Sorafenib

(4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide)

BAY 43-9006

Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

http://www.pharmaceutical-technology.com/news/newsbayers-nexavar-receives-japanese-approval-4300422?WT.mc_id=DN_News

Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

Nexavar’s approval in Japan is supported by data from the multicentre, placebo-controlled Phase III DECISION (‘stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer’) study.

The international Phase III DECISION study, which randomised a total of 417 patients, met its primary endpoint of extended progression-free survival. Safety and tolerability profile of sorafenib was generally consistent with the known profile of sorafenib.

The most common treatment-emergent adverse events in the sorafenib arm were hand-foot skin reaction, diarrhea, alopecia, weight loss, fatigue, hypertension and rash.

Nexavar was awarded orphan drug status by the MHLW for thyroid carcinoma in September 2013.

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),^[1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), and radioactive iodine resistant advanced thyroid carcinoma.

Medical uses

At the current time sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer.^[2][3][4][5]

Kidney cancer

An article in The New England Journal of Medicine, published January 2007, showed compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear cell renal cell carcinoma in whom previous therapy has failed. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01).^[6] A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.^[7] This is one of two TGA-labelled indications for sorafenib, although it is not listed on the Pharmaceutical Benefits Scheme for this indication.^[5][8]

Liver cancer

At ASCO 2007, results from the SHARP trial^[9] were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements. There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.^[10]

In a randomized, double-blind, phase II trial combining sorafenib with doxorubicin, the median time to progression was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone.^[10] A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC)concluding that the combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib.^[11] This is the only indication for which sorafenib is listed on the PBS and hence the only Government-subsidised indication for sorafenib in Australia.^[8] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.^[5]

Thyroid cancer

A phase 3 clinical trial has started recruiting (November 2009) to use sorafenib for non-responsive thyroid cancer.^[12] The results were presented at the ASCO 13th Annual Meeting and are the base for FDA approval. The Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The Phase 3 DECISION trial showed significant improvement in progression-free survival but not in overall survival. However, as is known, the side effects were very frequent, specially hand and foot skin reaction.^[13]

Adverse effects

Adverse effects by frequency
Note: Potentially serious side effects are in bold.
Very common (>10% frequency)

Common (1-10% frequency)

• Transient increase in transaminase

Uncommon (0.1-1% frequency)

Rare (0.01-0.1% frequency)

Mechanism of action

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases (VEGFR and PDGFR) and Raf kinases (more avidly C-Raf than B-Raf).^[16][17] Sorafenib also inhibits some intracellular serine/threonine kinases (e.g. C-Raf, wild-type B-Raf and mutant B-Raf).^[10] Sorafenib treatment induces autophagy,^[18] which may suppress tumor growth. However, autophagy can also cause drug resistance.^[19]

History

Renal cancer

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,^[20] and received European Commission marketing authorization in July 2006,^[21] both for use in the treatment of advanced renal cancer.

Liver cancer

The European Commission granted marketing authorization to the drug for the treatment of patients with hepatocellular carcinoma(HCC), the most common form of liver cancer, in October 2007,^[22] and FDA approval for this indication followed in November 2007.^[23]

In November 2009, the UK’s National Institute of Clinical Excellence declined to approve the drug for use within the NHS in England, Wales and Northern Ireland, stating that its effectiveness (increasing survival in primary liver cancer by 6 months) did not justify its high price, at up to £3000 per patient per month.^[24] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.^[24]

In March 2012, the Indian Patent Office granted a domestic company, Natco Pharma, a license to manufacture generic Sorafenib, bringing its price down by 97%. Bayer sells a month’s supply, 120 tablets, of Nexavar for280000 (US$4,700). Natco Pharma will sell 120 tablets for 8800 (US$150), while still paying a 6% royalty to Bayer.^[25][26] Under Indian Patents Act, 2005 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.^[27]

Thyroid Cancer

As of November 22, 2013, sorafenib has been approved by the FDA for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.^[28]

Research

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.^[29]

Brain (Recurrent Glioblastoma)

There is a phase I/II study at the Mayo Clinic^[30] of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma.

Desmoid Tumor (Aggressive Fibromatosis)

A study performed in 2011 showed that Sorafenib is active against Aggressive fibromatosis. This study is being used as justification for using Sorafenib as an initial course of treatment in some patients with Aggressive fibromatosis.^[31]

Nexavar Controversy

In January 2014, Bayer’s CEO stated that Nexavar was developed for “western patients who [could] afford it”. At the prevailing prices, a kidney cancer patient would pay $96,000 (£58,000) for a year’s course of the Bayer-made drug. However, the cost of the Indian version of the generic drug would be around $2,800 (£1,700).^[32]

Notes

Sorafenib

Systematic (IUPAC) name
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide
Clinical data
Trade names	Nexavar
AHFS/Drugs.com	monograph
MedlinePlus	a607051
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	D (AU) D (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	38–49%
Protein binding	99.5%
Metabolism	Hepatic oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)
Half-life	25–48 hours
Excretion	Faeces (77%) and urine (19%)
Identifiers
CAS number	284461-73-0
ATC code	L01XE05
PubChem	CID 216239
DrugBank	DB00398
ChemSpider	187440
UNII	9ZOQ3TZI87
KEGG	D08524
ChEBI	CHEBI:50924
ChEMBL	CHEMBL1336
Synonyms	Nexavar Sorafenib tosylate
PDB ligand ID	BAX (PDBe, RCSB PDB)
Chemical data
Formula	C21H16ClF3N4O3
Mol. mass	464.825 g/mol

 

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-Λ/²-methylpyridine-2- carboxamide is commonly known as sorafenib (I). Sorafenib is prepared as its tosylate salt. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.

Sorafenib, marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer). It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor.

 

Sorafenib and pharmaceutically acceptable salts thereof is disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patents disclose processes for the preparation of sorafenib.

WO0042012 and WO0041698 describe the process as given in scheme I which comprises reacting picolinic acid (II) with thionyl chloride in dimethyl formamide (DMF) to form acid chloride salt (III). This salt is then reacted with methylamine dissolved in tetrahydrofuran (THF) to give carboxamide (IV). This carboxamide when further reacted with 4- aminophenol in anhydrous DMF and potassium tert-butoxide 4-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline (V) is formed. Subsequent reaction of this aniline with 4-chloro-3- (trifluoromethyl) phenyl isocyanate (Vl) in methylene chloride yields sorafenib (I). The reaction is represented by Scheme I as given below.

Scheme I

 

Picolini

Sorafenib (I)

WO2006034796 also discloses a process for the preparation of sorafenib and its tosylate salt. The process comprises reacting 2-picolinic acid (II) with thionyl chloride in a solvent inert toward thionyl chloride without using dimethyl formamide to form acid chloride salt (III). This acid salt on further reaction with aqueous solution methylamine or gaseous methylamine gives compound (IV). Compound (IV) is then reacted with 4-aminophenol with addition of a carbonate salt in the presence of a base to yield compound (V).

Compound (V) can also be obtained by reacting compound (IV) with 4-aminophenol in the presence of water with addition of a phase transfer catalyst. Compound (V) when reacted with 4-chloro-3-(trifluoromethyl) phenyl isocyanate (Vl) in a non-chlorinated organic solvent, inert towards isocyanate gives sorafenib (I). Sorafenib by admixing with p- toluenesulfonic acid in a polar solvent gives sorafenib tosylate (VII). The reaction is represented by Scheme Il as given below.

Scheme Il

P

A key step in the synthesis of sorafenib is the formation of the urea bond. The processes disclosed in the prior art involve reactions of an isocyanate with an amine. These isocyanate compounds though commercially available are very expensive. Further synthesis of isocyanate is very difficult which requires careful and skillful handling of reagents.

Isocyanate is prepared by reaction of an amine with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) or trichloromethyl chloroformate (diphosgene). Isocyanate can also be prepared by using a hazardous reagent such as an azide. Also, the process for preparation of an isocyanate requires harsh reaction conditions such as strong acid, higher temperature etc. Further, this isocyanate is reacted with an amine to give urea.

Reactions of isocyanates suffer from one or more disadvantages. For example phosgene or phosgene equivalents are hazardous and dangerous to use and handle on a large scale. These reagents are also not environment friendly. Isocyanates themselves are thermally unstable compounds and undergo decomposition on storage and they are incompatible with a number of organic compounds. Thus, the use of isocyanate is not well suited for industrial scale application.

 

Sorafenib and its pharmaceutically acceptable salts and solvates are reported for the first time in WO0041698 (corresponding US 03139605) by Bayer. In the literature only one route is disclosed for the preparation of sorafenib. According to this route (Scheme-I), picolinic acid of formula III is reacted with thionyl chloride to give the 4-chloro derivative which on treatment

 

VII

Scheme-I with methanol gave the methyl ester of formula V. Compound of formula V is reacted with methylamine to get the corresponding amide of formula VL Compound of formula VI is reacted with 4-aminophenol to get the ether derivative of formula VII. Compound of formula VII is reacted with 4-chloro-3-trifluoromethylphenylisocyante to get sorafenib base of formula I. Overall yield of sorafenib in this process is 10% from commercially available 2-picolinic acid of formula II. Main drawback in this process is chromatographic purification of the intermediates involved in the process and low yield at every step.

Donald Bankston’s (Org. Proc. Res. Dev., 2002, 6, 777-781) development of an improved synthesis of the above basic route afforded sorafenib in an overall yield of 63% without involving any chromatographic purification. Process improvements like reduction of time in thionyl chloride reaction; avoid the isolation of intermediates of formulae IV and V₅ reduction of base quantity in p-aminophenol reaction, etc lead to the simplification of process and improvement in yield of final compound of formula I.

Above mentioned improvements could not reduce the number of steps in making sorafenib of formula-I. In the first step all the raw materials are charged and heated to target temperature (72°C). Such a process on commercial scale will lead to sudden evolution of gas emissions such as sulfur dioxide and hydrogen chloride. Also, in the aminophenol reaction two bases (potassium carbonate and potassium t-butoxide) were used in large excess to accomplish the required transformation.

