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Yearly Archives: 2013
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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GSK obtains FDA approval for bird flu vaccine
GlaxoSmithKline (GSK) has received approval from the US Food and Drug Administration (FDA) for the first adjuvanted vaccine to prevent H5N1 influenza, also known as bird flu.
GSK obtains FDA approval for bird flu vaccine http://www.pharmaceutical-technology.com/news/newsgsk-obtains-fda-approval-bird-flu-vaccine?WT.mc_id=DN_News
26 November 2013
GlaxoSmithKline (GSK) has received approval from the US Food and Drug Administration (FDA) for the first adjuvanted vaccine to prevent H5N1 influenza, also known as bird flu.
The FDA cleared the pandemic Influenza A (H5N1) virus monovalent vaccine, adjuvanted (also referred to as Q-Pan H5N1 influenza vaccine), for use in people aged 18 and older who are at increased risk of exposure to the virus.
The vaccine is composed of monovalent, inactivated, split A/H5N1 influenza virus antigen and GSK’s AS03 adjuvant.
The company said that in clinical studies, the adjuvanted formulation stimulated the required immune response while using a smaller amount of antigen as compared with a formulation without adjuvant.
Biosimilar of Roche’s Herceptin approved in India
November 26, 2013 | By Márcio Barra
A biosimilar version of Roche’s blockbuster breast cancer drug from Mylan and Biocon was approved today in India, following the Indian Kolkata Patent Office denial of Roche’s patent on the grounds that it hadn’t been properly submitted.
View original post 244 more words
FDA Breakthrough Therapy Designations: Statistics Updated (As of 11/22/13)
The changes are as follows:
• The total # of FDA CDER + CBER BT Requests received by the FDA increases from 115 to 121
• The total # of FDA CDER + CBER BTs Granted by the FDA increases from 31 to 34
• The total # of FDA CDER + CBER BTs Denied by the FDA increases from 56 to 61
• The total # of FDA CDER + CBER BTs Pending by the FDA decreases from 28 to 26.
The following are observations of the latest FDA BTD #s:
• 28% of the total # of BT Requests Received results in the BTD being granted
• 50.4% of the total # of BT Requests Received results in the BTD being denied
• 21.6 % of the total # of BT Requests Received results in the BTD pending.
The latest “FDA CDER + CBER Breakthrough Therapy Designation Statistics Chart” will always be located at…
View original post 53 more words
FDA Breakthrough Therapy Designation: 27 And Counting
On November 25, Protola Pharmaceuticals announces that the FDA grants the coveted Breakthrough Therapy Designation (BTD) for Andexanet Alfa (PRT4445), an investigational (first-in-class agent) Factor Xa inhibitor antidote. This is the 27th BTD that is announced by a sponsor company.
Portola Pharmaceuticals, a San Francisco-based biopharmaceutical company, focuses on the development and commercialization of therapies for thrombosis (blood clots), other hematologic disorders, and inflammation. The company is founded in 2003 and completes an Initial Public Offering (IPO) in May 2013. The company’s two main programs are in the area of thrombosis :
• Betrixaban – once-daily inhibitor of Factor Xa in Phase III trials
• Andexanet Alfa (PRT4445) – recombinant Factor Xa inhibitor antidote that reverses anticoagulant activity in patients treated with a Factor Xa inhibitor who experience uncontrolled bleeding.
Portola Pharmaceuticals plans on following the FDA’s Accelerated Approval route for Andexanet Alfa, with the start of registration-enabling studies…
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FDA Approves Olysio (simeprevir) for Hepatitis C Virus
Simeprevir
Inhibits HCV NS3/4A protease.
MEDIVIR … originator
launched 2013
923604-59-5 CAS
C38H47N5O7S MF
749.93908 MW
IUPAC standard name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – ({7-methoxy-8-methyl-2-[4 – (propan-2-yl) -1,3-thiazol-2 -yl] quinolin-4-yl} oxy)-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide
IUPAC traditional name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – {[2 – (4-isopropyl-1 ,3-thiazol-2-yl)-7-methoxy-8-methylquinolin-4- yl] oxy}-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide
- Olysio
- Simeprevir
- TMC 435
- TMC 435350
- TMC-435
- TMC435
- TMC435350
- UNII-9WS5RD66HZ
November 22, 2013 — The U.S. Food and Drug Administration approved Olysio (simeprevir), a new therapy to treat chronic hepatitis C virus infection.
OLYSIO™ is the first once-daily protease inhibitor approved for the treatment of chronic hepatitis C in a combination antiviral regimen for adults with compensated liver disease
Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with the hepatitis C virus have no symptoms of the disease until liver damage becomes apparent, which may take several years. Most of these people then go on to develop chronic hepatitis C. Some will also develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with the hepatitis C virus
Hepatitis C virus (HCV) infections affect approximately 3 percent of the worldwide population and often lead to cirrhosis and hepatocellular carcinoma. The standard therapy of pegylated- interferon and ribavirin induces serious side effects and provides viral eradication in less than 50% of patients. Combination therapy of HCV including ribavirin and interferonare currently is the approved therapy for HCV. Unfortunately, such combination therapy also produces side effects and is often poorly tolerated, resulting in major clinical challenges in a significant proportion of patients. Numerous direct acting agents (DAAs) have been or are being developed for treatment of HCV, such as telaprevir and boceprevir (both received MA approved in 2011 for use with interferon and ribavirin based therapy), however direct acting agents are linked to increased toxicity of treatment, the emergence of resistance, and to date do not provide a standard of care which is interferon free. The combination of direct acting agents can also result in drug-drug interactions. To date, no HCV therapy has been approved which is interferon free. There is therefore a need for new combination therapies which have reduced side effects, and interferon free, have a reduced emergence of resistance, reduced treatment periods and/or and enhanced cure rates.
