Ataluren (Translarna) drug for Duchenne Muscular Dystrophy

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Jun 302016

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Ataluren (Translarna)

3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid

3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

CAS 775304-57-9

PTC Therapeutics (Originator)

Molecular FormulaC₁₅H₉FN₂O₃
Average mass284.242 Da
EC-000.2051
NCGC00168759-02

PTC-124, PTC124,

UNII:K16AME9I3V
EU 2014-07-31 APPROVED

Ataluren, formerly known as PTC124, is a pharmaceutical drug for the treatment of Duchenne muscular dystrophy and potentially other genetic disorders. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union.

Ataluren was approved by European Medicine Agency (EMA) on July 31, 2014. It was developed and marketed as Translarna^® by PTC Therapeutics.

Ataluren was regulator of nonsense mutations indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older.

Translarna^® is available as granules for oral use, containing 125 mg, 250 mg or 1000 mg of free Ataluren. The recommended dose is 10 mg/kg body weight in the morning, 10 mg/kg body weight at midday, and 20 mg/kg body weight in the evening.

Medical uses

Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,^[1]^[2] such as some people with cystic fibrosis and Duchenne muscular dystrophy. It is approved for the use in Duchenne in the European Union.

Mechanism of action

Ataluren makes ribosomes less sensitive to premature stop codons (referred to as “read-through”). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. Studies have demonstrated that PTC124 treatment increases expression of full-length dystrophin protein in human and mouse primary muscle cells containing the premature stop codon mutation for Duchenne muscular dystrophy and rescues striated muscle function.^[3] Studies in mice with the premature stop codon mutation for cystic fibrosis demonstrated increased CFTR protein production and function.^[4] The European Medicines Agency review on the approval of ataluren concluded that “the non-clinical data available were considered sufficient to support the proposed mechanism of action and to alleviate earlier concerns on the selectivity of ataluren for premature stop codons.” ^[5]

In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.^[6] Ataluren appears to be most effective for the stop codon ‘UGA’.^[1]

History

Clinical trials

In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.^[7] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug.

Phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.^[8] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.^[9]

Approval

On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).^[10]Translarna was first available in Germany, the first EU country to launch the new medicine.^[11]

In August 2014, ataluren received market authorization from the European Commission to treat patients with nonsense mutation Duchenne muscular dystrophy. A confirmatory phase III clinical trial is ongoing.^[11] The drug does not yet have approval by the US Food and Drug Administration.

In October 2015, NICE asked for further evidence of benefit to justify the “very high cost”.^[12] NICE estimated that for a typical patient, treatment would cost £220,256 per year.

In February 2016, FDA declined to approve or even discuss PTC Therapeutics application for ataluren because it deemed the data presented by the developer “insufficient to warrant a review”.^[13]

Ataluren Molecule

PAPER

Auld, Douglas S.; Proceedings of the National Academy of Sciences of the United States of America 2009, V106(9), P3585-3590

http://www.pnas.org/content/106/9/3585.full

http://www.pnas.org/content/suppl/2009/02/10/0813345106.DCSupplemental

http://www.pnas.org/content/suppl/2009/02/10/0813345106.DCSupplemental/Appendix_PDF.pdf

Samples were analyzed for purity on an Agilent 1200 series LC/MS equipped with a Luna® C18 reverse phase (3 micron, 3 x 75 mm) column having a flow rate of 0.8-1.0 mL/min. The mobile phase was a mixture of acetonitrile (0.025% TFA) and H2O (0.05% TFA), and temperature was maintained at 50 °C. A gradient of 4% to 100% acetonitrile over 7 minutes was used during analytical analysis. Purity of final compounds was determined to be >95%, using a 5 μL injection with quantitation by AUC at 220 and 254 nM. High resolution mass spectra were obtained with an Agilent 6210 Time-of-Flight LC/MS with a 3.5 um Zorbax SB-C18 column (2.1 x 30 mm) (solvents are Water and ACN with 0.1% Formic Acid). A 3 minute gradient at 1 mL/min from 5% to 100% acetonitrile was used.

3-[5-(2-fluorophenyl)-[1,2,4]-oxadiazol-3-yl]-benzoic acid (1a, PTC124).

1 H NMR (d6-DMSO, 400 MHz) δ 13.15-13.68 (bs, 1H), 8.62 (s, 1H), 8.31 (d, 1H, JHH = 6.8 Hz), 8.24 (t, 1H, JHH = 7.2 Hz), 8.17 (d, 1H, JHH = 7.4 Hz), 7.77-7.82 (m, 1H), 7.73 (t, 1H, JHH = 7.6 Hz), 7.53 (dd, 1H, JHH = 10.8 Hz, JHH = 8.4 Hz), 7.48 (t, 1H, JHH = 6.8 Hz).

13C NMR (d6-DMSO, 400 MHz) δ 172.72 (d, JCF = 4.4 Hz), 167.39, 166.52, 159.95 (d, JCF = 258.0 Hz), 135.80 (d, JCF = 8.8 Hz), 132.28, 131.97, 131.97, 131.04, 130.94, 129.86, 127.76, 125.4 (d, JCF = 3.6 Hz), 117.2 (d, JCF = 20.4 Hz), 111.6 (d, JCF = 11.2 Hz). LC-

MS: rt (min) = 5.713; [M+H]+ 285.1;

HRMS: (CI+, m/z), calcd for C15H10FN2O3 (MH+ ), 285.06814; found, 285.06769.

CLIP

Ataluren (Translarna) Ataluren is a drug marketed under the trade name Translarna which was developed by PTC Therapeutics and approved by the European Union in May 2014 for the treatment of Duchenne’s muscular dystrophy (DMD) and potentially other genetic disorders.50

Ataluren renders ribosomes less sensitive to premature stop or ‘read-through’ codons, which are thought to be beneficial in diseases such as DMD and cystic fibrosis.51 Of the reported synthetic approaches to ataluren,52–55 the most likely process-scale approach consists of the sequence described in Scheme 7, which reportedly has been exemplified on kilogram scale.56

The sequence to construct ataluren, which was described by the authors at PTC Therapeutics, commenced with commercially available methyl 3-cyanobenzoate (38).56 This ester was exposed to hydroxylamine in aqueous tert-butanol and warmed gently until the reaction was deemed complete.

Then this mixture was treated with 2-fluorobenzoyl chloride dropwise and subsequently triethylamine dropwise. To minimize exotherm and undesired side products, careful control of the addition of reagents was achieved through slow dropwise addition of these liquid reagents.

Upon complete consumption of starting materials and formation of amidooxime 39, the aqueous reaction mixture was then heated to 85 C to facilitate 1,2,4-oxadiazole formation, resulting in the tricyclic ester 40 in excellent yield across the three steps.

Finally,saponification of ester 40 through the use of sodium hydroxide followed by acidic quench gave ataluren (V) in 96% over the two-step sequence.57

50. Welch, E. M.; Barton, E. R.; Zhuo, J.; Tomizawa, Y.; Friesen, W. J.; Trifillis, P.;Paushkin, S.; Patel, M.; Trotta, C. R.; Hwang, S.; Wilde, R. G.; Karp, G.; Takasugi,J.; Chen, G.; Jones, S.; Ren, H.; Moon, Y. C.; Corson, D.; Turpoff, A. A.; Campbell,J. A.; Conn, M. M.; Khan, A.; Almstead, N. G.; Hedrick, J.; Mollin, A.; Risher, N.;Weetall, M.; Yeh, S.; Branstrom, A. A.; Colacino, J. M.; Babiak, J.; Ju, W. D.;Hirawat, S.; Northcutt, V. J.; Miller, L. L.; Spatrick, P.; He, F.; Kawana, M.; Feng,H.; Jacobson, A.; Peltz, S. W.; Sweeney, H. L. Nature 2007, 447, 87.
51. Hirawat, S.; Welch, E. M.; Elfring, G. L.; Northcutt, V. J.; Paushkin, S.; Hwang,S.; Leonard, E. M.; Almstead, N. G.; Ju, W.; Peltz, S. W.; Miller, L. L. J. Clin.Pharmacol. 2007, 47, 430.

52Karp, G. M.; Hwang, S.; Chen, G.; Almstead, N. G. US Patent 2004204461A1,2004.
53. Andersen, T. L.; Caneschi, W.; Ayoub, A.; Lindhardt, A. T.; Couri, M. R. C.;Skrydstrup, T. Adv. Synth. Catal. 2014, 356, 3074.
54. Gupta, P. K.; Hussain, M. K.; Asad, M.; Kant, R.; Mahar, R.; Shukla, S. K.; Hajela,K. New J. Chem. 2014, 38, 3062.
55. Lentini, L.; Melfi, R.; Di Leonardo, A.; Spinello, A.; Barone, G.; Pace, A.; PalumboPiccionello, A.; Pibiri, I. Mol. Pharm. 2014, 11, 653.
56. Almstead, N. G.; Hwang, P. S.; Pines, S.; Moon, Y. -C.; Takasugi, J. J. WO Patent2008030570A1, 2008.
57. Almstead, N. G.; Chen, G.; Hirawat, S.; Hwang, S.; Karp, G. M.; Miller, L.; Moon,Y. C.; Ren, H.; Takasugi, J. J.; Welch, E. M.; Wilde, R. G. WO Patent2007117438A2, 2007.

CLIP

Ataluren trial success: trial aborted.

07 September 2011 – Pharma……..http://chem.vander-lingen.nl/info/item/September_2011/id/190/mid/140

Last week the newspaper NRC Handelsblad reported on a court case in which the parents of two young boys sued a pharmaceutical company over access to one of their developmental drugs. The drug in question wasAtaluren, the pharmaceutical companyPTC Therapeutics. The boys suffer from Duchenne muscular dystrophyand had taken part in a clinical trial. Whereas the results of this trial on the whole were inconclusive the boys did seriously benefit from the drug. Hardly any wonder the parents took action when the whole development program was canceled.

And the judge? He threw the case out arguing that doctors do not make the compound themselves and arguing that the compound is not commercially available. Are these arguments valid? and do the boys have options?

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).

Except for the fluorine atom in it the compound is unremarkable. If you have to believe the Internet many Chinese companies produce and sell it. Ataluren is also still in the running as a potential treatment for some other diseases. So if need be the compound will be around for some time to come.

CLIP

Ataluren [3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid] is an orally available, small molecule compound that targets nonsense mutation. It is the first drug in its class and appears to allow cellular machinery to read through premature stop codons in mRNA, and thus enables the translation process to produce full-length, functional proteins.
Ataluren is developed and approved for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) by EU in July 2014 [1].

Ataluren: 2D and 3D Structure

Nonsense Mutations as Target for DMD

A single nucleotide change in the DNA sequence that introduces a premature stop codon is known as a nonsense mutation, a subset of a major class of premature termination codon (PTC) mutations. Nonsense mutations cause premature termination of translation resulting in the production of truncated polypeptides, which in turn halts the ribosomal translation process at an earlier site than normal, producing a truncated, non-functional protein [1].

Nonsense mutations are implicated in 5-70 % of individual cases of most inherited diseases, including Duchenne muscular dystrophy (DMD) and cystic fibrosis. Ataluren appears to allow cellular machinery to read through premature stop codons in mRNA, enabling the translation process to produce full length, functional proteins.

Ataluren Synthesis

New J Chem 2014, 38, 3062-3070: The text reports one pot synthesis of Ataluren with an overall yield of 40%. It also reports few interesting and potent derivatives too.

WO 2007117438A2: It appears to be the industrial process. The patent also reports various pharmaceutically relevant assay and their results wrt Ataluren.
Identifications:

1H NMR (Estimated) for Ataluren

Experimental: ¹H NMR (d₆-DMSO, 400 MHz) δ 13.15-13.68 (bs, 1H), 8.62 (s, 1H), 8.31 (d, 1H, J_HH= 6.8 Hz), 8.24 (t, 1H, J_HH = 7.2 Hz), 8.17 (d, 1H, J_HH = 7.4 Hz), 7.77-7.82 (m, 1H), 7.73 (t, 1H, J_HH = 7.6 Hz), 7.53 (dd, 1H, J_HH = 10.8 Hz, J_HH = 8.4 Hz), 7.48 (t, 1H, J_HH = 6.8 Hz).

13C-NMR (Estimated) for Ataluren

Experimental: ¹³C NMR (d₆-DMSO, 400 MHz) δ 172.72 (d, J_CF = 4.4 Hz), 167.39, 166.52, 159.95 (d, J_CF = 258.0 Hz), 135.80 (d, J_CF = 8.8 Hz), 132.28, 131.97, 131.97, 131.04, 130.94, 129.86, 127.76, 125.4 (d, J_CF = 3.6 Hz), 117.2 (d, J_CF = 20.4 Hz), 111.6 (d, J_CF = 11.2 Hz)……https://ayurajan.blogspot.in/2016/05/ataluren-treatment-for-duchenne.html

CLIP

Route 1

Reference：1. WO2004091502A2 / US6992096B2.

2. WO2008045566A1 / US2008114039A1.

3. WO2008030570A1 / US2008139818A1.

4. Mol. Pharmaceutics 2014, 11, 653-664.

Route 2

Reference：1. New. J. Chem. 2014, 38, 3062-3070.

Route 3

Reference：1. Adv. Synth. Catal. 2014, 356, 3074-3082.

CLIP

Carcinogenicity

Carcinogenicity bioassays in transgenic mice (26 weeks) and in rats (24 months):

● For Tg.rasH2 mouse: Ataluren did not increase the incidence of tumors up to the HDs in males (600 mg/kg/day) and in females (300 mg/kg/day). The non-neoplastic findings included endometrial hyperplasia and nephropathy in females.

● For rats: Urinary bladder tumors (benign urothelial cell papilloma [2 rats] and malignant urothelial cell carcinoma [1 rat]) were observed in 3/60 female rats dosed at 300 mg/kg/day. In addition, one case of malignant hibernoma was observed in 1/60 male rats at the dose of 300 mg/kg/day. The non-neoplastic toxicity consisted of a decrease of body weight.

Drug@EMA, EMEA/H/C/002720 Translarna: EPAR-Assessment Report.

PATENT

CN 105461650

Example 1 (prepared by known ataluren)

Method ataluren according to Patent Document 2 is described in Example W02004091502A2 prepared.

Specific methods of preparation:

To a solution of 0.6 l of DMF was 44. 14g3- cyano acid 62.19 g of potassium carbonate was added, followed by stirring at room temperature for 30 minutes. 20 minutes To the suspension was added 28 ml of methyl iodide (450mmol), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 1.2 l of ice water, stirred for 30 minutes, the precipitate was filtered out thereof. The white cake was dissolved in 70 ml of methanol, and then reprecipitated in cold water. To give 79% yield of 3-cyano-benzoic acid methyl ester.

50 g of 3-cyano-benzoic acid methyl ester was dissolved in 500 ml of ethanol, to which was added 41 ml of 50% aqueous hydroxylamine (620mmol). 100 ° C and the reaction mixture was stirred for 1 hour, the solvent was removed under reduced pressure. So that the oily residue is dissolved in 100 ml of 20/80 ethanol / toluene, concentrated again. To give 61 g 3- (N- hydroxy amidino (carbamimidoyl)) – benzoic acid methyl ester.

60 g of 3- (N- hydroxy amidino (carbamimidoyl)) – benzoic acid methyl ester was dissolved in 200 ml of anhydrous tetrahydrofuran, followed by adding thereto 75 ml of diisopropylethylamine (434 mmol), and then 20 minutes this mixture was added 48.1 ml 2- fluorobenzoyl chloride (403mmol). The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in 400 ml of ethyl acetate, washed with 400 ml of water and then twice. The solvent was removed under reduced pressure, containing 60% ethyl acetate in hexane to give the desired product, generating 81 g 3- (N-2- amidino-fluorobenzoyl) – benzoate.

at 130 ° C with a Dean-Stark apparatus was dissolved in 500 ml of toluene was heated under reflux in 44 g of 3- (N-2- fluorobenzoyl) -1,2,3,4-_ benzoate 4 hours. 5 ° C and the reaction mixture was stirred for 18 hours. The white precipitate was filtered off, the filtrate was concentrated, recrystallized in toluene. To give 38 g of 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester.

33 g of 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester was dissolved in 400 ml of tetrahydrofuran, to which was added 100 ml of 1. 5M aqueous sodium hydroxide solution. At 100 ° C and the reaction mixture was heated at reflux for 2 hours. The solvent was removed under reduced pressure at 5 ° C the solution was stirred for 2 hours. The organic solvent was removed, washed with 50 mL of water. The aqueous solution was then acidified with hydrochloric acid to pH 1. The white precipitate was filtered off, the filter cake washed with cold water, then dried with a freeze dryer. To give 3.0 g of 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] benzoic acid. 1H-NMR (500MHz, d6-DMS0): 8. 31 (1H), 8 18 (2H), 8 08 (1H), 7 88 (2H), 7 51 (2H)….. Display: ataluren- Sample Preparation Example 1 prepared in Preparation Example 2 and TO2004091502A2 induced.

Each prepared in Example 2 (prepared according to known Form A)

Method [0084] A known polymorph according to Patent Document W02008039431A2 Example 5. 1. 1.1 prepared as described. Specifically: ataluren be prepared 1 100 mg Preparation Example, 60 ° C add 16.2 ml of isopropanol ultrasound clear solution, the solution by 2 square micron filter and the filtrate was kept covered with aluminum foil having a small hole. vial, 60 ° C and evaporated. The solid formed was isolated to give ataluren the A polymorph.

as needles.

its XRPD shown in Figure 1, the display ataluren polymorph A disclosed in Patent Document W02008039431A2 consistent.

