AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate

 MANUFACTURING  Comments Off on Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate
Jun 072016
 

 

The aim of this study was to prepare and evaluate solid dispersion tablets containing a poorly water-soluble drug using porous calcium silicate (PCS) by a wet granulation method. Nifedipine (NIF) was used as the model poorly water-soluble drug. Solid dispersion tablets were prepared with the wet granulation method using ethanol and water by a high-speed mixer granulator. The binder and disintegrant were selected from 7 and 4 candidates, respectively. The dissolution test was conducted using the JP 16 paddle method. The oral absorption of NIF was studied in fasted rats. Xylitol and crospovidone were selected as the binder and disintegrant, respectively. The dissolution rates of NIF from solid dispersion formulations were markedly enhanced compared with NIF powder and physical mixtures. Powder X-ray diffraction (PXRD) confirmed the reduced crystallinity of NIF in the solid dispersion formulations. Fourier transform infrared (FT-IR) showed the physical interaction between NIF and PCS in the solid dispersion formulations. NIF is present in an amorphous state in granules prepared by the wet granulation method using water. The area under the plasma concentration–time curve (AUC) and peak concentration (Cmax) values of NIF after dosing rats with the solid dispersion granules were significantly greater than those after dosing with NIF powder. The solid dispersion formulations of NIF prepared with PCS using the wet granulation method exhibited accelerated dissolution rates and superior oral bioavailability. This method is very simple, and may be applicable to the development of other poorly water-soluble drugs.

The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media………. read all

Conclusion

Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate

The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media………. read all

Conclusion

Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.

Share

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide having potent anti-norovirus activity

 Uncategorized  Comments Off on 3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide having potent anti-norovirus activity
Jun 072016
 

 

STR1

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide

New and novel anti-norovirus agents

There is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure–activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide 1 (50% effective concentration (EC50)=37 µM) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-di-boromo-thiophene derivative 2j (EC50=24 µM) and 4,6-di-fluoro-benzothiazole derivative 3j (EC50=5.6 µM) as more potent inhibitors than 1. Moreover, their hybrid compound, 3,5-di-bromo-thiophen-4,6-di-fluoro-benzothiazole 4b, showed the most potent anti-norovirus activity with a EC50 value of 0.53 µM (70-fold more potent than 1). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide (4b)

STR1

According to the same procedure used for 2f, starting from 3,5-dibromothiophene-2-carboxylic acid (286 mg, 1.00 mmol) and 4,6-difluorobenzo[d]thiazol-2-amine (204 mg, 1.10 mmol), 4b (270 mg, 60%) was obtained as white powder. mp: 245–246°C. 1H-NMR (DMSO-d6) δ: 7.43 (1H, dt, J=10.2, 2.0 Hz), 7.56 (1H, s), 7.83 (1H, dd, J=8.4, 2.0 Hz). 13C-NMR (DMSO-d6) δ: 102.2 (dd, J=28.0, 23.1 Hz), 104.7 (dd, J=26.4, 3.3 Hz), 114.3, 118.4, 131.4 (d, J=7.4 Hz), 134.3 (d, J=10.7 Hz), 134.9, 135.2, 152.7 (d, J=241.2, 20.7 Hz), 158.3 (dd, J=242.2, 10.7 Hz), 159.0, 159.7. HPLC purity: >99%, ESI-MS m/z 453 [M+H]+.

Antiviral Activity and Cytotoxicity of Tetra-halogenated Hybrid Compounds

Compound R6 R7 R8 EC50 (µM)a) CC50 (µM)b)
4a Cl H H 2.1 >100
4b Br H Br 0.53 >100
4c Cl H Cl 1.1 >100
4d Cl Cl H 1.4 31

a) EC50 was evaluated by the CPE reduction assay. 280 TCID50/50 µL of MNV and a dilution series of each compound were incubated for 30 min. The mixture was exposed to RAW264.7 cells for 1 h (in duplicate). b) Cytotoxicity was evaluated by the WST-8 assay. RAW264.7 cells were treated with dilution series of each compound (in triplicate) for 72 h.

Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents

How to Kill Norovirus

Three Methods:Killing Norovirus with Good HygieneKilling Norovirus in Your HomeTreating NorovirusCommunity Q&A

Norovirus is a contagious virus that affects many people each year. You can get norovirus through interaction with an infected person, by eating contaminated food, touching contaminated surfaces, or drinking contaminated water. However, there are ways to kill norovirus before it infects you. To do this, you will have to maintain personal hygiene and keep your home contamination-free.

Method1

Killing Norovirus with Good Hygiene

  1. Image titled Kill Norovirus Step 1
    1
    Wash your hands thoroughly. If you think you may have come into contact with the virus, you must wash your hands thoroughly to avoid the spread of infection. To wash your hands to avoid contamination, use soap and hot water. Alcohol hand sanitizer is generally considered ineffective against this particular kind of virus. You should wash your hands if[1]:

    • You have come into contact with someone who has norovirus.
    • Before and after you interact with someone with norovirus.
    • If you visit a hospital, even if you don’t think you interacted with anyone with norovirus.
    • After going to the bathroom.
    • Before and after eating.
    • If you are a nurse or doctor, wash your hands before and after coming into contact with an infected patient, even if you wear gloves.
  2. Image titled Kill Norovirus Step 2
    2
    Avoid cooking for others if you are sick. If you have been infected and are sick, do not handle any food or cook for others in your family. If you do, they are almost certain to get the infection too.

    • If a family member is contaminated, do not let them cook for anyone else. Try to limit the amount of time healthy family members spend with the sick family member.
  3. Image titled Kill Norovirus Step 3
    3
    Wash your food before eating or cooking it. Wash all food items such as meats, fruits and vegetables thoroughly before consumption or for use in cooking. This is important as norovirus has the tendency to survive even at temperatures well above 140 degrees Fahrenheit (60 degrees Celsius).[2]

    • Remember to carefully wash any vegetables or fruit, before consuming them, whether you prefer them fresh or cooked.
  4. Image titled Kill Norovirus Step 4
    4
    Cook your food thoroughly before eating it. Seafood should be cooked thoroughly before eating it. Quick steaming your food will generally not kill the virus, as it can survive the steaming process. Instead, bake or boil your food at temperatures higher than 140F (60C) if you are concerned about it’s origins.[3]

    • If you suspect any kind of food of being contaminated, you should dispose of it immediately. For instance, if a contaminated family member handled the food, you should either throw the food out or isolate it and make sure that only the person who already has the virus eats it.

Method2

Killing Norovirus in Your Home

  1. Image titled Kill Norovirus Step 5
    1
    Use bleach to clean surfaces. Chlorine bleach is an effective cleaning agent that kills norovirus. Increase the concentration or buy a new bottle of chlorine bleach if the bleach you have has been open for more than a month. Bleach becomes less effective the longer it remains open. Before applying bleach to a visible surface, test it somewhere that is not easily seen to make sure that it won’t damage the surface. If the surface is damaged by bleach, you can also use phenolic solutions, such as Pine-Sol, to clean the surface. There are certain concentrations of chlorine bleach you can use for different surfaces.[4]

    • For stainless steel surfaces and items used for food consumption: Dissolve one tablespoon of bleach in a gallon of water and clean the stainless steel.
    • For non-porous surfaces like countertops, sinks, or tile floors: Dissolve one third of a cup of bleach in a gallon of water.
    • For porous surfaces, like wooden floors: Dissolve one and two thirds of a cup of bleach in a gallon of water.
  2. Image titled Kill Norovirus Step 6
    2
    Rinse surfaces with clean water after using bleach. After cleaning the surfaces, leave the solution to work for 10 to 20 minutes. After the time period elapses, rinse the surface with clean water. After these two steps, close off the area, and leave it like that for one hour.