Simeprevir (formerly TMC435) is an experimental drug candidate for the treatment of hepatitis C. It is being developed byMedivir and Johnson & Johnson‘s pharmaceutical division Janssen Pharmaceutica and is currently in Phase III clinical trials.[1]
Simeprevir is a hepatitis C virus protease inhibitor.[2]
Simeprevir is being tested in combination regimens with pegylated interferon alfa-2a and ribavirin,[3] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir[4] and sofosbuvir [5]
Simeprevir has been launched in 2013 in Japan by Janssen Pharmaceutical (JP) for use in combination with pegylated interferon (Peg-IFN) and ribavirin for the treatment of genotype 1 chronic hepatitis C virus (HCV) patients who are treatment naïve, prior non responders or relapsed following treatment with Peg-IFN with or without ribavirin. In 2013, the product has also been approved in the U.S. by Medivir and Janssen R&D Ireland for the oral treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non-pegylated) with ribavirin.
The drug candidate was originally developed at Medivir, which was acquired by Janssen R&D Ireland in 2012. In November 2004, Medivir entered into a license and research collaboration agreement with Tibotec, a Johnson & Johnson subsidiary, for the discovery and development of orally active protease inhibitors of the NS3/4A protease of HCV. In 2011, a codevelopment agreement between Pharmasset (now Gilead Sciences) and Tibotec was signed for the treatment of chronic hepatitis C (HCV) in combination with PSI-7977. Also in 2011, fast track designation was received in the U.S. for the treatment of chronic hepatitis C (CHC) genotype-1 infection.
In 2011, Tibotec Therapeutics, Division of Centocor Ortho Biotech Products, L.P. announced that it had changed its name to Janssen Therapeutics, Division of Janssen Products, LP.
“Hepatitis C is a complex disease and Janssen is committed to working with the HCV community, caregivers, and health care systems to address this global epidemic,” said Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development. “We are pleased that the FDA has granted simeprevir Priority Review, as it is a significant step forward in making this therapy available to physicians and their hepatitis C patients.”
Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide.
Following initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. Chronic hepatitis can progress to liver fibrosis leading to cirrhosis, end- stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. This and the number of patients involved, has made HCV the focus of considerable medical research. Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A. NS3 serine protease is considered to be essential for viral replication and has become an attractive target for drug discovery.
Current anti-HCV therapy is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. Not only does this therapy result in a limited efficacy in that only part of the patients are treated successfully, but it also faces significant side effects and is poorly tolerated in many patients. Hence there is a need for further HCV inhibitors that overcome the disadvantages of current HCV therapy such as side effects, limited efficacy, poor tolerance, the emergence of resistance, as well as compliance failures.
Various agents have been described that inhibit HCV NS3 serine protease. WO05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentyl moiety. Amongst these, the macrocyclic derivatives are attractive by overcoming one or more of the disadvantages of current anti-HCV therapy
(I) simeprevir
The compound of formula (I) is an inhibitor of the Hepatitis C virus (HCV) serine protease and is described in WO 2007/014926, published on 8 February 2007. This compound overcomes several of the disadvantages of current anti-HCV therapy and in particular shows pronounced activity against HCV, has an attractive pharmacokinetic profile, and is well-tolerated. Following the synthesis procedure described in Example 5 of WO 2007/014926, an amorphous solid form is obtained.
It now has been found that the compound of formula (I) can be converted into crystalline forms, which can advantageously be used as active ingredients in anti-HCV therapy. To that purpose, these crystalline forms are converted into pharmaceutical formulations.
………………………………………………………………………………………….
SIMEPREVIR
…………………………
OLYSIO (simeprevir) is an inhibitor of the HCV NS3/4A protease.
The chemical name for simeprevir is (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2[[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14-dioxo2,3,3a,4,5,6,7,8,9,11a,12,13,14,14atetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide. Its molecular formula is C38H47N5O7S2 and its molecular weight is 749.94. Simeprevir has the following structural formula:
 |
Simeprevir drug substance is a white to almost white powder. Simeprevir is practically insoluble in water over a wide pH range. It is practically insoluble in propylene glycol, very slightly soluble in ethanol, and slightly soluble inacetone. It is soluble in dichloromethane and freely soluble in some organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide).
OLYSIO (simeprevir) for oral administration is available as 150 mg strength hard gelatin capsules. Each capsule contains 154.4 mg of simeprevir sodium salt, which is equivalent to 150 mg of simeprevir. OLYSIO (simeprevir) capsules contain the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate and sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904).
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Synthesis
Example 1 : preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.04‘6]octadec-7-ene- 4-carboxylic acid (16)
Synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (6) Step 1 : synthesis of Λ/-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline (2)
1 2
Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2- methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 h at room temperature, the reaction mixture was successively heated at 500C for 0.5 h, at 700C for 0.5 h then at 1000C for 1 h. To this solution, t-BuOH (30.5 g, 411 mmol) in toluene (40 mL) was added at 1000C and the resulting mixture was refluxed for 7h. The solution was cooled to room temperature then successively washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na2SO4), and evaporated to give 67 g of the target product: m/z = 237 (M)+.
_2: synthesis of 3-methoxy-2-methylaniline (3)
TFA (40.7 mL, 548 mmol) was added to a solution of jV-(teτt-butyloxycarbonyl)- 3-methoxy-2-methylaniline, in dichloro methane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z = 138 (M+H)+. The TFA salt was transformed to the free aniline by treatment with NaHCO3.
