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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Radiation therapy to treat uterine cancer linked with increased risk of bladder cancer later in life
Radiation therapy used to treat uterine cancer may increase a patient’s risk of developing bladder cancer. That is the conclusion of a recent study published in BJU International. The findings indicate the importance of monitoring patients for potential signs of bladder cancer to ensure early diagnosis and treatment.
In the United States, uterine cancer is the fourth most common cancer in women, with an estimated 49,560 women diagnosed in 2013. In addition to surgery, 38 percent ofpatients undergo pelvic radiation therapy to decrease uterine cancer recurrence. Studies have found that women treated with radiation therapy for uterine cancer, like men who received radiation therapy for prostate cancer, have an increased risk of developing bladder cancer later in life.
To investigate the issue, Guan Wu, MD, PhD, of the University of Rochester Medical Center, and his colleagues analyzed the records of 56,681 patients diagnosed with uterine cancer as their…
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ANTHONYFLOZIN………Find one if you can in this review
find here
http://medcheminternational.blogspot.in/p/flozin-series.html
1 TOFOGLIFLOZIN
2 SERGLIFLOZIN
3 DAPAGLIFLOZIN
4 IPRAGLIFLOZIN
5 EMPAGLIFLOZIN
6 LUSEOGLIFLOZIN
7 REMOGLIFLOZIN
8 ERTUGLIFLOZIN
9 SOTAGLIFLOZON
DR ANTHONY
BLOGS………
Fibroblasts could offer alternative to heart transplants
Cardiac fibroblasts
Fibroblasts, cells long thought to be boring and irrelevant, could offer an alternative to heart transplants for patients with heart disease. Researcher Dr Milena Furtado, and her team from the Australian Regenerative Medicine Institute (ARMI) at Monash University, found the heart cell fibroblast is a close relative to a cardiomyocyte, the cell responsible for a healthy beating heart.
In research published today in Circulation Research, Dr Furtado has found that cardiac fibroblasts are unique cells due to their genetic program, and will aid in the development of cell therapies for congenital heart disease and heart failure.
“Heart disease is still one of the major killers in our society and so far no effective therapeutic options are available. Our laboratory aims to understand how the various cell types present in a heart can improve the outcome of heart failure,’ Dr Furtado said.
“Fibroblasts were thought to act as…
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ALK Inhibitor CEP-28122
CAS: 1022958-60-6
Chemical Formula: C28H35ClN6O3
Molecular Weight: 539.06890
Elemental Analysis: C, 62.39; H, 6.54; Cl, 6.58; N, 15.59; O, 8.90
Various ALK inhibitors have been reported, such as indazoloisoquinolines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).
WO 2008/051547 discloses fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors. The lead drug candidate disclosed in the ‘547 application is CEP-28122, a potent ALK inhibitor with oral efficacy against SUP-M2 and Karpas-299 ALK-dependent tumors in mouse xenograft models. CEP-28122 progressed to IND- enabling studies until its development was terminated due to the unexpected occurrence of severe lung toxicity in CEP-28122-treated monke s.
CEP-28122
Example 1047: (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-moφholin-4-yl-6,7,8,9- tetrahydro-5H-benzocyclohepten-2-ylarnino)-pyrimidin-4-ylamino]- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Single Diasteromer A) 1047a) (2-Hydroxymethyl-4-methoxy-phenyl)-methanol To a stirred suspension of Lithium tetrahydroaluminate (16.6 g, 0.436 mol) in Tetrahydrofuran (300 mL, 4 mol) at 0 °C under nitrogen was added dropwise a solution of 4-Methoxy-phthalic acid dimethyl ester (24.46 g, 0.1091 mol) in Tetrahydrofuran (100 mL, 1 mol). The reaction was stirred at 0 °C for 1 h then warmed to room temperature overnight. HPLC indicated no starting material present. Reaction was recooled at 0 °C and quenched with addition of water (125 mL) carefully dropwise, 1 N NaOH (100 mL) and water (125 mL). Evolution of gas was observed upon initial quenching with water. A white solid precipitated out of solution (aluminum salts). Following complete quenching of the reaction mixture, the aluminum salts were removed by filtration. The filtrate was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 17.80 grams (97%) of (2-Hydroxvmethyl-4-methoxy- phenyl)-methanol as a colorless oil.