    • Leave the windows open, if possible, as breathing in bleach can be hazardous to your health.
  3. Image titled Kill Norovirus Step 7
    3
    Clean areas exposed to feces or vomit. For areas exposed to feces or vomit contamination there are special cleaning procedures that you should try to follow. This is because the vomit or feces of a person contaminated with norovirus can easily cause you to become infected. To clean the vomit or feces:

    • Put disposable gloves on. Consider wearing a facemask that covers your mouth and nose as well.
    • Using paper towels, gently clean the vomit and feces. Be careful not to splash or drip while cleaning.
    • Use disposable cloths to clean and disinfect the entire area with chlorine bleach.
    • Use sealed plastic bags to dispose of all the waste materials.
  4. Image titled Kill Norovirus Step 8
    4
    Clean your carpets. If the feces or vomit gets on a carpeted area, there are other steps you can take to make sure that the area is clean and disinfected. To clean the carpeted area:

    • Wear disposable gloves if you can while cleaning the carpets. You should also consider wearing a facemask that covers your mouth and nose.
    • Use any absorbent material to clean all the visible feces or vomit. Place all contaminated materials in a plastic bag to prevent aerosols from forming. The bag should be sealed and put into the garbage can.
    • The carpet should then be cleaned with steam at 170 degrees Fahrenheit (76 degrees Celsius) for about five minutes, or, if you want to save time, clean the carpet for one minute with 212 degrees Fahrenheit (100 degrees Celsius) steam.
  5. Image titled Kill Norovirus Step 9
    5
    Disinfect clothing. If any of your clothing or a family member’s clothing has become contaminated, or is suspected of having been contaminated, you should take care when washing the fabric. To clean clothing and linens:

    • Remove any traces of vomit or feces by wiping it away with paper towels or a disposable absorbent material.
    • Put the contaminated clothing into the washing machine in a pre-wash cycle. After this stage is complete, wash the clothes using a regular washing cycle and detergent. The clothes should be dried separately from the uncontaminated clothes. A drying temperature exceeding 170 degrees Fahrenheit is recommended.
    • Do not wash contaminated clothing with uncontaminated cleaning.

Method3

Treating Norovirus

  1. Image titled Kill Norovirus Step 10
    1
    Recognize symptoms. If you think you may have been infected with norovirus, it is helpful to know what symptoms to look for. If you do have the virus, the following steps will help you to deal with the illness while it lasts. Symptoms include[5]:

    • Fever. Just like in any other infection, the norovirus infection will cause fever. Fever is a way in which the body fights infection. The body temperature will rise, making the virus more vulnerable to the immune system. Your body temperature will most likely rise above 100.4 degrees Fahrenheit (38 degrees Celsius) when suffering from a Norovirus infection.
    • Headaches. High body temperatures will cause blood vessels to dilate in your entire body, including your head. The high amount of blood inside your head will cause pressure to build up, and the protective membranes covering your brain will suffer inflammation and become painful.
    • Stomach cramps. Norovirus infections usually settle in the stomach. Your stomach may become inflamed, causing pain.
    • Diarrhea. Diarrhea is a common symptom of Norovirus contamination. It occurs as a defense mechanism, through which the body is trying to flush out the virus.
    • Vomiting. Vomiting is another common symptom of an infection with Norovirus. Like in the case of diarrhea, the body is trying to eliminate the virus from the system by vomiting.
  2. Image titled Kill Norovirus Step 11
    2
    Understand that while there is no treatment, there are ways to manage symptoms. Unfortunately, there is no specific drug that acts against the virus. However, you can combat the symptoms that the norovirus causes. Remember that the virus is self-limiting, which means that it generally goes away on its own.

    • The virus generally lasts for a few days to a week.
  3. Image titled Kill Norovirus Step 12
    3
    Drink lots of fluids. Consuming a lot of water and other fluids will help to keep you hydrated. This can help to keep your fever low and your headaches to a minimum. It is also important to drink water if you have been vomiting or have had diarrhea. When these too symptoms occur, it is very likely that you will become dehydrated.

    • If you get bored with water, you can drink ginger tea, which may help to manage your stomach pains while also hydrating you.
  4. Image titled Kill Norovirus Step 13
    4
    Consider taking anti-vomiting drugs. Anti-emetic (vomit-preventing) drugs such as ondansetron and domperidone can be given to provide symptomatic relief if you are vomiting frequently.[6]

    • However, keep in mind that these drugs can only be obtained with a prescription from your doctor.
  5. Image titled Kill Norovirus Step 14
    5
    Seek medical help if the infection is severe. As mentioned above, most infections subside after a few days. If the virus persists for longer than a week, you should consider seeking medical help. This is particularly important if the person who is sick is a child or elderly person, or a person with lowered immunity

 

Share

Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder

 MANUFACTURING  Comments Off on Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder
Jun 072016
 

A larger SI indicates a greater likelihood that sticking will occur.

Defining SI for Assessing Adhesion of Powder to the Punch

One cause of sticking is that when a powder is being compacted, the adhesive force between powder particles of the tablet and the punch surface exceeds the adhesive forces of powder particles within the tablet. Φp represents the frictional force acting between particles in the powder bed, and Φw represents the frictional force between the powder and the punch surface. The larger these values, the higher the friction and adhesion of the powder. We defined SI, which represents the degree of adhesion of a powder to the punch surface, as the value obtained by dividing Φw by Φp according to the following formula.

Sticking is a failure of pharmaceutical production that occurs when a powder containing a large amount of adhesive is being tableted. This is most frequently observed when long-term tableting is carried out, making it extremely difficult to predict its occurrence during the tablet formula design stage. The efficiency of the pharmaceutical production process could be improved if it were possible to predict whether a particular formulation was likely to stick during tableting. To address this issue, in the present study we prepared tablets composed of blended ibuprofen (Ibu), a highly adhesive drug, and measured the degree of adherence of powder particles to the surface of the tablet punch. We also measured the shear stress of the powder to determine the practical angle of internal friction (Φp) of the powder bed as well as the angle of wall friction (Φw) relative to the punch surface. These values were used to define a sticking index (SI), which showed a high correlation with the amount of Ibu that adhered to the punch during tableting; sticking occurred at SI >0.3. When the amount of lubricant added to the formulation was changed to yield tablets exhibiting different SI values without changing the compounding ratio, sticking did not occur at SI ≤0.3. These results suggest that determining the SI of a pharmaceutical powder before tableting allows prediction of the likelihood of sticking during tableting.

