H NMR (500 MHz, de-DMSO) : 8.90 (br, IH); 8.75 (br, IH); 8.35 (s, IH); 7.75 (t, IH); 7.60 (d, IH); 7.50 (d, IH); 7.41 (s, IH); 7.38 (m, IH); 7.33 (m, IH); 7.25 (t, IH); 7.05 (d, IH); 6.85 (d, IH); 5.15 (m, IH); 4.15 (d, 2H); 3.90 (s, 3H); 3.77 (m, 2H); 3.70 (m, 2H); 2.10 (m, IH); 1.90 (m, IH) ppm.

(S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol- 5-yl)phenyl)ureido)benzylcarbamate (2h)

Figure imgf000064_0001

Added 2e (15 g, 1.0 eq) and 2g (8.58 g, 1.07 eq) into a jacketed reactor of suitable size before adding ethyl acetate (225 ml, 15 vol) and diisopropylethylamine (5.43 g, 1.0 eq) , then heated the mixture to reflux (75-85°C) for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stired for an additional 1 hour. Precipitated solid was filtered, washed with EtOAc 2 times (45 ml, 3 vol each wash) , then dried at 580C for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude 2h

(90.4% yield, 98.46% a/a) as a white crystalline solid. Crude 2h was recrystallized in a 500 ml 3-neck flask by the following procedure. 15 g of 2h was dissolved in 84 ml of NMP and stirred for 10 minutes at 200C. The mixture was heated to 48°C, then MeOH (67.5 ml) was added dropwise over 20 minutes using a syringe pump and the mixture seeded with 0.15 g of crude 2h. The mixture was stirred at 48°C for 10 minutes, during which time a thin slurry results. Additional MeOH (88.5 ml) was added dropwise using a syringe pump over 90 minutes at 48°C. After completed addition, the reactor was cooled to 00C over 5 hours and further stirred at 00C for 1 hour. The suspension was filtered, washed 2 times with MeOH (150 ml each) wherein each wash was stirred for 1 hour at ambient temperature and then pressed dry using nitrogen. The solid was dried at 500C in a house vacuum oven for 5 hours to give 11.7 g of S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5-yl)phenyl)ureido)benzylcarbamate 2h (78% recovery, 99.93% a/a) as a white crystalline solid with consistent

1H NMR (500 MHz, d6-DMSO) : 8.90 (br, IH); 8.75 (br, IH); 8.35 (s, IH); 7.75 (t, IH); 7.60 (d, IH); 7.50 (d, IH); 7.41 (s, IH); 7.38 (m, IH); 7.33 (m, IH); 7.25 (t, IH); 7.05 (d, IH); 6.85 (d, IH); 5.15 (m, IH); 4.15 (d, 2H); 3.90 (s, 3H); 3.77 (m, 2H); 3.70 (m, 2H); 2.10 (m, IH); 1.90 (m, IH) ppm.

References

1 McHutchison JG, Shiffman ML, Cheung RC, Gordon SC, Wright TL, Pottage JC Jr, McNair L, Ette E, Moseley S, Alam J. A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C. Antivir Ther. 2005;10(5):635-43. PubMed PMID: 16152757.

2: Decker CJ, Heiser AD, Chaturvedi PR, Faust TJ, Ku G, Moseley S, Nimmesgern E. The novel IMPDH inhibitor VX-497 prolongs skin graft survival and improves graft versus host disease in mice. Drugs Exp Clin Res. 2001;27(3):89-95. PubMed PMID: 11447770.

3: Phase II clinical trial of VX-497 for HCV infection begins. AIDS Patient Care STDS. 1998 Dec;12(12):944. PubMed PMID: 11362074.

4: Jain J, Almquist SJ, Shlyakhter D, Harding MW. VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent. J Pharm Sci. 2001 May;90(5):625-37. PubMed PMID: 11288107.

5: Markland W, McQuaid TJ, Jain J, Kwong AD. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother. 2000 Apr;44(4):859-66. PubMed PMID: 10722482; PubMed Central PMCID: PMC89783

 

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WO1997040028A1 * Apr 21, 1997 Oct 30, 1997 Vertex Pharma Urea derivatives as inhibitors of impdh enzyme
US5807876 * Apr 23, 1996 Sep 15, 1998 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
US6054472 * Apr 2, 1997 Apr 25, 2000 Vertex Pharmaceuticals, Incorporated Inhibitors of IMPDH enzyme
US20020011378 * Jun 20, 2001 Jan 31, 2002 Bailey Jeffrey R. Acoustic receiver

 

 

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