SEE

European Journal of Organic Chemistry (2016), 2016(3), 438-442

Russian Chemical Bulletin (2015), 64(1), 142-145.

European Journal of Medicinal Chemistry (2015), 101, 236-244.

Bioorganic & Medicinal Chemistry Letters (2014), 24(11), 2473-2476.

New Journal of Chemistry (2014), 38(7), 3062-3070.

Proceedings of the National Academy of Sciences of the United States of America (2010), 107(11), 4878-4883, S4878/1-S4878/14.

Adv. Synth. Catal. 2014, 356, 3074-3082.

Mol. Pharmaceutics 2014, 11, 653-664.

New. J. Chem. 2014, 38, 3062-3070.

WO 2008039431

WO 2008045566

WO 2008030570

WO 2007117438

WO 2006110483

WO 2007117438

WO 2006110483

US 20040204461

PATENT

WO 2008039431

novel crystalline forms of 3-[5-(2-fluorophenyl)-

[l,2,4]oxadiazol-3-yl]-benzoic acid, which has the following chemical structure (I):

(I)

In particular, crystalline forms of 3-[5-(2-fluorophenyl)-[l,2,4]oxadiazol-3-yl]- benzoic acid are useful for the treatment, prevention or management of diseases ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay, as described in U.S. Patent No. 6,992,096 B2, issued January 31, 2006, which is incorporated herein by reference in its entirety. In addition, the present provides a crystalline form of 3-[5-(2-fluorophenyl)-[l,2,4]oxadiazol-3-yl]-benzoic acid which is substantially pure, i.e., its purity greater than about 90%.

Processes for the preparation of 3-[5-(2-fluorophenyl)-[l,2,4]oxadiazol-3-yl]- benzoic acid are described in U.S. Patent No. 6,992,096 B2, issued January 31, 2006, and U.S. patent application no. 1 1/899,813, filed September 9, 2007, both of which are incorporated by reference in their entirety.

PATENT

CN101535284

https://worldwide.espacenet.com/publicationDetails/originalDocument?CC=CN&NR=101535284A&KC=A&FT=D&ND=&date=20090916&DB=&locale=

Example

3- ‘5- (2-fluorophenyl) – “1,2,41 oxadiazol-3-yl benzoate 1- Batch 1

The 3-cyano-benzoic acid methyl ester (105 kg) and t-butanol was added molten drying reactor. Under an inert atmosphere for about 2 hours 48 minutes, 50. /. Aqueous hydroxylamine (43L, 47.4 kg) was added to a clear solution of 3-cyano benzoic acid methyl ester in a molten in t-butanol. The addition of a 50% aqueous solution of hydroxylamine period, the maximum temperature batch of about 43 ° C. 50% aqueous solution of hydroxylamine addition rate of from about 9L / h when the changes start adding to about 30L / hr. To maintain the temperature of the batch by varying the reactor jacket set point. In particular, the set value is about 40.5 ° C, with the addition of a rate increase at the beginning join, change the setting to about 29.6 ° C. After about 40-45t stirred for about 4 hours, the reaction was deemed complete (i.e., less than about 0.5% ester).

The batch was transferred to a drying reactor, additional (chased through) approximately 10L molten tert-butanol. Jacket setpoint from about 33 when the batch was received when dried reactor. C is reduced to about 27 after the completion of the transfer. C. Batch crystallization was observed part, which does not adversely affect stirring. The batch was cooled to about 34.4 ° C, triethylamine (72.6 kg, IOOL) added to the reactor. The jacket temperature set value from about 20.4. C is increased to about 31.0 ° C, in order to maintain the batch temperature in the range of about 30-35t. With molten tert-butanol (IO L) was washed with a linear (line rinse) After the batch was added to the 2-fluorobenzoyl chloride (113.7 kg, 86.0L).Charge is added to the first third of the rate of about 25L / hr. In the meantime, the jacket inlet temperature was lowered to about 15 ° C, the batch temperature is maintained at about 34.6 ° C. In about 5.5 hours after the addition was complete.During the addition, the maximum temperature of the batch was about 38.8 ° C. Near the end of the addition, the addition rate slowed to about 11L / hr was added last 27 liters of 2-fluoro-benzoyl chloride. 30-35. C After stirring for about 2 hours, that the reaction was complete (i.e., less than about 0.5% of methyl 3-amidinophenoxy). Then, after about 1 hour 42 minutes, the batch was heated to reflux temperature (about 82 ° C), and then stirred for about 18 hours. During the stirring, a number of product partially crystallized to form a slurry. The slurry was cooled to about 40. C thus sampled, during which complete crystallization occurs. The batch was then heated to reflux temperature and stirred for about 1 hour 50 minutes.Then, after about two hours, the batch was cooled to about 69 ° C, and after about four hours and 15 minutes, slowly added 630L of pure water, while maintaining the batch temperature at about 66-69 ° C. After about 3 hours 14 minutes, the slurry was cooled to about 22.4 ° C, and transferred to 2x200L ceramic filter, the ceramic filter equipped 25-30n polypropylene mesh filter cloth. In about 55 minutes after the completion of material from the container to the filter transfer. With 50n /. The tert-butanol solution (210L) was washed cake was washed for about 10 minutes so that the cleaning liquid can penetrate into each cake. Then, the cake was dried in a vacuum for about 5-10 minutes. The purified water as a second washing (158L / cake) applied to the filter cake to remove residual t-butanol and triethylammonium chloride salt. Dried in a vacuum for about 5 minutes, the solution was removed. In vacuo and then the cake was dried for about 2 hours, and then sampled using liquid chromatography. The filter cake was measured by liquid chromatography purity of about 99.6%.

The filter cake was dried in vacuo for about 8 hours 25 minutes later, the wet cake (207.4kg) is transferred to an air oven. At about 50-55. C, the oven dried in air for about 52 hours. The product was isolated in a total yield of about 89.9% (174.65kg), in the calculation of cost of materials sampling, you can adjust the overall yield of about 90.7%.

Batch 2

The 3-cyano-benzoic acid methyl ester (105 kg) and t-butanol was added molten drying reactor. Under an inert atmosphere for about 3 hours 29 minutes, 50% aqueous solution of hydroxylamine (47.85 kg) was added to the reactor. During the addition, the temperature is maintained at about 40-45 ° C. At about 40-45. C After stirring for about 3 hours 16 minutes, that the reaction was complete (i.e., less than about 0.5% ester). As for the drying reactor, the batch was transferred to one of the batch in. The batch was cooled

To about 34.4 ° C, and triethylamine (72.6 kg, 100 L). During about 45 minutes was added, while maintaining the batch temperature between about 30-35 ° C. During the addition, the jacket inlet temperature of from about 31.4. C increased to about 32.6. C. After the molten tert-butanol linear washed, was added to the batch 2- fluorobenzoyl chloride (l 13.7 kg, 86.0 L). After about 3 hours, 27 minutes, add the acid chloride. 35. C under stirring for about 8 hours, that the reaction is not complete (i.e., more than about 0.5% residual 3-amidino-benzoyl ester). Then, 1.5% by weight of the original charge of triethylamine and 2-fluorobenzoyl chloride was added to the batch. Linear washed with tert-butanol (IO L) associated with each additional charge. During the addition of the acid chloride, no additional cooling. The batch was maintained at a temperature of about 30-35 ° C, the jacket inlet temperature range was maintained at about 30.3. C to about 33.0 ° C. After stirring for about 2 hours at 30-35t, that reaction was complete (i.e., less than 0.5% of methyl 3-amidinophenoxy).

After about 1 hour and 44 minutes, the batch was heated to reflux temperature (about 83 ° C), and stirred for about 18 hours.The same batch 1, during cooling the sample, the solid was completely crystallized. The batch was then heated to reflux temperature and stirred for about 1 hour and 2 minutes. Then, after about 2 hours and 20 minutes, the batch was cooled to about 69.2 ° C, and after about four hours and 30 minutes, slowly added 630 L of pure water, while the temperature of the batch was maintained at about 65.6-69.2 ° C. After about 3 hours and 30 minutes, the slurry was cooled to about 23.4 ° C, and, as for, the contents were transferred to one of the double batch of the ceramic filter. About 5 hours and 6 minutes, to complete the transfer of the material. With about 50% of t-butanol (2 volumes / cake) was washed filter cake was washed with 10 minutes to allow the cleaning liquid to penetrate into each cake, then dried in vacuo. About 1 hour and 40 minutes, the filter is completed. The purified water was added to a final wash the filter cake. The liquid was removed by drying under vacuum for about 10 minutes. In vacuo and then the cake was dried for about 2 hours and 5 minutes, and then sampled using liquid chromatography. The cake purity liquid chromatography were about 99.5% and 99.6%. After the cake was then dried in vacuo for about 2 hours and 5 minutes, the wet cake (191.5 kg) is transferred to an air oven. At about 50-55. C under dry in an air oven for about 48 hours. The product was isolated in a total yield of about 92.5% (179.7 kg).

Lot 3

The 3-cyano-benzoic acid methyl ester (52.5 kg) and molten tert-butanol (228 kg) added to the reaction vessel. The vessel was sealed, the batch temperature set of about 40-45 ° C, and the stirrer is started. Under an inert atmosphere, after 2 hours 40 minutes, 50% of the shoes amine solution (24 kg) was added to the reactor. During the addition, the temperature is maintained at about 40-45 ° C. In about 42. Under C, then further stirred for about 5 hours to complete the reaction.

The batch was cooled to 30-35 ° C, and after 15 minutes, was added triethylamine (36 kg). After about 2 hours 44 minutes, was added 2-fluorobenzoyl chloride (57 kg). During the addition, batch temperature was maintained at about 30-35 ° C.Under the 32t, the batch was stirred for 2 hours 10 minutes to complete the reaction.

After about 50 minutes, the batch was heated to reflux temperature (about 83-86 ° C), at about 8rc, stirred for about 18 hours. Then, over about two hours, the batch was cooled to about 65-70 ° C, and after about 6 hours 25 minutes, slowly added to purified water (315 L), while the batch temperature was maintained at about 65- 70 ° C. After about 2 hours and 15 minutes, the slurry was cooled to about 22 ° C, and the contents were transferred to a centrifuge filter (2 batches). About 1 hour and 40 minutes, the filter is completed. After about 20 minutes, with about 50% aqueous solution of tert-butyl alcohol (90 kg / cake), dried cake. The purified water (79 kg / cake) as the last added to the filter cake washed. At about 900 rpm drying the cake for about 1 hour and 5 minutes, then filled cylinder. Liquid chromatography wet cake (91.5 kg, LOD = 5% w / w) of a purity of about 99.75% area.

3- ‘5- (2-fluorophenyl) -fl, 2,41 oxadiazol-3-yl l- acid batch 1

3- [5- (2-fluorophenyl) – [l, 2,4] oxadiazol-3-yl] – benzoic acid methyl ester (74.0kg) added to the reaction vessel, the vessel is sealed, evacuated and purification. Jacket set value of about 35. C, start the stirrer in the container. Molten tert-butanol (222 L, 3 volumes) and purified water (355 L, 4.8 vol) was added to the vessel. After the addition was added 25.1% w / w aqueous sodium hydroxide solution (43.5 kg, 1.1 molar equivalents), and with additional purified water (100L, 1.35 mol) was washed linear. During the addition, the batch temperature from about 39.0t reduced to about 38.8 ° C. After about 1 hour and 54 minutes, the batch temperature to about 63-67. C, and then, after about 30 minutes, which was adjusted to about 68-72.C. About 68-72t, stirring the mixture for about 3 hours. Then, after about five hours 11 minutes, the solution was cooled to about 40-45 ° C. Then, after the above process, after about three hours 33 minutes, the solution was then heated to about 68-72. C.

Jacket temperature of the reaction vessel was set to about 60 ° C, the stirrer started, and at about 70 ° C, a slightly positive pressure of nitrogen (1.5 to 5.6 psig), the heat transfer liquid through a micron filter . During the transfer, the product temperature is reduced to about 64.3 ° C, the transfer is completed in about 45 minutes. Was added to the purified water container (61 L, 0.82 vol) and the contents were heated to about 68-72. C.

The batch temperature was adjusted to about 69.4 ° C, and after about four hours and 18 minutes, with 13.9% w / w sulfuric acid (100.7 kg, 1.15 mol equiv.). During the addition, batch temperature was maintained at about 68.0-70.8 ° C. After the addition of the acid, with purified water (50 L, 0.68 vol) line wash at about 68-72 ° C, the stirring was continued for 31 minutes.

After about 4 hours and 10 minutes, the batch in a linear fashion from about 69.2t cooled to about 41.2 ° C. The stirrer Rosenmund filter / dryer was elevated to the highest position and jacket set value is set at about 40 ° C. The slurry was transferred to the two portions of the filter / drier. Applying a constant nitrogen pressure to the first portion (less than about 15 psig). During the transfer, a pressure of about 23.9 to about 28.8 psi, the transfer is complete in about 1 hour and 5 minutes. The second part of the slurry was transferred onto the filter cake, and the composite was stirred briefly to homogenize the batch. Use about 26.1 to about 29.1 psi nitrogen pressure filters the second part, after about three hours, squeeze the cake so that it does not contain liquid. With about 38-42 ° C hot tert-butanol solution (352 kg, 5 volumes) and about 65-70 ° C in 3x hot purified water (370 L, 5 volumes) and the filter 々.

Said filter / dryer jacket temperature was set to about 43 ° C, the product was dried under vacuum for about 26 hours while stirring periodically. Determination of purity of about 99.7%. The product was isolated in a total yield of about 74.4% (52.45 kg).

Batch 2

Was added to the reactor vessel 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester (47 kg, wet cake) and melt-hyun tert-butyl alcohol (111.4 kg). A sealed container, and the batch temperature was set at 30-40t, and start the stirrer. The purified water (51.6 kg) was added to the vessel. After the addition was added 3.47% w / w aqueous sodium hydroxide solution (202.4 kg). After about l hour, the batch temperature to about 67-73. C, then, at about 7 (under TC, stirred for about three hours.

Under a slight positive pressure of nitrogen, with a 1 micron polypropylene bag filter the batch, and then transferred to the new reactor. Was added to the vessel pure water (146 kg), and heating the batch to about 68-72. C.

After about four hours, the 10.7% aqueous hydrochloric acid was added to the batch. During the addition, batch temperature was maintained at about 68-72 ° C. PH was measured by using the batch pH of about 2.2, and then stirring was continued at about 7 (under TC about 1 hour.

After about two hours, the batch in a linear fashion from about 70. C is cooled to about 60 ° C. After about two hours, about 60. C of the batch in a linear fashion from about 6 (TC was cooled to about 40 ° C. In 40t, the batch was stirred for 2 hours, and the slurry was transferred to a centrifuge filter. After about 30 minutes, filtered completion . After about 30 minutes, with about 42Mw / w in t-butanol solution (165kg) cake was washed. The purified water (118kg, 4 (TC) as the last added to the filter cake was washed. The filter cake was dried at about 900rpm about 1 hour, then filled cylinder.

The wet cake was transferred to a paddle dryer (a double cone drier also suitable for this step), the jacket temperature was set to about 70. C. At about 70. C, the product was dried under vacuum for about 48 hours while stirring periodically.Determination of purity of about 99.8%. The product was isolated overall yield of about 74% (68.5 kg).

Lot 3

To the reaction vessel was added 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester (10 g) and t-butanol fused (128mL ). The batch temperature was set to 30-40 ° C, and the stirrer is started. After about 30 minutes, the aqueous sodium hydroxide solution 4.48% w / w of (32.5 g) was added to the vessel. The batch was maintained at a temperature of about 40-50 ° C. After about l hour, the batch temperature is raised to about 78-82 ° C, and then, at about 78-82t, and then stirred for about one hour. Under positive pressure of nitrogen, a polyethylene bag with a 5 micron filter the batch, and then transferred to a new reaction vessel. The batch was maintained at a temperature of about 78-82 ° C.

It was added to a new vessel 37% aqueous hydrochloric acid (4 mL) and tert-butanol molten (8 mL). The temperature was maintained at about 30-40. Under C, and stirring the mixture for about 30 minutes.

After about four hours, using a metering pump was added to the batch of hydrochloric acid in tert-butanol. After about SO-SO minutes before adding half filled. The stirrer speed is set at about 200rpm. After about 3.5 hours, add the remaining charge. The stirrer speed is set at about 100 rpm. During the addition, batch temperature was maintained at about 78-82 ° C.PH meter with a final batch pH was adjusted to about 1.2, at about 78-82t, then continue stirring for about l hour. After about one hour, the batch in a linear fashion from about 78-82. C is cooled to about 70 ° C. After about four hours, about 7 (TC batches in a linear fashion from 70.C cooled to about 50 ° C, and the stirrer speed was set at about 80 rpm. After about four hours, about 50 ° C Batch linearly cooled from 50 ° C to about 40t, and stirrer speed was set at approximately 60rpm. In 40.C, the batch was stirred for a further 4 hours.

The temperature of the filter is set to about 40-45 ° C. The slurry was transferred to the filter. After about one minute to complete filtration. After about two minutes, with tert-butanol (50 mL, 50.C) washing the filter cake. The pure water (IOO mLx2, 60.C) as the last wash was added to the cake. Under vacuum at about 60-70 ° C the cake was dried for about 12 hours, and then loaded into the container.

Determination of HPLC purity of about 99.9% of the area. The yield of isolated product was about 94% (9.0g).