 

Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder

 

///////////sticking, shear stress, internal friction angle, wall friction angle, sticking index, ibuprofen,  Tablet Production, Shear Testing, Pharmaceutical Powder

Share

A Process Monitoring Solution that is Flexible and Scalable

 PROCESS  Comments Off on A Process Monitoring Solution that is Flexible and Scalable
Jun 072016
 

Multivariate Data Analysis Software for Pharmaceutical Production logo

A Process Monitoring Solution that is Flexible and Scalable
The Unscrambler® X Process Pulse II can be utilised in all levels of an organisation, providing solutions to a variety of challenges using real-time process…

A Process Monitoring Solution that is Flexible and Scalable

02 June 2016 by CAMO Software

The Unscrambler® X Process Pulse II can be utilised in all levels of an organisation, providing solutions to a variety of challenges using real-time process monitoring.

The device can be applied across many different industries and research fields to improve product development, manufacturing, and quality control, with powerful multivariate models.

Data analysts often face challenges with the data they want to analyse, which can be in different formats, coming from different systems, or it can be a mix of historical and live data and contain a large number of variables.

Unscrambler® X Process Pulse II handles all of these challenges, and translates the data into what is actually happening in the production process.

Download available at ………

 

http://www.pharmaceutical-technology.com/downloads/whitepapers/imaging-analysis/process-monitoring-solution/?WT.mc_id=WN_WP

 

 

/////////// Process Monitoring,  Solution,  Flexible, Scalable

Share

Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism

 PROCESS  Comments Off on Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism
Jun 062016
 


Fig. 1. Schematic Representation of a Complex Fluidized-Bed Granulator

1: Exhaust air, 2: bag filter, 3: partition tube, 4: impeller, 5: rotor disc, 6: inlet air, 7: screen, 8: spray nozzle.

 

Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism

Abstract

A new type of fluidized-bed granulator equipped with a particle-sizing mechanism was used for the preparation of fine particles that improved the solubility of a poorly water-soluble drug substance. Cefteram pivoxyl (CEF) was selected as a model drug substance, and its solution with a hydrophilic polymer, hydroxypropyl cellulose (HPC-L), was sprayed on granulation grade lactose monohydrate (Lac). Three types of treated particles were prepared under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable. By processing CEF with HPC-L using a complex fluidized-bed granulator equipped with a particle-sizing mechanism, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed CEF. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile. This technique may represent a method with which to design fine particles of approximately 100 µm in size with a narrow distribution, which can improve the solubility of a drug substance with low solubility.

Conclusion

Three types of treated particles were prepared using a complex fluidized-bed granulator equipped with a particle-sizing mechanism under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable.

By processing CEF with HPC-L using this device, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed one. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile.

The present method is applicable to the design of fine particles of approximately 100 µm in size with a narrow distribution, which improved the solubility of drug substance.

////////fine particle, particle size distribution, dissolution, complex fluidized-bed granulator

Share

Cyclopropylacetyl-(R)-carnitine

 Uncategorized  Comments Off on Cyclopropylacetyl-(R)-carnitine
Jun 062016
 
NMR Data of Cyclopropylacetyl-(R)-carnitine (4)

Position 1H-NMR (300 MHz, D2O) HOD=4.79 13C-NMR (75 MHz, D2O) DSSa)=−2.04 HMBC correlation
1 177.1 C2-Ha, Hb
2 a: 2.49 (1H, dd, J=8.0, 16.0 Hz) 40.9 C3-H, C4-Ha
b: 2.63 (1H, dd, J=5.6, 16.0 Hz)
3 5.63 (1H, m) 67.5 C2-Ha, Hb, C4-Hb
4 a: 3.60 (1H, d, J=14.0 Hz) 68.9 C2-Ha, Hb, C3-H, NMe
b: 3.86 (1H, dd, J=9.0, 14.0 Hz)
NMe3 3.18 (9H, s) 54.5 C4-Ha, Hb
1′ 175.6 C2′-Ha, Hb
2′ a: 2.27 (1H, dd, J=7.0, 16.0 Hz) 39.7 C4′-Ha, C5′-Ha
b: 2.36 (1H, dd, J=7.4, 16.0 Hz)
3′ 0.98 (1H, m) 6.7 C4′-Ha, C5′-Ha, C2′-Ha, Hb
4′ a: 0.15 (1H, m) 4.2 C2′-Ha, Hb
b: 0.52 (1H, m)
5′ a: 0.15 (1H, m) 4.4 C2′-Ha, Hb
b: 0.52 (1H, m)

a) DSS=sodium 2,2-dimethyl-2-silapentane-5-sulfonate.

To confirm the structure of 4, the identical carnitine ester was synthesized by condensation of (R)-carnitine and cyclopropylacetic acid using an acid chloride method (see Experimental). The 1H- and 13C-NMR data of the natural and synthetic samples were identical, and the absolute configuration was also determined to be R by comparing the specific rotation of the synthetic compound and that of the natural one. Thus, the isolated cyclopropane-containing new compound was confirmed to be cyclopropylacetyl-(R)-carnitine (4). Interestingly, carnitine esters, including a cyclopropylcarboxylic acid ester, were also isolated from a Boletaceae mushroom.9) We examined the toxicity of 4 in mouse by an intraperitoneal route; however, no toxicity was detected.

Cyclopropylacetyl-(R)-carnitine is specific to genuine R. subnigricans and sufficiently stable under ordinary experimental conditions. In addition, the upfield signals in the 1H-NMR spectrum corresponding to the cyclopropane core are easily recognizable in the 1H-NMR spectrum of crude mixtures of fruiting bodies; therefore, it would be a useful chemical marker for the identification of genuine R. subnigricans (Fig. 3).

Fig. 3. 1H-NMR Spectra (500 MHz, D2O, TSPa)=0.00 ppm)(A) Authentic sample of cyclopropylacetyl-(R)-carnitine (4). (B) Crude water extract of R. subnigricans collected in Kyoto. (C) Crude water extract of Russula sp. collected in Miyagi. (D) Crude water extract of Russula sp. collected in Saitama. a) TSP=3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt.

Cyclopropylacetyl-(R)-carnitine (4)

Isolation of Cyclopropylacetyl-(R)-carnitine (4) from the Russula subnigricans (Collected in Kyoto)