1047b) 1 ,2-Bis-bromomethyl-4-methoxy-benzene
Using the procedure outlined in J. Am. Chem. Soc. 1994, 116, 10593 – 10600, (2-
Hydroxymethyl-4-methoxy-phenyl)-methanol (17.80 g, 0.1058 mol) was dissolved in
Chloroform (200 mL, 2 mol) and the reaction was treated with Phosphorus tribromide (60.2 g, 0.222 mol) dropwise over 6 hours. After stirring overnight at room temperature, the mixture was cooled at 0 °C and was treated with 50 mL of water. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The product, 16.0 grams (51%), was used without further purification.
1047c) 2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloh eptene-6,8-dicarboxylic acid diethyl ester
From an adapted procedure in Helvetic Chimica Acta, 2001, 84, 2051-2063, to a stirred solution of Tetra-n-butyl ammonium iodide (12.1 g, 0.0326 mol) in 0.6 M of Sodium bicarbonate in Water (300 mL) and Methylene chloride (130 mL, 2.1 mol) was added a solution of 1 ,2-Bis-bromomethyl-4-methoxy-benzene (16.00 g, 0.05442 mol) and 3- Oxopentanedioic acid, diethyl ester (14.31 g, 0.07075 mol) in Methylene chloride (40 mL, 0.6 mol). The solution was stirred vigorously at room temperature for -20 h. Saturated ammonium chloride solution was added to the reaction mixture. The product was extracted with ethyl acetate (3 X 100 mL). The ethyl acetate extracts were washed with water and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. The oil was triturated with ether and a precipitate crashed out of solution and was removed by filtration (tetrabutyl ammonium salts). The filtrate was concentrated to an oil (20.0 grams, 100%) that was carried on to the next step without further purification. 1047d) 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one
2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6,8-dicarboxylic acid diethyl ester (18.2 g, 0.0544 mol) was dissolved in ethanol and the solution was treated with Potassium hydroxide (24.4 g, 0.435 mol) in Water (14O g, 7.6 mol). The reaction was then refluxed until HPLC showed consumption of starting material (~5 hours). The reaction was then acidified with IN HCl and the product was extracted with dichloromethane.
Organic extracts were dried over sodium sulfate, filtered and reduced. The crude mixture was filtered through a plug of silica rinsing with dichloromethane before purification. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 6.0 grams (58%) of 2-Methoxy- 5,6,8,9-tetrahydro-benzocyclohepten-7-one.
1047e) 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 2-Methoxy-l- nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (6.00 g, 0.0315 mol) was dissolved in Acetonitrile (280 mL, 5.4 mol) and was added to a mixture of Trifiuoroacetic anhydride (13.4 mL, 0.0946 mol) in Acetonitrile at 0 °C. Potassium nitrate (3.19 g, 0.0315 mol) was then added and the reaction was allowed to warm to room temperature. When HPLC showed consumption of starting material, the mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). The gradient run was 0% EA-50% EA. Combined fractions were reduced en vacuo to afford 3.62 (49%) of 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1.80 grams (25%). 1047f) 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (4.94 g, 0.0210 mol) in Methylene chloride (100 mL, 2 mol) was treated with Morpholine (18.30 g, 0.2100 mol) and then Acetic acid (12.61 g, 0.2100 mol). Two mass equivalents of powdered 4A molecular sieves were added and the mixture was heated to reflux and was allowed to stir for 4 hours. The solution was then cooled to room temp and Sodium triacetoxyborohydride (8.90 g, 0.0420 mol) was added. The reaction was then allowed to proceed until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (DCM/MeOH). Combined fractions were reduced en vacuo to afford 5.41 grams (84%) of 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-moφholine. 4-(2- Methoxy-l-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine was made in an analogous manner using the same conditions described above. 1047g) 3-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-moφholine (5.40 g, 0.0176 mol) was dissolved in Ethanol (100 mL, 2 mol) and the reaction mixture was carefully added to 10% Palladium on Carbon (0.750 g) under nitrogen in a Parr vessel. The reaction was then placed on a Parr shaker until uptake of hydrogen had ceased (~5 hours). Catalyst was filtered and the filtrate was reduced en vacuo to afford 4.10 grams (84%) of 3-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2- ylamine. 2-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-l – ylamine was made in an analogous fashion. The following intermediates were made in an analogous fashion as above utilizing the appropriate amine precursors: N*7*-(2,2-Difluoro-ethyl)-3-methoxy-6,7,8,9-tetrahydro- 5H-benzocycloheptene-2,7-diamine, 3-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9- tetrahydro-5H-benzocycloheptene-2,7-diamine, N*7*-(2,2-Difluoro-ethyl)-2-methoxy- 6,7,8,9-tetrahydro-5H-benzocycloheptene-l ,7-diamine, 2-(2-Amino-3-methoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and 3-Methoxy-7-(4-methyl- piperazin-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine.