3- “5- (2-fluorophenyl) -” 1,2,41-oxadiazol-3-yl 1- acid: One-pot

The methyl 3-cyanophenyl Yue (7.35 g) and tert-butanol molten (100 mL) added to the reactor vessel. Sealed containers, the batch temperature was set to 60 ° C, and the stirrer is started. The suspension was stirred for 1 hour and then the batch temperature was set to 40. C. Under an inert atmosphere, after three hours, 50% aqueous solution of hydroxylamine (3.63 g) was added to the reactor. During the addition, batch temperature was maintained at 38-41 ° C. 40. C After stirring for 18 hours, to complete the reaction.

The batch was cooled to 27 ° C, and after two minutes, triethylamine (5.56 g). After 3 hours, was added 2-fluorobenzoyl chloride (7.82 g). During the addition, batch temperature was maintained at 24-27 ° C. 40. C, the batch was stirred for a further 4 hours.

After 30 minutes, the batch was heated to 79 ° C, and at about 79. C was stirred for 16 hours. After 3 hours, the white suspension was added to the water (IOO mL), while the batch temperature was maintained at 70 ° C. After 20 minutes, a 37% aqueous hydrochloric acid were added to the batch. PH was measured by using the batch pH of about 2.2, stirring was continued at about 70t for about 1 hour.

After three hours, the batch in a linear manner from 7 (TC cooled to 30 ° C, and the slurry is transferred to the filter. After 5 minutes, the filtering is done. After five minutes, with tert-butanol (50mL, 40 .C) filter cake was washed. The purified water (IOO mL, 60.C) is added to a final wash the filter cake. In 70.C of the filter cake was dried in a vacuum oven for 18 hours and then removed. Determination of purity approximately 98.68%. The total yield of isolated product of about 76% (10.8g).

PICS

A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.

The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation — also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.

Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.

The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.

PTC124 has been developed by PTC Therapeutics.

References

Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (May 2007). “PTC124 targets genetic disorders caused by nonsense mutations”. Nature 447 (7140): 87–91. Bibcode:2007Natur.447…87W.doi:10.1038/nature05756. PMID 17450125.
Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (Apr 2007). “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers”. Journal of clinical pharmacology 47 (4): 430–444.doi:10.1177/0091270006297140. PMID 17389552.
Nature. 2007 May 3;447(7140):87-91.
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2064-9.
Neuromuscul Disord. 2015 Jan;25(1):5-13.
Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery Medicine 15 (81): 127–133. PMID 23449115.
“PTC Therapeutics and Genzyme Corporation announce preliminary results from the phase 2b clinical trial of ataluren for nonsense mutation Duchenne/Becker muscular dystrophy (NASDAQ:PTCT)”. Ptct.client.shareholder.com. Retrieved 2013-11-28.
Wilschanski, M.; Miller, L. L.; Shoseyov, D.; Blau, H.; Rivlin, J.; Aviram, M.; Cohen, M.; Armoni, S.; Yaakov, Y.; Pugatsch, T.; Cohen-Cymberknoh, M.; Miller, N. L.; Reha, A.; Northcutt, V. J.; Hirawat, S.; Donnelly, K.; Elfring, G. L.; Ajayi, T.; Kerem, E. (2011). “Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis”. European Respiratory Journal 38 (1): 59–69. doi:10.1183/09031936.00120910. PMID 21233271.Sermet-Gaudelus, I.; Boeck, K. D.; Casimir, G. J.; Vermeulen, F.; Leal, T.; Mogenet, A.; Roussel, D.; Fritsch, J.; Hanssens, L.; Hirawat, S.; Miller, N. L.; Constantine, S.; Reha, A.; Ajayi, T.; Elfring, G. L.; Miller, L. L. (November 2010). “Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis”. American Journal of Respiratory and Critical Care Medicine 182 (10): 1262–1272. doi:10.1164/rccm.201001-0137OC. PMID 20622033.
“PTC Therapeutics Completes Enrollment of Phase 3 Trial of Ataluren in Patients with Cystic Fibrosis (NASDAQ:PTCT)”. Ptct.client.shareholder.com. 2010-12-21. Retrieved2013-11-28.
http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23
“PTC Therapeutics Announces Launch of Translarna™ (ataluren) in Germany”.marketwatch.com. 3 Dec 2014. Retrieved 27 Dec 2014.
“NICE asks for further evidence for the benefits of a new treatment for Duchenne muscular dystrophy to justify its very high cost”.
http://uk.reuters.com/article/us-ptc-therapeutics-fda-idUKKCN0VW1FG

External links

Ataluren’s official page on PTC Therapeutics’s website

References:
1. Ryan, N. J. Ataluren: first global approval. Drugs 2014, 74(14), 1709-14. (FMO only)
2. Gupta, P. K.; et. al. A metal-free tandem approach to prepare structurally diverse N-heterocycles: synthesis of 1,2,4-oxadiazoles and pyrimidinones. New J Chem 2014, 38, 3062-3070 (FMO only)
3. Almstead, N. G.; et. al. Methods for the production of functional protein from dna having a nonsense mutation and the treatment of disorders associated therewith. WO2007117438A2

WO2004091502A2	Apr 9, 2004	Oct 28, 2004	Ptc Therapeutics, Inc.	1,2,4-oxadiazole benzoic acid compounds

Citing Patent	Filing date	Publication date	Applicant	Title
US8486982	Jun 22, 2012	Jul 16, 2013	Ptc Therapeutics, Inc.	1,2,4-oxadiazole benzoic acids
US8796322	Jun 19, 2013	Aug 5, 2014	Ptc Therapeutics, Inc.	Methods for using 1,2,4-oxadiazole benzoic acid compounds
US8975287	Jun 18, 2014	Mar 10, 2015	Ptc Therapeutics, Inc.	Methods for using 1,2,4-Oxadiazole benzoic acid compounds
US9205088	Jan 28, 2015	Dec 8, 2015	Ptc Therapeutics, Inc.	Compositions of 1,2,4-oxadiazol benzoic acid compounds and methods for their use
US9289398	Mar 29, 2007	Mar 22, 2016	Ptc Therapeutics, Inc.	Methods for the production of functional protein from DNA having a nonsense mutation and the treatment of disorders associated therewith

Preparation	CN101535284A	CN101535284B
10	Crystal	CN101541770A
11	Crystal	CN104341371A
12	Crystal	CN102382075A

Formula	CN1802360A	CN1802360B
2	Combination	CN104056278A
3	Indication	CN101076703A
4	Indication	CN101076332A
5	Indication	CN101076337A
6	Indication	CN101193632A
7	Formulation	CN103720688A
8	Indication	CN101505739A

Ataluren
Names


IUPAC name 3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
Other names PTC124
Identifiers
CAS Number	775304-57-9
ChEMBL	ChEMBL256997
ChemSpider	9394889
IUPHAR/BPS	7341
Jmol 3D model	Interactive image
KEGG	D09323
PubChem	11219835
UNII	K16AME9I3V
InChI [show]
SMILES [show]
Properties
Chemical formula	C₁₅H₉FN₂O₃
Molar mass	284.24 g/mol
Pharmacology
ATC code	M09AX03 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////ORPHAN DRUG, Ataluren, Translarna, Duchenne Muscular Dystrophy, EU, 775304-57-9, PTC Therapeutics, PTC 124

O=C(O)c1cccc(c1)c2nc(on2)c3ccccc3F

Chidamide (Epidaza), A New Cancer Drug, Made in China

Uncategorized Comments Off

Jun 292016

Figure CN103833626AD00031

Chidamide (Epidaza)

CS055; HBI-8000

CAS 743438-44-0 CORRECT

C₂₂ H₁₉ F N₄ O_2,Benzamide, N-(2-amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]-

Molecular Weight, 390.41

Benzamide, N-(2-amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propenyl]amino]methyl]-
N-(2-Amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]benzamide
CS 055
Chidamide
Epidaza

Activity: HDAC Inhibitor; Cancer Drug; Histone Deacetylase Inhibitor; HDAC-1, 2,3,10 Inhibitor; Treatment for Peripheral T-cell Lymphomas; Treatment for PTCL

Status: Launched 2014 (China)

Originator: Shenzhen Chipscreen Biosciences Ltd

Shenzhen Chipscreen Biosciences, Ltd.

SHENZHEN CHIPSCREEN BIOSCIENCES LTD. [CN/CN]; Research Institute of Tsinghua University, Suite C301, P.O. Box 28, High-Tech Industrial Park Nanshan District, Shenzhen, Guangdong 518057

ERROR IN STRUCTURE

FLUORO IN WRONG POSITION

CAS Registry Number: 743420-02-2

CN103833626A

As described for Example 2 according to the patent ZL03139760.3 obtained chidamide poor purity (about 95%). LC / MS analysis results shown in Figure 1, show that the product contains N- (2- amino-5-fluorophenyl) -4- (N- (3- pyridin-acryloyl group of 4.7% of the structure shown in formula II) aminomethyl) benzamide. 1H NMR analysis of the results shown in Figure 2, show that the product contains 1.80% of tetrahydrofuran, far beyond the technical requirements for people with drug registration International Conference on Harmonization (ICH, International Conference of Harmonizition) provided 0.072% residual solvent limits. Therefore, the solid

Body not for pharmaceutical manufacturing.

WRONG COMPD….https://www.google.com/patents/CN103833626A?cl=en

Chidamide (Epidaza) is an HDAC inhibitor (HDI) developed wholly in China.^[1] It was originally known as HBI-8000.^[2]

It is a benzamide HDI) and inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10.^[3]

It is approved by the Chinese FDA for relapsed or refractory peripheral T-cell lymphoma (PTCL), and having orphan drug status in Japan.^[2]

As of April 2015 it is only approved in China.^[1]

It shows potential in treating pancreatic cancer.^[4]^[5]^[6]

Is NOT approved for the treatment of pancreatic cancer.

Chidamide drug administration and clinical milestone

November 2005: China declared IND

November 2006: eligible for Phase I clinical documents of approval

November 2006: completion of the International Patent Licensing, China entered the international fray original new drug development

May 2008: completed Phase I clinical, showing international mechanism similar drugs have the potential to become the best

February 2009: eligible lymphoma indications II / III of this document

March 2009: Start of the Phase II clinical trial for the NDA to ①CTCL goal of clinical trials and ②PTCL

March 2009: IND by the FDA application is eligible to start Phase I clinical in the United States

July 2009: eligible for non-small cell lung cancer, breast cancer and prostate cancer clinical documents of approval

December 2010: of PTCL by a conventional phase II directly into Phase II clinical trial registered drug trial center and by recognition

March 2011: combination chemotherapy for non-small cell lung cancer clinical trials enter phase Ib

September 2012: of PTCL indication test deadline

December 2012: of PTCL clinical summary will be held

January 2013: Chidamide declare China NDA

December 2014: the State Food and Drug Administration (CFDA) approved the listing

Chidamide overview, location and clinical significance

Chidamide (Chidamide, love spectrum sand ® / Epidaza®) Shenzhen microchip biotechnology limited liability company developed a new subtype selective histone having a chemical structure and is eligible for a global patent licensing deacetylase inhibitor, belong to the new mechanisms of epigenetic regulation new class of targeted anticancer drugs, has now completed with relapsed or refractory peripheral T-cell lymphoma clinical trial study registered indications, was in March 2013 to the SFDA reporting new drug certificate (NDA) and the marketing authorization (MAA). While a number of Chinese Cancer clinical trials undertaken Chidamide is also China’s first approved by the US FDA clinical studies in the United States of Chinese chemical original new drug trials in the United States Phase I has been completed. Chidamide has won the national “Eleventh Five-Year” 863 major projects (project number: 2006AA020603) and the national “Eleventh Five-Year”, “significant Drug Discovery” science and technology and other major projects funded project (project number: 2009ZX09401-003), was chosen the Ministry of Science and one of the “Eleventh five-Year” major national scientific and technological achievements.

Relapsed or refractory peripheral T-cell lymphoma (PTCL) is Chidamide first approvedclinical indications, PTCL belongs to the category of rare diseases, the lack of standard drug currently recommended clinical treatment, conventional chemotherapy response rate is low, recur, 5-year overall survival rate was about 25%. The world’s first PTCL treatment Folotyn (intravenous drug use) is eligible for FDA clearance to market in 2009, the second drugs Istodax (intravenous drug use) approved by the FDA in 2011. Add a new drug information for these drugs is very expensive, and were listed in China. Chidamide album clinical trial results showed that the primary endpoint of objective response rate was 28%, reaching the intended target research and development; sustained remission rate of 24% three months; drug safety was significantly better than the international similar drugs, and oral medication.
Chidamide is a completely independent intellectual property rights China originator of innovative medicines, has been multi-national patent. In China, for patients with relapsed or refractory PTCL to carry out effective drug treatment is urgent clinical need, Chidamide expected to bring new treatment options for patients with PTCL, prolong survival and improve quality of life of patients.

In China, for the effective treatment of patients with relapsed or refractory PTCL has undertaken urgent clinical need

Chidamide is a completely independent intellectual property rights China originator of innovative medicines

Chidamide (Chidamide) has been multi-national invention patents

In October 2006, the US HUYA biological microchip company formally signed the International Patent Chidamide licensing and international clinical cooperative development agreement; the United States in the ongoing Phase I clinical

Chidamide (Epidaza), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I , as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.

Chidamide, the English called Chidamide, by the Shenzhen-core biotechnology limited liability company independent design and synthesis of a novel anti-cancer drugs with new chemical structures and global intellectual property, and its chemical name N- (2-amino-_4_ fluorophenyl) -4_ (N- (3- topiramate Li acryloyl) aminomethyl) benzamide, its chemical structure of the structural formula I

The patent ZL03139760.3 and said US7,244,751, Chidamide have histone deacetylase inhibitory activity can be used to treat the differentiation and proliferation-related diseases such as cancer and psoriasis, especially for leukemia and solid tumors with excellent results.

Patent No. ZL03139760.3 and US7,244,751 discloses a method for preparing chidamide, but did not specify whether the resulting product is a crystalline material, nor did the presence or absence of the compound polymorphism. In the above patent, the activity of the compound for evaluation is not conducted in a solid state and, therefore, does not disclose any description about characteristics of the crystal.

Chipscreen grabs CFDA approval for chidamide

Posted on 2015/01/10

Chipscreen BioSciences announced that the CFDA had approved chidamide for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in December 2014. The drug and Hengrui’s apatinib were the only two NCEs launched by domestic drug makers last year.

Chidamide (CS055/HBI-8000) is a HDAC1/2/3/10 inhibitor derived from entinostat (MS-27-275)[1] which was first discoved by Mitsui Pharmaceuticals in 1999. Chipscreen holds worldwide IP rights to chidamide (patents: WO2004071400, WO2014082354).

Syndax Pharmaceuticals (NASDAQ: SNDX) is testing entinostat in breast cancer and NSCLC in pivotal trials. The FDA granted Breakthrough Therapy Designation to entinostat for advanced breast cancer in 2013. Eddingpharm in-licensed China rights to entinostat from Syndax in September 2013.

Chipscreen disclosed positive results from Phase II study of chidamide in relapsed or refractory PTCL at 2013 ASCO Annual Meeting[2]. Out of 79 evaluable patients in the trial, 23 patients (29.1%) had confirmed responses (8 CR, 3 CRu, and 12 PR). The most common grade 3/4 AEs were thrombocytopenia (24%), leucocytopenia (13%), neutropenia(10%).

The FDA has approved three HDAC inhibitors, known as Zolinza (vorinostat), Istodax (romidepsin) and Beleodaq (belinostat), for the treatment of PTCL. Celgene priced Istodax at $12000-18000/month and reported annual sales of $54 million in 2013. The efficacy and safety profile of chidamide compares favorably with romidepsin.

Although a dozen of companies are developing generic vorinostat and romidepsin, no chemical 3.1 NDA has been submitted to the CFDA so far. Chipscreen will be the only domestic maker of HDAC inhibitor in the coming two years. Moreover, the company is testing chidamide in NSCLC and breast cancer in early clinical studies.

CLIP

Chiamide synthesis: US7244751B2

Procedure:

Step a: To a suspension of 0.33 g (2.01 mmol) of N,N’-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0 °C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.

Step b: To a suspension of 0.29 g (1.78 mmol) of N,N’-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45 °C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give N-(2-amino-4-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzamide (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): dppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.

http://www.google.co.in/patents/US7244751

EXAMPLE 1

Preparation of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid

To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.46 g, 82%). HRMS calcd for C₁₆H₁₄N₂O₃: 282.2988. Found: 282.2990. MA calcd for: C₁₆H₁₄N₂O₃: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.EXAMPLE 2

Preparation of N-(2-amino-4-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide

To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.40 g, 57%). ¹H NMR (300 MHz, DMSO-d₆): δppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm¹: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C₂₂H₁₉N₄O₂F: 390.4170. Found: 390.4172. MA calcd for C₂₂H₁₉N₄O₂F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.EXAMPLE 3

Preparation of 4-[N-cinnamoylaminomethyl]benzoic acid

To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of cinnamic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 7. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.51 g, 91%). HRMS calcd for C₁₇H₁₅NO₃: 281.3242. Found: 281.3240. MA calcd for C₁₇H₁₅NO₃: C, 72.58%; H, 5.38%; N, 4.98. Found: C, 72.42%; H, 5.37%; N, 4.98%.

