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A tiny pain-free jab every two weeks could be the future of cholesterol-lowering for high-risk patients, according to clinical researchers gathered in Amsterdam for the European Society of Cardiology congress.
Eli Roth at the University of Cincinnati said that two companies are currently neck and neck in the race to bring the first PCSK9 antibody to market. Partners Sanofi and Regeneron may have the edge, with Phase III data on their fully human monoclonal antibody alirocumab slated to be presented before the end of the year, while the chief competition comes from Amgen with its antibody AMG 145, said Dr Roth. Both antibodies can be delivered via subcutaneous auto-injectors, which many patients say they prefer to taking daily pills, he added.
http://www.pharmatimes.com/Article/13-09-02/Antibody_lipid_treatments_enter_final_furlong.aspx
Alirocumab is a human monoclonal antibody designed for the treatment ofhypercholesterolemia.[1]
This drug was discovered by Regeneron Pharmaceuticals and is being co-developed by Regeron and Sanofi.
THERAPEUTIC CLAIM Treatment of hypercholesterolemia
CHEMICAL NAMES
1. Immunoglobulin G1, anti-(human neural apoptosis-regulated proteinase 1) (human
REGN727 heavy chain), disulfide with human REGN727 κ-chain, dimer
2. Immunoglobulin G1, anti-(human proprotein convertase subtilisin/kexin type 9
(EC=3.4.21.-, neural apoptosis-regulated convertase 1, proprotein convertase 9,
subtilisin/kexin-like protease PC9)); human monoclonal REGN727 des-448-
lysine(CH3-K107)-1 heavy chain (221-220′)-disulfide with human monoclonal
REGN727 light chain dimer (227-227”:230-230”)-bisdisulfide
MOLECULAR FORMULA C6472H9996N1736O2032S42
MOLECULAR WEIGHT 146.0 kDa
SPONSOR Regeneron Pharmaceuticals
CODE DESIGNATION REGN727, SAR236553
CAS REGISTRY NUMBER 1245916-14-6
Boston, MA–(Marketwire) – While patent expirations on many top selling medicines are spurring the research-based drug industry to embrace new development paradigms to replenish sparse R&D pipelines, drug developers need to more fully identify and address root causes of R&D inefficiency, according to the Tufts Center for the Study of Drug Development.
read all at
EMD Serono
Teriflunomide,
CAMBRIDGE, Mass.–Aug. 30, 2013–(BUSINESS WIRE)–Genzyme, a Sanofi company (EURONEXT: SAN and NYSE: SNY), announced today that the European Commission has granted marketing authorization for Aubagio® (teriflunomide) 14 mg, a once-daily, oral therapy indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).
read all at
http://www.pharmalive.com/ec-approves-genzyme-s-aubagio-for-ms
Teriflunomide (trade name Aubagio, marketed by Sanofi, also known as A77 1726) is the active metabolite of leflunomide.[1]Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[2] 2-year results were positive.[3] However, the subsequent TENERE head-to-head superiority trial reported that “although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide.”[4] The drug was approved by the FDA on September 13, 2012.[5]
Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions.[6]
Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system.[7]
It has been found that teriflunomide blocks the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.[8]
→
↔
The structure which results from ring opening can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z enol being the most stable and therefore most predominant form.
Space filling model of the E isomer of teriflunomide
|source= ignored (help)
SYNTHESIS
………………………
http://www.google.com/patents/WO2014177978A3?cl=en
Formula i
Teriflunomide is an immunosuppressant, acting as a tyrosine kinase inhibitor. It is also evaluated in the treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis. An oral film coated tablet containing teriflunomide as the active ingredient is marked in the United States by Sanofi Aventis US using brand AUBAGIO™. AUBAGIO is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
U.S. Patent No. 5,679,709 appears to claim teriflunomide and its pharmaceutically acceptable salts, the same patent also further covers pharmaceutical composition and method of administering top a patients suffering from autoimmune disease.