The fruiting bodies (500 g) of Russula subnigricans (collected in Kyoto) were cut into pieces and soaked in aqueous 0.3% AcOH (1.5 L) at 4°C overnight. The extract was filtered through filter paper under suction and then the filtrate was concentrated to about 100 mL under reduced pressure. The concentrated solution was dialyzed (relative molecular mass (Mr) 14000) against aqueous 0.3% AcOH (2.0 L×2) overnight. The dialyzate was concentrated to dryness and lyophilized to give a crude extract (27.1 g). A part (4.8 g) of the crude extract was dissolved in 1% AcOH in MeOH (48 mL), and then the soluble part was applied to an alumina column (aluminium oxide 90 standardized, Merck, 32 g), which was eluted with 1% AcOH in MeOH (300 mL). The eluate was concentrated to 5 mL, and this was diluted with aqueous 0.3% AcOH (10 mL) and chromatographed on ODS (Cosmosil 140C18 OPN, 16 g) which was eluted with H2O (300 mL) and 50% aqueous MeOH (100 mL). After removal of MeOH from the 50% MeOH fraction, the aqueous solution was washed with EtOAc (100 mL×3). The aqueous layer was concentrated in vacuo and then chromatographed on ODS by elution with 20% MeOH. The obtained fractions which contained a cyclopropane derivative were concentrated (16.2 mg) and purified by preparative TLC (ODS, 20% CH3CN) followed by HPLC (ODS ϕ6×250 mm, eluted with H2O for 10 min and then linear gradient from H2O to 20% CH3CN for 50 min at a flow rate of 1.5 mL/min with monitoring at 210 nm) to give 4 (3.4 mg, tR=20.9 min) as colorless syrup. Rf=0.31 (ODS, 1 : 4 MeOH–H2O); IR νmax (KBr): 3735, 3468, 1732, 1594, 1398, 1188, 1054 cm−1; LR-FAB-MS m/z 244 [M+H]+, 162 [M−C5H6O]+, HR-FAB-MS m/z 244.1572 [M+H]+; Calcd for C12H22NO4, 244.1549; [α]D31 −14.5 (H2O, c=0.96).

 

 

Synthesis of Cyclopropylacetyl-(R)-carnitine (4)

To a stirred cyclopropylacetic acid (0.098 mL, 1.05 mmol) was added thionyl chloride (0.080 mL, 1.10 mmol) and the mixture was stirred at room temperature (rt) for 1 h. To the crude acid chloride was directly added (R)-carnitine (86.0 mg, 0.533 mmol) and the mixture was stirred at rt for 1.5 h. After evaporation, the residue was dissolved into H2O and the aqueous layer was washed with EtOAc. The aqueous layer was applied to ODS column chromatography (H2O). The eluate was neutralized by saturated aqueous NaHCO3 solution and then concentrated to dryness. The resulting residue was extracted with MeOH and it was filtered through Celite. The filtrate and washings were concentrated in vacuo to afford cyclopropylacetyl-(R)-carnitine (4) (60.4 mg, 47% yield) as colorless foam. mp 180°C (decomp.);Rf=0.31 (ODS, 1 : 4 MeOH–H2O); IR νmax (KBr): 3735, 3433, 1734, 1592, 1392, 1179, 1034 cm−1; 1H-NMR (D2O, HOD=4.79) δ: 0.15 (2H, m, H-4′, 5′), 0.52 (2H, m, H-4′, 5′), 0.99 (1H, m, H-3′), 2.28, (1H, dd, J=7.0, 16.0 Hz, H-2′), 2.36 (1H, dd, J=7.4, 16.0 Hz, H-2′), 2.49 (1H, dd, J=8.0, 16.0 Hz, H-2), 2.63 (1H, dd, J=5.6, 16.0 Hz, H-2), 3.18 (9H, s, 4-N+Me3), 3.61 (1H, d, J=14.0 Hz, H-4), 3.86 (1H, dd, J=9.0, 14.0 Hz, H-4), 5.63 (1H, m, H-3); 13C-NMR (D2O, DSS=–2.04) δ: 4.2 (C4′, 5′), 4.4 (C4′, 5′), 6.7 (C3′), 39.7 (C2′), 40.9 (C2), 54.5 (4-N+Me3), 67.5 (C3), 68.9 (C4), 175.7 (C1′), 177.2 (C1); LR-FAB-MS m/z 244 [M+H]+, 162 [M−C5H6O]+, HR-FAB-MS m/z 244.1555 [M+H]+; Calcd for C12H22NO4, 244.1549; [α]D34 −16.6 (H2O, c=0.67).

 

Identification of Cyclopropylacetyl-(R)-carnitine, a Unique Chemical Marker of the Fatally Toxic MushroomRussula subnigricans

Abstract

A toxic mushroom, Russula subnigricans, causes fatal poisoning by mistaken ingestion. In spite of the potent bioactivity, the responsible toxin had not been identified for about 50 years since its first documentation. Recently, we isolated an unstable toxin and determined the structure. The slow elucidation was partly due to the instability of the toxin and also due to misidentification of R. subnigricans for similar mushrooms. To discriminate genuine Russula subnigricans from similar unidentified Russula species, we searched for a unique chemical marker contained in the mushroom. Cyclopropylacetyl-(R)-carnitine specific to R. subnigricans was identified as a novel compound whose1H-NMR signals appearing in the upfield region were easily recognizable among the complicated signals of the crude extract.

/////////cyclopropylacetyl-(R)-carnitine, cycloprop-2-ene carboxylic acid, russuphelin G, mushroom poisoning, Russula subnigricans,Russulaceae

Share

AM 2394

 Uncategorized  Comments Off on AM 2394
Jun 062016
 

str1

AM 2394

1-(6′-(2-hydroxy-2-methylpropoxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3′-bipyridin]-6-yl)-3-methylurea

Urea, N-​[6′-​(2-​hydroxy-​2-​methylpropoxy)​-​4-​[(5-​methyl-​3-​pyridinyl)​oxy]​[3,​3′-​bipyridin]​-​6-​yl]​-​N‘-​methyl-

CAS 1442684-77-6
Chemical Formula: C22H25N5O4
Exact Mass: 423.1907

Array Biopharma Inc., Amgen Inc. INNOVATORS

AM-2394 is a potent and selective Glucokinase agonist (GKA), which catalyzes the phosphorylation of glucose to glucose-6-phosphate. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes

Type 2 diabetes mellitus (T2DM) is a disease characterized by elevated plasma glucose in the presence of insulin resistance and inadequate insulin secretion. Glucokinase (GK), a member of the hexokinase enzyme family, catalyzes the phosphorylation of glucose to glucose-6-phosphate in the presence of ATP.

img

str1

Glucokioase i exok ase IV or D> is a glycolytic enssyiris that plays, an importaat. role irt blood sugar regulation .related to glucose utifeattoti a»d metabolism in the liver and pancreatic beta cells. Serving as a glucose sessor, gtoeokiuase controls lasma glucose, levels. Glucokinaae plays a doal rob in .reducing plasma glucose levels; glucose-mediated activation of the en¾ymc in hepatocytes facilitates hepatic giocose npiafcc aad glycogen synthesis, while that la pancreatic beta ceils ultimately induces ins lin seeretio«. Both of these effects in turn reduce plasma glucose levels.

Clinical evidence has shown that, glueokitiase variants with, decreased, and increased activities are associated with mature easel, diabetes of the y ung { O0Y2) and persistent: hyperinsul nemic hypoglycemia &( infancy (PHHI), respectively. lso, aoo n.sulin dependent diabetes rneilitos (NIDDM) patients have been reported to have inappropriately lo giueokaiase activity; Ftirtherrnare. overexpressioa of glucokiuase it* dietary or gesetie animal models of diabetes either prevents, aoKiiorafes, or reverses the progress of pathological. symptoms in the disease. For these reasons, compounds that activate gfecokiaase have been sought by the pitasaaceatjeai liidustry.