Step 3: synthesis of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (4)
A solution Of BCl3 (1.0 M, 200 mL, 200 mmol) in CH2Cl2 was slowly added under nitrogen to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature was monitored during the addition and was kept below 100C. The reaction mixture was stirred at 5°C for 0.5 h. Then, dry acetonitrile (13 mL, 246 mmol) was added at 5°C. After 0.5 h at 5°C, the solution was transferred into a dropping funnel and slowly added at 5°C to a suspension OfAlCl3 (26.7 g, 200 mmol) in CH2Cl2 (150 mL). After 45 min at 5°C, the reaction mixture was heated at 700C under a nitrogen stream. After evaporation Of CH2Cl2, the temperature of the reaction mixture reached 65°C. After 12 h at 65°C, the reaction mixture was cooled at 00C, poured onto ice (300 g), and slowly heated to reflux for 7h. After 2 days at room temperature, 6 N NaOH (50 mL) was added. The pH of the resulting solution was 2-3. The xylene layer was decanted. The organic layer was extracted with CH2Cl2. The xylene and CH2Cl2 layers were combined, successively washed with water, IN NaOH, and brine, dried (Na2SO4) and evaporated. The residue was triturated in diisopropyl ether at O0C, filtered off and washed with diisopropylether to give 13.6 g (40 %) of the title product as a yellowish solid: m/z = 180 (M+H)+.
Step 4: synthesis of 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3 ‘- methylacetophenone (5)
A solution of the compound 4 (18.6 g, 104 mmol) in dioxane (50 rnL) was added under nitrogen to a suspension of 4-isopropylthiazole-2-carbonyl chloride in dioxane (250 rnL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution of NaHCOs and AcOEt, organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90 %) of the title product 5.
Step 5: synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinoline (6)
Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of the compound 5 (30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 1000C overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et2O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl IN. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, fϊltered off and dried to give 26 g (88%) of the compound 6 as a brownish solid: m/z = 315 (M+H)+.
Synthesis of (hex-5-enyl)(methyl)amine (8)
O CF,
FX N Br’ N O NH
H 7
(a) Sodium hydride (1.05 eq) was slowly added at 00C to a solution of JV-methyl- trifluoro-acetamide (25 g) in DMF (140 mL). The mixture was stirred for Ih at room temperature under nitrogen. Then, a solution of bromohexene (32,1 g) in DMF
(25 mL) was added dropwise and the mixture was heated to 700C for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and evaporated to give 35 g of the target product 7 as a yellowish oil which was used without further purification in the next step.
(b) A solution of KOH (187.7 g) in water (130 mL) was added dropwise to a solution of 7 (35 g) in methanol (200 mL). The mixture was stirred at room temperature for
12 hours. Then, the reaction mixture was poured on water (100 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and the ether was distilled under atmospheric pressure. The resulting oil was purified by distillation under vacuum (13 mm Hg pressure, 500C) to give 7,4 g (34 %) of the title product 8 as a colourless oil: 1H-NMR (CDCl3): δ 5.8 (m, IH), 5 (ddd, J = Yl 2 Hz, 3.5 Hz, 1.8 Hz, IH), 4.95 (m, IH), 2.5 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J= 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, IH).
Preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxyl- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.04‘6loctadec-7-ene-4-carboxylic acid (16)
3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid 9 (500 mg, 3.2 mmol) in 4 mL DMF was added at 00C to HATU (1.34 g, 3.52 mmol) and JV-methylhex-5-enylamine (435 mg, 3.84 mmol) in DMF (3 mL), followed by DIPEA. After stirring for 40 min at 00C, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue dissolved in EtOAc (70 rnL) and washed with saturated NaHCOs (IO mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated NaCl (20 mL), dried (Na2SO4), and evaporated. Purification by flash chromatography (EtO Ac/petroleum ether, 2:1) afforded 550 mg (68%) of the target product 10 as a colorless oil: m/z = 252 (M+H)+.
A solution of LiOH (105 mg in 4 mlof water) was added at 00C to the lactone amide 10. After Ih, the conversion was completed (HPLC). The mixture was acidified to pH 2 – 3 with IN HCl, extracted with AcOEt, dried (MgSO4), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give 520 mg (88%) of the target product 11: m/z = 270 (M+H)+.
The l-(amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride 12
(4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to 11 (8.14 g,
30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were successively added. After 30 min at 00C, the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2 x 20 mL), and dried (Na2SO4). Purification by flash chromatography (AcOEt/CH2Cl2/Petroleum ether, 1 :1 :1) afforded 7.41 g (60%) of the target product 13 as a colorless oil: m/z = 407 (M+H)+.
DIAD (1.02 niL, 5.17 mmol) was added at -15°C under nitrogen atmosphere to a solution of 13 (1.5 g, 3.69 mmol), quinoline 6 (1.39 g, 4.43 mmol) and triphenyl- phosphine (1.26 g, 4.80 mmol) in dry THF (40 mL). After 4.5 h, at -15°C, the reaction mixture was partitioned between ice-cold water and AcOEt, dried (Na2SO4) and evaporated. The crude material was purified by flash column chromatography (gradient of petroleum AcOEt/CH2Cl2, 1 :9 to 2:8) to give 1.45 g (56 %) of the target product 14: m/z = 703 (M+H)+.
A solution of 14 (1.07 g, 1.524 mmol) and Hoveyda-Grubbs 1st generation catalyst (33 mg, 0.03 eq) in dried and degassed 1 ,2-dichloroethane (900 mL) was heated at 75°C under nitrogen for 12 h. Then, the solvent was evaporated and the residue purified by silica gel chromatography (25% EtOAc in CH2Cl2). 620 mg (60%) of pure macrocycle 15 were obtained, m/z = 674 (M+H)+. 1H NMR (CDCl3): 1.18-1.39 (m, 12H), 1.59 (m, IH), 1.70-2.08 (m, 5H), 2.28 (m, IH), 2.38 (m, IH), 2.62 (m, 2H), 2.68 (s, 3H), 2.83 (m, IH), 3.06 (s, 3H), 3.19 (sept, J= 6.7 Hz, IH), 3.36 (m, IH), 3.83 (m, IH), 3.97 (s, 3H), 4.09 (m, 2H), 4.65 (td, J= 4 Hz, 14 Hz, IH), 5.19 (dd, J= 4 Hz,
10 Hz, IH), 5.31 (m, IH), 5.65 (td, J= 4 Hz, 8 Hz, IH), 7.00 (s, IH), 7.18 (s, IH), 7.46
(d, J= 9 Hz, IH), 7.48 (s, IH), 8.03 (d, J= 9 Hz, IH).
A solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 rnL) was added to a stirred solution of ester 15 (620 mg, 0.920 mmol) in THF (30 mL) and MeOH (20 mL). After 16 h at room temperature, the reaction mixture was quenched with NH4Cl sat., concentrated under reduced pressure, acidified to pH 3 with HCl IN and extracted with CH2Cl2, dried (MgSO4) and evaporated to give 560 mg (88%) of carboxylic acid 16. m/z = 647 (M+H)+. 1H NMR (CDCl3): 1.11-1.40 (m, 8H), 1.42-1.57 (m, 2H), 1.74 (m, 2H), 1.88-2.00 (m, 2H), 2.13 (m, IH), 2.28 (m, IH), 2.40 (m, IH), 2.59 (m, 2H), 2.67 (s, 3H), 2.81 (m, IH), 2.97 (s, 3H), 3.19 (m, IH), 3.31 (m, IH), 3.71 (m, IH), 3.96 (s, 3H), 4.56 (dt, J= 4 Hz, 12 Hz, IH), 5.23 (m, 2H), 5.66 (m, IH), 7.01 (s, IH), 7.10 (s, IH), 7.22 (d, J= IO Hz, IH), 7.45 (s, IH), 8.00 (d, J= 10 Hz, IH).
Example 2: Preparation of Λ/-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.04‘6]octadec-7-ene- 4-carbonyll(cvclopropyl)sulfonamide (17) SIMEPREVIR
A solution of the compound 16 (560mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 500C for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 17, which is the compound of formula (I) SIMEPREVIR , as a white powder: m/z = 750 (M+H)+.
1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, IH), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, IH), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J= 13 Hz, IH), 5.04 (t, J= 11 Hz, IH), 5.37 (m, IH), 5.66 (m, IH), 6.21 (s, IH), 7.02 (s, IH), 7.22 (d, J= IO Hz, IH), 7.45 (s, IH), 7.99 (d, J= 10 Hz, IH), 10.82 (broad s, IH).
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SYNTHESIS
Example 4: preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy] – 13 -methyl-2, 14-dioxo-3 , 13 -diazatricyclo[ 13.3.0.04‘6]octadec-7-ene- 4-carboxylic acid (46) FREE ACID
Synthesis of 4-hvdroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (36) Step 1: synthesis of iV-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline (32)
31 32
Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2- methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 h at room temperature, the reaction mixture was successively heated at 50°C for 0.5 h, at 70°C for 0.5 h then at 100°C for 1 h. To this solution, t-BuOH (30.5 g, 411 mmol) in toluene (40 mL) was added at 100°C and the resulting mixture was refluxed for 7h. The solution was cooled to room temperature then successively washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na2SO4), and evaporated to give 67 g of the target product: m/z = 237 (M)+.
Step 2: synthesis of 3-methoxy-2-methylaniline (33)
TFA (40.7 mL, 548 mmol) was added to a solution of iV-(tert-butyloxycarbonyl)-3- methoxy-2-methylaniline, in dichloromethane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z = 138 (M+H)+. The TFA salt was transformed to the free aniline by treatment with NaHCO3.
Step 3: synthesis of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (34)
A solution OfBCl3 (1.0 M, 200 mL, 200 mmol) in CH2Cl2 was slowly added under nitrogen to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature was monitored during the addition and was kept below 10°C. The reaction mixture was stirred at 5°C for 0.5 h. Then, dry acetonitrile (13 mL, 246 mmol) was added at 5°C. After 0.5 h at 5°C, the solution was transferred into a dropping funnel and slowly added at 5°C to a suspension OfAlCl3 (26.7 g, 200 mmol) in CH2Cl2 (150 mL). After 45 min at 5°C, the reaction mixture was heated at 70°C under a nitrogen stream. After evaporation Of CH2Cl2, the temperature of the reaction mixture reached 65°C. After 12 h at 65°C, the reaction mixture was cooled at 0°C, poured onto ice (300 g), and slowly heated to reflux for 7h. After 2 days at room temperature, 6 N NaOH (50 mL) was added. The pH of the resulting solution was 2-3. The xylene layer was decanted. The organic layer was extracted with CH2Cl2. The xylene and CH2Cl2 layers were combined, successively washed with water, IN NaOH, and brine, dried (Na2SO4) and evaporated. The residue was triturated in diisopropyl ether at O0C, filtered off and washed with diisopropylether to give 13.6 g (40 %) of the title product as a yellowish solid: m/z = 180 (M+H)+.
Step 4: synthesis of 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3 ‘- methylacetophenone (35)
A solution of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (18.6 g, 104 mmol) in dioxane (50 mL) was added under nitrogen to a suspension of 4-isopropylthiazole-2- carbonyl chloride in dioxane (250 mL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution OfNaHCO3and AcOEt, organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90 %) of the title product 35.
Step 5: synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinoline (36)
Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of 2′-[[(4-iso- propylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3′-methylacetophenone (35, 30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 100°C overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et2O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl IN. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, filtered off and dried to give 26 g (88%) of the title product 36 as a brownish solid: m/z = 315 (M+H)+.
Synthesis of (hex-5-enyl)(methyl)amine (38)
Sodium hydride (1.05 eq) was slowly added at 0°C to a solution of iV-methyltrifluoro- acetamide (25 g) in DMF (140 mL). The mixture was stirred for Ih at room temperature under nitrogen. Then, a solution of bromohexene (32,1 g) in DMF (25 mL) was added dropwise and the mixture was heated to 70°C for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and evaporated to give 35 g of the target product 37 as a yellowish oil which was used without further purification in the next step.