U.S. Patent No. 5,494,91 I disclosesthe process for the preparation of teriflunomide by reacting 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline in the presence of acetonitrile to yield Leflunomide with on further hydrolysis with aqueous sodium hydroxide solution in methanol gives teriflunomide of formula I.
U.S. Patent No. 5,990,141 discloses the process for the preparation of teriflunomide by reacting 4-trifluoromethyl aniline with cyano acetic acid ethyl ester to yield cyanoaceto-(4-trifluromethyl)-aniline, with on further reacted with acetyl chloride in the presence of sodium hydride base and THF and acetonitrile solvent to give teriflunomide of formula I.
U.S. patent No. 6,365,626 discloses the process for the preparation of teriflunomide by reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetyl chloride in the presence of sodium hydride to give teriflunomide of formula I.
U.S. Patent No. 6,894,184 discloses the process for the preparation of teriflunomide involves reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetic anhydride in the presence of base to give teriflunomide of formula I.
International PCT application No. WO 2009/147624 discloses the process for the preparation of teriflunomide involves condensation of ethyl-2-cyano-3-hydroxybut-2-enoate and 4-(trifluoromethyl) aniline in presence of xylene solvent at reflux temperatures for 16 hours to give teriflunomide of formula I.
preparation of teriflunomide (I) comprises steps of;
1 ) condensation of cyanoacetic acid of formula (II) with 4-trifluoromethyl aniline of formula (III) in the presence of chlorinating agent to give 2-cyano-N-[4-(trifluromethyl)phenyl]acetamide of formula (IV);
(II I) (IV)
2) acetylation of 2-cyano-N-[4-(trifluromethyl)phenyl] acetamide of
formula (IV) with an acetylating agent in the presence of base and suitable solvents to yield teriflunomide of formula (I).
EXAMPLE 1 : Preparation of 2-cvano-N-f4-(trifluoromethyl> phenyl! acetamide (IV)
A round bottom flask is charged with cyanoacetic acid (100 g) and phosphorous pentachloride and tetrahydrofuran (300 ml) and the reaction mixture is stirred at room temperature for 4 hours. 4-trifluoromethyl aniline (161 g) dissolved in tetrahydrofuran (100 ml) is slowly added to the reaction mixture and stirred for completion of reaction. The resultant reaction mass is cooled and separated solid is filtered and washed with slurry of Isoproapnol and cyclohexane and dried under reduced pressure to afford the title compound. Weight: 196 gm.
Purity by HPLC: 98%
EXAMPLE 2: preparation of 2-cyano-3-hvdroxy-N-f4-( trifluoromethyl) phenyl] but-2-enamide (Teriflunomide crude)
A round bottom flask is charged with 2-cyano-N-[4-{trifluromethyl} phenyl] acetamide (100g), sodium hydroxide (70 gm) and dimethyl formamide is added and the reaction mixture is stirred for 30 minutes. Isopropenyl acetate (60 ml) is added slowly and the resultant mixture is stirred for about 4-5 hours at room temperature. After completion of the reaction, the resulting reaction mixture is diluted with water and acidified with Cone. HCI solution and stirred for solid separation. The separated solid is filtered and washed with water and dried under reduced pressure to afford Teriflunomide.
The obtained teriflunomide is charged in round bottom flask and aqueous solution of sodium hydroxide solution (29.6 g in 300 ml water) is added slowly at 25-35°C and stirred for 1 to 2 hours. The mixture is brought to 5 to 10°C and dichloromethane is added, the mixture is stirred for 15 minutes. The organic and the aqueous layer are separated, and the resultant aqueous layer is acidified with aq. Hcl and stirred. The separated solid is filtered and washed with water and dried under vacuum at 65-70°C for 10-12 hours to afford teriflunomide.
Weight: 101 gm
Purity by HPLC: 95%
EXAMPLE 3; Purification of Teriflunomide:
Teriflunomide (5 g) is charged into a flask followed by addition of acetonitrile (125 ml) and heated to reflux and stirred for 2 hours. The resultant reaction solution is filtered through highflow bed to obtain a clear solution and cooled to room temperature and stirred for solid separation. The separated solid is filtered, washed with Isopropanol (50 ml) and dried under vacuum to afford pure teriflunomide.
Weight: 3.8 gm
Purity by HPLC: 99.7%
…………………………………………………………………………………………………………
EP 0527736; JP 1993506425; JP 1999322700; JP 1999343285; US 5494911; US 5532259; WO 9117748
5-Methylisoxazole-4-carboxylic acid (I) was converted to the corresponding acid chloride (II) upon refluxing with SOCl2. Coupling of acid chloride (II) with 4-(trifluoromethyl)aniline (III) produced anilide (IV). Finally, isoxazole ring opening in the presence of NaOH gave rise to the title cyano amide.
|source= ignored (help)Teriflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, is the active metabolite of leflunomide a synthetic, low-molecular-weight drug currently used in the treatment of rheumatoid arthritis. The mechanisms by which teriflunomide exerts its antiinflammatory, antiproliferative and immunosuppressive effects are not yet completely understood, although inhibition of pyrimidine biosynthesis (via suppression of DHODH) and interference with tyrosine kinase activity both appear to be involved. Based on its efficacy shown in animal models of experimental allergic encephalomyelitis, teriflunomide was tested in a phase II study in patients with multiple sclerosis with relapses. Recruitment is ongoing for a phase III study to determine the efficacy of teriflunomide in reducing the frequency of relapses and accumulation of disability in multiple sclerosis patients.
The chemical name of Teriflunomide is 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is C12H9F3N2O2 and molecular weight is 270.207.
Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.
Teriflunomide was first disclosed and claimed in U.S. Pat. No. 5,679,709 but this patent does not mention any process of preparation for salt formation.
U.S. Pat. No. 5,494,911, U.S. Pat. No. 5,990,141 disclose various processes for preparing Teriflunomide. These patents do not disclose process for preparation Teriflunomide salts or mention any its polymorphic form.
EP 2280938 A2
HISTORY OF SYNTHESIS
The chemical name of Teriflunomide is
2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is Ci2H9 F3N2O2 and molecular weight is 270.207.
Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.
Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.
US patent no. 5,494,911 discloses a process for preparation of Teriflunomide as shown in given below
4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below
Teriflunomide (I)
The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).
US patent no. 6,365,626 discloses a process for preparation of Teriflunomide which is as given in below
Teriflunomide
ONE MORE
http://pubs.rsc.org/en/content/articlelanding/2012/cc/c2cc36352f GET ABOVE DETAILS HERE
Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.
Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.
[H] US patent no. 5,494,911 discloses a process for preparation of Teriflunomide in Example-4 as shown in given below scheme-I
(V) (IV) (VI) (D
Scheme-I
The proces; 5 involves re acting 5-metlr
4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below scheme-II.
Teriflunomide (I)
Scheme-II The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).
US patent no. 6,365,626 discloses a process for preparation of Teriflunomide in Fig. 19 which is as given in below scheme-Ill.
Teriflunomide
(I)
Scheme-Ill The process involves reacting 4-trifluoromethyl aniline (IV) with cyanoacetic acid (Ha) to give compound of formula (VII). This compound is further reacted first with sodium hydride and then with acetylchloride to give Teriflunomide (I)
………………………….
Example-1 Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).
Yield: 84.6%Example-2 ] Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.
Yield: 71.0%
Purity: 99.4%
! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);
7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.
13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3, 122.2, 126.5, 126.9, 142.1, 167.4,
187.8 ppm.
MS(FD) : m/e 269(M”, 100). [88] IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,
842, 684 cm-1.
…………………
see
http://pubs.rsc.org/en/Content/ArticleLanding/2004/OB/b312682j#!divAbstract
………………………………
http://www.google.com/patents/CN103848756A?cl=en
Currently, for the preparation of teriflunomide mainly in the following three categories:
The first synthetic methods: mainly 5-methyl-isoxazole-4-carboxylic acid starting materials or by Synthesis of 5-methyl-isoxazole-4-carboxylic acid intermediate, then reacted with 4- trifluoromethyl base – aniline was synthesized teriflunomide, specific synthetic route is as follows:
[0007]
The general reaction step above normal class methods, not easy to intermediate purification, total yield is low, and the synthesis process using a large number of chloride corrosion of equipment can easily produce large amounts of acid mist and acidic water, thus polluting the environment .
The second class of methods: 2-cyano-acetic acid derivatives and 4-trifluoromethyl aniline. Such methods will be first prepared as a 2-cyano acetic acid chloride, and then 4-trifluoromethyl-aniline to give the corresponding amide, and then acetyl chloride for
With, the condensation reaction between the molecules to give the desired product, the synthesis route is as follows:
This class methods used in the reaction process large amounts of chloride reagent for large equipment and environmental damage.
The third method: This method is quite similar to the second type of method, mainly in the 2-cyano-acetic acid derivatives and 4-trifluoromethyl-aniline; The method of the second type is different, In the last step with 1-methyl-2-chloro-propylene oxide as raw materials to build α, β-unsaturated nitrile of the enol structure, i.e., to give the desired product, the synthesis route is as follows:
Teriflunomide Preparation Example 18 [0185] Implementation
Example 17 was obtained as a pale yellow solid of 61.2g crude compound was used directly in the synthesis of teriflunomide. In a 2L round bottom flask was added compound 27.2g (0.32mol) having the structure shown in formula IV, dry dioxane (620mL), sodium hydride 4g (0.16mol, in g / mL count, mass volume ratio 60% saving in kerosene), calcium hydride
6.7g (0.16mol), 15 ° C was stirred for I h, then slowly added dropwise in Example 17 was obtained as a pale yellow solid compound 61.2g (0.32mol) embodiment of dioxane 200mL, approximately I hour addition was complete, After the addition was complete the reaction was heated to reflux, the reaction at 80 ° C for 24 hours, the reaction process using a nitrogen blanket. After completion of the reaction was added 500mL of ice water to quench the reaction, with 2mol / L of HCl (aq.) And the reaction solution was adjusted to neutral pH, and extracted with EtOAc three times each in an amount of 500mL, and the combined organic phase was washed with saturated aqueous NaCl solution 800mL, dried over anhydrous Na2SO4, concentrated under reduced pressure, the mixed solution was twice recrystallized from methanol i_PrOH, the volume ratio of 1-PrOH and methanol is 2: 1, by volume of each recrystallized with a mixed solution of methanol with i_PrOH for 600mL, the crystallization temperature of 10 ° C, to give 58.8g of white solid compound in a yield of 66%, the total yield of 54% ο
using mass spectrometry, nuclear magnetic resonance spectroscopy and NMR spectra of the resulting white solid carbon compound structures were identified. MS data [M-H +] = 269.1, H NMR data = 1H-NMR (DMSO-Cie) δ the white solid compound: 10.88 (s, 1Η), 10.07 (br, s, 1H), 7.79 ( d, 2H), 7.66 (d, 2H), 2.26 (s, 3H), carbon NMR spectral data for: 13C-NMR (DMS0-d6) δ: 23.5,80.2,119.1,119.9,120.3,122.4,122.0, 123.5,125.3,126.2,141.8,166.2,186.0. Structural analysis by a white solid compound obtained in the present embodiment example for teriflunomide. Cases detected by HPLC obtained teriflunomide the embodiment of purity, calculated based on the peak area normalization method available, the present embodiment obtained teriflunomide a purity of 99.9%.
………………………
http://www.google.com/patents/WO2015029063A2?cl=en
Scheme-A
Scheme-A
Pure Teriflunomide ………………………………………….Crude Teriflunomide
xamples
Example- 1: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (Formula-2)
Methylene chloride (125 ml) and dimethyl formamide (2.87 gms) were added to 5-methylisoxazole-4-carboxylic acid (25 gms) at 25-30°C. Heated the reaction mixture to 35-40°C and thionyl chloride (47.59 gms) was slowly added and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. To the obtained compound, dichloromethane was added at 25-30°C. Distilled off the solvent completely from the reaction mixture. Acetonitrile (50 ml) was added to the obtained compound at 25-30°C and slowly added to a mixture of acetonitrile (300 ml) and 4-(trifluoromethyl)aniline (64.45 gms) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (225 ml), followed by activated carbon (2.5 gms) were added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (250 ml) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 39.8 gms; Melting point: 165-168°C. Purity by HPLC: 99.63%.
Example-2: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazoIe-4-carboxamide (FormuIa-2)
Methylene chloride (15 Its) and dimethyl formamide (40 ml) were added to 5-methylisoxazole-4-carboxylic acid (3 kgs) at 25-30°C. Thionyl chloride (5.70 kgs) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dichloromethane was added at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dissolved the obtained compound in acetonitrile (6.0 Its) at the same temperature. Slowly added to a mixture of acetonitrile (36 Its) and 4-(trifluoromethyl)aniline (7.70 kgs) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. After completion of the reaction, filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (27 Its), followed by activated carbon (30 gms) was added to obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (30 Its) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water. To the obtained wet compound, toluene (9 Its) was added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 4.7 kg.
Example-3: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-l)
Methanol (150 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (50 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 2 hours at 0-5°C. Water was added to the reaction mixture. Adjust the pH of the reaction mixture to 7.5 by using dilute hydrochloric acid at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 46.0 gms;
Example-4: Preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-1)
Dimethylformamide (300 ml) was added to (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide (50 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with dimethyl formamide. To the obtained filtrate, methanol (350 ml) was added at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the title compound. Yield: 41 gms;
Melting point: 228-231°C; Water content: 0.06% w/w; Phenyl isoxazole impurity: 0.004%; Purity by HPLC: 99.97%.
Particle size distribution before micronisation: D10: 6.71 μιτι; D50: 34.4 μπι; D90: 109.8 μηι; Particle size distribution after micronisation: DIO: 1.35 μητ, D50: 4.52 μητ, D90: 10.26 μιη.
The P-XRD of the obtained compound is shown in figure- 1.
The DSC thermogram of the obtained compound is shown in figure-2.
Reference Example- 1: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethylphenyl)-amide according to US5494911 (Formula-1)
Methanol (74 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (20 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution {prepared by dissolving sodium hydroxide (3.26 gms) in water (74 ml)} was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 1 hour at 0-5°C. After completion of the reaction, 20% aqueous hydrochloric acid solution was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 8.7 gms.
The P-XRD pattern of the obtained compound is shown in figure-3.
The DSC thermogram of the obtained compound is shown in figure-4.
………………….
…………….
SPECTROSCOPY DATA
nmr……….http://www.medkoo.com/Product-Data/Teriflunomide/QCData-Teriflunomide-BBC20130720-web.pdf
http://file.selleckchem.com/downloads/nmr/S416901-Teriflunomide-HNMR-Selleck.pdf
17= US2011/0105795A1
1H NMR AND 13C NMR
above 13C NMR
! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);
REF EP 2280938 A2
Example-1 Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).
Yield: 84.6% Example-2 Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.
Yield: 71.0%
Purity: 99.4%
! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);
7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.
13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3,
122.2, 126.5,
126.9, 142.1, 167.4,
187.8 ppm.
MS(FD) : m/e 269(M”, 100).
IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,
842, 684 cm-1.
1H NMR PREDICT
COSY
HPLC
HPLC method of analysis:
N-(4′-trifluoromethylphenyI)-5-methylisoxazole-4-carboxamide of formula-2:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Cosmicsil APT CI 8, 100 x 4.6 mm, 3 μιη (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 20 μί; Run time: 40 min; Diluent: Mobile phase; Needle wash: Tetrahydrofuran; Elution: Isocratic; Mobile phase: 5 ml of triethyl amine into a 650 ml of water. Adjusted the pH to 3.4 with dil. Orthophosphoric acid and filter this solution through 0.22 μπι nylon membrane filter paper and sonicate to degas it. (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethyl phenyl)-amide compound of formula- 1:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Kromasil 100 C18, 250 x 4.6 mm, 5 μηι (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 250 nm; Column Temperature: 35°C; Injection volume: 5 μί; Run time: 37 min; Diluent: 0.01 M dipotassium hydrogen orthophosphate in 1000 ml of water; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Buffer (70:30 v/v); Buffer: 1 ml of ortho phosphoric acid into a 1000 ml of water and 3.0 grams of 1 -octane sulfonic acid sodium salt anhydrous. Adjust pH to 6.0 with potassium hydroxide solution and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it……..http://www.google.com/patents/WO2015029063A2?cl=en
| WO2009147624A2 * | 3 Jun 2009 | 10 Dec 2009 | Alembic Limited | A process for preparing teriflunomide |
| WO2011004282A2 * | 22 Jun 2010 | 13 Jan 2011 | Alembic Limited | Novel polymorphic form of teriflunomide salts |
| US5494911 | 24 Oct 1990 | 27 Feb 1996 | Hoechst Aktiengesellschaft | Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use |
| US5679709 | 7 Jun 1995 | 21 Oct 1997 | Hoechst Aktiengesellschaft | N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide or salts, used for reduction of b-cell produced self-antibodies |
| US5990141 | 6 Jan 1995 | 23 Nov 1999 | Sugen Inc. | Administering 5-methyl-isoxazole-4-carboxylic acid-n-(4-trifluoromethyl)anilide or 2-cyano-3-hydroxy-n-(4-trifluoro-methyl)phenyl-2-butenamide; antitumor,-carcinogenic and proliferative agents; kinase inhibitors |
GLIPTINS: BETTER APPROACH FOR TYPE 2 DIABETES
Diabetes Mellitus is a metabolic disorder which results from defects in insulin secretion, insulin action, or both, further characterized by hyperglycemia, and causes long term damage and failure of various organs. It is estimated that 366 million people had Diabetes Mellitus in 2011; by 2030 this would have risen to 552 million. Many oral hypoglycaemic agents are…
read more: http://www.pharmatutor.org/articles/gliptins-better-approach-type-2-diabetes
TOLVAPTAN
may 30 2013
(Tokyo, Japan, May 30, 2013) – Otsuka Pharmaceutical Co., Ltd. Today announced it filed an application with the Pharmaceutical and Medical Devices Agency in Japan (PMDA) to market its novel compound tolvaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine in November 2012. The MHLW has designated tolvaptan as an Orphan Drug.http://www.otsuka.co.jp/en/release/2013/0603_02.html
Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.
Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]
Chemical synthesis:[5] 
WHIPPANY, N.J. and SOUTH SAN FRANCISCO, Calif., Aug. 30, 2013 /PRNewswire/ — Bayer HealthCare and Onyx Pharmaceuticals, Inc. (NASDAQ: ONXX) announced today that the European Commission has approved Stivarga® (regorafenib) tablets for the treatment of adult patients with metastatic colorectal cancer (mCRC).
In September 2012, Stivarga was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
READ ALL AT http://www.pharmalive.com/ec-approves-bayer-s-stivarga
OLD ARTICLE PASTED
Regorafenib
cas 755037-03-7
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate
February 25, 2013 — The U.S. Food and Drug Administration today expanded the approved use of Stivarga (regorafenib) to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to other FDA-approved treatments for this disease.
GIST is a tumor in which cancerous cells form in the tissues of the gastrointestinal tract, part of the body’s digestive system. According to the National Cancer Institute, an estimated 3,300 to 6,000 new cases of GIST occur yearly in the United States, most often in older adults.
Stivarga, a multi-kinase inhibitor, blocks several enzymes that promote cancer growth. With this new approval, Stivarga is intended to be used in patients whose GIST cancer cannot be removed by surgery or has spread to other parts of the body (metastatic) and is no longer responding to Gleevec (imatinib) and Sutent (sunitinib), two other FDA-approved drugs to treat GIST.
“Stivarga is the third drug approved by the FDA to treat gastrointestinal stromal tumors,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective.”
Stivarga was approved in September 2012 to treat colorectal cancer. It is marketed by Bayer HealthCare Pharmaceuticals, based in Wayne, N.J. Gleevec is marketed by East Hanover, N.J.-based Novartis, and Sutent is marketed by New York City-based Pfizer.
Regorafenib (BAY 73-4506, commercial name Stivarga) is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targetedVEGFR2-TIE2 tyrosine kinase inhibition. It is currently being studied as a potential treatment option in multiple tumor types.[1]
Regorafenib demonstrated to increase the overall survival of patients with metastaticcolorectal cancer[2] and has been approved by the US FDA on September 27, 2012.[3]Stivarga is being approved with a Boxed Warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in patients treated with Stivarga during clinical studies. The most common side effects reported in patients treated with Stivarga include weakness or fatigue, loss of appetite, hand-foot syndrome (also called palmar-plantar erythrodysesthesia), diarrhea, mouth sores (mucositis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).[4]
Regorafenib from the structure consists of three simple aromatic ring structure, which fragments can be connected from urea by the corresponding two aniline with phosgene or triphosgene prepared by oxygen fragments can be connected SNAr from the corresponding phenol by reaction of. Carboxylic acid 1 by esterification of Thionyl Chloride 2 , methyl amine solution to 2 the ester group is converted to an amide to obtain 3 , 3 , and 4 in alkaline conditions by SNAr reaction of 5 , 5 , and then the isocyanate 6 ( from the corresponding aniline with phosgene or triphosgene was obtained) to obtain the Regorafenib.
NEW weapons are emerging in the war on cancer. That is good news not just for patients but also for drug companies. The biggest ones, faced with falling sales as their existing medicines go off-patent, are investing in smaller firms with promising cancer treatments under development, hoping to secure the next blockbuster.
Countless studies have shown the seemingly countless benefits of fruits for a person’s health.
The U.S. Government recommends that people get some servings of fruits every day. Of all the fruits ready in the shop today,
one fruit is at its height of popularity because of its legendary Greek mythology connection and its exoticism-the pomegranate fruit.
READ COMPLETE ARTICLE AT
http://www.askveda.in/blog/health-benefits-of-pomegranate/
ibrutinib
FDA grants priority review to Pharmacyclics drug
Pharmacyclics is getting a priority review of its blood cancer treatment by federal regulators. A priority review shortens a drug evaluation by the U.S. Food and Drug Administration from 10 months to six. The acceptance of the application triggers a $75 million milestone payment to Pharmacyclics from Johnson & Johnson’s Janssen unit.
Ibrutinib (USAN[1]), also known as PCI-32765, is an experimental drug candidate for the treatment of various types of cancer. It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton tyrosine kinase (Btk).[2][3][4] Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson’s Janssen Pharmaceutical division for B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.[6][7][8]. Ibrutinib was first designed and synthesized at Celera Genomics by Zhengying Pan, who along with a team of chemists and biologists reported in 2007 a structure-based approach for creating a series of small molecules that inactivate BTK through covalent binding to cysteine-481 near the ATP binding domain of BTK[2]. These small molecules irreversibly inhibited BTK by using a Michael acceptor for binding to the target cysteine. In April 2006, Pharmacyclics acquired Celera’s small molecule BTK inhibitor discovery program, which included a compound, PCI-32765 (known as compound 13 in the Pan et al paper) that was subsequently chosen for further preclinical development based on the discovery of anti-lymphoma properties in vivo [5]. Since 2006, Pharmacyclics’ scientists have advanced the molecule into clinical trials and identified specific clinical indications for the drug. [2][3][4] [5] [6][7][8] It also has potential effects against autoimmune arthritis.[9]
It has given good results in two phase II clinical trials.[10]
In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment.[11] In this study, treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.
In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.[12]
Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor.[13][14] Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments.
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New Drug Approvals 