International patent application, Publication No. WO 2 7/OS3345, which was published on May 10, 200?, discloses as giocokinase act ators certain 2-an«.aopyridiiie derivatives bearing at the 3 -position a meihyieneoxy-dkrked aromatic group a d on. the ammo group a heteroaryl ring, such as dna/oly! or i A4-lmadiazoiyl

it has .now been found that pyridyl ureas are useful as glneokirtase activators. Cettain of these •compounds have been, found to have an outstanding combination of properties that especially adapts them, for oral use to control plasma glucose levels.

 

 

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States
Departments of Metabolic Disorders, Comparative Biology and Safety Sciences and Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
§ Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00140

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00140

 

Abstract Image

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure–activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

PATENT

WO 2013086397

 http://www.google.com/patents/WO2013086397A1?cl=en

 COPYING ERROR

Example. 1734 t¾^Jtiyi¾rea

Figure imgf000643_0007

Step A: In 100 mL of DMA were corafeiaed 1 ^545miSO- -ll«omp ridinr2-yl)-3-i«e hir8a- (17.5 g, 70,5 ii!-!to!). 5-o:ieS:t}yI yiidlii~3- ). (9,24 g, S4.7 ΪΗΪΪΪΟ!}, sad CO · (10.1 g, 77.6 mmo!) mid heated to 90 *C for 5 days. After that time, the reaction was om lete a d to it was added water arid DCM and stirred vigorously for 3 hr. The resulting solid was isolated via vacuum .filtratiott nd the cake was wasted mill rater and DCM. The DCM in tli aqueous rime was dried vdth a stream of aidogeji aad vigorous sbrriug. Use resulting solid was then collected via vacuum filtration aad these solids were

Stirred vig rousl in f 0% MeOH irt EtOAc arid die res dtipg solid was colleeied. via vactiiars fiirfati m.

Trie two batches wen i coiiibiaed to yield I-(5-bmmo-4 5^»ie†fey pyiidin-3-yl xy)p Tidin-2- d 3~ metbySurea (I S J g, 5 3.7 om»)i, 76% yield).

S e .8: In 2 niL ofc ioxane

Figure imgf000644_0001

yI) iyridMJ-2-yios:y)pf¾ps3i-2-oI (0,098 g, 0.33 «ΜΠΟΪ), -i5-bs¾tao-4-{5-a3fidiy I py f idia-3 – ylosy)f5yridia-2-yl)-3-raethyl«rea (0.075 g, 0.22 tn ol.. t, and.2M poiass.ua» carbonate (0.33 ml, 0.67 m oi} artd tfets was s parged wi h At .for 10 mia before PdC§4dppl)*DCM (0.01 g g, 0.022 msttol) was added and dre reae!io a was sparged for aaotber 5 ma-, ir efore a was sealed and heated to 100 oversight The react! art was then loaded directly onto s ilica gel (50% acetone to PCM w4i. }%

MH40H) to afford i – (6′-(2diydioxy-2i-H5eth:ylpropCis:y) -4-{ 5″i:t re th y Ipy r i d i rt -3- io s y ) -3 ,3 : -bipyr id i rt -6- yl)-3-aie5¾ylt)rea φ.? 42 , 0.096 m ol, 43 % yield). !1 1 HMR (400 Mife, CDCij) 3 ppm 9.06 is,. !H),

S.33 is, 1H>, 8,27 (rs 2H), 8. Π (s, I H): K. (s, IHU 82 (dd, j-S.fi, 5.9 H HI), 1.21 (S !H), 6,«8

(d, Hz, i i i ). 6. ,4 (s:. m>, 4.25 (s, 2H), 2,87 (dj =4,3 Hz„ 3H) 2,37 (s, 3H>. 1 .33 is, <SH). Mass speetram (apci) tar/, : – 423.9 (M÷H).

REFERENCES

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394
Paul J. Dransfield, Vatee Pattaropong, Sujen Lai, Zice Fu, Todd J. Kohn, Xiaohui Du, Alan Cheng, Yumei Xiong, Renee Komorowski, Lixia Jin, Marion Conn, Eric Tien, Walter E. DeWolf Jr., Ronald J. Hinklin, Thomas D. Aicher, Christopher F. Kraser, Steven A. Boyd, Walter C. Voegtli, Kevin R. Condroski, Murielle Veniant-Ellison, Julio C. Medina, Jonathan Houze, and Peter Coward
Publication Date (Web): May 23, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00140

/////////Glucokinase activator,  GKA,  AM-2394, 1442684-77-6, AM 2394, Amgen

O=C(NC)NC1=CC(OC2=CC(C)=CN=C2)=C(C3=CC=C(OCC(C)(O)C)N=C3)C=N1

Share

JNJ-54257099

 PRECLINICAL, Uncategorized  Comments Off on JNJ-54257099
Jun 062016
 

STR1

 

 

 

Abstract Image

JNJ-54257099,

1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphosphinine-7,2′-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione

MW 374.28, C14 H19 N2 O8 P

CAS 1491140-67-0

2,​4(1H,​3H)​-​Pyrimidinedione, 1-​[(2R,​2′R,​4aR,​6R,​7aR)​-​dihydro-​2-​(1-​methylethoxy)​-​2-​oxidospiro[4H-​furo[3,​2-​d]​-​1,​3,​2-​dioxaphosphorin-​7(6H)​,​2′-​oxetan]​-​6-​yl]​-

1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphos-phinine-7,2′-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione

Janssen R&D Ireland INNOVATOR

Ioannis Nicolaos Houpis, Tim Hugo Maria Jonckers, Pierre Jean-Marie Bernard Raboisson, Abdellah Tahri

 

 

 

STR1

Tim Hugo Maria Jonckers

 

Tim Jonckers was born in Antwerp in 1974. He studied Chemistry at the University of Antwerp and obtained his Ph.D. in organic chemistry in 2002. His Ph.D. work covered the synthesis of new necryptolepine derivatives which have potential antimalarial activity. Currently he works as a Senior Scientist at Tibotec, a pharmaceutical research and development company based in Mechelen, Belgium, that focuses on viral diseases mainly AIDS and hepatitis. The company was acquired by Johnson & Johnson in April 2002 and recently gained FDA approval for its HIV-protease inhibitor PREZISTA™.

Abdellah TAHRI

Principal Scientist at Janssen, Pharmaceutical Companies of Johnson and Johnson

 

 

Pierre Raboisson

Pierre Raboisson

PhD, Pharm.D
Head of Medicinal Chemistry

DATA

Chiral SFC using the methods described(Method 1, Rt= 5.12 min, >99%; Method 2, Rt = 7.95 min, >99%).

1H NMR (400 MHz, chloroform-d) δ ppm 1.45 (dd, J = 7.53, 6.27 Hz, 6 H), 2.65–2.84 (m, 2 H), 3.98 (td, J = 10.29, 4.77 Hz, 1 H), 4.27 (t,J = 9.66 Hz, 1 H), 4.43 (ddd, J = 8.91, 5.77, 5.65 Hz, 1 H), 4.49–4.61 (m, 1 H), 4.65 (td, J = 7.78, 5.77 Hz, 1 H), 4.73 (d, J = 7.78 Hz, 1 H), 4.87 (dq, J = 12.74, 6.30 Hz, 1 H), 5.55 (br. s., 1 H), 5.82 (d, J = 8.03 Hz, 1 H), 7.20 (d, J = 8.03 Hz, 1 H), 8.78 (br. s., 1 H);

31P NMR (chloroform-d) δ ppm −7.13. LC-MS: 375 (M + H)+.