EXAMPLE 4

Preparation of N-(2-amino-4-fluorophenyl)-4-[N-cinnamoylaminomethyl]benzamide

To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-cinnamoylaminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofunan (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 16 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.45 g, 64%). ¹H NMR (300 MHz, DMSO-d₆): δppm: 4.42 (2H, d), 4.92 (2H, br.s), 6.62 (1H, t), 6.78 (2H, m), 7.01 (1H, t), 7.32 (5H, m), 7.54 (5H, m), 8.76 (1H, br.t), 9.58 (1H, br.s). IR (KBr) cm⁻¹: 3306, 1618, 1517, 1308, 745. HRMS calcd for C₂₃H₂₀N₃O₂F: 389.4292. Found: 389.4294. MA calcd for C₂₃H₂₀N₃O₂F: C, 70.94%; H, 5.18%; N, 10.79%. Found: C, 70.72%; H, 5.18%; N, 10.88%.

PATENT

https://www.google.com/patents/US20150299126

FIG. 2 is the ¹H NMR spectrum of the solid prepared according to Example 2 of patent ZL 03139760.3;

NMR, MS ETC CLICK TO VIEW

CLIP

Chidamide (Epidaza), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I 1–3, as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.74

This agent also inhibits the expression of signaling kinases in the PI3K/ Akt and MAPK/Ras pathways and may result in cell cycle arrest and the induction of tumor cell apoptosis.75

Currently, phases I and II clinical trials are underway for the treatment of non-small cell lung cancer and for the treatment of breast cancer, respectively.76 The scalable synthetic approach to chidamide very closely follows the discovery route,77–79 and is described in Scheme 10. The sequence began with the condensation of commercial nicotinaldehyde (52) and malonic acid (53) in a mixture of pyridine and piperidine. Next, activation of acid 54 with N,N0-carbonyldiimidazole (CDI) and subsequent reaction with 4-aminomethyl benzoic acid (55) under basic conditions afforded amide 56 in 82% yield.

Finally, activation of 56 with CDI prior to treatment with 4-fluorobenzene- 1,2-diamine (57) and subsequent treatment with TFA and THF yielded chidamide (VIII) in 38% overall yield from 52. However, no publication reported that mono-N-Boc-protected bis-aniline was used to approach Chidamide.

74. Ning, Z. Q.; Li, Z. B.; Newman, M. J.; Shan, S.; Wang, X. H.; Pan, D. S.; Zhang, J.;
Dong, M.; Du, X.; Lu, X. P. Cancer Chemother. Pharmacol. 2012, 69, 901.
75. Liu, L.; Chen, B.; Qin, S.; Li, S.; He, X.; Qiu, S.; Zhao, W.; Zhao, H. Biochem.
Biophys. Res. Commun. 2010, 392, 190.
76. Gong, K.; Xie, J.; Yi, H.; Li, W. Bio. Chem. J. 2012, 443, 735.
77. Lu, X. P.; Li, Z. B.; Xie, A. H.; Shi, L. M.; Li, B. Y.; Ning, Z. Q.; Shan, S.; Deng, T.;
Hu, W. M. US Patent 2004224991A1, 2004.
78. Lu, X. P.; Li, Z. B.; Xie, A. H.; Shi, L. M.; Li, B. Y.; Ning, Z. Q.; Shan, S.; Deng, T.;
Hu, W. M. CN Patent 1513839A, 2003.
79. Yin, Z. H.; Wu, Z. W.; Lan, Y. K.; Liao, C. Z.; Shan, S.; Li, Z. L.; Ning, Z. Q.; Lu, X.
P.; Li, Z. B. Chin. J. New Drugs 2004, 13, 536.

see CN 105457038

CN 1513839

WRONG COMPD

WO2004071400

Example 2. Preparation of
N-(2-amino-5-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide

To a suspension of 0.29 g (1.78 mmol) of N, N’-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45°C for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofunan (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d₆): δppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (IH, t), 6.80 (2H, m), 6.96 (IH, t), 7.18 (IH, d), 7.42 (2H, d), 7.52 (IH, d), 7.95 (2H, d), 8.02 (IH, d), 8.56 (IH, d), 8.72 (IH, br. t), 8.78 (IH, s), 9.60 (IH, br.s). IR (KBr) cm^“1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C₂₂Hι₉N₄O₂F: 390.4170. Found: 390.4172. MA calcd for C₂₂Hι₉N₄O₂F: C, 67.68%; H, 4.40%; N, 14.35. Found: C, 67.52%; H, 4.38%; N, 14.42%.

Photo taken on May 22, 2015 shows a box of Chidamide in Shenzhen, south China’s Guangdong Province. Chidamide is the world’s first oral HDAC inhibitor …

A New Cancer Drug, Made in China

After 14 years, Shenzhen biotech’s medicine is one of the few locally developed from start to finish

HONG KONG— Xian-Ping Lu left his job as director of research at drug maker Galderma R&D in Princeton, N.J., to co-found a biotech company to develop new medicines in his native China.

It took more than 14 years but the bet could be paying off. In February, Shenzhen Chipscreen Biosciences’ first therapy, a medication for a rare type of lymph-node cancer, hit the market in China.

The willingness of veterans like Dr. Lu and others to leave multinational drug companies for Chinese startups reflects a growing optimism in the industry here. The goal, encouraged by the government, is to move the Chinese drug industry beyond generic medicines and drugs based on ones developed in the West.

Chipscreen’s drug, called chidamide, or Epidaza, was developed from start to finish in China. The medicine is the first of its kind approved for sale in China, and just the fourth in a new class globally. Dr. Lu estimates the research cost of chidamide was about $70 million, or about one-tenth what it would have cost to develop in the U.S.

“They are a good example of the potential for innovation in China,” said Angus Cole, director at Monitor Deloitte and pharmaceuticals and biotechnology lead in China.

China’s spending on pharmaceuticals is expected to top $107 billion in 2015, up from $26 billion in 2007, according to Deloitte China. It will become the world’s second-largest drug market, after the U.S., by 2020, according to an analysis published last year in the Journal of Pharmaceutical Policy and Practice.

China has on-the-ground infrastructure labs, a critical mass of leading scientists and interested investors, according to Franck Le Deu, head of consultancy McKinsey & Co.’s pharmaceuticals and medical-products practice in China. “There’re all the elements for the recipe for potential in China,” he said.

But there are obstacles to an industry where companies want big payoffs for a decade or more of work and tremendous costs it takes to develop a drug.

While the protection of intellectual property has improved, China’s cumbersome rules for drug approval and a government effort to cut health-care costs, particularly spending on drugs, could hurt the Chinese drug companies’ efforts, said Mr. Cole of Deloitte.

“Will you start to see success? Of course you will,” said Mr. Cole. However, “I’ve yet to see convincing or compelling evidence that it’s imminent.”

To date, many of the Chinese companies that are flourishing in the life sciences are contract research organizations that help carry out clinical trials, as well as providers of related services.

Some companies, like Shanghai-based Hua Medicine, are buying the rights to develop new compounds in China from multinational drug companies, what some experts consider more akin to an intermediate step to innovation.

Late last year, Hua Medicine completed an early-stage human clinical trial of a diabetes drug in China and in March filed an application to the Food and Drug Administration to develop it in the U.S. as well. The company has raised $45 million in venture funding to date.

Li Chen, who left an 18-year career at Roche Holding AG as head of research and development in China to help start Hua Medicine, said the company’s goal is to “create a game-changer of drug discovery.”

At Chipscreen Biosciences, Dr. Lu and his co-founders set up the company in 2001 in Shenzhen, a city that was quickly growing into a technology and research hub, just over the border from Hong Kong. They created a lab of 10 scientists to use a new analytic technique known as “chemical genomics” to examine the relationships between molecular structures of the existing and failed drugs, how they act on different targets in the body and what genes were being activated or repressed. Now they have more than 60 scientists.

By better predicting how chemicals would act on the body before entering human testing, they hoped they would be more likely get a drug to market.

“How can a small company compete with a multinational?” said Dr. Lu. “The only thing we can compete with is the scientific brain.”

The biggest challenges for the company have been financing and the Chinese regulatory system, said Dr. Lu. The company has raised a total of 300 million yuan ($48 million) over five rounds of venture funding, said Dr. Lu. Chipscreen also receives grant money from the Chinese government.

The company filed its application for approval of chidamide to the Chinese Food and Drug Administration, or CFDA, in early 2013. It had to wait nearly two years for approval, receiving the OK only in December.

Chidamide now is on the market in China for 26,500 yuan ($4,275) a month, a price far lower than patients in the U.S. pay for some of the newest cancer medicines but much more than the typical Chinese patient pays for drugs. Dr. Lu said the price reflects a balance between affordability for patients and return for shareholders. Some investors wanted to price the drug higher.

PAPER

Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment

De-Si Pan,^a Qian-Jiao Yang,^a Xin Fu,^a Song Shan,^a Jing-Zhong Zhu,^a Kun Zhang,^a Zhi-Bin Li,^a Zhi-Qiang Ning^a and Xian-Ping Lu*^a

Corresponding authors

^aShenzhen Chipscreen Biosciences Ltd., BIO-Incubator, Suit 2-601, Shenzhen Hi-Tech Industrial Park, Shenzhen, P. R. China
E-mail: xplu@chipscreen.com

Med. Chem. Commun., 2014,5, 1789-1796

DOI: 10.1039/C4MD00350K, http://pubs.rsc.org/en/content/articlelanding/2014/md/c4md00350k#!divAbstract

Tumorigenesis is maintained through a complex interplay of multiple cellular biological processes and is regulated to some extent by epigenetic control of gene expression. Targeting one signaling pathway or biological function in cancer treatment often results in compensatory modulation of others, such as off-target drivers of cell survival. As a result, overall survival of cancer patients is still far from satisfactory. Epigenetic-modulating agents can concurrently target multiple aberrant or compensatory signaling pathways found in cancer cells. However, existing epigenetic-modulating agents in cancer treatment have not yet fully translated into survival benefits beyond hematological tumors. In this article, we present a historical rationale for use of chidamide (CS055/Epidaza), an orally active and subtype-selective histone deacetylase (HDAC) inhibitor of the benzamide chemical class. This compound was discovered and successfully developed as mono-therapy for relapsed and refractory peripheral T cell lymphoma (PTCL) in China. We discuss the evidence supporting chidamide as a durable epigenetic modulator that allows cellular reprogramming with little cytotoxicity in cancer treatments.

Graphical abstract: Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment

CLIPS

Chinese scientists develop world’s 1st oral HDAC inhibitor

Lu Xianping works in a lab at Shenzhen Chipscreen Biosciences Ltd. in Shenzhen, south China’s Guangdong Province, May 20, 2015. Lu Xianping, together with other four returned overseas scientists, spent 14 years to develop Chidamide, the world’s first oral HDAC inhibitor, which was given regulatory approval in January. (Xinhua/Mao Siqian)

GNT Biotech and Medicals Corporation Licenses Novel Cancer Molecule from Shenzhen Chipscreen Biosciences Ltd.

PR Newswire

SHENZHEN, China, Oct. 10, 2013

SHENZHEN, China, Oct. 10, 2013 /PRNewswire/ — GNT Biotech and Medicals Corporation announces the grant of an exclusive license from Shenzhen Chipscreen Biosciences Ltd.for the development and commercialization of Chidamide in Taiwan. Chidamide, an oral, selective histone deacetylase (HDAC) inhibitor, is currently being evaluated in Phase II trials by Chipscreen Biosciences in Peripheral T-Cell Lymphoma (PTCL), Cutaneous T-Cell Lymphoma (CTCL) and Non-Small Cell Lung Cancer patients (NSCLC). GNTbm will develop and commercialize Chidamide primarily in PTCL, NSCLC and will also retain the rights to develop and commercialize Chidamide in other oncology indications in Taiwan.

About Chidamide

Chidamide is a selective HDAC inhibitor against subtype 1, 2, 3 and 10, and being studied in multiple clinical trials as a single agent or in combination with chemotherapeutic agents for the treatment of various hematological and solid cancers. Its anticancer effects are thought to be mediated through epigenetic modulation via multiple mechanisms of action, including the inhibition of cell proliferation and induction of apoptosis in blood derived cells, inhibition of epithelial to mesenchymal transition (EMT, a process that is highly relevant to tumor cell metastasis and drug resistance), induction of tumor specific antigen and antigen-specific T cell cytotoxicity, enhancement of NK cell anti-tumor activity, induction of cancer stem cell differentiation, and resensitization of tumor cells that have become resistant to anticancer agents such as platinums, taxanes and topoisomerase II inhibitors. Chidamide has demonstrated clinical efficacy in pivotal phase II trials on Cutaneous T-Cell Lymphoma (CTCL) and Peripheral T-Cell Lymphoma (PTCL) conducted in China, and is currently undergoing phase II trial in NSCLC together with first line PC therapeutic treatment. Due to its superior pharmacokinetic properties and selectivity, Chidamide may offer better clinical profile over the other HDAC inhibitors currently under development or being marketed.

About GNTbm

GNTbm is a subsidiary of GNT Inc, a Taiwanese company focused on the manufacture of nano-scale metallic particles for food and medical purposes. Founded in 1992 by a team of electronic professionals, GNT has successfully developed the innovative technology of physical metal miniaturization based on the patent of MBE (Molecular Beam Epitaxy). Further information about GNT Inc is available at www.gnt.com.tw.

GNTbm was established in August 2013, and housed in the Nankang Biotech Incubation Center, (NBIC), in Nankang, Taipei. Lead by Dr. Chia-Nan Chenalong with an experienced team of scientists, GNTbm will explore development and commercialization of novel drug delivery systems, Innovative biomedical and diagnostic tools based on gold nanoparticles.

About Shenzhen Chipscreen Biosciences Ltd.

Chipscreen is a leading integrated biotech company in China specialized in discovery and development of novel small molecule pharmaceuticals. The company has utilized its proprietary chemical genomics-based discovery platform to successfully develop a portfolio of clinical and preclinical stage programs in a number of therapeutic areas. Chipscreen’s business strategy is to generate differentiated drug candidates across multiple therapeutic areas. Drug candidates are either developed by Chipscreen or co-developed and commercialized in a partnership at the research, preclinical and clinical stages. The company was established as Sino-foreign joint venture in 2001. Further details about Chipscreen Bioscience is available atwww.chipscreen.com.

GNT Biotech and Medicals Corporation

Ekambaranellore Prakash, PhD

Director of International Department

GNT Biotech and Medicals Corporation

TEL: +886-2-7722-0388 #303

E-mail: prakash@gntbm.com.tw

Web site: www.gnt.com.tw

Shenzhen Chipscreen Biosciences Ltd.

Rebecca Hai

Investor Relations

Shenzhen Chipscreen Biosciences Ltd.

TEL: +86-755-26957317

E-mail: rebeccai_hai@chipscreen.com

Web site: www.chipscreen.com

SOURCE GNT Biotech and Medicals Corporation

CN101397295B	Nov 12, 2008	Apr 25, 2012	深圳微芯生物科技有限责任公司	2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof
CN101648920B	Aug 20, 2009	Feb 8, 2012	苏州东南药物研发有限责任公司	用作组蛋白去乙酰酶抑制剂的三氟甲基酮类化合物及其用途
CN101648921B	Aug 20, 2009	Nov 2, 2011	苏州东南药物研发有限责任公司	Benzamide compound used as histone deacetylase inhibitor and application thereof
CN103833626A *	Nov 27, 2012	Jun 4, 2014	深圳微芯生物科技有限责任公司	Crystal form of chidamide and preparation method and application thereof
CN103833626B *	Nov 27, 2012	Nov 25, 2015	深圳微芯生物科技有限责任公司	西达本胺的晶型及其制备方法与应用
CN104876857A *	May 12, 2015	Sep 2, 2015	亿腾药业（泰州）有限公司	Preparation of benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity
EP2205563A2 *	Oct 8, 2008	Jul 14, 2010	Orchid Research Laboratories Limited	Novel histone deacetylase inhibitors
WO2009152735A1 *	Jun 9, 2009	Dec 23, 2009	Jiangsu Goworth Investment Co. Ltd	Histone deacetylase inhibitors and uses thereof
WO2010135908A1 *	May 20, 2010	Dec 2, 2010	Jiangsu Goworth Investment Co. Ltd.	N-(2-amino-4-pyridyl) benzamide derivatives and uses thereof
WO2014082354A1 *	Dec 18, 2012	Jun 5, 2014	Shenzhen Chipscreen Biosciences, Ltd.	Crystal form of chidamide, preparation method and use thereof

Chidamide
Systematic (IUPAC) name

N-(2-Amino-5-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]-benzamide
Clinical data
Trade names	Epidaza
Identifiers
CAS Number	743420-02-2
PubChem	CID 9800555
ChemSpider	7976319
UNII	87CIC980Y0
Chemical data
Formula	C₂₂H₁₉FN₄O₂
Molar mass	390.4 g/mol

Patent ID	Date	Patent Title
US2015299126	2015-10-22	CRYSTAL FORM OF CHIDAMIDE, PREPARATION METHOD AND USE THEREOF
US2010222379	2010-09-02	NOVEL HISTONE DEACETYLASE INHIBITORS
US7244751	2007-07-17	Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity

References

“China’s First Homegrown Pharma.”. April 2015.
^ Jump up to:^a ^b [1]
HUYA Bioscience International Grants An Exclusive License For HBI-8000 In Japan And Other Asian Countries To Eisai. Feb 2016
Qiao, Z (2013-04-26). “Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells.”. Biochem Biophys Res Commun. 434 (1): 95–101. doi:10.1016/j.bbrc.2013.03.059. PMID 23541946.
Guha, Malini (2015-04-01). “HDAC inhibitors still need a home run, despite recent approval”. Nature Reviews Drug Discovery 14: 225–226. doi:10.1038/nrd4583.
Wang, Shirley S. (2015-04-02). “A New Cancer Drug, Made in China”. The Wall Street Journal. Retrieved 13 April 2015.
References:
1. Ning, Z. Q.; et. al. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol2012, 69(4), 901-909. (activity)
2. Gong, K.; et. al. CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 2012, 443(3), 735-746. (activity)

3. Hu, W.; et. al. N-(2-amino-5-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl) aminomethyl ]benzamide or other derivatives for treating cancer and psoriasis. US7244751B2
4. Lu, X.; et. al. Crystal form of chidamide, preparation method and use thereof. WO2014082354A1
5. Yin, Z.-H.; et. al. Synthesis of chidamide,a new histone deacetylase (HDAC) inhibitor. Chin J New Drugs 2004, 13(6), 536-538. (starts with basic raw materials)
Zhongguo Xinyao Zazhi (2004), 13(6), 536-538.

/////////Chidamide, Epidaza, CS055, HBI-8000, orally active subtype-selective HDAC inhibitor, epigenetic modulator, cancer treatment

Fc3ccc(NC(=O)c1ccc(cc1)CNC(=O)/C=C/c2cccnc2)c(N)c3

Selectbio’s 4th International conference on Drug Discovery India 2016, 29-30 Sept 2016, Bengaluru, India

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Jun 292016

Drug Discovery India 2016

Selectbio’s Drug Discovery India 2016, 29 – 30 September 2016, Bengaluru, India

see

https://selectbiosciences.com/conferences/index.aspx?conf=DDI16&se=india

Overview

SELECTBIO is delighted to announce its 4^th International Drug Discovery India 2016 Conference and Exhibition. This conference will be held in Le Méridien Bangalore Hotel, Bengaluru on September 29-30, 2016. The theme of the conference is “Deriving Best Out of Chemistry, Biotechnology and Natural Products“.

The event aims to expand knowledge by providing insights into the latest developments and innovations in the field of drug discovery, medicinal chemistry, natural products and chemical biology. Every year this event bring together about 200 drug discovery scientists together at a platform to discuss and share drug discovery related research and facilitates collaborations amongst scientists from across the globe.

This meeting will be co-located with our 2^nd International Conference Antibodies and Antibody Drug Conjugates. Registered delegates will have unrestricted access to all co-located meetings ensuring a comprehensive learning and sharing experience as well as being financially beneficial for attendees.

Running alongside the Drug Discovery India 2016 conference will be an Exhibition covering the latest technological advances within these fields. We look forward to welcoming you at the Drug Discovery India 2016 Conference and Exhibition and hope that the two days will be both informative and enjoyable.

Who Should Attend

Drug Discovery Scientists, Medicinal Chemists, Biotechnologists & Researchers from Pharmaceutical Industry R&D and Academic institutions working in the area of New Drug Discovery Research, Discovery and Development of New Chemical entities, Biomolecular Screening Technologies, Drug Target Identification, Structure-based and Target-based, Drug Design, Protein-Protein Interactions, Drug Repurposing, Orphan Drugs, Chemical Biology, Stem Cell, Epigenetics as well as Natural Products.

Conference Chair

Dr. Rathnam Chaguturu

Dr Rathnam Chaguturu
Founder & CEO, iDDPartners

Dr. Sanjay Bajaj, Ph.D.

Managing Director

Unit 21, Level 2, Berkeley Square, Plot 24,

Industrial Area Phase I, Chandigarh 160002, India

Phone: +91 172 5025050, M: +91 9814412082

Email: s.bajaj@selectbio.com; Website: www.selectbiosciences.com; www.selectbioindia.net

Upcoming Events in India

Show Calender 2016

3for2_emailsig .

https://selectbiosciences.com/conferences/index.aspx?conf=DDI16&se=india

//////////Sanjay Bajaj, Selectbio, Drug Discovery India 2016, 29 – 30 September 2016, Bengaluru, India

タバルマブ（遺伝子組換え) Tabalumab

MONOCLONAL ANTIBODIES, Uncategorized Comments Off

Jun 272016

Tabalumab

タバルマブ（遺伝子組換え)
Tabalumab (Genetical Recombination)

[1143503-67-6]

Tabalumab (LY 2127399) is an anti-B-cell activating factor (BAFF) human monoclonal antibody designed for the treatment of autoimmune diseases and B cell malignancies.^[1]^[2] Tabalumab was developed by Eli Lilly and Company.

A phase III clinical trial for rheumatoid arthritis was halted in Feb 2013.^[3] In September 2014, a second phase III trial focussing on treating systemic lupus erythematosus, was terminated early as the study failed to meet its primary endpoint.^[4]

References

abalumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	BAFF
Identifiers
CAS Number	1143503-67-6
ATC code	none
ChemSpider	none
Chemical data
Formula	C₆₅₁₈H₁₀₀₀₈N₁₇₂₄O₂₀₃₂S₃₈
Molar mass	146.25 kg/mol

////////////タバルマブ , 遺伝子組換え, Tabalumab, 1143503-67-6, antibody, Monoclonal antibody

Review, Continuous Processing

PROCESS, spectroscopy, SYNTHESIS, Uncategorized Comments Off

Jun 272016

Continuous Processing

Continuous production is a flow production method used to manufacture, produce, or process materials without interruption. Continuous production is called a continuous process or a continuous flow process because the materials, either dry bulk or fluids that are being processed are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. Continuous processing is contrasted with batch production.

Continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. Some chemical plants can operate for more than one or two years without a shutdown. Blast furnaces can run four to ten years without stopping.^[1]

Production workers in continuous production commonly work in rotating shifts.

Processes are operated continuously for practical as well as economic reasons. Most of these industries are very capital intensive and the management is therefore very concerned about lost operating time.

Shutting down and starting up many continuous processes typically results in off quality product that must be reprocessed or disposed of. Many tanks, vessels and pipes cannot be left full of materials because of unwanted chemical reactions, settling of suspended materials or crystallization or hardening of materials. Also, cycling temperatures and pressures from starting up and shutting down certain processes (line kilns, boilers, blast furnaces, pressure vessels, etc.) may cause metal fatigue or other wear from pressure or thermal cycling.

In the more complex operations there are sequential shut down and start up procedures that must be carefully followed in order to protect personnel and equipment. Typically a start up or shut down will take several hours.

Continuous processes use process control to automate and control operational variables such as flow rates, tank levels, pressures, temperatures and machine speeds.^[2]

Semi-continuous processes

Many processes such as assembly lines and light manufacturing that can be easily shut down and restarted are today considered semi-continuous. These can be operated for one or two shifts if necessary.

History

The oldest continuous flow processes is the blast furnace for producing pig iron. The blast furnace is intermittently charged with ore, fuel and flux and intermittently tapped for molten pig iron and slag; however, the chemical reaction of reducing the iron and silicon and later oxidizing the silicon is continuous.

Semi-continuous processes, such as machine manufacturing of cigarettes, were called “continuous” when they appeared.

Many truly continuous processes of today were originally batch operations.

The Fourdrinier paper machine, patented in 1799, was one of the earliest of the industrial revolution era continuous manufacturing processes. It produced a continuous web of paper that was formed, pressed, dried and reeled up in a roll. Previously paper had been made in individual sheets.

Another early continuous processes was Oliver Evans‘es flour mill (ca. 1785), which was fully automated.

Early chemical production and oil refining was done in batches until process control was sufficiently developed to allow remote control and automation for continuous processing. Processes began to operate continuously during the 19th century. By the early 20th century continuous processes were common.

Shut-downs

In addition to performing maintenance, shut downs are also when process modifications are performed. These include installing new equipment in the main process flow or tying-in or making provisions to tie-in sub-processes or equipment that can be installed while the process is operating.

Shut-downs of complicated processes may take weeks or months of planning. Typically a series of meetings takes place for co-ordination and planning. These typically involve the various departments such as maintenance, power, engineering, safety and operating units.

All work is done according to a carefully sequenced schedule that incorporates the various trades involved, such as pipe-fitters, millwrights, mechanics, laborers, etc., and the necessary equipment (cranes, mobile equipment, air compressors, welding machines, scaffolding, etc.) and all supplies (spare parts, steel, pipe, wiring, nuts and bolts) and provisions for power in case power will also be off as part of the outage. Often one or more outside contractors perform some of the work, especially if new equipment is installed.

Safety

Safety meetings are typically held before and during shutdowns. Other safety measures include providing adequate ventilation to hot areas or areas where oxygen may become depleted or toxic gases may be present and checking vessels and other enclosed areas for adequate levels of oxygen and insure absence of toxic or explosive gases. Any machines that are going to be worked on must be electrically disconnected, usually through the motor starter, so that it cannot operate. It is common practice to put a padlock on the motor starter, which can only be unlocked by the person or persons who is or are endangered by performing the work. Other disconnect means include removing couplings between the motor and the equipment or by using mechanical means to keep the equipment from moving. Valves on pipes connected to vessels that workers will enter are chained and locked closed, unless some other means is taken to insure that nothing will come through the pipes.

Continuous processor (equipment)

Continuous Production can be supplemented using a Continuous Processor. Continuous Processors are designed to mix viscous products on a continuous basis by utilizing a combination of mixing and conveying action. The Paddles within the mixing chamber (barrel) are mounted on two co-rotating shafts that are responsible for mixing the material. The barrels and paddles are contoured in such a way that the paddles create a self-wiping action between themselves minimizing buildup of product except for the normal operating clearances of the moving parts. Barrels may also be heated or cooled to optimize the mixing cycle. Unlike an extruder, the Continuous Processor void volume mixing area is consistent the entire length of the barrel ensuring better mixing and little to no pressure build up. The Continuous Processor works by metering powders, granules, liquids, etc. into the mixing chamber of the machine. Several variables allow the Continuous Processor to be versatile for a wide variety of mixing operations:^[3]

Barrel Temperature
Agitator speed
Fed rate, accuracy of feed
Retention time (function of feed rate and volume of product within mixing chamber)

Continuous Processors are used in the following processes:

Compounding
Mixing
Kneading
Shearing
Crystallizing
Encapsulating

The Continuous Processor has an unlimited material mixing capabilities but, it has proven its ability to mix:

Plastics
Adhesives
Pigments
Composites
Candy
Gum
Paste
Toners
Peanut Butter
Waste Products

EXAMPLE…………….

In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous flow hydrogenation for the reaction was investigated at lab scale using the commercially available H-Cube. The process was then scaled successfully, generating kilogram quantities on the H-Cube Midi. This flow process eliminated the safety concerns about the use of hydrogen gas and pyrophoric catalysts and also showed 1200-fold increase in space–time yield versus the batch processing.

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

Org. Process Res. Dev., 2014, 18 (11), pp 1427–1433

DOI: 10.1021/op400179f, http://pubs.acs.org/doi/full/10.1021/op400179f

EXAMPLE…………….

Correia et al. have published a three-step flow synthesis of rac-Effavirenz. This short synthetic route begins with cryogenic trifluoroacetylation of 1,4-dichlorobenzene. After quench and removal of morpholine using silica gel, this intermediate could either be isolated, or the product stream could be used directly in the next alkynylation step. Nucleophilic addition of lithium cyclopropylacetylide to the trifluoroacetate gave the propargyl alcohol intermediate in 90% yield in under 2 min residence time. This reaction was temperature-sensitive, and low temperatures were required to minimize decomposition. Again silica gel proved effective in the quench of the reaction. However, residual alkyne and other byproducts were difficult to remove. Thus, isolation of this intermediate was performed to minimize the impact of impurities on the final copper catalyzed cyanate installation/cyclization step to afford Effavirenz. Optimization of this step in batch mode for both copper source and ligand identified Cu(NO₃)₂ and CyDMEDA in a 1:4 molar ratio (20 mol % and 80 mol %, respectively) produced the product in 60% yield. Adaptation of this procedure to flow conditions resulted in poor conversion due to slow in situ reduction of the Cu(II) to Cu(I). Thus, a packed bed reactor of NaOCN and Cu(0) was used. Under these conditions, the ligand and catalyst loading could be reduced without compromising yield. Due to solubility limitations of Cu(NO₃)₂, Cu(OTf)₂ was used with CyDMEDA in 1:2 molar ratio (5 mol % and 10 mol % loading, respectively). Under these optimized conditions, rac-Effavirenz was obtained in 62% isolated yield in reaction time of 1 h. This three-step process provides 45% overall yield of rac-Effavirenz and represents the shortest synthesis of this HIV drug reported to date

1H NMR (400 MHz, CDCl3, ppm) δ9.45 (s, 1H), 7.49 (s, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 1.43-1.36 (m, 1H); 0.93-0.85 (m, 4H);

13C NMR (100 MHz, CDCl3, ppm) δ 149.2, 133.2, 131.7, 129.2, 127.8, 122.1 (q, JC-F = 286 Hz), 116.3, 115.1, 95.9, 79.6 (q, JC-F = 35 Hz), 66.1, 8.8, 0.6;

19F NMR (376 MHz, CDCl3, ppm) δ -80.98.

1 T. J. Connolly; A. W.-Y Chan; Z. Ding; M. R. Ghosh; X. Shi; J. Ren, E. Hansen; R. Farr; M. MacEwan; A. Alimardanov; et al, PCT Int. Appl. WO 2009012201 A2 20090122, 2009.

2 (a) Z. Dai, X. Long, B. Luo, A. Kulesza, J. Reichwagen, Y. Guo, (Lonza Ltd), PCT Int. Appl. WO2012097510, 2012; (b) D. D. Christ; J. A. Markwalder; J. M. Fortunak; S. S. Ko; A. E. Mutlib; R. L. Parsons; M. Patel; S. P. Seitz, PCT Int. Appl. WO 9814436 A1 19980409, 1998 (c) C. A. Correia; D. T. McQuade; P. H. Seeberger, Adv. Synth. Catal. 2013, 355, 3517−3521.

A Concise Flow Synthesis of Efavirenz^†

DOI: 10.1002/anie.201411728

http://onlinelibrary.wiley.com/doi/10.1002/anie.201411728/abstract

SUPP INFO

http://onlinelibrary.wiley.com/store/10.1002/anie.201411728/asset/supinfo/anie_201411728_sm_miscellaneous_information.pdf?v=1&s=e1b253efab4a6f4cd5bd245694623e2459700ff5

NEXT EXAMPLE…………….

Wang et al. developed a flow process that uses metal catalyzed hydrogenation of NAB (2-nitro-2′-hydroxy-5′-methylazobenzene) to BTA (2-(2′-hydroxy-5′-methylphenyl)benzotriazole), a commonly used ultraviolet absorber. The major challenge in this process was to optimize the reduction of the diazo functionality over the nitro group and control formation of over reduction side products. The initial screen of metals adsorbed onto a γ-Al₂O₃ support indicated Pd to be superior to the other metals and also confirmed that catalyst preparation plays an important role in selectivity. To better understand the characteristics of the supported metal catalyst systems, the best performing were analyzed by TEM, XRD, H₂-TPR, and N₂ adsorption–desorption. Finally, solvents and bases were screened ultimately arriving at the optimized conditions using toluene, 2 equiv n-butylamine over 1% Pd/Al₂O₃, which provided 90% yield BTA in process with 98% conversion. The process can run over 200 h without a decrease in performance

( ACS Sustainable Chem. Eng. 2015, 3,1890−1896)

The synthesis of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole from 2-nitro-2′-hydroxy-5′-methylazobenzene over Pd/γ-Al₂O₃ in a fixed-bed reactor was investigated. Pd/γ-Al₂O₃ catalysts were prepared by two methods and characterized by XRD, TEM, H₂-TPR, and N₂ adsorption–desorption. Employed in the above reaction, the palladium catalyst impregnated in hydrochloric acid exhibited much better catalytic performance than that impregnated in ammonia–water, which was possibly attributed to the better dispersion of palladium crystals on γ-Al₂O₃. This result demonstrated that the preparation process of the catalyst was very important. Furthermore, the reaction parameters were optimized. Under the optimized conditions (toluene, NAB/triethylamine molar ratio 1:2, 60 °C, 2.5 MPa hydrogen pressure, 0.23 h^–1 liquid hourly space velocity), about 90% yield of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole was obtained. Finally, the time on stream performance of the catalyst was evaluated, and the reaction could proceed effectively over 200 h without deactivation of the catalyst.

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al₂O₃ by a Continuous Process

ACS Sustainable Chem. Eng., 2015, 3 (8), pp 1890–1896

DOI: 10.1021/acssuschemeng.5b00507

Publication Date (Web): July 06, 2015

http://pubs.acs.org/doi/abs/10.1021/acssuschemeng.5b00507

NEXT EXAMPLE…………….

Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

continuous flow processing of organometallic reagents

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

https://www.vapourtec.com/flow-chemistry-resource-centre/publications-citing-vapourtec/continuous-flow-processing-of-organometallic-reagents-using-an-advanced-peristaltic-pumping-system-and-the-telescoped-flow-synthesis-of-ez-tamoxifen/

NEXT EXAMPLE…………….

Multi-step Continuous Flow Pyrazole Synthesis via a Metal-free Amine-redox Process

A versatile multi-step continuous flow synthesis for the preparation of substituted pyrazoles is presented.

The automated synthesis utilises a metal-free ascorbic acid mediated reduction of diazonium salts prepared from aniline starting materials followed by hydrolysis of the intermediate hydazide and cyclo-condensation with various 1,3-dicarbonyl equivalents to afford good yields of isolated functionalised pyrazole products.

The synthesis of the COX-2 selective NSAID was demonstrated using this approach.

J.-S. Poh, D. L. Browne, S. V. Ley, React. Chem. Eng., 2016, DOI: 10.1039/C5RE00082C

NEXT EXAMPLE…………….

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.

In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient

S.-H. Lau, S. L. Bourne, B. Martin, B. Schenkel, G. Penn, S. V. Ley, Org. Lett., 2015, 17 (21), pp 5436–5439

NEXT EXAMPLE…………….

RAFT RAFT (Reversible Addition Fragmentation chain Transfer), a type of controlled radical polymerization, was invented by CSIRO in 1998 but developed in partnership with DuPont over a long term collaboration. Conventional polymerisation is fast but gives a wide distribution of polymer chain lengths. (known as a high polydispersity index ). RAFT is more versatile than other living polymerization techniques, such as atom transfer radical polymerization (ATRP) or nitroxide-mediated polymerization (NMP), it not only leads to polymers with a low polydispersity index and a predetermined molecular weight, but it permits the creation of complex architectures, such as linear block copolymers, comblike, star, brush polymers and dendrimers. Monomers capable of polymerizing by RAFT include styrenes, acrylates, acrylamides, and many vinyl monomers. CSIRO is the owner of the RAFT patents and is actively commercialising the technology. There are 12 licences in force and CSIRO is pursuing interest in a number of fields including human health, agriculture, animal health and personal care. RAFT is the dominant polymerization technique for the creation of polymer-protein or polymer-drug conjugates, permitting (for example) the combination of a polymer exhibiting high solubility with a drug molecule with poor solubility.. Though RAFT can be carried out in batch, it also lends itself to continuous flow processing, as this processing method offers an easy and reproducible scale-up route of the oxygen sensitive RAFT process. The possibility to effectively exclude oxygen using continuous flow reactors in combination with inline degassing methods offers advantages over batch processing at scales beyond the laboratory environment. Challenges associated with the high viscosity of the polymer product solution can be controlled using pressuriseable continuous flow reactor systems. http://www.csiro.au/products/RAFT.html

Examples………..

Cyclohexaneperoxycarboxylic acid (6, has been developed as a safe, inexpensive oxidant, with demonstrated utility in a Baeyer−Villiger rearrangement.³⁴ Solutions of cyclohexanecarboxylic acid in hexane and 50% aqueous H₂O₂ were continuously added to 45% H₂SO₄ at 50−70 °C and slightly reduced pressure. The byproduct H₂O was removed azeotropically, and the residence time in the reactor was 3 h. Processing was adjusted to maintain a concentration of 6 at 17−19%, below the detonable level, and the product was kept as a stable solution in hexane. These operations enhanced the safety margin in preparing 6.

Scheme . Generation of cyclohexaneperoxycarboxylic acid

Examples………..

The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4,d-erythronolactone at kilogram scale was used as an example. Fully continuousprocessing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation step continuously, so hybrid batch–continuous options were explored. It was found that very little additional laboratory or process safety work other than that required for the batch process was required to develop the hybrid process. A hybrid process was chosen because of the difficulty caused by the precipitation of solid byproduct during the isolation stage. While the project was a technical success, the performance benefits of the hybrid process over the batch were not seen as commercially significant for this system.

Multikilogram Synthesis of 4-d-Erythronolactone via Batch andContinuous Processing

Org. Process Res. Dev., 2012, 16 (5), pp 1003–1012

DOI: 10.1021/op200352k, http://pubs.acs.org/doi/full/10.1021/op200352k

Examples………..

Abstract Image

Continuous Biocatalytic Processes

Org. Process Res. Dev., 2009, 13 (3), pp 607–616

DOI: 10.1021/op800314f, http://pubs.acs.org/doi/full/10.1021/op800314f

Scheme . Biotransformation of sodium l-glutamate to γ-aminobutyric acid (GABA) by single-step α-decarboxylation with glutamate decarboxylase

PICS…………..

References

American Iron and Steel Institute
Benett, Stuart (1986). A History of Control Engineering 1800-1930. Institution of Engineering and Technology. ISBN 978-0-86341-047-5.
Ziegler, Gregory R.; Aguilar, Carlos A. (2003). “Residence Time Distribution in a Co-rotating, Twin-screw Continuous Mixer by the Step Change Method”. Journal of Food Engineering(Elsevier) 59 (2-3): 1–7.

Sources and further reading

R H Perry, C H Chilton, C W Green (Ed), Perry’s Chemical Engineers’ Handbook (7th Ed), McGraw-Hill (1997), ISBN 978-0-07-049841-9
Major industries typically each have one or more trade magazines that constantly feature articles about plant operations, new equipment and processes and operating and maintenance tips. Trade magazines are one of the best ways to keep informed of state of the art developments.

/////////////

EP 03031800, New patent, Miglustat, Navinta LLC

PATENTS, Uncategorized Comments Off

Jun 272016

MIGLUSTAT

Gauchers disease type I; Niemann Pick disease type C

EP-03031800, Process for the preparation of high purity miglustat

Navinta, LLC ; Shah, Shrenik K. ; Kharatkar, Raju Mahadev ; Bhatt, Chiragkumar Anilkumar ; Kevat, Jitendra Bhagwandas

The present invention provides a process for the preparation and isolation of crystalline miglustat without the use of a column chromatography or ion exchange purification. The crystalline miglustat has a high purity and a melting point of 128 °C and an endothermic peak is 133 °C.

Process for preparing and isolating crystalline form of miglustat with a high purity is claimed. Represents a first PCT filing from the inventors on miglustat. Actelion, under license from Oxford GlycoSciences (OGS; then Celltech, now UCB), which licensed the compound from GD Searle & Co, has developed and launched miglustat.

Product patent WO9426714, will expire in the US in 2018.

Kharatkar is affiliated with Sterling Biotech, Bhatt is affiliated with Intas and Kevat is affiliated with Orchid Chemicals & Pharmaceuticals.

INVENTORS Shah, Shrenik K.; Kharatkar, Raju Mahadev; Bhatt, Chiragkumar Anilkumar; Kevat, Jitendra Bhagwandas

About Navinta

Navinta, LLC in Ewing, N.J. is a technology driven Pharmaceutical Company that focuses on novel routes of synthesis of new and existing drug molecules, complex pharmaceutical ingredients, novel formulations of liquid dosage form, novel oral dosage form, novel injectable dosage form and implantable drug delivery devices. Navinta has currently at least fifteen (15) patents granted or pending with the United States Patent and Trademark Office.

EP-03031800 LINK EMBEDDED

Miglustat is a potent inhibitor of glycosyltransferase. It is primarily used in the treatment of Gaucher’s disease. Miglustat is chemically known as N-butyl-1,5-dideoxy-1,5-imino-D-glucitol of formula (I) and is sometimes referred as N-butyl-1-deoxynojirimycin. Miglustat is a white to off-white crystalline solid with a melting point of 125-126° C. Its empirical formula is C₁₀H₂₁NO₄and has a molecular weight of 219.28 g/mol.

(MOL) (CDX)

Miglustat belongs to the class of azasugars or iminosugars. Ever since the discovery of iminosugars in the 1960s, iminosugars have been subject of extensive studies in both the organic chemistry and biochemistry fields. Iminosugars are polyhydroxylated alkaloids, which may be described as monosaccharide analogues with nitrogen replacing oxygen in the ring. A well-known member of this extensive family of compounds is 1-deoxynojirimycin of formula (II).

(MOL) (CDX)

1-Deoxynojirimycin was initially synthesized in a laboratory. Subsequently, 1-deoxynojirimycin was isolated from natural sources, such as from leaves of mulberry trees and certain species of bacteria. 1-Deoxynojirimycin was shown to be an enzyme inhibitor.

Further research on 1-deoxynojirimycin analogs revealed that N-alkylated derivatives of 1-deoxynojirimycin exhibited greater biological activity than 1-deoxynojirimycin. Among them, N-butyl-1-deoxynojirimycin or miglustat of formula (I), was identified as a very potent inhibitor of glycosyltransferase. Miglustat was later approved by the FDA for human use.

Preparation of azasugars has been a very active area of research for a long time. A seminal synthesis of the compounds of formulas (I) and (II) by double reductive aminations of 5-keto-D-glucose was developed by Baxter and Reitz (J. Org. Chem. 1994, 59, 3175). This method was later refined by Matos and Lopes (Synthesis 1999, 571), in which tetra-O-benzyl-glucose was used as a starting material. Synthesis of miglustat can be traced back to 1977, when chemists from Bayer reported a synthesis of miglustat from 1-deoxynojirimycin and patented in U.S. Pat. No. 4,639,436. Other variations of this general scheme have also appeared in patents and non-patent literature, for example, U.S. Pat. No. 8,802,155 and U.S. Application Publication No. 2014/0243369.

A major drawback of those protocols is that all of them require the use of ion-exchange resins for purification of miglustat. In those protocols, an aqueous solution of miglustat obtained after running an ion-exchange column was concentrated to isolate miglustat. Due to the presence of four hydroxyl groups and a tertiary amine moiety in its chemical structure, miglustat is extremely hydrophilic. Thus, isolation of miglustat from an aqueous solution is quite challenging. In particular, it was very difficult to remove diastereomers and inorganic impurities formed during the reactions from miglustat by those protocols. Sometimes a second chromatographic purification was required to separate these impurities from miglustat. As a result, the yields of miglustat were generally low. The requirement to use a column purification (e.g. ion exchange column, flash column chromatography) further limits the scale of miglustat that could be prepared.

Scheme 1 is a synthetic scheme of miglustat in accordance with one embodiment of the invention:

(MOL) (CDX)

As depicted in scheme 1, the method of preparing miglustat may include the steps of: (1) providing or synthesizing a compound of formula (V); (2) conducting a reductive amination to provide a compound of formula (VI); (3) performing a hydrogenation reaction; and (4) isolating a free base miglustat.

The starting material, 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin hydrochloride of formula (V) may be prepared by following the methods described in Organic Process Research and Development, 2008, 12, 414-423.

Example 1

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-N-butyl-1-deoxynojirimycin hydrochloride of Formula (VI)

To a solution of 2, 3, 4, 6-tetra-O-benzyl-1-deoxynojirimycin hydrochloride (V) (prepared as in Organic Process Research & Development, 2008, 12, 414-423) (45 g, 0.08 mol) in 1575 mL of methanol, n-butyraldehyde (21.6 g, 0.24 mol) and sodium cyanoborohydride (25.2 g, 0.4 mol) were added and stirred. The reaction was maintained under stirring at a temperature from about 25.degree. C. to about 30.degree. C. After the completion of the reaction, the reaction was quenched by adding 765 ml of 10% HCl in methanol, while keeping the temperature between 25.degree. C. to 30.degree. C. The reaction mass was cooled to 0.degree. C. to 5.degree. C. and the resulting precipitate solids were filtered. The filtrate was treated with aqueous HCl and the solid formed was filtered, suspended in 1 N HCl, stirred for 1 hour and filtered. The collected solid was washed with diisopropylether and dried under vacuum to furnish 46.2 g of compound (IV) (46.2 g, 0.075 mol, 94% yield) of high chemical purity based on HPLC analysis (>99.0%).

Example 2

Synthesis of Miglustat Hydrochloride of Formula (III)

A solution of 2, 3, 4, 6-tetra-O-benzyl-N-butyl-1-deoxynojirimycin hydrochloride (VI) (100 g, 0.16 mol) in methanol (1000 mL), 10% HCl solution in methanol (100 mL), and 10% Pd/C (50% wet) (10 g) were mixed and stirred under hydrogen atmosphere at a temperature of about 25.degree. C. to about 30.degree. C. until completion of the reaction. The reaction mass was filtered and the solvent was removed from the filtrate by rotary evaporation. Ethyl acetate (1000 mL) was added to the residue from the rotary evaporation to precipitate the solid. The solid was filtered and dried to isolate Miglustat hydrochloride (III) (42 g, 0.16 mol, 100% yield) of >99.5% purity as measured by HPLC analysis. The DSC thermogram of this product is provided as FIG. 3, and the FTIR spectrum of this product is provided as FIG. 4.

Example 3

Synthesis of Miglustat of Formula (I)

Miglustat hydrochloride (III) (42 g, 0.16 mol) obtained from Example 2 was dissolved in 420 mL of methanol and DBU (1,8-diazabicycloundec-7-ene) (34.1 mL) was added. The reaction mass was warmed slightly and stirred for about 2 hours. The reaction was concentrated by removal of methanol. Dichloromethane (900 mL) was added to the residue. The resulting solid was filtered and dried to obtain crystalline miglustat (I) (27 g, 0.12 mol, 75% yield) of >99.5% purity as measured by HPLC analysis. The melting point of the crystalline miglustat (I) is 128.degree. C. The DSC thermogram and FTIR spectrum of the product are provided as FIG. 1 and FIG. 2, respectively. The crystalline miglustat (I) contained <0.05% of the 5R isomer (IV) as measured by HPLC.

////////////EP 03031800, new patent, miglustat, Kharatkar, Sterling Biotech, Bhatt, Intas , Kevat, Orchid Chemicals & Pharmaceuticals.

Tenatoprazole, テナトプラゾール

phase 1, Uncategorized Comments Off

Jun 232016

Tenatoprazole

泰妥拉唑

Tenatoprazole; 113712-98-4; Ulsacare; Protop; TU 199; TU-199;
Molecular Formula:	C₁₆H₁₈N₄O₃S
Molecular Weight:	346.40412 g/mol

2-[2-(3,5-Dimethyl)pyridylmethylsulfinyl]-5-methoxyimidazo[4,5-b]pyridine

PHASE 1 FOR ………..A proton pump inhibitor potentially for the treatment of gastroesophageal reflux disease.

Research Code TU-199

CAS No. 113712-98-4

Mitsubishi Tanabe Pharma and was licensed to Negma Laboratories

Tenatoprazole is a proton pump inhibitor drug candidate that was undergoing clinical testing as a potential treatment for refluxoesophagitis and peptic ulcer as far back as 2003.^[1] The compound was invented by Mitsubishi Tanabe Pharma and was licensed to Negma Laboratories (part of Wockhardt as of 2007^[2]).^[3]^:22

Mitsubishi reported that tenatoprazole was still in Phase I clinical trials in 2007^[4]^:27 and again in 2012.^[3]^:17

Tenatoprazole has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, and has a half-life about seven times longer than other PPIs.^[5]

Tenatoprazole is a novel imidazopyridine derivative and has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors. It is activated more slowly than other proton pump inhibitor, but its inhibition is resistant to reversal.Tenatoprazole has an extended plasma half-life in comparison with those of all other proton pump inhibitors; this makes it more potent in the treatment of nocturnal acid breakthrough than esomeprazole, one of the most popular proton pump inhibitors.

Tenatoprazole belongs to the class of covalent proton pump inhibitors (PPIs), which is converted to the active sulfenamide or sulfenic acid by acid in the secretory canaliculus of the stimulated parietal cell of the stomach.This active species binds to luminally accessible cysteines of the gastric H⁺,K⁺-ATPase, resulting in disulfide formation and acid secretion inhibition.Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg⁻¹ of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg⁻¹of the enzyme at 2 h after intravenous (IV) administration.

Tenatoprazole, or (+)-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} imidazo-[4,5-b] pyridine, is described in Patent No. EP 254,588. It belongs to the group of drugs considered as proton pump inhibitors, which inhibit the secretion of gastric acid and are useful in the treatment of gastric and duodenal ulcers. It can also be used to treat gastro-oesophageal reflux, digestive bleeding and dyspepsia, because of its relatively long elimination half-life, as described in the application for French patent No. FR 02. 13113.

The first known derivative of this series of proton pump inhibitors was omeprazole, described in Patent No. EP 001,529, which is endowed with properties which inhibit the secretion of gastric acid and is widely employed as an anti-ulcerative in human therapeutics.

In addition to omeprazole, other proton pump inhibitors are well known, and particular mention can be made of rabeprazole, pantoprazole and lansoprazole, which all exhibit structural analogy and lansoprazole, which all exhibit structural analogy and belong to the group of pyridinyl methyl sulfinyl benzimidazoles. These compounds are sulfoxides presenting with asymmetry at the level of the sulphur atom, and therefore generally take the form of a racemic mixture of two enantiomers.

Like omeprazole and other sulfoxide with an analogue structure, tenatoprazole has an asymmetric structure and may therefore be present in the form of a racemic mixture or of its enantiomers. Thus it may exist in the form of its two enantiomers with R and S configurations, or (+) or (−), respectively.

Recent studies have shown that, unlike all the other proton pump inhibitors such as, for example, omeprazole or lansoprazole, and unexpectedly, tenatoprazole is endowed with a markedly prolonged duration of action, resulting from a plasma half-life which is about seven times longer. Thus the clinical data collected have shown that tenatoprazole enables a degree of symptom relief and healing of gastric lesions which is superior to that achieved by other drugs belonging to the same therapeutic category of proton pump inhibitors, which thus allows its effective use in the treatment of atypical and oesophageal symptoms of gastro-oesophageal reflux, digestive bleeding and dyspepsia, as indicated above.

Studies performed by the application have made it possible to show that the two enantiomers contribute differently to the properties of tenatoprazole, and that the two enantiomers, (+) and (−) exhibit significantly different pharmacokinetic properties. Thus it is possible to prepare medicinal products with specific activity by isolating the enantiomers, and these enantiomers themselves exhibit a different pharmacokinetic profile from that of the known racemic mixture. It then becomes possible to use each of these enantiomers more effectively in precise indications for the treatment of perfectly identified pathologies.

Anti-ulcer drug
tenatoprazole (tenatoprazole) is a new proton pump inhibitor, by the Japanese company Tokyo Tanabe, Japan’s Mitsubishi Corporation and Japan’s Hokuriku pharmaceutical companies jointly developed, has passed Phase II clinical trials. It acts on gastric parietal cells, reducing treatment of gastric ulcer, duodenal ulcer, reflux wall cell H + / K + -ATP activity, inhibition of gastric acid secretion, and H. pylori antibacterial activity, mainly for esophagitis and Zhuo – Ellison syndrome and gastric acid secretion disorders related diseases. Compared with the same types of drugs, Tenatoprazole suppress H + / K + -ATP enzyme activity is stronger, more stable, its efficacy than similar products currently widely used in clinical omeprazole strong 7 times. It has not been in the domestic market, nor ratified the production, with broad market prospects and development potential.
Proton pump inhibitors (proton pump inhibitors) for the treatment of acid-related diseases, the past ten years a wide range of clinical applications, better effect of the drug. It can quickly pass through the stomach wall membrane, gathered in a strongly acidic secretory tubules, and H + / K + -ATP enzyme (proton pump) thiol groups covalently bonded to form a disulfide bond, proton pump inactivation, inhibition of the enzyme H + / K + transport, so as to achieve the effect of acid suppression. Proton pump inhibitors and conventional clinical application of gastric acid suppression drugs H2 receptor antagonists compared with different sites of action and have different characteristics, namely acid-suppressing effect at night is good, rapid onset of acid inhibition strong and long time, easy to take these drugs can quickly and efficiently inhibit gastric acid secretion and clearance of Helicobacter pylori, it is widely used gastric ulcer, duodenal ulcer, reflux esophagitis and Zhuo – Ellison syndrome and other diseases treatment. Currently, proton pump inhibitors has been listed on the main omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole.Physical and

chemical properties ofwhite or white crystalline powder, melting point 174 ~ 175 ℃. Soluble in chloroform, insoluble in alcohol and water.
This product and other proton pump inhibitors as compared to chemically stable. China had 34 omeprazole preparations from Portugal, Brazil, India, China and other 13 countries, the stability of the measurements were made. The results showed that only six products (18%) during the trial showing good physical and chemical stability of. 27 products (79%) less (including Chinese product), the active ingredient a significant chemical decomposition, color and physical properties such as dissolution, are also a corresponding change. The results of a stability test designed to compare the various proton pump inhibitors show investigated eight days at 60 ℃, relative humidity of 75%, after omeprazole decomposition only 3% of the active ingredient, the tenatoprazole 77% of the data, said Alpha pantoprazole stability far superior to omeprazole, is already developed similar products in the most promising products.

Synthesis

Matsuishi, N.; Takeda, H.; Iizumi, K.; Murakami, K.; Hisamitsu, A. US Patent 4,808,596, 1989

Synthesis of Tenatoprazole 1 commences with the coupling of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 in the presence of potassium hydroxide affords 4 with 73% yield in ethanol and chloroform. The oxidation of the penultimate sulfide intermediate4 with m-CPBA in chloroform (100 vol) afforded 1

Syn 2

Org. Process Res. Dev., 2009, 13 (4), pp 804–806

DOI: 10.1021/op800173u

http://pubs.acs.org/doi/full/10.1021/op800173u

synthesis of 1 begins with the solvent-free condensation of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to deliver the sulfide intermediate4 with 98% yield.

The final step of the synthesis is the oxidation of the sulfide intermediate with m-CPBA to form tenatoprazole 1. The sulfide intermediate 4 on treatment with 0.9 equiv of m-chloroperbenzoic acid (m-CPBA) at −10 to −15 °C afforded the crude tenatoprazole which was isolated as its sodium salt. The sodium salt of tenatoprazole 5 was purified by recrystallsation using dimethyl formamide and ethyl acetate (2:1 ratio) to yield the pure crystalline tenatoprazole sodium 5. Treatment of tenatoprazole sodium 5 with dil. HCl in the presence of acetone and water afforded the pure tenatoprazole 1

PATENT

CN 1861600

CN 1982311

WO 2009116072

CN 101429192

WO 2010043601

IN 2010CH00462

IN 251400

CN 102304127

WO 2012004802

CN 102703922

IN 2009DE01392

WO 2014111957

IN 2013MU00181

IN 2014CH01419

PAPER

Dai, Liyan; Synthetic Communications 2008, V38(4), P576-582

Advanced Materials Research (Durnten-Zurich, Switzerland) (2011), 233-235(Pt. 1, Fundamental of Chemical Engineering), 160-164.

Organic Process Research & Development (2013), 17(10), 1293-1299

Enantiomeric separation of proton pump inhibitors on new generation chiral columns using LC and supercritical fluid chromatography
Journal of Separation Science (2013), 36, (18), 3004-3010………http://onlinelibrary.wiley.com/doi/10.1002/jssc.201300419/abstract

PATENT

CN 102304127

https://www.google.com/patents/CN102304127A?cl=en

Tenatoprazole is a new type of gastric H + / K + -ATP enzyme inhibitors (proton pump inhibitor PPI), the chemical name 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-methylsulfinyl) imidazole and W, 5-b] pyridine, useful in the treatment of gastric ulcer, duodenal ulcer, reflux esophagitis and Zhuo – Ai syndrome and gastric acid secretion disorders related diseases. The drug was developed by Japan’s Tokyo Tanabe, Japan’s Mitsubishi Corporation and Japan’s Hokuriku pharmaceutical companies. Compared with other varieties of the same type, which inhibit H + / K + -ATP enzyme activity is stronger, ulcers of various tests are effective, and significantly improve the stability compared with other proton pump inhibitors.

US patent US4808596 “hidazo [4,5_b] pyridine compounds and pharmaceutical compositions containing same)) synthesis process disclosed Tenatoprazole the below formula:

By The route of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride with 2-mercapto-5-methoxy-imidazole, 5-b] pyridine under basic conditions condensation of Intermediate 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine, and then oxidizing the Thai duly omeprazole. This route for the synthesis of pull azole classic line, many pull azoles such as omeprazole can be synthesized by a similar route, this route mild condition, simple operation. But the route condensation, oxidation treatment after use of large amounts of toxic solvent chloroform, is not conducive to industrial scale; lower oxidation yields, the resulting Tenatoprazole containing unreacted starting materials 2- [2_ (3,5 – dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine, further comprising a sulfone by-product, N- oxide, N- oxide sulfone, These by-products may interfere with purification of tenatoprazole.

Japanese Patent invention Wo 丨 J JP05222038 “5_methoxy-2- [[(4_methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5 ~ b] pyridine and intermediates)) male

Synthesis open Tenatoprazole the below formula:

4-chloro-2-chloromethyl-3,5-dimethylpyridine -N- oxide 2_ mercapto _5_ methoxy-imidazo – [4, 5-b] pyridine in alkaline under condensation of Intermediate 5-Methoxy-2- (4-chloro-3,5-dimethyl-2-methylthio Bi) imidazo W, 5-b] pyridine-oxide -N- ( yield 82%), then refluxed in a solution of sodium methoxide in methanol to give 5-methoxy-2- (4-oxo-3,5-dimethyl-2-methyl sulfide) imidazo W , 5-b] pyridine -N- oxide (income ¥ 71%), and then at room temperature in methylene chloride, phosphorus trichloride treated with deoxy (yield 95%), and finally oxidation in Tenatoprazole (income Rate not reported). The novel synthetic route, mild reaction conditions, simple operation, the yield of each step is higher, but the route is too long resulting in a total yield is not high, prolonged and rising production costs.

Reaction route is as follows:

Example 1:

] a) 2- [2- (3,5-dimethyl) -4-methoxy-picolyl thioether _5_ methoxy] imidazo [4,5_b] pyridine:

To a reaction flask was added 2-mercapto-5-methoxy-imidazole, 5-b] pyridine 18. lg, 12g of sodium hydroxide and water 144. 8g, stirred and dissolved at 25 ° C, was added dropwise within Ih 20g of the 2-chloromethyl-dimethyl-4-methoxy _3,5- pyridine hydrochloride and 60g of water were mixed solution dropwise at 25 ° C the reaction 2h, the reaction is completed, filtered, washed with water 144. 8g, 36. 2mL ethanol and washed to obtain a wet powder; wet powder was dried at 50 ° C in vacuo to constant weight to give 2- [2_ (3,5-dimethyl) -4-methoxy-pyridylmethyl sulfide -5 – methoxy] imidazo [4,5-b] pyridine 32. Og;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine 30g, dichloromethane 300g, methanol 15g, and dissolved with stirring; cooled to -10 ° C, was added dropwise the 15g and 485g m-chloroperbenzoic acid in methylene chloride mixed solution, dropwise addition the reaction temperature was controlled at -10 ° C, the dropping time of the pool; the dropwise addition, the temperature control at -10 ° C, the reaction 30min; completion of the reaction, at 10 ° C by the dropwise addition of lithium hydroxide and 135g water 15g mixed solution, drip complete, insulation stirred Ih; filtered cake was washed with acetone 60mL, get wet powder; wet powder was dried at 35 ° C under vacuum to constant weight to give Tenatoprazole lithium salt ^ g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, acetone 63mL, water IOOmL, cooling M0 ° C, dropping lmol within lh / L hydrochloric pH7 0, drops. Albert, stirring 30min; the filter cake washed with water 50mL, washed with acetone and 50mL, wet powder was dried at 35 ° C under vacuum to constant weight to give Tenatoprazole 19. Sg.

Example 2:

a) 2- [2- (3,5-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5_b] pyridine (4) Preparation: To the reaction flask was added 2-mercapto-5-methoxy-imidazo 44,5-b] pyridine 18. lg, 11. 2g of potassium hydroxide and water 217mL, stirred and dissolved at! 35 ° C, was added dropwise within 2h by the 33. 3g of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride and 133. 2mL water mixed solution, dropwise at 35 ° C the reaction 4h, the reaction is completed, filtration, water 217mL, 72. 4mL ethanol and washed to obtain a wet powder; wet powder was dried at 60 ° C in vacuo to constant weight to give 2- [2- (3,5-dimethyl) -4-methoxy-pyridylmethyl sulfide -5-methoxy-yl] imidazo W, 5-b] pyridine 33. Ig;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 400mL, methanol 50mL, stirring to dissolve; cooled to _15 ° C, was added drop by the m-chloroperoxybenzoic acid 16g of mixed solution of dichloromethane and 400mL , the process reactor temperature control was added dropwise at -20 ° C, the dropping time 2. 5h; the dropwise addition, the temperature control _15 ° C, the reaction 35min; completion of the reaction, at 15 ° C by the dropwise addition of 20g of hydrogen Lithium oxide and 200mL water mixed solution, drip completed, insulation mixing 1. 5h; filtration, the filter cake washed with acetone 90mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 6g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, ethanol 75mL, water 150mL, cooled to 10 ° C, dropping 6mol / L hydrochloric pH8 0 within 2h,. drops Albert, stirring 40min; the filter cake washed with water 100mL, washed with acetone IOOmL, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 5g.

Example 3:

a) 2- [2- (3,5-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5_b] pyridine (4) Preparation: To the reaction flask was added 2-mercapto-5-methoxy-imidazo 44,5-b] pyridine 18. lg, 8.4g of lithium hydroxide and water 180ml, stirred and dissolved at 30 ° C, was added dropwise within 1. 5h by the Guang .6g 2-chloro-3,5-dimethyl-4-methoxy-pyridine hydrochloride and 90mL water mixed solution, drop end at 30 ° C reaction 3h, the reaction is complete, filtration, water 217mL , washed with 85mL ethanol to obtain a wet powder; wet powder was dried at 55 ° C in vacuo to constant weight to give 2- [2- (3,5-dimethyl) -4-methoxy-5-pyridylmethyl sulfide oxy] imidazo [4,5-b] pyridine 32. 4g;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 600mL, methanol 60mL, stirring to dissolve; cooled to -20 ° C, was added drop by the m-chloroperoxybenzoic acid 18g of mixed solution of dichloromethane and 600mL , dropwise addition the reaction temperature is controlled at _20 ° C, the dropping time of the pool; the dropwise addition, the temperature control at _20 ° C, the reaction 40min; completion of the reaction, at 20 ° C by the dropwise addition of lithium hydroxide and 300mL 30g water mixed solution, drip complete insulation mixing tank; filter, the filter cake washed with acetone and 120mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 7g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, methanol 75mL, water 120mL, cooled to 5 ° C, dropping dilute hydrochloric acid within 1 5h tune pH7 5,.. drops Albert, stirring 35min; the filter cake washed with water 75mL, 75mL acetone washed, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 6g.

Example 4:

a) 2- [2- (3,5-dimethyl) -4-methoxy-picolyl thioether _5_ methoxy] imidazo [4,5_b] pyridine ⑷ Preparation of: To a solution The reaction flask was added 2-mercapto-5-methoxy imidazole -½, 5-b] pyridine 18. lg, IOg sodium hydroxide and water 150ml, stirred and dissolved at 30 ° C, the 1. 5h dropwise added from 21 . 5g of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride and 90mL water mixed solution, dropwise at 30 ° C the reaction 3h, completion of the reaction, was filtered, washed with water 217mL, The wet powder was washed with ethanol to give 85mL; wet powder was dried at 55 ° C in vacuo to constant weight to give 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide ] imidazo [4,5-b] pyridine 32. 3g;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 500mL, methanol 60mL, stirring to dissolve; cooled to -20 ° C, was added drop by the m-chloroperoxybenzoic acid 18g of mixed solution of dichloromethane and 500mL , the process reactor temperature control was added dropwise at -20 ° C, the dropping time pool; the dropwise addition, the temperature control in -20 ° C, the reaction 40min; completion of the reaction, at 20 ° C by the dropwise addition of lithium hydroxide 30g and 300mL water mixed solution, drip complete insulation mixing tank; filter, the filter cake washed with acetone and 120mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 6g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, isopropanol 75mL, water 120mL, cooled to 5 ° C, dropping 3mol / L hydrochloric within 1 5h. . pH7 5, drops Albert, stirring 35min; the filter cake washed with water 75mL, 75mL acetone washed, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 7g.

PAPER

An Improved Synthesis of Antiulcerative Drug: Tenatoprazole

http://pubs.acs.org/doi/full/10.1021/op800173u

Somaiah Sripathi^†, Ramachandra Reddy Bojja^†, Venugopal Reddy Karnati*^‡, V. V. N. K. V. Prasada Raju^§ andMayur D. Khunt^§

Department of Research and Development, Srini Pharmaceuticals Ltd., Plot No. 10, Type-C, Road No. 8, Film Nagar, Jubilee Hills, Hyderabad-500033, Andhra Pradesh, India, Department of Chemistry, Osmania University, Tarnaka, Hyderabad-500007, Andhra Pradesh, India and Research and Development, Integrated Product Development Organization, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally, Qutubullapur, R. R. Dist. 500 072, Andhra Pradesh, India

Org. Process Res. Dev., 2009, 13 (4), pp 804–806

DOI: 10.1021/op800173u

Publication Date (Web): November 12, 2008

* To whom correspondence should be addressed. Telephone: +91 9490783736. E-mail: drkvr_ou@yahoo.com;kvgr1951@rediffmail.com., †Srini Pharmaceuticals Ltd.
, ‡Osmania University.
, §Dr. Reddy’s Laboratory Ltd.

An efficient, cost-effective and multikilogram-scale process for the synthesis of tenatoprazole 1, an antiulcerative drug, is described. The key steps in this synthesis involve the coupling of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to yield 4 and its subsequent oxidation with m-CPBA to produce sulfoxide 1. The process has been scaled up for the multikilogram-scale of compound 1 with an overall yield of 72%. The new process requires no purification process and affords the target compound 1 with 99.8% purity by HPLC.

2-[2-(3,5-dimethyl)pyridylmethylsulfinyl]-5-methoxyimidazo[4,5-b]pyridine (1, 15.5 kg, 74%). Purity by HPLC 99.8%; ¹H NMR (200 MHz, DMSO) δ 2.2 (s, 6H), 3.8 (s, 6H), 4.8 (s, 2H), 6.6 (d, 1H), 7.8 (d, 1H), 8.2 (s, 1H), 13.0 (s, 1H).

PATENT

http://www.google.co.in/patents/US7507746

the (+) enantiomer of tenatoplazole can be obtained by using chloroform, an industrially acceptable solvent, in accordance with the method proposed by Umemura et al. (J. Org. Chem. 1993, 58, 4592) as follows:

Example 1 (−)-5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridineThe conditions for preparative chromatography, shown as an example, are as follows:

Column: 265×110 mm ChiralPak®

Chiral Stationary Phase selector of the Amylose tris type [(S)-a methylbenzylcarbamate]

Flow rate: 570 ml/min

Detection: UV 240 nm

Temperature: Ambient temperature

These conditions are implemented on a liquid preparative chromatography apparatus.

Introduce approximately 2 g of the racemic mixture if tenatoprazole exhibiting purity higher than 99.5%. The (−) enantiomer is identified by measuring the angle of optical rotation, which must be laevogyre. This measurement can be performed directly on the column, the product being dissolved in the solvent (acetonitrile).