A scalable process for the preparation of sorafenib is disclosed in WO2006034796. In this process also above mentioned chemistry is used in making sorafenib of formula I. In the first step, catalytic quantity. of DMF used in the prior art process is replaced with reagents like hydrogen bromide, thionyl bromide and sodium bromide. Yield of required product remained same without any advantages from newly introduced corrosive reagents. Process improvements like change of solvents, reagents, etc were applied in subsequent steps making the process scalable. Overall yield of sorafenib is increased to 74% from the prior art 63% yield. Purity of sorafenib is only 95% and was obtained as light brown colored solid.

Main drawbacks in this process are production of low quality sorafenib and requirement of corrosive and difficult to handle reagents such as thionyl bromide and hydrogen bromide. Also, there is no major improvement in the yield of sorafenib.

 

Sorafenib tosylate ( Brand name: Nexavar ®, BAY 43-9006 other name, Chinese name: Nexavar, sorafenib, Leisha Wa) was Approved by U.S. FDA for the treatment of advanced kidney cancer in 2005 and liver cancer in 2007 .

Sorafenib, co-Developed and co-marketed by Germany-based Bayer AG and South San Francisco-based Onyx Pharmaceuticals , is an Oral Multi-kinase inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRbeta, Kit, RET and Raf-1.

In March 2012 Indian drugmaker Natco Pharma received the first compulsory license ever from Indian Patent Office to make a generic Version of Bayer’s Nexavar despite the FACT that Nexavar is still on Patent. This Decision was based on the Bayer Drug being too expensive to most patients. The Nexavar price is expected to drop from $ 5,500 per person each month to $ 175, a 97 percent decline. The drug generated $ 934 million in global sales in 2010, according to India’s Patent Office.

Sorafenib tosylate

Chemical Name: 4-Methyl-3-((4 – (3-pyridinyl)-2-pyrimidinyl) amino)-N-(5 – (4-methyl-1H-imidazol-1-yl) -3 – (trifluoromethyl) phenyl) benzamide monomethanesulfonate, Sorafenib tosylate

CAS Number 475207-59-1 (Sorafenib tosylate ) , 284461-73-0 (Sorafenib)

References for the Preparation of Sorafenib References

1) Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl Substituted diphenyl Ureas as RAF kinase inhibitors ; U.S. Patent numberUS7235576
2) Rossetto, Pierluigi; Macdonald, Peter, Lindsay; Canavesi, Augusto; Process for preparation of sorafenib and Intermediates thereof , PCT Int. Appl., WO2009111061
3) Lögers, Michael; gehring, Reinhold; Kuhn, Oliver; Matthäus, Mike; Mohrs, Klaus; müller-gliemann, Matthias; Stiehl, jürgen; berwe, Mathias; Lenz, Jana; Heilmann, Werner; Process for the preparation of 4 – {4 – [( {[4-chloro-3-(TRIFLUOROMETHYL) phenyl] amino} carbonyl) amino] phenoxy}-N-methylpyridine-2-carboxamide , PCT Int. Appl., WO2006034796
4) Shikai Xiang, Liu Qingwei, Xieyou Rong, sorafenib preparation methods, invention patent application Publication No. CN102311384 , Application No. CN201010212039
5) Zhao multiply there, Chenlin Jie, Xu Xu, MASS MEDIA Ji Yafei; sorafenib tosylate synthesis ,Chinese Journal of Pharmaceuticals , 2007 (9): 614 -616

Preparation of Sorafenib Tosylate (Nexavar) Nexavar, sorafenib Preparation of methyl sulfonate

Sorafenib (Sorafenib) chemical name 4 – {4 – [({[4 - chloro -3 - (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl-pyridine -2 – formamide by Bayer (Bayer) research and development, in 2005 the U.S. Food and Drug Administration (FDA) approval. Trade name Nexavar (Nexavar). This product is an oral multi-kinase inhibitor, for the treatment of liver cancer and kidney cancer.

Indian Patent Office in March this year for Bayer’s Nexavar in liver and kidney cancer drugs (Nexavar) has released a landmark “compulsory licensing” (compulsory license). Indian Patent Office that due to the high price Nexavar in India, the vast majority of patients can not afford the drug locally, thus requiring local Indian pharmaceutical company Natco cheap Nexavar sales. Nexavar in 2017 before patent expiry, Natco pay only Bayer’s pharmaceutical sales to 6% royalties. The move to make Nexavar patent drug prices, the supply price from $ 5,500 per month dropped to $ 175, the price reduction of 97%. Compulsory licensing in India for other life-saving drugs and patent medicines overpriced open a road, the Indian Patent Office through this decision made it clear that the patent monopoly does not guarantee that the price is too high. Nexavar is a fight against advanced renal cell carcinoma, liver cancer cure. In China, a box of 60 capsules of Nexavar price of more than 25,000 yuan. In accordance with the recommended dose, which barely enough to eat half of patients with advanced cancer. In September this year India a patent court rejected Bayer Group in India cheap drugmaker emergency appeal. Indian government to refuse patent medicine overpriced undo “compulsory licensing rules,” allowing the production of generic drugs Nexavar.

Sorafenat by Natco – Sorafenib – Nexavar – India natco Nexavar

Chemical Synthesis of  Sorafenib Tosylate (Nexavar)

Sorafenib tosylate (brand name :Nexavar®, other name BAY 43-9006, was approved by US FDA for the treatment of kidney cancer in 2005 and advanced liver cancer in 2007.

US Patent US7235576, WO2006034796, WO2009111061 and Faming Zhuanli Shenqing(CN102311384) disclosed processes for preparation of sorafenib base and its salt sorafenib tosylate.

References

1)Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors; US patent numberUS7235576
2)Rossetto, pierluigi; Macdonald, peter, lindsay; Canavesi, augusto; Process for preparation of sorafenib and intermediates thereof, PCT Int. Appl., WO2009111061
3)Lögers, michael; gehring, reinhold; kuhn, oliver; matthäus, mike; mohrs, klaus; müller-gliemann, matthias; stiehl, jürgen; berwe, mathias; lenz, jana; heilmann, werner; Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide, PCT Int. Appl., WO2006034796CN102311384, CN201010212039

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar) 

Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro- N -methyl-2-pyridinecarboxamide (15.0 g, 87.9mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80°C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35°C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%):. 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA’BB’ quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz; 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+).

Synthesis of 4-{4-[({[4-Chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide (sorafenib)

4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals. m.p. 206-208° C. 1H-NMR (DMSO-d6, 500 MHz): δ =2.79 (d, J=4.4 Hz, 3H, NCH3); 7.16 (dd, J=2.5, 5.6 Hz, 1H, 5-H); 7.18 (d, J=8.8 Hz, 2H, 3′-H, 5′-H); 7.38 (d, J=2.4 Hz, 1H, 3-H); 7.60-7.68 (m, 4H, 2′-H, 6′-H, 5″-H, 6″-H); 8.13 (d, J=1.9 Hz, 1H, 2″-H); 8.51 (d, J=5.6 Hz, 1H, 6-H); 8.81 (d, J=4.5 Hz, 1H, NHCH3); 9.05 (br. s, 1H, NHCO); 9.25 (br. s, 1H, NHCO) MS (ESI, CH3CN/H2O): m/e=465 [M+H]+.

Synthesis of Sorafenib Tosylate (Nexavar)

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (50g, 0.1076 mol) is suspended in ethyl acetate (500 g) and water (10g). The mixture is heated to 69°C within 0.5 h, and a filtered solution of p-toluenesulfonic acid monohydrate (3.26 g, 0.017 mol) in a mixture of water (0.65 g) and ethyl acetate (7.2 g) is added. After filtration a filtered solution of p-toluenesulfonic acid monohydrate (22g, 0.11 mol) in a mixture of ethyl acetate (48 g) and water (4.34 g) is added. The mixture is cooled to 23°C within 2 h. The product is filtered off, washed twice with ethyl acetate (92.5 g each time) and dried under reduced pressure. The sorafenib tosylate (65.5 g, 96% of theory) is obtained as colorless to slightly brownish crystals.

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http://www.google.com/patents/EP2195286A2?cl=en

Example 22: Synthesis of Sorafenib

Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4- aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N₁N- dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was agitated at 40-45⁰C for 2-3 hours, cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCI (250ml) and finally with brine (250 ml). The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).

Example 23: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)urea (Compound 4)

Sodium cyanate (1.7 g, 0.02mol) was dissolved in water (17ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3- trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40°C-45°C within 1- 2 hours. The reaction mass was agitated for whole day and cooled gradually to room temperature. The obtained solid was filtered washed with water and vacuum dried at 50⁰C to afford the desired product (5.8 g) i.e. 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.

Example 24: Synthesis of Sorafenib

1-(4-chloro-3-(trifluoromethyl) phenyl)urea (15 g, 0.0628 mol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N- methylpicolinamide (15.27 g, 0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and the reaction mass was then heated to 110-120⁰C for 12-18 hours. The reaction mass was cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).

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http://www.google.com/patents/WO2009054004A2?cl=en

http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009054004A2&KC=A2&FT=D&date=20090430&DB=EPODOC&locale=en_gb

EXAMPLES

Example 1

Preparation of l-(4-chloro-3-(trifluoromethyl)phenyI)-3-(4-hydroxyphenyl)urea Into a 250 ml, four-necked RB flask was charged 1O g of 4-aminophenol and 100 ml of toluene. A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyante (20.4 g) in toluene (50 ml) was added to the reaction mass at 25-30⁰C. The reaction mass was stirred at room temperature for 16 h. The reaction mass was filtered and washed the. solid with 50 ml of toluene. The wet material was dried in the oven at 50-60°C to get 29.8 g of title compound as white solid. M.P. is 218-222°C. IR (KBr): 3306, 1673, 1625, 1590, 1560, 1517, 1482, 1435, 1404, 1328, 1261, 1182, 1160, 1146, 1125, 1095, 1032, 884, 849, 832, 812, 766, 746, 724, 683, 539 and 434 cm^“1.

Example 2 Preparation of sorafenib tosylate

Into a 100 ml, three-necked RB flask was charged 2.0 g of l-(4-chloro-3- (trifluoromethyl)-phenyl)-3-(4-hydroxyphenyl)urea and 10 ml of DMF. Potassium tert- butoxide (2.3 g) was added to the reaction mass and stirred for 45 min at RT. 4-Chlro-N- methylpicolinamide (1.14 g) and potassium carbonate (0.42 g) were added to the reaction mass and heated to 80°C. The reaction mass was maintained at 80-85°C for 8 h and cooled to 30°C. The reaction mass was poured into water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine and dried over sodium sulphate. Solvent was distilled of under reduced pressure.

The crude compound (4.7 g) was dissolved in 10 ml of IPA and added 1.9 g of p- toluenesulfonic acid. The reaction mass was stirred at RT for 15 h and filtered. The wet solid was washed with 10 ml of IPA and dried at 50-60°C to get 3.4 g of title compound as off-white crystalline solid.

 

…………………..

A Scaleable Synthesis of BAY 43-9006:  A Potent Raf Kinase Inhibitor for the Treatment of Cancer

Donald Bankston,*Jacques Dumas,Reina Natero,Bernd Riedl,Mary-Katherine Monahan, andRobert Sibley

Bayer Research Center, Pharmaceutical Division, 400 Morgan Lane, West Haven, Connecticut 06516, U.S.A.

Org. Proc. Res. Dev., 2002, 6 (6), pp 777–781

DOI: 10.1021/op020205n

http://pubs.acs.org/doi/abs/10.1021/op020205n

Urea 3 (BAY 43-9006), a potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases >50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43-9006).

A suspension of 9 (67.00 g, 275.43 mmol) in methylene chloride ———————-DELETE………………………………The solids were washed with methylene chloride (2 × 50 mL) and dried under vacuum for 4 h at 35 °C to afford 3 (118.19 g, 254.27 mmol, 92%) as an off-white solid.

Mp = 210−212 °C.

¹H NMR (DMSO-d₆, 300 MHz):

δ 2.77 (d, J = 4.8 Hz, 3H, −NHCH₃);

7.16 (m, 3H, aromatic);

7.37 (d, J = 2.5 Hz, 1H, aromatic);

7.62 (m, 4H, aromatic);

8.11 (d, J = 2.5 Hz, 1H, aromatic);

8.49 (d, J = 5.5 Hz, 1H, aromatic);

8.77 (br d, 1H, −NHCH₃);

8.99 (s, 1H, −NHCO−); 9.21 (s, 1H, −NHCO−).

Mass spectrum (HPLC/ES):  m/e = 465 (M + 1).

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃:  C, 54.26; H, 3.47; N, 12.05. Found:  C, 54.11; H, 3.49; N, 12.03.

HPLC (ELS) purity >98%:  t_R = 3.5 min.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43-9006):  Use of CDI.

A solution of 11 (1.25 g, 6.39 mmol) in methylene chloride———————-DELETED……………………. high vacuum at 35 °C for 2 h to afford 3 (2.55 g, 5.49 mmol, 91%) as a white solid. Proton NMR and mass-spectral data were consistent with structure.

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃:   C, 54.26; H, 3.47; N, 12.05; Cl, 7.63. Found:  C, 54.24; H, 3.31; N, 12.30; Cl, 7.84.

Mp (differential scanning calorimetry, 10 °C/min):  205.6 °C;

no polymorphs observed.

References

1. “FDA Approves Nexavar for Patients with Inoperable Liver Cancer” (Press release). FDA. November 19, 2007. Retrieved November 10, 2012.
2. “Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 26 December 2013.
3. “NEXAVAR (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]“. DailyMed. Bayer HealthCare Pharmaceuticals Inc. November 2013. Retrieved 26 December 2013.
4. “Nexavar 200mg film-coated tablets – Summary of Product Characteristics (SPC) – (eMC)”. electronic Medicines Compendium. Bayer plc. 27 March 2013. Retrieved 26 December 2013.
5. “PRODUCT INFORMATION NEXAVAR® (sorafenib tosylate)” (PDF). TGA eBusiness Services. Bayer Australia Ltd. 12 December 2012. Retrieved 26 December 2013.
6. Escudier, B; Eisen, T; Stadler, WM; Szczylik, C; Oudard, S; Siebels, M; Negrier, S; Chevreau, C; Solska, E; Desai, AA; Rolland, F; Demkow, T; Hutson, TE; Gore, M; Freeman, S; Schwartz, B; Shan, M; Simantov, R; Bukowski, RM (January 2007). “Sorafenib in advanced clear-cell renal-cell carcinoma”. New England Journal of Medicine 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530.
7. Walid, MS; Johnston, KW (October 2009). “Successful treatment of a brain-metastasized renal cell carcinoma”. German Medical Science 7: Doc28. doi:10.3205/000087. PMC 2775194. PMID 19911072.
8. “Pharmaceutical Benefits Scheme (PBS) -SORAFENIB”. Pharmaceutical Benefits Scheme. Australian Government Department of Health. Retrieved 27 December 2013.
9. Llovet, et al. (2008). “Sorafenib in Advanced Hepatocellular Carcinoma” (PDF). New England Journal of Medicine 359 (4): 378–90.
10. Keating GM, Santoro A (2009). “Sorafenib: a review of its use in advanced hepatocellular carcinoma”. Drugs 69 (2): 223–40. doi:10.2165/00003495-200969020-00006. PMID 19228077.
11. Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF (October 2011). “Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma”. J. Clin. Oncol. 29 (30): 3960–7. doi:10.1200/JCO.2011.37.1021. PMID 21911714.
12. “Phase 3 Trial of Nexavar in Patients With Non-Responsive Thyroid Cancer”^{[dead link]}
13. [1]
14. “Chemotherapy-Induced Nausea and Vomiting Treatment & Management”. Medscape Reference. WebMD. 3 July 2012. Retrieved 26 December 2013.
15. Hagopian, Benjamin (August 2010). “Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report”. Journal of Medical Cases 1 (1): 1–3. doi:10.4021/jmc112e. Retrieved 11 February 2014.
16. Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M (January 2009). “CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations”. Oncogene 28 (1): 85–94. doi:10.1038/onc.2008.362. PMC 2898184. PMID 18794803.
17. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (October 2008). “Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling”. Mol. Cancer Ther. 7 (10): 3129–40. doi:10.1158/1535-7163.MCT-08-0013. PMID 18852116.
18. Zhang Y (Jan 2014). “Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways.”. J Mol Med Rep 9 (1): 83–90. PMID 24213221.
19. Gauthier A (Feb 2013). “Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update..”. Hepatol Res 43 (2): 147–154. doi:10.1111/j.1872-034x.2012.01113.x. PMID 23145926.
20. FDA Approval letter for use of sorafenib in advanced renal cancer
21. European Commission – Enterprise and industry. Nexavar. Retrieved April 24, 2007.
22. “Nexavar® (Sorafenib) Approved for Hepatocellular Carcinoma in Europe” (Press release). Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. October 30, 2007. Retrieved November 10, 2012.
23. FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
24. “Liver drug ‘too expensive‘“. BBC News. November 19, 2009. Retrieved November 10, 2012.
25. http://www.ipindia.nic.in/ipoNew/compulsory_License_12032012.pdf
26. “Seven days: 9–15 March 2012″. Nature 483 (7389): 250–1. 2012. doi:10.1038/483250a.
27. “India Patents (Amendment) Act, 2005″. WIPO. Retrieved 16 January 2013.
28. [2]
29. “Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients”
30. ClinicalTrials.gov NCT00329719 Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma
31. “Activity of sorafenib against desmoid tumor/deep fibromatosis”
32. “‘We didn’t make this medicine for Indians… we made it for western patients who can afford it‘“. Daily Mail Reporter. 24 Jan 2014.

External links

• Nexavar.com – Manufacturer’s website
• Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau gene)
• Patient Information from FDA
• Sorafenib in Treating Patients With Soft Tissue Sarcomas
• Sorafenib Sunitinib differences – diagram
• ClinicalTrials.gov NCT00217399  – Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
• Cipla launches Nexavar generic at 1/10 of Bayer’s price

 

 

Reference
1	*	D. BANKSTON ET AL.: “A Scalable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer” ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 6, no. 6, 2002, pages 777-781, XP002523918 cited in the application
2	*	PAN W ET AL: “Pyrimido-oxazepine as a versatile template for the development of inhibitors of specific kinases” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 24, 15 December 2005 (2005-12-15), pages 5474-5477, XP025314229 ISSN: 0960-894X [retrieved on 2005-12-15]

 

Citing Patent	Filing date	Publication date	Applicant	Title
WO2011036647A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
WO2011036648A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
WO2011058522A1	Nov 12, 2010	May 19, 2011	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
WO2011092663A2	Jan 28, 2011	Aug 4, 2011	Ranbaxy Laboratories Limited	4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-n2-methylpyridine-2-carboxamide dimethyl sulphoxide solvate
WO2011113367A1 *	Mar 17, 2011	Sep 22, 2011	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated ω-diphenylurea
US8552197	Nov 12, 2010	Oct 8, 2013	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
US8604208	Sep 24, 2010	Dec 10, 2013	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
US8609854	Sep 24, 2010	Dec 17, 2013	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
US8618305	Jan 28, 2011	Dec 31, 2013	Ranbaxy Laboratories Limited	Sorafenib dimethyl sulphoxide solvate
US8669369	Mar 17, 2011	Mar 11, 2014	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated Ω-diphenylurea

View PDF Version

Minisci reactions: Versatile CH-functionalizations for medicinal chemists

Matthew A. J. Duncton† *
Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. E-mail: mattduncton@yahoo.com; Tel: +1 917-345-3183

First published on the web 22nd August 2011

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

The addition of a radical to a heteroaromatic base is commonly referred to as a Minsici reaction. Such reactions constitute a broad-set of selective CH-functionalization processes. This review describes some of the major applications of Minisci reactions and related processes to medicinal or biological chemistry, and highlights some potential developments within this area.

Introduction

The aim of this review is to summarize the use of Minisci reactions within medicinal chemistry, and to highlight some future opportunities to continue progression of this chemistry. As such, it is not an aim that detailed mechanistic information, or a comprehensive list of examples be described. For this, the reader is directed to excellent articles from Minisci, Harrowven and Bowman.^1–3 Rather, the review is written to show that Minisci reactions are extremely valuable CH-functionalization processes within medicinal chemistry. However, their use has been somewhat under-utilized when compared with other well-known selective transformations (e.g. palladium-catalysed cross-couplings). Therefore, it is hoped that in the future, Minisci chemistry will continue to develop, such that the reactions become a staple-set of methods for medicinal and biological chemists alike.

To aid discussion, the review is divided in to several sections. First, some historical perspective is given. This is followed by a discussion of scope and limitations. The main-body of the review describes some specific examples of Minisci reactions and related processes, with a focus on their use within medicinal, or biological chemistry. Finally, brief mention is given to potential future applications, some of which may be beneficial in providing ‘high-content’ diverse libraries for screening.

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

…………………….

WIKI

The Minisci reaction is a named reaction in organic chemistry. It is a radical substitution to an aromatic compound, in particular to a heteroaromatic base, that introduces an alkyl group. The reaction was published about in 1971 by F. Minisci.^[1] The aromatic compound is generally electron-deficient and with N-aromatic compounds the nitrogen atom is protonated.^[2] A typical reaction is that between pyridine and pivalic acid to 2-tert-butylpyridine with silver nitrate, sulfuric acid and ammonium persulfate. The reaction resembles Friedel-Crafts alkylation but with opposite reactivity and selectivity.^[3]

The Minisci reaction proceeds regioselectively and enables the introduction of a wide range of alkyl groups.^[4] A side-reaction is acylation.^[5] The ratio between alkylation and acylation depends on the substrate and the reaction conditions. Due to the simple raw materials and the simple reaction conditions the reaction has many applications in heterocyclic chemistry.^[6][7]

Mechanism

A free radical is formed from the carboxylic acid in an oxidative decarboxylation with silver salts and an oxidizing agent. The oxidizing agent reoxidizes the silver salt. The radical then reacts with the aromatic compound. The ultimate product is formed by rearomatisation. The acylated product is formed from the acyl radical.^[4][5]

References

http://seekingalpha.com/article/2283763-mast-therapeutics-mstminus-188-would-fit-well-in-mercks-drug-development-pipeline

MST-188 (purified poloxamer 188)

MST-188 is an investigational agent, formulated using a purified form of poloxamer 188. Substantial research has demonstrated that poloxamer 188 has cytoprotective and hemorrheologic properties and inhibits inflammatory processes and thrombosis. We believe the pharmacologic effects of poloxamer 188 support the development of MST-188 in multiple clinical indications for diseases and conditions characterized by microcirculatory insufficiency (endothelial dysfunction and/or impaired blood flow). We are enrolling patients in EPIC, a pivotal phase 3 study of MST-188 in sickle cell disease. In addition, our MST-188 pipeline includes development programs in adjunctive thrombolytic therapy (e.g., acute limb ischemia, stroke), heart failure, and resuscitation (i.e., restoration of circulating blood volume and pressure) following major trauma.

POTENTIAL APPLICATIONS OF MST-188

We believe the pharmacodynamic properties of MST-188 (cytoprotective, hemorheologic, anti-inflammatory, antithrombotic/pro-fibrinolytic) enable it simultaneously to address, or prevent activation of, multiple biochemical pathways that can result in microcirculatory insufficiency, a multifaceted condition principally characterized by endothelial dysfunction and impaired blood flow. The microcirculation is responsible for the delivery of blood through the smallest blood vessels (arterioles and capillaries) embedded within tissues. A healthy endothelium is critical to a functional microcirculation. Without the regular delivery of blood and transfer of oxygen to tissue from the microcirculation, individual cells (in both the endothelium and tissue) are unable to maintain aerobic metabolism and, through a series of complex and interrelated events, eventually die. If microcirculatory insufficiency continues, the patient will suffer tissue necrosis, organ damage and, eventually, death.

EPIC’s study drug, MST-188, is a new class of drug that acts by attaching to the damaged surfaces of the cell membranes, potentially improving blood flow and oxygen delivery.

Improving blood flow and oxygen delivery may reduce the duration and severity of pain crises faced by sickle cell patients.

http://www.selfsufficiencymagazine.com/how-to-treat-migraines-with-red-raspberry-leaf/

If you, or someone close to you, suffers from migraines then you’ll know just how frustrating it can be. You can try all sorts of approaches and conventional medications, but often they don’t work!

Why not try some red raspberry leaf tea? It’s packed full of essential vitamins and minerals and is widely used for helping to cure those painful headaches.

http://www.thefutureofhealthnow.com/little-weed-one-useful-medicines-planet/

There are two major types of plantain in BC, Canada: Lance and Broadleaf. Generally, all 200-plus varieties of plantain yield the same results. It grows especially well in poor, rocky soil (such as driveways) and is often seen alongside dandelion. More often than not, you will see plantain growing in gravel pits and construction sites as nature seeks to regenerate the soil. Introduced to North America in the 1600s, it was once called “White Man’s Foot” by the Native Americans who witnessed that where the Europeans tread and disrupted the soil, plantain sprung up.

Social Media in Pharma: Should you bother?

http://links.genericpharma20.mkt6146.com/servlet/MailView?ms=NjY5NjcyNQS2&r=NTEzNjM3NjI3NDgS1&j=NDYyOTA1OTY2S0&mt=2&rj=NDYyOTA1OTY1S0&rt=0

Generic Pharma 2.0
Our mailing address is: 12 Dunlop Street E.

Barrie, Ontario L4M 1A3

info@genericpharma20.com

XP 23829  from Xenoport is an interesting molecule and as on 27 July 2014, I did not find conclusive evidence

See some structures below

Not sure about the structure of XP 23829

OR

Best fit

OR

Not sure?

(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

OR

I AM NOT SURE ABOUT THIS ONE ALSO????????

As Football worldcup2014 goes on in Brazil

A thought for it is due…………

……………………………………………………

Best fit is probably is as shown below, and there are reasons

(N,N- Diethylcarbamoyl)methyl methyl (2E)but-2-ene-l,4-dioate 

Introduction

(N,​N-​Diethylcarbamoyl)​methyl methyl (2E)​-​but-​2-​ene-​1,​4-​dioate

As per patent……..http://www.google.com/patents/WO2014031844A1?cl=en

C₁₁ H₁₇ N O_{5, mw 243.13}

M.p.: 53-56 °C.

¹ H NMR (CDCI₃, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J = 1.1 Hz, 2H), 3.26 (q, J = 7.2 Hz, 2H), 1 .24 (t, J = 7.2 Hz, 3H), 1 .14 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)⁺.

Cas…….1208229-58-6

XP-23829 PROBABLE

For the treatment of moderate-to-severe chronic plaque-type psoriasis.

XP-H-093

US8148414 Basic patent

Xenoport, Inc.  Innovator

XenoPort has initiated a phase II trial of XP-23829, a proprietary investigational next-generation fumaric acid product candidate (ClinicalTrials.gov Identifier NCT02173301). The multicenter, randomized, double-blind, placebo-controlled study is designed to assess the efficacy and safety of XP-23829 as a potential treatment of patients with moderate to severe chronic plaque-type psoriasis. XenoPort expects to enroll approximately 200 subjects in this trial, which is being conducted in the U.S. The study will include a screening and washout phase of up to 4 weeks, a 12-week treatment phase and a 4-week post-treatment phase. Eligible study subjects will be randomized to placebo or one of three treatment arms of XP-23829: 400 or 800 mg once daily or 400 mg twice daily. The primary endpoint will examine the percent change in Psoriasis Area and Severity Index (PASI) score from baseline at the end of week 12. Secondary endpoints will include the proportion of subjects who achieve a reduction of 75% or greater from baseline in PASI (PASI75) score and subjects who achieve a Static Physicians Global Assessment score of “clear” or “almost clear.” Topline results are expected in the third quarter of 2015 (XenoPort News Release).

XP23829 — A Prodrug of Monomethyl Fumarate

Our third product candidate, XP23829, is in Phase 1 clinical development. Provided we are able to demonstrate the safety and desired pharmacokinetic, or PK, profile of XP23829 in our Phase 1 trials, we believe that XP23829 could be a potential treatment of patients with RRMS, psoriasis and/or certain other disorders where the mechanism of action of XP23829 may be relevant. For example, we are exploring the potential of XP23829 to protect against neurodegeneration in experimental preclinical models of Parkinson’s disease through a grant from The Michael J. Fox Foundation. We hold a composition-of-matter patent and a formulation patent in the United States on XP23829 and hold patents or pending patent applications directed to the XP23829 methods of synthesis and use in the United States. We have also filed applications directed to the XP23829 composition of matter and methods of synthesis and use in other jurisdictions.

Prodrug Background

XP23829 is a fumaric acid ester compound and a patented prodrug of MMF. Fumaric acid ester compounds have shown immuno-modulatory and neuroprotective effects in cell-based systems and preclinical models of disease. A product containing a combination of fumaric acid ester compounds, known as Fumaderm, is approved in Germany for the treatment of psoriasis. Tecfidera (a formulation of DMF, also known as BG-12) from Biogen Idec Inc. is another fumaric acid ester prodrug that converts to MMF in the body. Phase 3 clinical trials of Tecfidera as a potential treatment for RRMS showed statistically significant benefits of Tecfidera versus placebo. Tecfidera is currently under U.S. regulatory review as a potential treatment for RRMS.

Our Prodrug

XP23829 is a novel prodrug of MMF that we believe may provide improved tolerability and efficacy compared to DMF. In preclinical studies that compared molar equivalent doses of XP23829 to DMF, XP23829 provided higher blood levels of the biologically active molecule MMF and a similar or greater degree of efficacy in MS and psoriasis animal models. Toxicology studies conducted in two species showed that XP23829 caused less stomach irritation when compared to DMF.

Phase 1 Clinical Trial in Healthy Volunteers

In October 2012, we reported favorable preliminary results from our first Phase 1 clinical trial in healthy adults designed to assess the pharmacokinetics, safety and tolerability of single doses of four different formulations of XP23829. The trial was a randomized, double-blind, two-period crossover, food effect comparison clinical trial of XP23829. Sixty subjects were assigned to five cohorts of 12, with each cohort receiving one of four different formulations of XP23829 or placebo. The trial demonstrated that administration of XP23829 resulted in the expected levels of MMF in the blood. As anticipated, the four formulations produced

April 4, 2012

http://investor.xenoport.com/releasedetail.cfm?ReleaseID=708145
XenoPort Awarded U.S. Patent Directed to Composition and Formulations of XP23829, a Novel Fumarate Analog for the Potential Treatment of Relapsing-Remitting Multiple Sclerosis and Psoriasis
SANTA CLARA, Calif.–(BUSINESS WIRE)–Apr. 4, 2012– XenoPort, Inc. (Nasdaq: XNPT) announced today that it was awarded U.S. Patent 8,148,414 for “Prodrugs of Methyl Hydrogen Fumarate, Pharmaceutical Compositions Thereof, and Methods of Use.” The term of the patent extends until 2029, subject to potential Hatch-Waxman patent term extensions.

The patent is directed to the XP23829 compound, analogs thereof and formulations thereof. A related U.S. patent application directed to therapeutic uses of XP23829 is now pending.

XP23829 is a prodrug of methyl hydrogen fumarate, also known as monomethyl fumarate (MMF). In cell- and animal-based models, MMF has been shown to exhibit immuno-modulatory properties and inhibit damage from oxidative stress.

In XenoPort’s preclinical animal studies that compared molar equivalent doses of XP23829 to dimethyl fumarate (DMF), another prodrug of MMF, XP23829 demonstrated a greater degree of efficacy in animal models of both multiple sclerosis (MS) and psoriasis. Toxicology studies conducted in two species showed that XP23829 caused less stomach irritation compared to DMF.

XenoPort intends to file an Investigational New Drug Application (IND) for XP23829 for the treatment of relapsing remitting MS with the U.S. Food and Drug Administration (FDA) in the second quarter of 2012 and expects to initiate human clinical trials later this year.

XenoPort owns all rights to XP23829.

About XenoPort

XenoPort is a biopharmaceutical company focused on developing and commercializing a portfolio of internally discovered product candidates for the potential treatment of neurological disorders. Horizant® (gabapentin enacarbil) Extended-Release Tablets is XenoPort’s first FDA-approved product. GlaxoSmithKline holds commercialization rights and certain development rights for Horizant in the United States. Regnite® (gabapentin enacarbil) is approved for the treatment of moderate-to-severe primary restless legs syndrome in Japan. Astellas Pharma Inc. holds all development and commercialization rights for Regnite in Japan and five Asian countries. XenoPort holds all other world-wide rights and has co-promotion and certain development rights to gabapentin enacarbil in the United States. XenoPort’s pipeline of product candidates includes potential treatments for patients with postherpetic neuralgia, spasticity and Parkinson’s disease.

To learn more about XenoPort, please visit the company Website at http://www.XenoPort.com.

More info about this drug

SEE a patent

WO 2010022177

……………………………………….

WO 2013181451

http://www.google.com/patents/WO2013181451A1?cl=en

Scheme 5:

ONE OUT OF THESE

Example 6: (/V,/V-Diethylcarbamoyl)methyl methyl (2£)but-2-ene-1 ,4-dioate

[0138] Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at about 55 °C with 2-chloro-/V,/V-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHC0₃ (0.69 g, 3.60 mmol) to afford 0.37 g (51 % yield) of the title compound after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1 :1 ) as eluent. M.p.: 53-56 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J = 1.1 Hz, 2H), 3.26 (q, J = 7.2 Hz, 2H), 1 .24 (t, J = 7.2 Hz, 3H), 1 .14 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)⁺.

Example 7: Methyl 2-morpholin-4-yl-2-oxoethyl (2 £)but-2-ene-1 ,4-dioate

[0139] Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at about 55 °C with 4-(chloroacetyl) morpholine (0.75 g, 4.61 mmol) in the presence of CsHC0₃ (0.89 g, 4.61 mmol) to afford 0.34 g (35% yield) of the title compound as a white solid after purification by mass-guided preparative HPLC and lyophilization. M.p.: 124 to 126°C; ¹ H NMR (CDCI₃, 400 MHz): δ 6.97-6.91 (m, 2H), 4.84 (s, 2H), 3.82 (s, 3H), 3.72-3.70 (m, 4H), 3.64-3.62 (m, 2H), 3.46-3.41 (m, 2H). MS (ESI): m/z 258.04 (M+H)⁺. Example 8: A/,A/-Dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4-dioate

[0140] Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at about 55 °C with /V,/V-dimethyl chloroacetamide (0.56 g, 4.61 mmol) in the presence of CsHC0₃ (0.89 g, 4.61 mmol). The crude material was precipitated out from a mixture of ethyl acetate (EtOAc) and hexanes (Hxn) (1 :1 ) to provide a white solid. This solid was further dissolved in dichloromethane (DCM) and the organic layer washed with water. After removal of the solvents 0.55 g (67% yield) of the title compound was obtained as a white solid. ¹ H NMR (CDCI₃, 400 MHz): δ 6.98- 6.90 (m, 2H), 4.84 (s, 2H), 3.80 (s, 3H), 2.99-2.97 (2s, 6H). MS (ESI): m/z 216 (M+H)⁺.

Example 9: Methyl (2-morpholino-4-ylethyl) fumarate

[0141] Following general Procedure A, methyl hydrogen fumarate (MHF) dissolved in NMP is reacted at about 55 °C with 4-(chloroethyl) morpholine (0.75 g, 4.61 mmol) in the presence of CsHC0₃ to afford the title compound after purification by mass-guided preparative HPLC and lyophilization. Example 10: Methyl (3-mor holino-4-ylpropyl) fumarate

[0142] Following the procedure of Methyl (2-morpholino-4-ylethyl) fumarate, and replacing 4-(chloroethyl) morpholine with 4-(chloropropyl) morpholine provides the title compound.

Example 11 : Methyl (4-morpholino-4-ylbutyl) fumarate

[0143] Following the procedure of Methyl (2-morpholino-4-ylethyl) fumarate, and replacing 4-(chloroethyl) morpholine with 4-(chlorobutyl) morpholine provides the title compound. Example 12: Methyl 5-morpholino-4-ylpentyl) fumarate

[0144] Following the procedure of Methyl (2-morpholino-4-ylethyl) fumarate, and replacing 4-(chloroethyl) morpholine with 4-(chloropentyl) morpholine provides the title compound. Example 13: (A/-cyclopropyl-W-ethylcarbamoyl)methyl methyl 2(E)but-2-ene-1 ,4-dioate

[0145] Following the general procedure A, methyl hydrogen fumarate (MHF) (38.7 g, 0.297 mol) suspended in toluene (100 mL) was reacted at about 80 °C with 2-chloro-/V-cyclopropyl- N-ethylacetamide (48 g, 0.297 mol) in the presence of W,/V-diisopropylethylamine (DIEA; 42.3 g, 57 mL, 0.327 mol) to afford 50 g (63.3%) of the title compound after recrystallization using methyl ferf-butyl ether. The crystalline compound had a melting point of 92.1 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 7.01 -6.92 (m, 2H), 4.99 (s, 2H), 3.81 (s, 3H), 3.44 (q, J = 7.2 Hz, 2H), 2.69-2.66 (m, 1 H), 1 .14 (t, J = 7.2 Hz, 3H), 0.94-0.91 (m, 2H), 0.83-0.81 (m, 2H). MS (ESI): m/z 256.2 (M+H)⁺.

Example 14: (/V-cyclopropyl-/V-methylcarbamoyl)methyl methyl 2(E)but-2-ene-1 , 4- dioate

[0146] Following general procedure A, methyl hydrogen fumarate (MHF) (38.7 g, 0.40 mol) suspended in toluene (100 mL) was reacted at about 80 °C with 2-chloro-/V-cyclopropyl-/V- methylacetamide (60 g, 0.40 mol) in the presence of Ν,Ν-diisopropylethylamine (DIEA; 57.8 g, 78 mL, 0.44 mol) to afford 50 g (50.86%) of the title compound after recrystallization using methyl fe/t-butyl ether. The crystalline compound had a melting point of 93.6 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 7.01 -6.91 (m, 2H), 5.01 (s, 2H), 3.82 (s, 3H), 2.94 (s, 3H), 2.73-2.68 (m, 1 H), 0.94-0.86 (m, 2H), 0.83-0.78 (m, 2H). MS (ESI): m/z 242.2 (M+H)⁺.

Example 15: Methyl 2-oxo-2-pyrrolidinylethyl 2(E)but-2-ene-1 ,4-dioate

[0147] Following general procedure A, methyl hydrogen fumarate (MHF) (20.78 g, 0.159 mol) suspended in toluene (60 mL) was reacted at about 80 °C with 2-chloro-1 -pyrrolidin-1 -yl- ethanone (23.5 g, 0.159 mol) in the presence of N,N-diisopropylethylamine (DIEA; 22.69 g, 31 .5 mL, 0.175 mol) to afford 24 g (62.3%) of the title compound after recrystallization using methyl fe/t-butyl ether. The crystalline compound had a melting point of 102.1 °C. ¹ H NMR (CDCI₃, 400 MHz): δ 7.00-6.92 (m, 2H), 4.75 (s, 2H), 3.81 (s, 3H), 3.53-3.49 (t, J = 6.8 Hz, 2H), 3.42-3.39 (t, J = 6.8 Hz, 2H), 2.20-1 .97 (m, 2H), 1 .91 -1 .82 (m, 2H). MS (ESI): m/z 242 (M+H)⁺.

………………………………

Patent

 http://www.google.co.in/patents/US8148414

(I):

Example 1(N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate (1)…………. best fit

Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at ca. 55° C. with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHCO₃ (0.69 g, 3.60 mmol) to afford 0.37 g (51% yield) of the title compound (1) after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. M.p.: 53-56° C. ¹H NMR (CDCl₃, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J=7.2 Hz, 2H), 3.26 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)⁺.

Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.20 g, 0.68 mmol) was reacted with acetyl chloride (AcCl) (0.60 mL, 0.66 g, 0.84 mmol) and diisopropylethylamine (0.70 mL, 0.52 g, 4.0 mmol) in dichloromethane (DCM). Following aqueous work-up, the crude product was purified by silica gel flash chromatography to afford 0.12 g (54% yield) of the title compound (16) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 6.98-6.93 (m, 2H), 4.86 (s, 2H), 3.83 (s, 3H), 3.66 3.63 (m, 4H), 3.50-3.40 (m, 4H), 2.14 (s, 3H). MS (ESI): m/z 299.12 (M+H)⁺.

Example 9N,N-Dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate (9)

Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N,N-dimethyl chloroacetamide (0.56 g, 4.61 mmol) in the presence of CsHCO₃ (0.89 g, 4.61 mmol). The crude material was precipitated out from a mixture of ethyl acetate (EtOAc) and hexanes (Hxn) (1:1) to provide a white solid. This solid was further dissolved in dichloromethane (DCM) and the organic layer washed with water. After removal of the solvents 0.55 g (67% yield) of the title compound (9) was obtained as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 6.98-6.90 (m, 2H), 4.84 (s, 2H), 3.80 (s, 3H), 2.99-2.97 (2s, 6H). MS (ESI): m/z 216 (M+H)⁺.

………………………..

http://www.google.com/patents/WO2014031844A1?cl=en

Compound (1).

Table 1 : Flushing Incidence as a Function of MMF Cmax

*Formulation 2 is the dosage form described in Example 10; Formulation 3 is the dosage form described in Example 3 ; Formulation 4 is the dosage form described in Example 5 ;

** maximum average Concentration; ***average Cmax; Poster (see above); Compound (1) referred to in the above table is an MMF prodrug of Formula (II); (N,N- Diethylcarbamoyl)methyl methyl (2£)but-2-ene-l,4-dioate having the following chemical structure:

Compound (1).

The maximum slope values ( dose and ng) for different dosage treatments are given in Table 2. The Figures 15-16 show plots of maximum MMF slope vs flushing incidence. The curves in the figures were fitted using a Hill Em_ax model. Table 2

Compound, Flushing

Table 3: Composition of Enteric Coated Sustained Release Tablet (15% HPMC in Core)

Quantity Quantity

Component Manufacturer Role

(mg tablet) (%w/w)

Vertellus (Greensboro,

Triethyl Citrate Plasticizer 1.25 0.42

NC)

Emerson Resources Anti- tacking

PlasAC YL™ T20 2.41 0.80

(Norristown, PA) agent

Total Enteric

27.87 9.30 Coating

Total Tablet 334.69 111.68

[00191] The tablets were made according to the following steps. The core tablets were prepared using a wet granulation process. The granulation was performed in two batches at 456 g per batch. Compound (1) and hydroxypropyl cellulose were passed through a conical mill with a 610 micron round holed screen. Compound (1) and hydroxypropyl cellulose were then combined in a Key KG- 5 granulator bowl and mixed with water addition for approximately 7 minutes. The wet granules were dried in a Glatt GPCG-1 fluid bed dryer at 40 °C. The two portions of dried granules were sized by passing through a conical mill with an approximately 1300 micron grater type screen. The milled granules were blended with the hypromellose 2208, silicon dioxide, and lactose monohydrate for 10 minutes in an 8 quart (7.6 1) V-blender. This blend was passed through an 850 micron mesh screen. The magnesium stearate was passed through a 600 micron mesh screen and blended with the additional core materials in the V-blender for 5 minutes. Core tablets (299.69 mg) were compressed using a GlobePharma Minipress II rotary tablet press with 8.6 mm round concave tooling. The core tablets had a final mean hardness of approximately 12 kp. For the coating, an aqueous suspension was prepared by mixing with an impeller 63.8 g Opadry 03019184 with 770.7 g of purified water. The water contained in the suspension is removed during the film coating process and therefore not included in the final formulation in Table 3. The tablets were coated with the aqueous suspension in an O’ Hara Technologies Labcoat M coater with a 12″ (30.5 cm) diameter perforated pan until the desired weight gain of barrier coat was achieved. The coating process occurred at an inlet temperature of approximately 52 °C and an outlet temperature of 36 °C. After coating, the tablets were dried for 2 hours at 40 °C. An aqueous suspension was prepared by mixing with an impeller 405.1 g methacrylic acid copolymer dispersion, 6.3 g triethyl citrate, 60.6 g PlasACRYL™ T20 with 228.1 g water. The water contained in the methacrylic acid copolymer dispersion and the

PlasACRYL™ T20 is removed during the film coating process and therefore not included in the final formulation in Table 3. The tablets were coated with the aqueous suspension in the O’ Hara Technologies Labcoat M coater until the desired weight gain of enteric film was achieved. The coating process occurred at an inlet temperature of approximately 40 °C and an outlet temperature of 30 °C. After coating, the tablets were dried for 2 hours at 40 °C.

Example 2

In Vitro Dissolution Profile of Example 1 Dosage Form

[00192] A two-stage dissolution method was used to determine the in vitro dissolution profile of dosage forms prepared according to Example 1. The 2-stage dissolution test was used to better approximate the pH conditions experienced by a dosage form after swallowing by a patient, i.e., low pH of the stomach followed by near neutral pH of the intestines. The dosage forms were first placed into a dissolution vessel (USP, Type I, basket) containing 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL of 200 mM tribasic sodium phosphate was added to the vessel resulting in a pH adjustment from 1.2 to 6.8. The dissolution medium was kept at 37 °C and was agitated at 100 rpm.

[00193] For the Example 1 dosage forms, samples of the dissolution medium were withdrawn after 1 and 2 hours in the low pH stage, and at 0.5, 2, 4, 7, 10, and 14 hours following buffer addition. The released amount of the MMF prodrug in the samples was determined by reverse phase HPLC using a C18 column and a 7 minute gradient method according to Table 4 where Mobile Phase A is water/0.1 ]¾Ρθ4 and Mobile Phase B is water/acetonitrile/H₃PC>4 (10/90/0.1 by volume) with UV detection at 210 nm.

Table 4: HPLC Gradient Conditions

[00194] As shown in FIG. 1, for dosage forms prepared according to Example 1, drug release is delayed for approximately 2 hours, followed by sustained release reaching >90 at 12 hours.

Example 3

Preparation of Delayed Sustained Release Dosage Form (Enteric Coated, 15% HPMC in Core, without Barrier Layer) [00195] Delayed sustained release tablets containing compound (1) were made having the ingredients shown in Table 5:

Table 5: Composition of Enteric Coated Sustained Release Tablet (15% HPMC in Core, without Barrier Layer)

[00196] The tablets were made according to the following steps. The core tablets were prepared using a wet granulation process. The granulation was performed in two batches at 463.9 g per batch. Compound (1) and hydroxypropyl cellulose were passed through a conical mill with a 610 micron round holed screen. Compound (1) and hydroxypropyl cellulose were then combined in a Key KG- 5 granulator bowl and mixed with water addition for approximately 10 minutes. The wet granules were dried in a Glatt GPCG-1 fluid bed dryer at 40 °C. The two portions of dried granules were blended with silicon dioxide and sized by passing through a conical mill with an approximately 1300 micron grater type screen. The milled granules were blended with the hypromellose 2208 and lactose monohydrate for 10 minutes in an 8 quart (7.6 1) V-blender. This blend was passed through an 850 micron mesh screen. The magnesium stearate was passed through a 600 micron mesh screen and blended with the additional core materials in the V-blender for 5 minutes. Core tablets (299.68 mg) were compressed using a GlobePharma Minipress II rotary tablet press with 11/32″ round concave tooling. The core tablets had a final mean hardness of approximately 11 kp. For the coating, an aqueous suspension was prepared by mixing with an impeller 578.7 g methacrylic acid copolymer dispersion, 9.0 g triethyl citrate, 86.5 g PlasACRYL™ T20 with 325.8 g water. The water contained in the methacrylic acid copolymer dispersion and the

PlasACRYL™ T20 is removed during the film coating process and therefore not included in the final formulation in Table 4. The tablets were coated with the aqueous suspension in the O’ Hara Technologies Labcoat M coater until the desired weight gain of enteric film was achieved. The coating process occurred at an inlet temperature of approximately 41 °C and an outlet temperature of 31 °C. After coating, the tablets were dried for 2 hours at 40 °C.

…………………………

WO 2014071371

http://www.google.com/patents/WO2014071371A1?cl=en

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4-dioate has the following chemical structure:

This compound was synthesized in Example 1 of Gangakhedkar et al., U.S. Patent No. 8,148,414. The compound is a prodrug of methyl hydrogen fumarate (MHF) and has a disclosed melting point of between 53 °C and 56 °C.

Cocrystals are crystals that contain two or more non-identical molecules that form a crystalline structure. The intermolecular interactions between the non-identical molecules in the resulting crystal structures can result in physical and chemical properties that differ from the properties of the individual components. Such properties can include, for example, melting point, solubility, chemical stability, mechanical properties and others. Examples of cocrystals may be found in the Cambridge Structural Database and in Etter, et al.,

“The use of cocrystallization as a method of studying hydrogen bond preferences of 2-aminopyridine” J. Chem. Soc, Chem. Commun. (1990), 589-591 ; Etter, et al., “Graph-set analysis of hydrogen-bond patterns in organic crystals” Acta Crystallogr., Sect. B, Struct. Sci. (1990), B46: 256-262; and Etter, et al., “Hydrogen bond directed cocrystallization and molecular recognition properties of diarylureas” J. Am. Chem. Soc. (1990), 1 12: 8415-8426. Additional information relating to cocrystals can be found in: Carl Henrik Gorbotz and Hans-Petter Hersleth,

“On the inclusion of solvent molecules in the crystal structures of organic compounds”; Acta Cryst. (2000), B56: 625-534; and Senthil Kumar, et al., “Molecular Complexes of Some Mono- and Dicarboxylic Acids with trans-1 ,4,-Dithiane-1 ,4-dioxide” American Chemical Society, Crystal Growth & Design (2002) , 2(4) : 313-318.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4-dioate is a prodrug of methyl hydrogen fumarate. Once administered, the compound is metabolized in vivo into an active metabolite, namely, methyl hydrogen fumarate (MHF) which is also referred to herein as monomethyl fumarate (MMF). The in vivo metabolism of (N,N-Diethylcarbamoyl)methyl

(N,N-Diethylcarbamoyl)methyl methyl Methyl hydrogen fumarate N ^ diethyl glycolamide

(2E)but-2-ene-1 ,4-dioate

Table 1

As can be seen from the data in Table 1 , the six cocrystals disclosed herein each exhibit a higher melting point than crystalline (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4- dioate.

…………………………….

Steady state pharmacokinetics of formulations of XP23829, a novel prodrug of monomethyl fumarate (MMF), in healthy subjects
66th Annu Meet Am Acad Neurol (AAN) (April 26-May 3, Philadelphia) 2014, Abst P1.188

………………………………….

Lymphocyte and eosinophil responses in healthy subjects dosed with Tecfidera and XP23829, a novel fumaric acid ester (FAE)
66th Annu Meet Am Acad Neurol (AAN) (April 26-May 3, Philadelphia) 2014, Abst P1.201

………………………..

A comparison of XP23829 with DMF, the active ingredient of BG-12
4th Cooperative Meet Consorti Mult Scler Cent (CMSC) Am Comm Treat Res Mult Scler (ACTRIMS) (May 30-June 2, San Diego) 2012, Abst SC03

 http://annualmeeting.mscare.org/index.php?option=com_content&view=article&id=174&Itemid=101

…………………………..

Favorable metabolism and pharmacokinetics of formulations of XP23829, a novel fumaric acid ester, in healthy subjects
65th Annu Meet Am Acad Neurol (AAN) (March 16-23, San Diego) 2013, Abst P05.189

…………………………………..

Comparison of the efficacy and tolerability of a novel methyl hydrogenfumarate prodrug with dimethyl fumarate in rodent EAE and GI irritation models
Neurology 2011, 76(9): Abst P05.040

A VAPOURTEC POST

http://www.vapourtec.co.uk/products/eseriessystem/pumping/organometallic

Philip R D Murray 1 Duncan L Browne 1 Julio C Pastre 1,2 Chris Butters 3 Duncan Guthrie 3 Steven V Ley 1

¹ Department of Chemistry, University of Cambridge, UK
² Instituto de Quí­mica, University of Campinas, Brazil
³ Vapourtec Ltd, UK

http://www.vapourtec.co.uk/products/eseriessystem/pumping/organometallic

A new enabling-technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents and DIBAL-H is reported, which utilizes a newly developed chemically-resistant peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addition, addition-elimination, conjugate addition and partial reduction are reported, along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances and examples are demonstrated over periods of several hours, to generate multi-gram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-Tamoxifen using continuous-flow organometallic reagent mediated transformations………..http://www.vapourtec.co.uk/products/eseriessystem/pumping/organometallic.

For description see at synfacts

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505

Contributor: Philip Kocienski

Philip Kocienski, Professor of Organic Chemistry.

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505

Bao H, Bayeh L, Tambar UK * The University of Texas Southwestern Medical Center at Dallas, USA
Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.

Synlett 2013;
24: 2459-2463

gsk 2262167

3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate

synthesis will be updated.watch out?????????????

………………………

paper

A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P₁ receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium acetate for the Saegusa oxidation, near complete recovery of the palladium has been demonstrated. The remaining steps have been optimised including the removal of all chromatography. An alternative to the Saegusa oxidation is described as well as the development of a flow process to facilitate further scale-up of the amidoxime preparation using hydroxylamine at elevated temperature.

http://pubs.acs.org/doi/abs/10.1021/op400162p?tokenDomain=campaign&tokenAccess=noteworthy&forwardService=showFullText&journalCode=oprdfk

AND

http://pubs.acs.org/doi/suppl/10.1021/op400162p/suppl_file/op400162p_si_001.pdf

………………………….

Will watson

http://www.allfordrugs.com/scientific-update/

WILL WATSON in  ACS noteworthy chemistry wrote

http://www.acs.org/content/acs/en/noteworthy-chemistry/2014-archive/june-23.html

Researchers make a profit from a pilot plant reaction. R. H. Harris and co-workers at GlaxoSmithKline Research and Development (Stevenage, UK) developed a “fit-for-purpose” method for scaling up the synthesis of a sphingosine 1-phosphate receptor agonist. They shortened the route to the 5-hydroxytetrahydroisoquinoline intermediate from eight to two steps by carrying out a Robinson annulation on N-Boc-4-piperidone followed by aromatization of the cyclohexane ring. (Boc is tert-butoxycarbonyl.)

The authors found, however, that only a Saegusa oxidation that uses stoichiometric quantities of Pd(OAc)₂ catalyst gives good conversion in the aromatization. Optimizing the workup by adding HCO₂K at the end of the reaction to reduce the Pd(II) and precipitate the palladium as Pd(0) made it possible to recover 10.3 kg of the 10.5kg of palladium used in the pilot plant.

The price of palladium doubled during the campaign, so GlaxoSmithKline sold the palladium back to supplier Johnson Matthey at a profit of UK£62,500. Subsequently, the authors developed a more economical CuBr₂-mediated aromatization reaction. (Org. Process Res. Dev. 2013, 17, 1239–1246; Will Watson)

………………………

paper

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P₁ and S1P₃₋₅). It has been postulated that fingolimod’s efficacy is due to S1P₁ agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P₃ agonism. We have discovered a series of selective S1P₁ agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P₃-sparing, orally active S1P₁ agonist. Compound20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P₃ is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

http://pubs.acs.org/doi/abs/10.1021/ml2000214

Discovery of a Selective S1P₁ Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

–

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Metadoxine

Alcobra Ltd.

http://regulatoryaffairs.pharmaceutical-business-review.com/news/fda-approves-alcobras-protocol-for-phase-iib-study-of-metadoxine-drug-candidate-090514-4262995

Israel-based Alcobra has received approval from the US Food and Drug Administration (FDA) for its protocol for planned Phase IIb clinical study of Metadoxine Extended Release (MDX) drug candidate for the treatment of Fragile X Syndrome.

 

The multi-center, randomized, placebo-controlled, Phase IIb study, will be conducted primarily in the US and patient enrollment is expected to begin in the near future.

The study is supported by data collected from multiple earlier pre-clinical studies which demonstrated significant improvement in behavioral and cognitive outcomes based on evaluations of memory, learning, and social interaction.

 

 

Metadoxine, or Pyridoxol L-2-pyrrolidone-5-carboxylate, whose structure formula is reported hereinbelow

 

is known for its effectiveness in acute and chronic alcoholism and for the prevention of alcohol related pathology

 

 

Metadoxine

Systematic (IUPAC) name
L-Proline, 5-oxo-, compd. with 5-hydroxy-6-methylpyridine-3,4-dimethanol (1:1)
Clinical data
Legal status	PHASE 2
Routes	Oral, IV
Identifiers
CAS number	0074536-44-0
ATC code	N07BB
Chemical data
Formula	C13H18N2O6
Mol. mass	298 g/mol

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Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol abuse.^[1] Metadoxine improved the clinical signs of acute alcohol intoxication and accelerated alcohol clearance from the blood ^[2]It is presently in human clinical trials as an attention-deficit/hyperactivity disorder predominantly inattentive treatment.^[3]

Pyridoxine is one form of vitamin B₆ and a precursor to the metabolically active pyridoxal phosphate. Pyridoxal phosphate is a coenzyme to many enzymes: see vitamin B6 metabolic functions.

Pyrrolidone carboxylate is involved in amino acid metabolism through the glutathione pathway.^[4] Glutathione is an important antioxidant and combats redox imbalance. It also supports de novo ATP synthesis.^[5]

Alcohol-induced liver diseases are a common disorder in modern communities and societies. For example, in Europe there are more than 45 million individuals showing signs of alcohol-related damage such as liver disease and myopathies. Chronic alcohol consumption increases hepatic accumulation of triglycerides and leads to hepatic steatosis, which is the earliest and most common response to severe alcohol intoxication.

Thus, severe alcohol intoxication is a serious disease that should be treated with medication in order to reduce the damage to the human body of the alcohol intoxicated individual. For example, alcohol intoxication can be treated with metadoxine (pyridoxine L-2-pyrrolidone-5-carboxylate). Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following structures:

(1) (2)

WO 2008/066353 discloses the use of Metadoxine in the treatment of alcohol intoxication either alone or in combination with other active agents. WO 2008/066353 mentions that metadoxine does not inhibit the expression and activation of an alcohol-induced cytochrome P450 2El, which is the key enzyme involved in alcohol-induced toxicity. Thus, the use of metadoxine may be limited.

Several studies have shown that in order to effectively treat alcohol intoxication, there is a need for a relatively high daily dose (ca. 900 mg) administered intravenously (see, e.g., Lu et al. Chin. Med. J. 2007, 120 (2), 155-168 and Shpilenya et al. Alcohol Clin. Exp. Res. 2002, 26 (3), 340-346). These studies disclose side effects associated with the use of metadoxine, including nausea and vomiting.

Thus, there exists a need in the art for effective and safe drugs for treating alcohol intoxication and other associated diseases.

History

Metadoxine is predominantly used in developing nations for acute alcohol intoxication. Alternate names include: Abrixone (Eurodrug, Mexico), Alcotel (Il Yang, South Korea), Ganxin (Qidu Pharmaceutical, China), Metadoxil (Baldacci, Georgia; Baldacci, Italy; Baldacci, Lithuania; CSC, Russian Federation; Eurodrug, Colombia; Eurodrug, Hungary; Eurodrug, Thailand; Micro HC, India), Viboliv (Dr. Reddy’s, India), and Xin Li De (Zhenyuan Pharm, China).^[6]

Fatty liver refers to a pathogenic condition where fat comprises more than 5% of the total weight of the liver. Liver diseases including the fatty liver, hepatitis, fibrosis and cirrhosis are known to be the most serious disease next to cancer causing death in people with ages 40 to 50, in the advanced countries. In advanced countries, nearly about 30% of the population is with fatty liver, and about 20% of people with fatty liver progresses to cirrhosis. About half of the cirrhosis patients die of liver diseases within 10 years after the diagnosis. Fatty liver and steatohepatitis are frequently found in people who intake excessive alcohols and who have obesity, diabetes, hyperlipemia, etc. Among them, alcoholic steatohepatitis (ASH), which is caused by excessive alcohol intake, is at high risk of progressing to hepatitis, cirrhosis and hepatoma, along with non-alcoholic steatohepatitis (NASH).

When taken in, alcohol is carried to the liver and oxidized to acetaldehyde by such enzymes as alcohol dehydrogenase, catalase, etc. The acetaldehyde is metabolized and converted into acetate and is used as energy source. Repeated alcohol intake induces the increase of NADH and NADP⁺ during the metabolism and acetaldehyde which as the metabolite product of alcohol depletes GSH, thereby changing intracellular oxidation-reduction homeostasis and inducing oxidative stress. Oxidative stress may cause mitochondrial dysfunction, lipid peroxidation and protein modification, thereby leading to death of hepatocytes, inflammation, activation of astrocytes, and the like. In addition, the increase of NADH promotes lipid synthesis, thereby inducing fatty liver.

At present, there are few therapeutically effective drugs for treating fatty liver. Exercise and controlled diet are recommended, but these are not so effective in treating fatty liver. The development of an effective treatment drug is in desperate need. As it is known that fatty liver is related with insulin resistance which is found in diabetes and obesity, the therapeutic effect of some anti-diabetic drugs, e.g., metformin, on fatty liver has been reported. But, the drug has the problem that it may induce adverse reactions such as hepatotoxicity or lactic acidosis. Betaine, glucuronate, methionine, choline and lipotrophic agents are often used as alternative supplementary drug therapy, but they are not fully proven on medical or pharmaceutical basis. Accordingly, development of a fatty liver treatment having superior effect and safety with no adverse reactions is in need.

Metadoxine (pyridoxol 1-2-pyrrolidone-5-carboxylate) is a complex compound of pyridoxine and pyrrolidone carboxylate represented by the formula (1) below:

Metadoxine is a drug used to treat alcoholic liver disease. It is used to treat liver fibrosis and fatty liver through increasing alcohol metabolism and turnover, reducing toxicity of free radicals and restoring the level of ATP and glutathione (Arosio, et al., Pharmacol. Toxicol. 73: 301-304, 1993; Calabrese, et al., Int. J. Tissue React. 17: 101-108, 1995; Calabrese, et al., Drugs Exp. Clin. Res. 24: 85-91, 1998; Caballeria, et al., J. Hepatol. 28: 54-60, 1998; and Muriel, et al., Liver Int. 23: 262-268, 2003).

However, metadoxine is unable to inhibit the expression and activation of alcohol-induced cytochrome P4502E1 (CYP2E1), which is a key enzyme involved in alcohol-induced toxicity, and thus unable to control the augmentation of inflammation mediated by CYP2E1. Therefore, the treatment of alcohol-induced fatty liver using metadoxine is very limited. Further, the expression of CYP2E1 is related with insulin resistance, thus metadoxine cannot not overcome insulin resistance.

Garlic oil is a liquid including about 1% of allicin along with reduced allicin and other sulfur-containing substances. Upon binding to vitamin B₁, allicin is turned into allithiamin, which is chemically stable, acts swiftly, and is easily absorbed by the digestive organs. The substance inhibits carcinogenesis induced by chemicals in white rats (Brady, et al., Cancer Res. 48: 5937-5940, 1988; and Reddy, et al., Cancer Res. 53: 3493-3498, 1993), induces phase II enzyme (Hayes, et al., Carcinogenesis 8: 1155-1157, 1987; and Sparnins, et al., Carcinogenesis 9: 131-134, 1988), and inactivates CYP2E1 (Brady, et al., Chem. Res. Toxicol. 4:642-647, 1991). In addition, garlic oil is reported to have antithrombotic, anti-atherosclerotic, antimutagenic, anticancer and antibacterial activities (Agarwal, Med. Res. Rev. 16: 111-124, 1996; and Augusti, Indian J. Exp. Biol. 34: 634-660, 1996).

Pharmacology

Treatment for acute alcohol abuse

In an animal model, metadoxine treatment increased the clearance of alcohol and acetaldehyde, reduced the damaging effect of free radicals, and enabled cells to restore cellular ATP and glutathione levels. ^[7][8] It increases the urinary elimination of ketones, which are formed when the oxidation rate of acetaldehyde into acetate is exceeded on massive alcohol intoxication.^[8][4]

As a medical treatment, it is typically given intravenously.

Treatment for AD/HD-PI

Metadoxine is a selective antagonist to the 5-HT2B receptor, a member of the serotonin receptor family.^[3] Electrophysiological studies also showed that Metadoxine caused a dose-dependent, reversible reduction in glutamatergic excitatory transmission and enhancement of GABAergic inhibitory transmission, changes that may be associated with cognitive regulation.^[3] It is given orally in an extended release pill, which differs from the instant release alcohol treatment.

Treatment for liver disease

Metadoxine may block the differentiation step of preadipocytes by inhibiting CREB phosphorylation and binding to the cAMP response element, thereby repressing CCAAT/enhancer-binding protein b during hormone-induced adipogenesis.^[7]

Treatment for Fragile X Syndrome

Metadoxine treatment led to significant improvement in blood and brain biological markers (AKT and ERK), which may have a role in learning and memory.^[3] The study also demonstrated a reduction in the amount of immature neurons and abnormally increased protein levels.^[3]

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PATENT

http://www.google.com/patents/WO2010013242A1?cl=en

Scheme 1

[0054] In another aspect, the invention provides methods of synthetically preparing, e.g., carboxylated lactam ring of formula (II) (e.g. wherein n=2 for a reactant of formula (IVb) in Scheme 2), carboxylated lactam ring of (III) (e.g. wherein n=3 for a reactant of formula (IVb) in Scheme 2) and carboxylated lactam ring of formula (IV) (e.g. wherein n=4 for a reactant of formula (IVb) in Scheme 2), as depicted in Scheme 2.

Scheme 2

pyridoxine

Compound IVb, n=2,3,4

[0055] In another aspect, the invention provides methods of preparing a salt adduct including a positively charged pyridoxine moiety, or a derivative thereof, and a carboxylated 5- to 7-membered lactam ring, including the steps of:

(a) suspending an optionally substituted amino dioic acid in water and heating for a sufficient period of time to allow completing lactamization reaction;

(b) optionally decolorizing the reaction mixture to eliminate impurities;

(c) isolating the lactam carboxylate;

(d) optionally purifying the obtained lactam carboxylate by crystallization;

(e) admixing the obtained lactam carboxylate and a pyridoxine base or a derivative thereof in a solvent mixture optionally under heating; and

(f) isolating the product.

In certain embodiments, a solvent mixture of step (e) includes a mixture of an alcohol such as methanol, ethanol, isopropanol and the like, and water. [0059] According to yet another embodiment, there is provided methods of preparing N-substituted L-pyroglutamic acid and the carboxylate thereof, such as, for example, N-methyl-L-pyroglutamic acid (1-methyl-L-pyroglutamic acid), starting from L-pyroglutamic acid ethyl ester, as depicted in Scheme 3 below. Scheme 3

1-methyl-L-pyroglutamic acid

[0060] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 4 below. The starting reagent is 2-methyl-3-hydroxy-4- methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound (V)). The preparation of the corresponding salt is described in Example 1. Scheme 4

HCI NH ₃ / MeOH 2 L-pyroglutamic acid

Compound V Compound Vl

Salt lid

[0061] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 5 below. The starting reagent in scheme 5 is 2-methyl-3-hydroxy- 4-methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound V). The preparation of the corresponding salt is described in Example 2. Scheme 5

Compound V

HCI

Compound VIII IX Compound L-pyroglutamic acid

, SaIt IIe

References

• 1-​225-​Immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus γ1-​chain) (225→219′)​-​disulfide with immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus κ-​chain)Protein SequenceSequence Length: 444, 225, 219

BI 655075, Idarucizumab

• Idarucizumab [INN]
• UNII-97RWB5S1U6

 CAS 1362509-93-0

Treatment of dabigatran associated haemorrhage

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Boehringer Ingelheim Pharmaceuticals’ idarucizumab, an investigational fully humanised antibody fragment being studied as a specific antidote for Pradaxa.
Boehringer Ingelheim Pharmaceuticals Medicine & Regulatory Affairs senior vice-president Sabine Luik said: “We are committed to innovative research and to advancing care in patients taking Pradaxa.

http://www.pharmaceutical-technology.com/news/newsfda-grants-breakthrough-therapy-designation-boehringers-idarucizumab-4304367

http://apps.who.int/trialsearch/Trial.aspx?TrialID=EUCTR2013-004813-41-EE

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-001438-PIP01-13/pip_001159.jsp&mid=WC0b01ac058001d129

1. IDARUCIZUMAB (BI 655075)
   • What is it?  It is a humanized antibody fragment directed against dabigatran; generated from mouse monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment.
   • What anticoagulant drugs might it reverse?  Dabigatran.
   • Clinical trial status:  (a) A phase 3 study of patients on dabigatran with major bleeding or needing emergency surgery is in the planning stages and will likely start in 2014. (b) A phase 1 study to determine the effect of idarucizumab on coagulation tests in dabigatran-treated healthy volunteers has been completed (NCT01688830), another two are ongoing (NCT01955720; NCT02028780).

June 26, 2014

Pradaxa Antidote, Idarucizumab Designated Breakthrough Therapy

Boehringer Ingelheim announced that the FDA has granted Breakthrough Therapy designation to idarucizumab, an investigational fully humanized antibody fragment (Fab), being evaluated as a specific antidote for Pradaxa (dabigatran etexilate mesylate).

Data from a Phase 1 trial demonstrated that idarucizumab was able to achieve immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy humans. The on-set of action of the antidote was detected immediately following a 5-minute infusion while thrombin time was reversed with idarucizumab. Reversal of the anticoagulation effect was complete and sustained in 7 of 9 subjects who received the 2g dose and in 8 out of 8 subjects who received the 4g dose. The 1g dose resulted in complete reversal of anticoagulation effect; however, after approximately 30 minutes there was some return of the anticoagulation effects of dabigatran.

RELATED: Anticoagulant Dosing Conversions

A global Phase 3 study, RE-VERSE AD, is underway in patients taking Pradaxa who have uncontrolled bleeding or require emergency surgery or procedures. Currently there are no specific antidotes for newer oral anticoagulants.

Pradaxa is approved to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (AF). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with parenteral anticoagulant for 5–10 days. To reduce risk of recurrent DVT/PE in patients who have been previously treated.

For more information call (800) 542-6257 or visit Boehringer-Ingelheim.com.

P/0069/2014: European Medicines Agency decision of 17 March 2014 on the agreement of apaediatric investigation plan and on the granting of a deferral for idarucizumab (EMEA-001438-PIP01-13)