 

HCV is a single stranded, positive-sense R A virus belonging to the Flaviviridae family of viruses in the hepacivirus genus. The NS5B region of the RNA polygene encodes a RNA dependent RNA polymerase (RdRp), which is essential to viral replication. Following the initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection. Chronic hepatitis can progress to liver fibrosis, leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. There are six major HCV genotypes and more than 50 subtypes, which are differently distributed geographically. HCV genotype 1 is the predominant genotype in Europe and in the US. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to current therapy.

Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use. The introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence. However, given the slow progression to the end-stage liver disease, the existing infections will continue to present a serious medical and economic burden for decades.

Therapy possibilities have extended towards the combination of a HCV protease inhibitor (e.g. Telaprevir or boceprevir) and (pegylated) interferon-alpha (IFN-a) / ribavirin. This combination therapy has significant side effects and is poorly tolerated in many patients. Major side effects include influenza-like symptoms, hematologic

abnormalities, and neuropsychiatric symptoms. Hence there is a need for more effective, convenient and better-tolerated treatments.

The NS5B RdRp is essential for replication of the single-stranded, positive sense, HCV RNA genome. This enzyme has elicited significant interest among medicinal chemists. Both nucleoside and non-nucleoside inhibitors of NS5B are known. Nucleoside inhibitors can act as a chain terminator or as a competitive inhibitor, or as both. In order to be active, nucleoside inhibitors have to be taken up by the cell and converted in vivo to a triphosphate. This conversion to the triphosphate is commonly mediated by cellular kinases, which imparts additional structural requirements on a potential nucleoside polymerase inhibitor. In addition this limits the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays capable of in situ phosphorylation.

Several attempts have been made to develop nucleosides as inhibitors of HCV RdRp, but while a handful of compounds have progressed into clinical development, none have proceeded to registration. Amongst the problems which HCV-targeted

nucleosides have encountered to date are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, sub-optimal dosage regimes and ensuing high pill burden and cost of goods.

Spirooxetane nucleosides, in particular l-(8-hydroxy-7-(hydroxy- methyl)- 1,6-dioxaspiro[3.4]octan-5-yl)pyrimidine-2,4-dione derivatives and their use as HCV inhibitors are known from WO2010/130726, and WO2012/062869, including

CAS-1375074-52-4.

There is a need for HCV inhibitors that may overcome at least one of the disadvantages of current HCV therapy such as side effects, limited efficacy, the emerging of resistance, and compliance failures, or improve the sustained viral response.

The present invention concerns HCV-inhibiting uracyl spirooxetane derivatives with useful properties regarding one or more of the following parameters: antiviral efficacy towards at least one of the following genotypes la, lb, 2a, 2b, 3,4 and 6, favorable

profile of resistance development, lack of toxicity and genotoxicity, favorable pharmacokinetics and pharmacodynamics and ease of formulation and administration.

Such an HCV-inhibiting uracyl spirooxetane derivative is a compound with formula I

including any pharmaceutically acceptable salt or solvate thereof.

PATENT

WO 2015077966

https://www.google.com/patents/WO2015077966A1?cl=en

Synthesis of compound (I)

(5) (6a)

Synthesis of compound (6a)

A solution of isopropyl alcohol (3.86 mL,0.05mol) and triethylamine (6.983 mL, 0.05mol) in dichloromethane (50 mL) was added to a stirred solution of POCI3 (5)

(5.0 mL, 0.055 lmol) in DCM (50 mL) dropwise over a period of 25 min at -5°C. After the mixture stirred for lh, the solvent was evaporated, and the residue was suspended in ether (100 mL). The triethylamine hydrochloride salt was filtered and washed with ether (20 mL). The filtrate was concentrated, and the residue was distilled to give the (6) as a colorless liquid (6.1g, 69 %yield).

Synthesis of compound (4):

CAS 1255860-33-3 is dissolved in pyridine and 1,3-dichloro-l, 1,3,3-tetraisopropyldisiloxane is added. The reaction is stirred at room temperature until complete. The solvent is removed and the product redissolved in CH2CI2 and washed with saturated NaHC03 solution. Drying on MgSC^ and removal of the solvent gives compound (2). Compound (3) is prepared by reacting compound (2) with p-methoxybenzylchloride in the presence of DBU as the base in CH3CN. Compound (4) is prepared by cleavage of the bis-silyl protecting group in compound (3) using TBAF as the fluoride source.

Synthesis of compound (7a)

To a stirred suspension of (4) (2.0 g, 5.13 mmol) in dichloromethane (50 mL) was added triethylamine (2.07 g, 20.46 mmol) at room temperature. The reaction mixture was cooled to -20°C, and then (6a) (1.2 g, 6.78mmol) was added dropwise over a period of lOmin. The mixture was stirred at this temperature for 15min and then NMI was added (0.84 g, 10.23 mmol), dropwise over a period of 15 min. The mixture was stirred at -15°C for lh and then slowly warmed to room temperature in 20 h. The solvent was evaporated, the mixture was concentrated and purified by column chromatography using petroleum ether/EtOAc (10: 1 to 5: 1 as a gradient) to give (7a) as white solid (0.8 g, 32 % yield).

Synthesis of compound (I)

To a solution of (7a) in CH3CN (30 mL) and H20 (7 mL) was add CAN portion wise below 20° C. The mixture was stirred at 15-20° C for 5h under N2. Na2S03 (370 mL) was added dropwise into the reaction mixture below 15°C, and then Na2C03 (370 mL) was added. The mixture was filtered and the filtrate was extracted with CH2C12

(100 mL*3). The organic layer was dried and concentrated to give the residue. The residue was purified by column chromatography to give the target compound (8a) as white solid. (Yield: 55%)

1H NMR (400 MHz, CHLOROFORM- ) δ ppm 1.45 (dd, J=7.53, 6.27 Hz, 6 H), 2.65 -2.84 (m, 2 H), 3.98 (td, J=10.29, 4.77 Hz, 1 H), 4.27 (t, J=9.66 Hz, 1 H), 4.43 (ddd, J=8.91, 5.77, 5.65 Hz, 1 H), 4.49 – 4.61 (m, 1 H), 4.65 (td, J=7.78, 5.77 Hz, 1 H), 4.73 (d, J=7.78 Hz, 1 H), 4.87 (dq, J=12.74, 6.30 Hz, 1 H), 5.55 (br. s., 1 H), 5.82 (d, J=8.03 Hz, 1 H), 7.20 (d, J=8.03 Hz, 1 H), 8.78 (br. s., 1 H); 31P NMR (CHLOROFORM-^) δ ppm -7.13; LC-MS: 375 (M+l)+

 

PATENT

https://www.google.co.in/patents/WO2013174962A1?cl=en

The starting material l-[(4R,5R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-l,6-dioxa- spiro[3.4]octan-5-yl]pyrimidine-2,4(lH,3H)-dione (1) can be prepared as exemplified in WO2010/130726. Compound (1) is converted into compounds of the present invention via a p-methoxybenzyl protected derivative (4) as exemplified in the following Scheme 1. cheme 1

Figure imgf000011_0001

Examples

Scheme 2

Synthesis of compound (8a)

Figure imgf000015_0001

Synthesis of compound (2)

Compound (2) can be prepared by dissolving compound (1) in pyridine and adding l,3-dichloro-l,l,3,3-tetraisopropyldisiloxane. The reaction is stirred at room temperature until complete. The solvent is removed and the product redissolved in CH2CI2and washed with saturated NaHC03 solution. Drying on MgSC^ and removal of the solvent gives compound (2).