1047h) (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro- 5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1 ]hept-5-ene-2- carboxylic acid amide (Single Diasteromer A)
3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (880.0 mg, 0.003184 mol), (l S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (952 mg, 0.00318 mol) and 4M of Hydrogen Chloride in 1 ,4-Dioxane (2 mL) were dissolved in 2-Methoxyethanol (30.0 mL, 0.380 mol) and the reaction was heated at 100 °C until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude residue was isolated and purified by Gilson prep HPLC as the first peak to elute to afford the desired product as a TFA salt. The TFA salt was taken up in dichloromethane and was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo to afford 439 mg (26%) of (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-morpholin-4-yl- 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Single Diasteromer A). LC/MS (ESI): 539.22. 1H NMR (400 MHz, DMSO, d6) δ 9.60 (m, IH), 8.12 (s, IH), 7.90 (s, IH), 7.79 (m, IH), 7.39 (s, IH), 6.98 (s, IH), 6.36 (m, IH), 6.16 (m, IH), 4.00 (m, 3H), 3.83 (s, 3H), 3.30 (m, 5H), 2.74 – 2.90 (m, 6H), 2.39 (m, 3H), 1.94 (d, IH, J = 4.80 Hz), 1.44 (m, 3H), 1.28 (m, IH), 1.04 (s, IH), 0.74 (s, IH).
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Mosse, Y. P.; Wood, A.; Maris, J. M. Clin. Cancer Res. 2009, 15, 5608– 5614Gingrich, D. et al: J. Med Chem, 55, 4580 (2012);…
An easier, safer, and more accurate treatment for pancreatic cancer
(a) A single axial slice of the pancreas from the pre-treatment CT scans is overlaid with computed contours of light fluence levels around the fiber location. This was simulated using blood content information for tissue absorption from contrast CT. (b) A volume rendering of the blood vessels around the pancreas overlaid with the light dose map in the fiber location, in the same patient. Please see supplementary material at stacks.iop.org/PMB/59/1911/mmedia. Credit: NCCC
Using CT scans with contrast enhancement, Dartmouth researchers measured treatment response to pancreatic cancer photodynamic therapy (PDT) according to a paper published in Physics in Medicine and Biology.
The research team at Dartmouth set out to reduce the imaging obstacles for PDT, a minimally invasive and nontoxic treatment for cancer. “This study implies that treatment response can be reliably predicted using contrast CT. This would represent a major breakthrough in PDT for pancreas cancer that allows…
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New treatment could ‘protect against any strain of the flu’
The new biologic (green) binding to the surface of cells (blue nuclei), protecting the cells from invasion by the influenza virus.
Scots scientists have developed a novel treatment that could protect against any strain of the flu.
It is hoped that the new development, led by researchers at the University of St Andrews, has the potential to guard against current, future and even pandemic strains of the virus.
In an international effort, the scientists involved say that the preventative treatment could be used as a ‘frontline defence’ before an effective flu vaccine is developed. Leading influenza experts say the new development is ‘very exciting and potentially of great importance in this era’.
The BBSRC and MRC-funded research was led by Professor Garry Taylor and Dr Helen Connaris in the Biomedical Sciences Research Complex at St Andrews. They said “We have developed an alternative host-targeted approach to prevent influenza by synthesising…
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New method to analyse how cancer cells die
A team from The University of Manchester – part of the Manchester Cancer Research Centre – have found a new method to more efficiently manufacture a chemical used to monitor cancer cells.
The technique could lead to clearer and better quality images on PET scans.
The number of cells within tissue is controlled through apoptosis – a process where cells shrink and their components break up, also known as programmed cell death. Cancer is often characterised by a disruption to the normal process of this cell death.
Being able to study this process accurately would allow doctors to more effectively diagnose and monitor cancer and to test and develop new treatments designed to kill cancer cells.
Ideally, cell death would be measured non-invasively to avoid surgery and current methods are focused on using radioactive tracers – molecules that are taken up in regions of tissue where cells are…
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RG 7388 is a MDM2 inhibitor with superior potency and selectivity in phase 1 trials
- RG-7388
- Hoffmann-La Roche, Inc. , INNOVATOR
- 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid
- 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid
- 4-[[(3S,4R,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-D-prolyl]amino]-3-methoxybenzoic acid
- CAS Number:1229705-06-9
- Mol. Formula:C31H29Cl2F2N3O4
- MW:616.5
- RG-7388 is an MDM2 (hdm2) inhibitor in early clinical trials at Roche for the oral treatment of solid tumors and hematologic cancer.