Step B:
A solution of potassium hydroxide (187.7 g) in water (130 mL) was added dropwise to a solution of 37 (35 g) in methanol (200 mL). The mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was poured on water (100 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and the ether was distilled under atmospheric pressure. The resulting oil was purified by distillation under vacuum (13 mm Hg pressure, 50°C) to give 7,4 g (34 %) of the title product 38 as a colourless oil: 1H-NMR (CDCl3): δ 5.8 (m, IH), 5 (ddd, J= 17.2 Hz, 3.5 Hz, 1.8 Hz, IH), 4.95 (m, IH), 2.5 (t, J= 7.0 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J= 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, IH).
Preparation of 17-r2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxyl-
13-methyl-2,14-dioxo-3,13-diazatricvclori3.3.0.04‘6loctadec-7-ene-4-carboxylic acid
£46}
3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid 39 (500 mg, 3.2 mmol) in 4 mlDMF was added at 0°C to HATU (1.34 g, 3.52 mmol) and iV-methylhex-5- enylamine (435 mg, 3.84 mmol) in DMF (3 mL), followed by DIPEA. After stirring for 40 min at 0°C, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue dissolved in EtOAc (70 mL) and washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated NaCl (20 mL), dried (Na2SO4), and evaporated. Purification by flash chromatography (EtOAc/petroleum ether, 2:1) afforded 550 mg (68%) of the target product 40 as a colorless oil: m/z = 252 (M+H)+.
A solution of LiOH (105 mg in 4 mlof water) was added at 0°C to the lactone amide 40. After Ih, the conversion was completed (HPLC). The mixture was acidified to pH 2 – 3 with IN HCl, extracted with AcOEt, dried (MgSO4), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give 520 mg (88%) of the target product 41: m/z = 270 (M+H)+.
The l-(amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride 42 (4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to 41 (8.14 g, 30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were successively added. After 30 min at 0°C, the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2 x 20 mL), and dried (Na2SO4). Purification by flash chromatography (AcOEt/CH2Cl2/Petroleum ether, 1:1:1) afforded 7.41 g (60%) of the target product 43 as a colorless oil: m/z = 407 (M+H)+.
DIAD (1.02 mL, 5.17 mmol) was added at -15°C under nitrogen atmosphere to a solution of 43 (1.5 g, 3.69 mmol), quinoline 36 (1.39 g, 4.43 mmol) and triphenyl- phosphine (1.26 g, 4.80 mmol) in dry THF (40 mL). After 4.5 h, at -15°C, the reaction mixture was partitioned between ice-cold water and AcOEt, dried (Na2SO4) and evaporated. The crude material was purified by flash column chromatography (gradient of petroleum AcOEt/CH2Cl2, 1 :9 to 2:8) to give 1.45 g (56 %) of the target product 44: m/z = 703 (M+H)+.
A solution of 44 (1.07 g, 1.524 mmol) and Hoveyda-Grubbs 1st generation catalyst (33 mg, 0.03 eq) in dried and degassed 1,2-dichloroethane (900 mL) was heated at 75°C under nitrogen for 12 h. Then, the solvent was evaporated and the residue purified by silica gel chromatography (25% EtOAc in CH2Cl2). 620 mg (60%) of pure macrocycle 45 were obtained, m/z = 674 (M+H)+. 1H NMR (CDCl3): 1.18-1.39 (m, 12H), 1.59 (m, IH), 1.70-2.08 (m, 5H), 2.28 (m, IH), 2.38 (m, IH), 2.62 (m, 2H), 2.68 (s, 3H), 2.83 (m, IH), 3.06 (s, 3H), 3.19 (sept, J= 6.7 Hz, IH), 3.36 (m, IH), 3.83 (m, IH), 3.97 (s, 3H), 4.09 (m, 2H), 4.65 (td, J= 4 Hz, 14 Hz, IH), 5.19 (dd, J= 4 Hz, 10 Hz, IH), 5.31 (m, IH), 5.65 (td, J= 4 Hz, 8 Hz, IH), 7.00 (s, IH), 7.18 (s, IH), 7.46 (d, J= 9 Hz, IH), 7.48 (s, IH), 8.03 (d, J= 9 Hz, IH).
Step F
A solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 mL) was added to a stirred solution of ester 45 (620 mg, 0.920 mmol) in THF (30 mL) and MeOH (20 mL). After 16 h at room temperature, the reaction mixture was quenched with NH4Cl sat., concentrated under reduced pressure, acidified to pH 3 with HCl IN and extracted with CH2Cl2, dried (MgSO4) and evaporated to give 560 mg (88%) of carboxylic acid 46. m/z = 647 (M+H)+. 1H NMR (CDCl3): 1.11-1.40 (m, 8H), 1.42-1.57 (m, 2H), 1.74 (m, 2H), 1.88-2.00 (m, 2H), 2.13 (m, IH), 2.28 (m, IH), 2.40 (m, IH), 2.59 (m, 2H), 2.67 (s, 3H), 2.81 (m, IH), 2.97 (s, 3H), 3.19 (m, IH), 3.31 (m, IH), 3.71 (m, IH), 3.96 (s, 3H), 4.56 (dt, J= 4 Hz, 12 Hz, IH), 5.23 (m, 2H), 5.66 (m, IH), 7.01 (s, IH), 7.10 (s, IH), 7.22 (d, J= 10 Hz, IH), 7.45 (s, IH), 8.00 (d, J= 10 Hz, IH).
Example 5: Preparation of JV-ri7-r2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinolin-4- yloxyl – 13 -methyl-2, 14-dioxo-3 , 13 -diazatricyclol“ 13.3.0.04‘6loctadec- 7-ene-4-carbonyll (cvclopropyPsulfonamide (47) SIMEPREVIR
A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[l 3.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50°C for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2CI2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2CI2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 SIMEPREVIR as a white powder: m/z = 750 (M+H)+.
1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, IH), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, IH), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J= 13 Hz, IH), 5.04 (t, J= 11 Hz, IH), 5.37 (m, IH), 5.66 (m, IH), 6.21 (s, IH), 7.02 (s, IH), 7.22 (d, J= 10 Hz, IH), 7.45 (s, IH), 7.99 (d, J= 10 Hz, IH), 10.82 (broad s, IH).
…………………..
REFERENCES
- “Medivir Announces That Simeprevir (TMC435) Data Will Be Presented at the Upcoming AASLD Meeting”. Yahoo News. October 1, 2012. Retrieved November 6, 2012.
- Lin, TI; Lenz, O; Fanning, G; Verbinnen, T; Delouvroy, F; Scholliers, A; Vermeiren, K; Rosenquist, A et al. (2009). “In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor”. Antimicrobial agents and chemotherapy 53 (4): 1377–85. doi:10.1128/AAC.01058-08. PMC 2663092. PMID 19171797.
|displayauthors=suggested (help) - “Phase 3 Studies Show Simeprevir plus Interferon/Ribavirin Cures Most Patients in 24 Weeks”. hivandhepatitis.com. December 27, 2012.
- Medivir announces TMC435 in an expanded clinical collaboration. Medivir. 18 April 2012.
- Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. 6 March 2013.
- TMC-435350
Drugs Fut 2009, 34(7): 545 - Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350
Bioorg Med Chem Lett 2008, 18(17): 4853 - Synthesis of enantiomerically pure trans-3,4-substituted cyclopentanols by enzymatic resolution
Acta Chem Scand (1989) 1992, 46: 1127
PATENTS
- WO 2008092954
- WO 2007014926
- WO 2008092955
- WO 2000009543
- CN 102531932
- WO 2013061285
- WO 2011113859
- WO 2013041655
| WO2010097229A2 * | 26 Feb 2010 | 2 Sep 2010 | Ortho-Mcneil-Janssen Pharmaceuticals Inc | Amorphous salt of a macrocyclic inhibitor of hcv |
| WO2013037705A2 * | 7 Sep 2012 | 21 Mar 2013 | Fovea Pharmaceuticals | Aniline derivatives,their preparation and their therapeutic application |
| WO2005073195A2 * | 28 Jan 2005 | 11 Aug 2005 | Per-Ola Johansson | Hcv ns-3 serine protease inhibitors |
| WO2007014926A1 * | 28 Jul 2006 | 8 Feb 2007 | Tibotec Pharm Ltd | Macrocyclic inhibitors of hepatitis c virus |
The compound ritonavir, and pharmaceutically acceptable salts thereof, and methods for its preparation are described in WO94/14436. For preferred dosage forms of ritonavir, see US6,037, 157, and the documents cited therein: US5,484, 801, US08/402,690, and WO95/07696 and WO95/09614. Ritonavir has the following formula:
Rare Diseases And Orphan Drugs: FDA’s FDASIA Calendar
The FDA Safety & Innovation Act (S. 3187), FDASIA, is signed by President Obama in July 2012. FDASIA provides for the development of effective and safe treatments for rare diseases and orphan drug development in the United States. FDASIA provides for the following :
• Acceleration of new medical treatments for patient access
• Development of Humanitarian Use Devices (medical devices) for small patient populations
• “Breakthrough Therapy” designation for drugs that show early promise in the development process
• Consultation with rare disease medical experts
• Creation of a rare pediatric disease priority review voucher incentive program.
The task of implementing FDASIA is complex and a large undertaking. FDASIA is a 140-page law that is divided into 11 separate sections, with each section addressing different aspects of the new drug and device law. To ensure that FDASIA is implemented successfully, the FDA set up a steering committee. One of the committee’s projects is to create a table that tracks…
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Otsuka and Lundbeck’s Once-Monthly Abilify Maintena(R) (Aripiprazole) Now Approved in Europe
Otsuka and Lundbeck’s Once-Monthly Abilify Maintena(R) (Aripiprazole) Now Approved in Europe for Maintenance Treatment of Schizophrenia in Adult Patients Stabilized with Oral Aripiprazole
do not forget to see my old blog post, contains synthesis
Preventing relapse is critical in the treatment of schizophrenia. Pivotal
studies, that supported the EU submission, demonstrate that Abilify
Maintena can reduce the risk of relapse relative to placebo and is
non-inferior to oral aripiprazole in patients with schizophrenia1,2
-- The approval of Abilify Maintena now provides patients with schizophrenia
access to a once-monthly formulation with established efficacy together
with a tolerability profile that is comparable to that of oral ABILIFY(R)
(aripiprazole)2
-- At the end of the randomized, double-blind treatment phase in one of the
pivotal trials, 93 percent of patients reported being extremely, very or
somewhat satisfied with Abilify Maintena treatment3
-- Abilify Maintena is the only dopamine D2 partial agonist in a
once-monthly, injectable form to receive marketing authorization in
Europe for maintenance treatment of schizophrenia
-- Abilify Maintena will be the first commercialized product in Europe from
the global alliance between Otsuka and Lundbeck which is focused on
developing Central Nervous System (CNS) therapies worldwide
TOKYO & COPENHAGEN, Denmark--(BUSINESS WIRE)--November 21, 2013--
Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) today announced marketing authorization approval from the European Commission for Abilify Maintena (aripiprazole), an intramuscular (IM) once-monthly injectable formulation for maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole.
Abilify Maintena reduces the risk of relapse relative to placebo over the long-term and provides effective treatment of schizophrenia.(1,2) It has a tolerability profile similar to oral aripiprazole(1) , and demonstrated statistically significant benefits on patients’ personal and social functioning as compared to placebo.(1,4) 93 percent of patients treated with Abilify Maintena were extremely, very or somewhat satisfied with their treatment at the end of the double-blind treatment phase.(4)
“We strongly believe the schizophrenia community will welcome the availability of Abilify Maintena to help improve outcomes for patients living with schizophrenia. As a company, our focus is to develop treatments to help protect against relapse and preserve brain function,” said Ole Vahlgren, CEO & President, Otsuka Europe. “We must partner with health care professionals and caregivers to help patients get the best treatments that focus on reducing the risk of relapse.”
“Studies have shown that the early use of long-acting injectables can prevent a person with schizophrenia from experiencing a relapse,”(5) said Ole Chrintz, SVP International Markets & Europe, Lundbeck. “Efficacy is important, but a treatment for a chronic condition such as schizophrenia also needs to be well tolerated so patients will stay on it over the long-term. We believe Abilify Maintena meets this need.”(1,2,3)
About the Studies
The efficacy of Abilify Maintena was demonstrated in two double-blind, Phase III, randomized trials. The safety profile for Abilify Maintena was demonstrated to be similar to that of oral ABILIFY. The most frequently observed adverse drug reactions (ADRs) reported in >=5 percent of patients in two double-blind controlled clinical trials of Abilify Maintena were weight increases (9.0 percent), akathisia (7.9 percent), insomnia (5.8 percent), and injection site pain (5.1 percent).(1,2)
About Abilify Maintena
Abilify Maintena is the only dopamine D2 partial agonist in once-monthly, injectable form to receive marketing authorization for maintenance treatment in schizophrenia. Physicians now have an alternative treatment option, with a tolerability profile comparable to the well-established oral ABILIFY, to address the on-going need to reduce the risk of relapse in patients with schizophrenia.
The European label states that Abilify Maintena is a powder and solvent for prolonged-release suspension for intra-muscular (IM) injection. It is a once-monthly formulation of aripiprazole in a sterile lyophilized powder that is reconstituted with sterile water. Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole.
After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.
About Schizophrenia and Disease Relapse
Schizophrenia is a disease characterized by a distortion in the process of thinking and of emotional responsiveness. It most commonly manifests as hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and is accompanied by significant social or occupational dysfunction. Onset of symptoms typically occurs in young adulthood, and the condition is chronic, often requiring lifelong treatment to mitigate symptoms.
Relapse of schizophrenia refers to an exacerbation or acute psychotic break that is characterised primarily by the emergence of positive symptoms such as hallucinations, delusions and disordered thinking.(6)
Relapse can occur when a patient no longer responds to antipsychotic medication, does not take the medication as prescribed, or stops taking their medication altogether. There are many reasons patients stop taking their medication, including poor insight about their illness, side effects from current treatments, complicated medication regimen or lack of support from family.(7) Abilify Maintena is able to significantly reduce the risk of relapse in patients with schizophrenia.(1)
It has been estimated that schizophrenia affects approximately one percent of the adult population in the U.S. and Europe, and approximately 24 million people worldwide.(8,9) In Europe there are approximately 4.4 million adults with schizophrenia,(10) prevalent equally in both genders.(11,12) While there is no cure for the disease, symptoms and risk of relapse can be managed in most patients with appropriate antipsychotic treatment. However, when the disease is not managed, patients are at increased risk of disease relapse, which can cause the re-emergence or worsening of psychotic symptoms.(13)
Schizophrenia places a significant burden on society. It is regarded among the most financially costly illnesses and is according to the World Health Organization (WHO), the 8(th) leading cause of DALYs (lost healthy years) worldwide among patients between the age of 15-44.(11) With 50 percent of patients not receiving appropriate care and 80 percent of patients relapsing within the first 5 years,(14) there is a significant unmet need to be addressed in schizophrenia.
About the Lundbeck and Otsuka Global Alliance
Lundbeck and Otsuka established a global alliance in November 2011 to bring to bear their considerable experience and resources in the CNS area to introduce next-generation treatments for conditions such as schizophrenia, depression, Alzheimer’s disease and alcohol dependency.
About Otsuka Pharmaceutical Co., Ltd.
Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: ‘Otsuka-people creating new products for better health worldwide.’ Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and nutraceutical products for the maintenance of everyday health.
In pharmaceuticals, Otsuka is a leading firm in the challenging area of mental health and also has research programs for several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate more powerfully than words how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.
Otsuka is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The chairman Akihiko Otsuka is the third generation of Otsuka family members to lead the business, whose origins date from 1921. The Otsuka Group employs approximately 42,000 people globally and its products are available in more than 80 countries worldwide. Consolidated sales were approximately EUR10 billion or USD 13 billion for fiscal year 2012 (4/1/2012-3/31/2013). Otsuka Pharmaceutical welcomes you to visit its global website at https://www.otsuka.co.jp/en/
About H. Lundbeck A/S
Lundbeck is a global pharmaceutical company highly committed to improving the quality of life of people living with brain diseases. For this purpose, Lundbeck is engaged in the entire value chain throughout research, development, production, marketing and sales of pharmaceuticals across the world. The company’s products are targeted at disorders such as depression and anxiety, psychotic disorders, epilepsy, Huntington’s, Alzheimer’s and Parkinson’s diseases. Lundbeck’s pipeline consists of several mid- to late-stage development programmes.
Lundbeck employs more than 5,800 people worldwide, 2,000 of whom are based in Denmark. We have research in 57 countries and our products are registered in more than 100 countries. We have research centers in Denmark, China and the United States and production facilities in Italy, France, Mexico, China and Denmark. Lundbeck generated revenue of approximately DKK 15 billion in 2012. For additional information, we encourage you to visit our corporate site http://www.lundbeck.com.
REFERENCES:
1. Kane, JM et al. Aripiprazole intramuscular depot as maintenance treatment in
patients with schizophrenia: a 52-week, multicenter, randomized,
double-blind, placebo-controlled study. J Clin Psychiatry 2012;73(5):617-62
2. Fleischhacker WW, Sanchez R, Perry PP, et al. Aripiprazole once-monthly for
the treatment of schizophrenia: a double-blind, randomized, non-inferiority
study vs. oral aripiprazole. Annual Meeting of the American Psychiatric
Association, 18--22 May, 2013 (poster).
3. Sanchez R, et al. Patient-reported Outcomes with
Aripiprazole-Intramuscular-Depot for Long-term Maintenance Treatment in
Schiziphrenia. NR6-42 2012 (poster)
4. Carson WH, Perry P, Sanchez R, et al. Effects of a Once-Monthly Formulation
of Aripiprazole on Secondary Efficacy Outcomes in Maintenance Treatment of
Schizophrenia. Institute on Psychiatric Services meeting, October 4--7, 2012
(Poster)
5. Long-acting injectable antipsychotics in the treatment of schizophrenia:
their role in relapse prevention. Agid O, et al. Expert Opin. Pharmacother.
(2010) 11(14):2301-2317
6. Ayuso-Gutierrez JL, del Rio Vega JM. Factors influencing relapse in the
long-term course of schizophrenia. Schizophr Res. 1997; 28(2-3): 199-206
7. Baloush-Kleinman V, et al. Adherence to antipsychotic drug treatment in
early-episode schizophrenia: a six-month naturalistic follow-up study.
Schizophr Res. 2011;130(1-3):176-81.
8. National Institute of Mental Health (NIMH). Health Topics: Statistics.
Available at http://www.nimh.nih.gov/statistics/1SCHIZ.shtml. Accessed
October 22, 2013
9. World Health Organization (WHO). Schizophrenia Fact Sheet. 2010. Available
at: http://www.who.int/mental_health/management/schizophrenia/en/. Accessed
October 22, 2013.
10. World Health Organization (WHO) The global burden of disease:2004 update
(2008)
11. National Institute of Mental Health (NIMH). The Numbers Count: Mental
Disorders in America. 2010. Available at
http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorde
rs-in-America/index.shtml#Schizophrenia. Accessed October 22, 2013
12. Regier DA, et al. The de facto US mental and addictive disorders service
system. Epidemiologic catchment area prospective 1-year prevalence rates of
disorders and services. Arch Gen Psychiatry. 1993;50(2):85-94.
13. American Psychiatric Association. Practice guideline for the treatment of
patients with schizophrenia. Second edition. 2004. Available at
http://psychiatryonline.org/content.aspx?bookid=28§ionid=1665359.
Accessed October 28, 2013
14. Robinson D, et al. Predictors of relapse following response from a first
episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry.
1999;56(3):241-247
read my earlier blog post
https://newdrugapprovals.wordpress.com/2013/02/07/the-european-medicines-agency-ema-approves-otsukas-aripiprazole-abilify-for-the-treatment-of-moderate-to-severe-manic-episodes-in-bipolar-i-disorder-in-adolescents/
Bayer, Onyx win early FDA OK for Nexavar (sorafenib) in thyroid cancer
The U.S. Food and Drug Administration said on Friday it has expanded the approved use of the cancer drug Nexavar to include late-stage differentiated thyroid cancer.
Differentiated thyroid cancer is the most common type of thyroid cancer, the FDA said. The National Cancer Institute estimates that 60,220 people in the United States will be diagnosed with it and 1,850 will die from the disease in 2013.
The drug, made by Germany’s Bayer AG and Onyx Pharmaceuticals, is already approved to treat advanced kidney cancer and liver cancer that cannot be surgically removed. Onyx was acquired by Amgen Inc earlier this year.
READ ABOUT SORAFENIB IN MY EARLIER BLOGPOST
https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/
SCRIP Awards 2013 -Best Company in an Emerging Market – Dr Reddy’s Laboratories – India, Novartis’s Bexsero, Best New Drug
The SCRIP Awards 2013 celebrated achievements in the global biopharma industry last night at the Lancaster, London.
Hosted by Justin Webb, the evening was a fantastic mix of dining, entertainment and awards.
Among the winners were:
- Novartis’s Bexsero, Best New Drug
- Genmab, Biotech Company of the Year
- Regeneron Pharmaceuticals and Sanofi’s Phase IIa study dupilumab in asthma, Clinical Advance of the Year
You can view the full roll of honour by clicking on the button below.
It was a great night and we would like to thank all those who entered and attended this year’s awards.
Finally congratulations to our winners and a huge thanks to our sponsors for helping us make it such a fantastic success.
Don’t forget to check our website in the next couple of days for all the pictures from the night.
2013 Winners
Best Company in an Emerging Market – Sponsored by Clinigen Group
- Dr Reddy’s Laboratories – India
Best Technological Development in Clinical Trials
- Quintiles’s Infosario Safety
Best Partnership Alliance
- AstraZeneca with Bristol-Myers Squibb and Amylin in diabetes
Financing Deal of the Year
- Mesoblast’s equity financing of Aus$170m
Best Advance in an Emerging Market
- Novartis’s Jian Kang Kuai Che Healthcare Project in China
Clinical Advance of the Year – Sponsored by Quintiles
- Regeneron Pharmaceuticals and Sanofi’s Phase IIa study dupilumab in in asthma
Licensing Deal of the Year – Sponsored by Hume Brophy
- AstraZeneca and Horizon Discovery for the development and commercialization of the HD-001 kinase target program for multiple cancer types
Executive of the Year
- Roch Doliveux, chairman and chief executive officer of UCB
Biotech Company of the Year
- Genmab
Best Contract Research Organization
- Quintiles
Management Team of the Year
- Regeneron Pharmaceuticals’ CEO Leonard S Schleifer and CSO George D Yancopoulos
Best New Drug – Sponsored by INC Research
- Novartis’ Bexsero (meningococcal group B vaccine)
Pharma Company of the Year – Sponsored by ICON
- Astellas
Lifetime Achievement Award
- Prof Dr Désiré Collen
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DR ANTHONY MELVIN CRASTO Ph.D
New Drug Approvals 