Synthesis of compound (3)

Compound (3) is prepared by reacting compound (2) with p-methoxybenzylchloride in the presence of DBU as the base in CH3CN.

Synthesis of compound (4)

Compound (4) is prepared by cleavage of the bis-silyl protecting group in compound (3) using TBAF as the fluoride source.

Synthesis of compound (6a)

A solution of isopropyl alcohol (3.86 mL,0.05mol) and triethylamine (6.983 mL, 0.05mol) in dichloromethane (50 mL) was added to a stirred solution of POCl3 (5) (5.0 mL, 0.055 lmol) in DCM (50 mL) dropwise over a period of 25 min at -5°C. After the mixture stirred for lh, the solvent was evaporated, and the residue was suspended in ether (100 mL). The triethylamine hydrochloride salt was filtered and washed with ether (20 mL). The filtrate was concentrated, and the residue was distilled to give the (6) as a colorless liquid (6.1g, 69 %yield).

Synthesis of compound (7a)

To a stirred suspension of (4) (2.0 g, 5.13 mmol) in dichloromethane (50 mL) was added triethylamine (2.07 g, 20.46 mmol) at room temperature. The reaction mixture was cooled to -20°C, and then (6a) (1.2 g, 6.78mmol) was added dropwise over a period of lOmin. The mixture was stirred at this temperature for 15min and then NMI was added (0.84 g, 10.23 mmol), dropwise over a period of 15 min. The mixture was stirred at -15°C for lh and then slowly warmed to room temperature in 20 h. The solvent was evaporated, the mixture was concentrated and purified by column chromatography using petroleum ether/EtOAc (10:1 to 5: 1 as a gradient) to give (7a) as white solid (0.8 g, 32 % yield).

Synthesis of compound (8a)

To a solution of (7a) in CH3CN (30 mL) and H20 (7 mL) was add CAN portion wise below 20°C. The mixture was stirred at 15-20°C for 5h under N2. Na2S03 (370 mL) was added dropwise into the reaction mixture below 15°C, and then Na2C03 (370 mL) was added. The mixture was filtered and the filtrate was extracted with CH2C12

(100 mL*3). The organic layer was dried and concentrated to give the residue. The residue was purified by column chromatography to give the target compound (8a) as white solid. (Yield: 55%)

1H NMR (400 MHz, CHLOROFORM- ) δ ppm 1.45 (dd, J=7.53, 6.27 Hz, 6 H), 2.65 – 2.84 (m, 2 H), 3.98 (td, J=10.29, 4.77 Hz, 1 H), 4.27 (t, J=9.66 Hz, 1 H), 4.43 (ddd, J=8.91, 5.77, 5.65 Hz, 1 H), 4.49 – 4.61 (m, 1 H), 4.65 (td, J=7.78, 5.77 Hz, 1 H), 4.73 (d, J=7.78 Hz, 1 H), 4.87 (dq, J=12.74, 6.30 Hz, 1 H), 5.55 (br. s., 1 H), 5.82 (d, J=8.03 Hz, 1 H), 7.20 (d, J=8.03 Hz, 1 H), 8.78 (br. s., 1 H); 31P NMR (CHLOROFORM-^) δ ppm -7.13; LC-MS: 375 (M+l)+ Scheme 3

Synthesis of compound (VI)

Figure imgf000017_0001

Step 1: Synthesis of compound (9)Compound (1), CAS 1255860-33-3 ( 1200 mg, 4.33 mmol ) and l,8-bis(dimethyl- amino)naphthalene (3707 mg, 17.3 mmol) were dissolved in 24.3 mL of

trimethylphosphate. The solution was cooled to 0°C. Compound (5) (1.21 mL, 12.98 mmol) was added, and the mixture was stirred well maintaining the temperature at 0°C for 5 hours. The reaction was quenched by addition of 120 mL of tetraethyl- ammonium bromide solution (1M) and extracted with CH2CI2 (2×80 mL). Purification was done by preparative HPLC (Stationary phase: RP XBridge Prep CI 8 ΟΒϋ-10μιη, 30x150mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) , yielding two fractions. The purest fraction was dissolved in water (15 mL) and passed through a manually packed Dowex (H+) column by elution with water. The end of the elution was determined by checking UV absorbance of eluting fractions. Combined fractions were frozen at -78°C and lyophilized. Compound (9) was obtained as a white fluffy solid (303 mg, (0.86 mmol, 20%> yield), which was used immediately in the following reaction. Step 2: Preparation of compound (VI)

Compound (9) (303 mg, 0.86 mmol) was dissolved in 8 mL water and to this solution was added N . N’- D ic y c ! he y !-4- mo rph line carboxamidine (253.8 mg, 0.86 mmol) dissolved in pyridine (8.4 mi.). The mixture was kept for 5 minutes and then

evaporated to dryness, dried overnight in vacuo overnight at 37°C. The residu was dissolved in pyridine (80 mL). This solution was added dropwise to vigorously stirred DCC (892.6 mg, 4.326 mmol) in pyridine (80 mL) at reflux temperature. The solution was kept refluxing for 1.5h during which some turbidity was observed in the solution. The reaction mixture was cooled and evaporated to dryness. Diethylether (50 mL) and water (50 mL) were added to the solid residu. N’N-dicyclohexylurea was filtered off, and the aqueous fraction was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-ΙΟμιη, 30x150mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) , yielding a white solid which was dried overnight in vacuo at 38°C. (185 mg, 0.56 mmol, 65% yield). LC-MS: (M+H)+: 333.

1H NMR (400 MHz, DMSO-d6) d ppm 2.44 – 2.59 (m, 2 H) signal falls under DMSO signal, 3.51 (td, J=9.90, 5.50 Hz, 1 H), 3.95 – 4.11 (m, 2 H), 4.16 (d, J=10.34 Hz, 1 H), 4.25 – 4.40 (m, 2 H), 5.65 (d, J=8.14 Hz, 1 H), 5.93 (br. s., 1 H), 7.46 (d, J=7.92 Hz, 1 H), 2H’s not observed

Paper

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00382,

Discovery of 1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphosphinine-7,2′-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione (JNJ-54257099), a 3′-5′-Cyclic Phosphate Ester Prodrug of 2′-Deoxy-2′-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition

Janssen Infectious Diseases − Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.6b00382
Publication Date (Web): May 14, 2016
Copyright © 2016 American Chemical Society
*Phone: +32 014601168. E-mail: tjoncker@its.jnj.com.

JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2′-deoxy-2′-spirooxetane uridine nucleotide prodrugs which are known as inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype (GT) 1b replicon-containing cell line 9 is devoid of any anti-HCV activity, an observation attributable to inefficient prodrug metabolism which was found to be CYP3A4-dependent. In contrast, in vitro incubation of 9 in primary human hepatocytes as well as pharmacokinetic evaluation thereof in different preclinical species reveals the formation of substantial levels of 2′-deoxy-2′-spirooxetane uridine triphosphate (8), a potent inhibitor of the HCV NS5B polymerase. Overall, it was found that 9 displays a superior profile compared to its phosphoramidate prodrug analogues (e.g., 4) described previously. Of particular interest is the in vivo dose dependent reduction of HCV RNA observed in HCV infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days of oral administration of 9

////////////JNJ-54257099, 1491140-67-0, JNJ54257099, JNJ 54257099

O=C(C=C1)NC(N1[C@H]2[C@]3(OCC3)[C@H](O4)[C@@H](CO[P@@]4(OC(C)C)=O)O2)=O

Share

Asian International Continuous Flow Chemistry Summit/Chemtrix BV at CPhI-China 2016

 Uncategorized  Comments Off on Asian International Continuous Flow Chemistry Summit/Chemtrix BV at CPhI-China 2016
Jun 042016
 

str1

Asian International Continuous Flow Chemistry Summit at CPhI-China 2016

str1

str1

weblink…….http://www.chemtrix.com/news/65/Asian-International-Continuous-Flow-Chemistry-Summit

CPhI – China on 22nd June 2016

Asian International Continuous Flow Chemistry Summit at CPhI-China 2016

Asian International Continuous Flow Chemistry Summit

The Asian International Continuous Flow Chemistry Summit is this year held during CPhI China 2016, in Shanghai. Focussing on industrial applications, this summit provides usefull in-depth insights and perspectives for companies looking to apply continuous flow chemistry on an industrial scale. The ICFCS provides the opportunity to engage with experienced industrial flow chemistry users through interactive discussion sessions. With international speakers from DSM, Cipla, Zhejiang Technology University and more, join us to hear about;

  • Industrial case studies and drivers
  • Methods to transfer from batch to flow
  • Useful insights from experienced flow chemistry users
  • Robust, chemical resistant industrial flow reactors

The summit is held in the Shanghai Expo Center (SNIEC), on Wednesday 22nd June, from 13:30 – 16:30.

see…….weblink…….http://www.chemtrix.com/news/65/Asian-International-Continuous-Flow-Chemistry-Summit

Click here for more information. Click here for directions to the summit.

If you would like to register please send this registration form back to info@chemtrix.com.

 

ORGANISERS

Charlotte Wiles

Dr Charlotte Wiles , CHEMTRIX

UK &THE NETHERLANDS,UNIV OF HULL

 

 

SPEAKERS

Vijay Kirpalani

Mr Vijay Kirpalani

President
Flow Chemistry Society – India Chapter, INDIA

CEO,  PI PROCESS INTENSIFICATION EXPERTS INDIA

 

 

 

 

Manjinder Singh

 

 

Chemtrix BV, a pioneer in the field of continuous flow reactors, further strengthens ties with the Chinese chemical market. China is a very important market for Chemtrix and the Chinese Government actively supporting programs to make the chemical industry more sustainable and safe, means interest in flow reactors is bigger than ever.

To actively support our Chinese clients with this transition, it is important to have facilities in China where Customers can test their chemistry using continuous flow reactors. ‘Our test facility at Zhejiang University of Technology & Shanghai Advanced Research Institute, Chinese Academy of Sciences enables us to show our flow reactors to clients and more importantly, it enables us to test the Customers’ chemistry and develop a program for implementation with the Customer’, comments Imee Zhong, commercial manager at Shenzhen E-Zheng Technology Co. Ltd.(www.e-zheng.com).

E-Zheng is Chemtrix’ local representative in China and their flow chemists have tested 100’s of reactions over the past years for industrial clients. ‘Working with Chemtrix we have built up a strong local experience that we bring to each new Customer case’, states Zhong.

‘Being able to test chemistry for Customers is one thing, but as a leading flow reactor company we also take responsibility to educate students using this technology’, comments Stan Hoeijmakers, Marketing Manager at Chemtrix. ‘This secures the future of the technology as students will enter industrial companies with the knowledge needed to keep the transformation going’. To do so, Chemtrix is building strong relationships with Chinese Universities such as  Zhejiang University of Technology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Sichuan University, Xuzhou College, Beijing University and Nanjing Tech University, to name a few.

‘This combination of efforts in teaching & research at Universities and feasibility studies for industrial companies provides a strong base for further developing change in the Chinese chemical market’, concludes Hoeijmakers.

////////////Asian International,  Continuous , Flow Chemistry, Chemtrix BV, CPhI-China 2016

Share

Cs2CO3 as a source of carbonyl and ethereal oxygen in a Cu-catalysed cascade synthesis of benzofuran [3,2-c] quinolin-6[5-H]ones

 SYNTHESIS  Comments Off on Cs2CO3 as a source of carbonyl and ethereal oxygen in a Cu-catalysed cascade synthesis of benzofuran [3,2-c] quinolin-6[5-H]ones
Jun 032016
 

Org. Biomol. Chem., 2016, Advance Article
DOI: 10.1039/C6OB01029F, Communication
Wajid Ali, Anju Modi, Ahalya Behera, Prakash Ranjan Mohanta, Bhisma K. Patel
Simultaneous construction of C-C, C-O, and C-N bonds utilizing Cs2CO3 as a source of carbonyl (CO) and ethereal oxygen and a cascade synthesis of benzofuro[3,2-c]quinolin-6(5H)-one are achieved using a combination of Cu(OAc)2 and Ag2CO3.

Cs2CO3 as a source of carbonyl and ethereal oxygen in a Cu-catalysed cascade synthesis of benzofuran [3,2-c] quinolin-6[5-H]ones

Cs2CO3 as a source of carbonyl and ethereal oxygen in a Cu-catalysed cascade synthesis of benzofuran [3,2-c] quinolin-6[5-H]ones

*Corresponing authors
a
Department of Chemistry, Indian Institute of Technology Guwahati, India
E-mail: patel@iitg.ernet.in
Fax: +91-3612690762
Org. Biomol. Chem., 2016, Advance Article

DOI: 10.1039/C6OB01029F

http://pubs.rsc.org/en/Content/ArticleLanding/2016/OB/C6OB01029F?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FOB+%28RSC+-+Org.+Biomol.+Chem.+latest+articles%29#!divAbstract

 

The simultaneous construction of C–C, C–O, and C–N bonds utilizing Cs2CO3 as a source of both carbonyl (CO) and ethereal oxygen and a cascade synthesis of benzofuro[3,2-c]quinolin-6(5H)-one have been achieved using a combination of Cu(OAc)2 and Ag2CO3. A plausible mechanism has been proposed for this unprecedented transformation.

 

STR1

 

 

STR1

 

STR1

STR1

//////Cs2CO3,  carbonyl, ethereal oxygen,  Cu-catalysed , cascade synthesis,  o benzofuran [3,2-c] quinolin-6[5-H]ones

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: