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)
Lymphopenia
Hypophosphataemia[Note 1]
Haemorrhage[Note 2]
Hypertension[Note 3]
Diarrhea
Rash
Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib)
Hand-foot syndrome
Pruritus (itchiness)
Erythema
Increased amylase
Increased lipase
Fatigue
Pain[Note 4]
Nausea
Vomiting[Note 5][14]
Common (1-10% frequency)
Leucopoenia[Note 6]
Neutropoenia[Note 7]
Anaemia[Note 8]
Thrombocytopenia[Note 9]
Anorexia (weight loss)
Hypocalcaemia[Note 10]
Hypokalaemia[Note 11]
Depression
Peripheral sensory neuropathy
Tinnitus[Note 12]
Congestive heart failure
Myocardial infarction[Note 13]
Myocardial ischaemia[Note 14]
Hoarseness
Constipation
Stomatitis[Note 15]
Dyspepsia[Note 16]
Dysphagia[Note 17]
Dry skin
Exfoliative dermatitis
Acne
Skin desquamation
Arthralgia[Note 18]
Myalgia[Note 19]
Renal failure[Note 20]
Proteinuria[Note 21]
Erectile dysfunction
Asthenia (weakness)
Fever
Influenza-like illness
Transient increase in transaminase
Uncommon (0.1-1% frequency)
Folliculitis
Infection
Hypersensitivity reactions[Note 22]
Hypothyroidism[Note 23]
Hyperthyroidism[Note 24]
Hyponatraemia[Note 25]
Dehydration
Reversible posterior leukoencephalopathy
Hypertensive crisis
Rhinorrhoea[Note 26]
Interstitial lung disease-like events[Note 27]
Gastro-oesophageal reflux disease (GORD)
Pancreatitis[Note 28]
Gastritis[Note 29]
Gastrointestinal perforations[Note 30]
Increase in bilirubin leading, potentially, to jaundice[Note 31]
Cholecystitis[Note 32]
Cholangitis[Note 33]
Eczema
Erythema multiforme[Note 34]
Keratoacanthoma[Note 35]
Squamous cell carcinoma
Gynaecomastia (swelling of the breast tissue in men)
Transient increase in blood alkaline phosphatase
INR abnormal
Prothrombin level abnormal
bulbous skin reaction[15]
Rare (0.01-0.1% frequency)
QT interval prolongation[Note 36]
Angiooedema[Note 37]
Anaphylactic reaction[Note 38]
Hepatitis[Note 39]
Radiation recall dermatitis
Stevens-Johnson syndrome[Note 40]
Leucocytoclastic vasculitis
Toxic epidermal necrolysis[Note 41]
Nephrotic syndrome
Rhabdomyolysis[Note 42]
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 for
280000 (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
Low blood phosphate levels
Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
High blood pressure
Including abdominal pain, headache, tumour pain, etc.
Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
Low level of white blood cells in the blood
Low level of neutrophils in the blood
Low level of red blood cells in the blood
Low level of plasma cells in the blood
Low blood calcium
Low blood potassium
Hearing ringing in the ears
Heart attack
Lack of blood supply for the heart muscle
Mouth swelling, also dry mouth and glossodynia
Indigestion
Not being able to swallow
Sore joints
Muscle aches
Kidney failure
Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
Including skin reactions and urticaria (hives)
Underactive thyroid
Overactive thyroid
Low blood sodium
Runny nose
Pneumonitis, radiation pneumonitis, acute respiratory distress, etc.
Swelling of the pancreas
Swelling of the stomach
Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
Yellowing of the skin and eyes due to a failure of the liver to adequately cope with the amount of bilirubin produced by the day-to-day actions of the body
Swelling of the gallbladder
Swelling of the bile duct
A potentially fatal skin reaction
A fairly benign form of skin cancer
A potentially fatal abnormality in the electrical activity of the heart
Swelling of the skin and mucous membranes
A potentially fatal allergic reaction
Swelling of the liver
A potentially fatal skin reaction
A potentially fatal skin reaction
The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys
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