- INTRO
- RG7388 is a MDM2 inhibitor with superior potency and selectivity
- RG7388 is an oral, selective, small molecule MDM2 antagonist that inhibits binding of MDM2 to p53.
RG7388 is the second generation inhibitor of P53-MDM2 interaction. It is orally active, potently and selectively antagonizing the P53-MDM2 interaction with Ki at low nM. It is designed to selectively target MDM2, a key negative regulator of the p53 tumor suppressor protein. Blocking this essential interaction may lead to apoptosis via activation of p53 in tumor cells with functional p53 signaling. It is currently in clinical evaluation.
Description:
Value IC50: 30 nM (IC50 Average of three wt-p53 SJSA1 Cancer cell lines, RKO, HCT116)
. RG7388 is an Oral, Selective, small molecule antagonist that inhibits binding of MDM2 to p53 MDM2 Blocking the MDM2-p53 Interaction stabilizes p53 and activates p53-mediated cell death and inhibition of cell Growth.
RG7388 Showed all the Characteristics expected of an MDM2 inhibitor in terms of speci? c binding to the target, mechanistic outcomes Resulting from Activation of the p53 pathway, and in vivo ?. Although e cacy Mechanism of Action of the cellular is identical to that of RG7388 RG7112, it is much More potent and Selective.
Tumor suppressor p53 is a powerful growth suppressive and pro-apoptotic protein that plays a central role in protection from tumor development.A potent transcription factor, p53 is activated following cellular stress and regulates multiple downstream genes implicated in cell cycle control, apoptosis, DNA repair, and senescence.While p53 is inactivated in about 50% of human cancers by mutation or deletion, it remains wild-type in the remaining cases but its function is impaired by other mechanisms. One such mechanism is the overproduction of MDM2, the primary negative regulator of p53, which effectively disables p53 function.An E3 ligase, MDM2 binds p53 and regulates p53 protein levels through an autoregulatory feedback loop. Stabilization and activation of wild-type p53 by inhibition of MDM2 binding has been explored as a novel approach for cancer therapy.
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Restoration of p53 activity by inhibition of the p53–MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein–protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53–MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
http://pubs.acs.org/doi/suppl/10.1021/jm400487c/suppl_file/jm400487c_si_001.pdf …………..for exptal section
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US20100152190
http://www.google.com/patents/US20100152190
(Scheme 4).
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (250 mg, 535 μmol), was combined with CH2Cl2 (5 ml). DIPEA (277 mg, 374 μl, 2.14 mmol) and dipenylphospenic chloride (380 mg, 306 μl, 1.6 mmol) were added and the reaction was stirred at RT for 20 minutes. Methyl 4-amino-3-methoxybenzoate (100 mg, 552 μumol) was added and the reaction mixture was stirred at RT overnight.
The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 25% EtOAc/Hexanes) to give the desired product as a white solid (275 mg, 81% yield).
Example 448 Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid
In a 25 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (150 mg, 238 μmol, Eq: 1.00) was combined with CH2Cl2 (2 ml) to give a colorless solution. Aluminum bromide (Aldrich, 254 mg, 952 μmol, Eq: 4) and dimethyl sulfide (1.69 g, 2 mL, 27.2 mmol, Eq: 114) were added. The reaction mixture was stirred for overnight.
The reaction mixture was diluted with CH3CN (6 ml), EtOAc (10 ml) and water (10 ml), stirred and layers separated. The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with saturated NaCl (1×15 mL), dried over MgSO4 and concentrated in vacuum.
The crude material was dissolved in DMSO (4 ml) and was purified by preparative HPLC (70-100% ACETONITRILE/water). The fractions were combined, concentrated and freeze dried to give a white powder as desired product (75 mg, 51% yield). (ES+) m/z Calcd: [(M+H)+]: 616, found: 616.
Alternatively, the title compound could be prepared by the following method.
In a 500 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (3.74 g, 5.93 mmol, Eq: 1.00) was combined with THF (140 ml) and MeOH (160 ml) at 50° C. to give a colorless solution. 1 N NaOH (23.7 ml, 23.7 mmol, Eq: 4) was added. The reaction mixture was stirred at 40° C. for 18 hrs.
The reaction mixture was concentrated to remove about ½ of the solvent, filtered to removed the insoluble, acidified with 1N HCl to PH=4-5 and the resulting solid was collected by filtration and was washed with water, small amount of MeOH and diethyl ether. It was then dried in vacuum oven (60° C.) overnight. Obtained was a white solid as the desired product (2.96 g, 80.5% yield). H1NMR and LC/MASS data were the same as that in the above procedure.
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (5 g, 30 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (21 mL, 92 mmol) in methanol (200 mL) at 45° C. for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (9 g, 97%).
Example 52b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).
Example 52c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 52b (0.4 g, 0.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).
HRMS (ES+) m/z Calcd for C23H22Cl2F2N2O2+H [(M+H)+]: 467.1099, found: 467.1098.
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.5 g, 0.86 mmol) was reacted with a dioxane solution (0.5 M) of ammonia (2 mL, 1 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid amide as a white solid (0.3 g, 75%).
HRMS (ES+) m/z Calcd for C23H23Cl2F2N3O+H [(M+H)+]: 466.1259, found: 466.1259.
REFERENCES
1 Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development. By Ding, Qingjie; Zhang, Zhuming; Liu, Jin-Jun; Jiang, Nan; Zhang, Jing; Ross, Tina M.; Chu, Xin-Jie; Bartkovitz, David; Podlaski, Frank; Janson, Cheryl; et al From Journal of Medicinal Chemistry (2013), 56(14), 5979-5983.
2. Pyrrolo[1,2-c]imidazolone derivatives as inhibitors of MDM2-p53 interactions and their preparation and use for the treatment of cancer. By Chu, Xin-Jie; Ding, Qingjie; Jiang, Nan; Liu, Jin-Jun; Ross, Tina Morgan; Zhang, Zhuming From U.S. Pat. Appl. Publ. (2012), US 20120065210 A1 20120315.
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4. Preparation of substituted pyrrolidine-2-carboxamides as anticancer agents. By Bartkovitz, David Joseph; Chu, Xin-Jie; Ding, Qingjie; Jiang, Nan; Liu, Jin-Jun; Ross, Tina Morgan; Zhang, Jing; Zhang, Zhuming
From PCT Int. Appl. (2011), WO 2011098398 A1 20110818.
5. Preparation of substituted pyrrolidine-2-carboxamides as anticancer agents. By Bartkovitz, David Joseph; Chu, Xin-Jie; Ding, Qingjie; Jiang, Nan; Liu, Jin-Jun; Ross, Tina Morgan; Zhang, Jing; Zhang, Zhuming
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6 B. Higgins, et al, Antitumor Activity of the MDM2 Antagonist RG7388, Mol Cancer Ther 2013;12(11 Suppl):B55
Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development
J Med Chem 2013, 46(14): 5979
Erectile dysfunction can be reversed without medication
Men suffering from sexual dysfunction can be successful at reversing their problem, by focusing on lifestyle factors and not just relying on medication, according to new research at the University of Adelaide.
In a new paper published in the Journal of Sexual Medicine, researchers highlight the incidence of erectile dysfunction and lack of sexual desire among Australian men aged 35-80 years.
Over a five-year period, 31% of the 810 men involved in the study developed some form of erectile dysfunction.
“Sexual relations are not only an important part of people’s wellbeing. From a clinical point of view, the inability of some men to perform sexually can also be linked to a range of other health problems, many of which can be debilitating or potentially fatal,” says Professor Gary Wittert, Head of the Discipline of Medicine at the University of Adelaide and Director of the University’s Freemasons Foundation Centre for…
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How the body fights against viruses
Illustration “structure”: This is a model of the RNA-binding domain of ADAR1 (green), bound to double-stranded RNA (yellow). Transportin1, which mediates the nuclear transport of ADAR1, is depicted in gray. The structural model reveals that ADAR1 cannot enter the nucleus when bound to RNA, as RNA (yellow) and Transportin1 (gray) clash. Credit: PNAS
Scientists of the Max F. Perutz Laboratories of the University of Vienna and the Medical University of Vienna, together with colleagues of the ETH Zurich, have now shown how double stranded RNA, such as viral genetic information, is prevented from entering the nucleus of a cell. During the immune response against viral infection, the protein ADAR1 moves from the cell nucleus into the surrounding cytoplasm. There it modifies viral RNA to inhibit reproduction of the virus. But how is the human genome protected from inadvertent import of viral RNA into the nucleus? The current study of the research…
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New Drug Approvals 