Example 2 (+)-5-methoxy-2-{(4-methoxy-3, 5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridine(R)-(+)-binaphthol 85 g (0.311 mol, 0.2 equivalence), ortho titanic acid isopropyl 42 g (0.148 mol, 0.1 equivalence), water 55 g (3.06 mol) and chloroform 7.5 L were stirred for 1 hour at room temperature. To the resultant, 5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio}imidazo[4,5-b]pyridine (MPI), 0.5 kg, was added and stirred for 0.5 hours at room temperature. The thus-prepared mixture was cooled to 5° C. and then 70% aqueous solution of tert-butylhydroperoxide, 0.4 L (approx. 3.0 mol, 2.0 equivalence) was added and stirred for 72 hours at the same temperature as above. After the reaction endpoint was confirmed by HPLC, an aqueous solution of sodium hydroxide was added thereto to separate the aqueous layer, thus removing foreign matter. Then, the resultant was concentrated. Ethyl acetate was added to concentrated residues, which were then heated and suspended. The thus-prepared crude crystalline substances were dissolved in water and neutralized to pH 6.8 with a diluted sulfuric acid solution which was chilled with ice. Deposited crystals were filtered, dried and recrystallized by addition of ethanol to obtain (+)-5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridine {(+)-TU-199}

Yield: 77%

Optical purity: 96.6% ee

Chemical purity: 94.5%

Melting point: 135° C.

Optical rotation: +184° (conditions: C=1.0, N,N-dimethylformaldehyde solution)

Ultraviolet absorption spectrum: (10 μg/mL)λmax (nm): 316, 273, 206

When measurements were carried out, for a solubility of (+), (−) forms and a racemic form (±) of tenatoprazole in relation to water, it was found that the (+) form dissolved almost 3 times greater than the racemic body and (−) form dissolved over 2 times greater than the racemic form, exhibiting favorable physical properties in preparing drugs (refer to Table 2 below).

TABLE 2
(+) form	(−) form	(±)racemic form
Solubility (water) μg/mL	93.0	74.4	34.6

CLIPS

Tenatoprazole is a pyridinylmethylsulfinyl imidazopyridine compound, which is a weak base. This compound has three pKas. One is the pyridine pKa of pyridinylmethyl moiety and the others are the imidazole pKa and the pyridine pKa of the imidazopyridine moiety. The pyridine pKa1 enables tenatoprazole accumulation in the acidic canaliculus of the parietal cell. Protonation of the imidazopyridine ring enhances electron deficiency at the C-2 position, allowing intramolecular rearrangement to the active form. The active form is the sulfenic acid and/or cyclic sulfonamide, and reacts with luminal cysteine thiols of the enzyme to inhibit the enzyme activity

Synthesis route
from 2-mercapto-5-methoxy-imidazo [4,5-b] pyridine (2) and 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride ( 3) by nucleophilic substitution synthesis of 2- (4-methoxy-3,5-dimethyl-2-methylthio) -5-methoxy-imidazo [4,5-b] pyridine (4) the oxidation of 4 1. Figure 1 is a synthesis route of tenatoprazole

References

DataMonitor. March 2003. Gastrointestinal Disease Update: Digestive Disease Week 2003
Economic Times. 3 March, 2011. Investors unwilling to forgive Wockhardt, promoter for failings
Mitsubishi Tanabe Pharma State of New Product Development (as of May 8, 2012)
Mitsubishi Tanabe Pharma FY2007 Interim Financial Results
Li H et al. H+/K+-ATPase inhibitors: a patent review. Expert Opin Ther Pat. 2013 Jan;23(1):99-111. PMID 23205582

US4808596 *	24 Jul 1987	28 Feb 1989	Tokyo Tanabe Company, Ltd.	Imidazo[4,5-b]pyridine compounds and pharmaceutical compositions containing same
US5753265 *	7 Jun 1995	19 May 1998	Astra Aktiebolag	Multiple unit pharmaceutical preparation
US5798120 *	6 Oct 1994	25 Aug 1998	Tokyo Tanabe Company Limited	Enteric granule-containing tablets
EP0124495A2	28 Feb 1984	7 Nov 1984	Aktiebolaget Hässle	Omeprazole salts
EP0254588A1	24 Jul 1987	27 Jan 1988	Tokyo Tanabe Company Limited	Imidazo[4,5-b] pyridine compounds, process for preparing same and pharmaceutical compositions containing same

Reference
1	*	Andersson et al., Pharmacology & Therapeutics, 2005, vol. 108, pp. 294-307.
2	*	Anon et al., Drugs in R&D, 2002, vol. 3, pp. 276-277.
3	Kakinoki et al., Methods and Findings in Experimental and Clinical Pharmacology, 21(3): 179-187 (1999).
4	Komatsu et al., J. Org. Chem., 58(17): 4529-4533 (1993).
5	Uchiyama et al., Journal of Pharmacy and Pharmacology, 51(4): 457-464 (1999).
6	Uchiyama et al., Methods and Findings in Experimental and Clinical Pharmacology, 21(2): 115-122 (1999).

Citing Patent	Filing date	Publication date	Applicant	Title
US20120220623 *	30 Aug 2012	Mitsubishi Tanabe Pharma Corporation	The enantiomer of tenatoprazole and the use thereof in therapy

CN1453278A *	May 10, 2002	Nov 5, 2003	中国人民解放军军事医学科学院放射医学研究所	Omprazole compound and its prepn and application
CN1861600A *	Jun 14, 2006	Nov 15, 2006	浙江大学	Preparation process of taytrolazole

Reference
1	*	《Organic Process Research & Development》 20081112 Somaiah Sripathi et al. An Improved Synthesis of Antiulcerative Drug:Tenatoprazole 第804-806页 1-6 第13卷,
2	*	《Synthetic Communication》 20080101 Liyan Dai et al. Improved Synthetic Approach to Tenatoprazole 第576-582页 1-6 第38卷,
3	*	《中国药物化学杂志》 20061231 赵冬梅等抗溃疡药泰妥拉唑的合成第360-362页 1-6 第16卷, 第6期

Tenatoprazole
Systematic (IUPAC) name

5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine
Clinical data
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hepatic (CYP2C19-mediated)
Biological half-life	4.8 to 7.7 hours
Identifiers
CAS Number	113712-98-4
ATC code	none
PubChem	CID 636411
ChemSpider	552196
UNII	RE0689TX2K
Chemical data
Formula	C₁₆H₁₈N₄O₃S
Molar mass	346.405 g/mol
Chirality	Racemic mixture

テナトプラゾール
Tenatoprazole

C16H18N4O3S : 346.4
[113712-98-4]

/////////////Tenatoprazole, 113712-98-4, TU-199, proton pump inhibitor, treatment of gastroesophageal reflux disease, Mitsubishi Tanabe Pharma, Negma Laboratories, PHASE 1, テナトプラゾール

CC1=CN=C(C(=C1OC)C)CS(=O)C2=NC3=C(N2)C=CC(=N3)OC

ViridisChem offers software solutions that help scientists define environmentally friendly product development processes that are greener, safer, and economical

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Jun 232016

Neelam Vaidya

Experienced executive with passion to bring most needed solutions to market.

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Experienced executive with over 25 years of experience in both high-tech and bio-tech industries. Extensive experience in business development, contract negotiation, risk management and managing cross-functional global teams. Specific expertise includes delivering high performance, high security software infrastructures in multi-domain WEB environment, building and managing Cloud/SaaS based products with high traffic demands; and successfully building and launching pharma-centric products for the benefit for scientific community worldwide.
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ViridisChem offers a suite of software products that provide critical information scientists would need to define environmentally-friendly product development processes. Utilizing its internal proprietary chemical database with full chemical and toxicological profiles of over 60 million compounds, and supporting citation and reaction databases that provide related citations and reactions, the products help scientists understand the toxicological implications about the decision they have to make during day-to-day research without having to go through any training.

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GREEN POCKET

Full chemical profiles of over 60 million chemicals at your fingertips
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Identifies US and international regulatory concerns
Data available any-time, any-where, on any device

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Roxadustat, ASP 1517, FG 4592

Phase 3 drug, Uncategorized Comments Off

Jun 212016

ROXADUSTAT

ASP1517; ASP 1517; ASP-1517; FG-4592; FG 4592; FG4592; Roxadustat.

CAS 808118-40-3
Chemical Formula: C19H16N2O5
Exact Mass: 352.10592

Fibrogen, Inc.

THERAPEUTIC CLAIM, Treatment of anemia

Roxadustat nonproprietary drug name

CHEMICAL NAMES

(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine

1. Glycine, N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]-

2. N-[(4-hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl)carbonyl]glycine

MF C19H16N2O5
MW 352.3
SPONSOR FibroGen
CODE FG-4592; ASP1517
CAS 808118-40-3
WHO NUMBER 9717

Roxadustat, also known as ASP1517 and FG-4592, is an HIF α prolyl hydroxylase inhibitor in a cell-free assay. It stabilizes HIF-2 and induces EPO production and stimulates erythropoiesis. Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin

FG-4592 (also known as ASP1517), 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid, is a potent small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), an enzyme up-regulating the expression of endogenous human erythropoietin (Epo). It is currently being investigated as an oral treatment for anemia associated with chronic kidney disease (CKD). Unlike other anemia treating agents, erythropoiesis-stimulating agents (ESAs), FG-4592 inhibits HIF, through a distinctive mechanism, by stabilization of HIF. According to previous studies, FG-4592 is capable of correcting and maintaining hemoglobin levels in CKD patients not receiving dialysis and in patients of end-stage renal disease who receives dialysis but do not need intravenous iron supplement. Reference 1. Luis Borges. Different modalities of erythropoiesis stimulating agents. Port J Nephrol Hypert 2010; 24(2): 137-145 2. “FibroGen and Astellas announce initiation of phase 3 trial of FG-4592/ASP1517 for treatment of anemia of chronic kidney disease” Fibrogen Press Release. Dec 11 2012 3. “FibroGen announces initiation of phase 2b studies of FG-4592, an oral HIF prolyl hydroxylase inhibitor, for treatment of anemia”

Originator FibroGen
Developer Astellas Pharma; AstraZeneca; FibroGen
Class Amides; Antianaemics; Carboxylic acids; Isoquinolines; Small molecules
Mechanism of Action Basic helix loop helix transcription factor modulators; Hypoxia-inducible factor-proline dioxygenase inhibitors

Phase III Anaemia
Discontinued Sickle cell anaemia

Most Recent Events

09 Jun 2016 Phase-III clinical trials in Anaemia in Japan (PO)
20 May 2016 In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In chronic kidney disease patients undergoing peritoneal dialysis) in Japan (PO) (NCT02780726)
19 May 2016 In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In erythropoiesis stimulating agent-naive, chronic kidney disease patients undergoing haemodialysis) in Japan (PO) (NCT02780141)

Roxadustat (FG-4592) is a novel new-generation oral hypoxia-induciblefactor (HIF) prolyl hydroxylase inhibitor (PHI) for the treatment of ane-mia in patients with chronic kidney disease (CKD). HIF is a cytosolic tran-scription factor that induces the natural physiological response to lowoxygen conditions, by stimulating erythropoiesis and other protectivepathways. Roxadustat has been shown to stabilize HIF and induce ery-thropoiesis. Consequently, it corrects anemia and maintains hemoglo-bin levels without the need for intravenous iron supplementation in CKDpatients not yet receiving dialysis and in end-stage renal disease pa-tients receiving dialysis. There are many concerns about the use of ery-thropoiesis-stimulating agents (ESA) to treat anemia as they causesupra-physiologic circulating erythropoietin (EPO) levels and are asso-ciated with adverse cardiovascular effects and mortality. Available clin-ical data show that modest and transient increases of endogenous EPOinduced by HIF-PHI (10- to 40-fold lower than ESA levels) are sufficientto mediate erythropoiesis in CKD patients. Evidence suggests that rox-adustat is well tolerated and, to date, no increased risk of cardiovascu-lar events has been found. This suggests that roxadustat provides adistinct pharmacological and clinical profile that may provide a saferand more convenient treatment of CKD anemia

FG-4592 is a new-generation hypoxia-inducible factor prolyl hydroxylase inhibitor in early clinical trials at FibroGen for the oral treatment of iron deficiency anemia and renal failure anemia. Preclinical studies are ongoing for the treatment of sickle cell anemia.

The investigational therapy is designed to restore balance to the body’s natural process of erythropoiesis through mechanisms including: natural EPO production, suppression of the effects of inflammation, downregulation of the iron sequestration hormone hepcidin, and an upregulation of other iron genes, ensuring efficient mobilization and utilization of the body’s own iron stores. In April 2006, FG-4592 was licensed to Astellas Pharma by originator FibroGen in Asia, Europe and South Africa for the treatment of anemia. FibroGen retains rights in the rest of the world. In 2007, the FDA put the trial on clinical hold due to one case of death by fulminant hepatitis during a phase II clinical trial for patients with anemia associated with chronic kidney disease and not requiring dialysis. However, in 2008, the FDA informed the company that clinical trials could be resumed. Phase II/III clinical trials for this indication resumed in 2012. In 2013, the compound was licensed to AstraZeneca by FibroGen for development and marketing in US, CN and all major markets excluding JP, Europe, the Commonwealth of Independent States, the Middle East and South Africa, for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).
PATENTS
WO 2004108681
WO 2008042800
WO 2009058403
WO 2009075822
WO 2009075824
WO 2012037212
WO 2013013609
WO 2013070908

PATENT

CN 104892509

MACHINE TRANSLATED

Connaught orlistat (Roxadustat) by the US company Phibro root (FibroGen) R & D, Astellas AstraZeneca and licensed by a hypoxia-inducible factor (HIF) prolyl hydroxylase small molecule inhibitors, codenamed FG-4592.As a first new oral drug, FG-4592 is currently in Phase III clinical testing stage, for the treatment of chronic kidney disease and end-stage renal disease related anemia. Because the drug does not have a standard Chinese translation, so the applicant where it is transliterated as “Connaught Secretary him.”

Connaught orlistat (Roxadustat, I) the chemical name: N_ [(4- hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl) carbonyl] glycine, its structural formula is:

The original research company’s international patent W02004108681 Division provides a promise he was prepared from the intermediate and intermediate Connaught Secretary for his synthetic route:

Zhejiang Beida company’s international patent W02013013609 preparation and acylation of core intermediate was further optimized synthesis route is:

n PhO. eight XOOH

original research company’s international patent W02014014834 and W02014014835 also provides another synthetic route he Connaught Secretary prepared:

Analysis of the above synthetic route, although he continued to Connaught Division to improve and optimize the synthesis, but its essence rings manner that different form quinoline ring is basically the same mother. Especially methyl isoquinoline replaced either by way of introducing the Suzuki reaction catalyzed by a noble metal element, either through amine reduction achieved. Moreover, the above reaction scheme revelation raw materials are readily available, many times during the reaction need to be protected and then deprotected. Clearly, the preparation process is relatively complicated, high cost, industrial production has brought some difficulties.

Example One:

tyrosine was added to the reaction flask and dried (18. lg, 0.1 mmol) and methanol 250mL, cooling to ice bath 0_5 ° C, was added dropwise over 1 hour a percentage by weight of 98% concentrated sulfuric acid 10g. Drops Albert, heating to reflux. The reaction was stirred for 16-20 hours, TLC the reaction was complete. Concentrated under atmosphere pressure, the residue was added water 100mL, using 10% by weight sodium hydroxide to adjust the pH to 6. 5-7.0, precipitated solid was filtered, washed with methanol and water chloro cake (I: 1) and dried in vacuo tyrosine methyl ester as a white solid (11) 15.38, yield 78.5% out 1–] \ ^ 111/2: 196 [] \ 1 + 1] +!.

Example Two:

[0041] a nitrogen atmosphere and ice bath, was added to the reaction flask tyrosine methyl ester (II) (9. 8g, 50mmol), potassium methoxide (3. 5g, 50mmol) and methanol 50mL, until no gas generation after, was heated to reflux, the reaction was stirred for 2 hours. Concentrated under atmosphere pressure to remove the solvent, the residue was added dimethylsulfoxide 25mL, freshly prepared copper powder (0.2g, 3. Lmmol), was slowly warmed to 150-155 ° C, for about half an hour later, a solution of bromobenzene ( 7. 9g, 50mmol), continue to heat up to 170-175 ° C, the reaction was stirred for 3 hours, TLC detection of the end of the reaction. Was cooled to 60 ° C, and methanol was added to keep micro-boiling, filtered while hot, the filter cake washed three times with hot ethanol, and the combined organic phases, was cooled to square ° C, filtered, and dried in vacuo to give a white solid of 2-amino-3- ( 4-phenoxyphenyl) propanoate (111) 8 11.5, yield 84.9% as 1 -] \ ^ 111/2:! 272 [] \ 1 + 1] +.

Example Three:

in the reaction flask was added 2-amino-3- (4-phenoxyphenyl) propionic acid methyl ester (III) (10. 8g, 40mmol), 40% by weight acetaldehyde (20g, 0. 2mol ) and the percentage by weight of 35% concentrated hydrochloric acid 50mL, refluxed for 1 hour. Continue 40% by weight was added acetaldehyde (10g, 0.1mol), and the percentage by weight of 35% concentrated hydrochloric acid 25mL, and then the reaction was refluxed for 3-5 hours. Was cooled to 4-7 ° C, ethyl acetate was added, and extracted layers were separated. The aqueous layer was adjusted with sodium hydroxide solution to pH 11-12, extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid of 1-methyl-3-carboxylate -7- phenoxy-1,2,3,4-tetrahydroisoquinoline (IV) 8 4g, 70.7% yield; Mass spectrum (EI): EI-MS m / z: 298 [M + H] + .

Example Four:

Under ice bath, the reaction flask was added methyl 3-carboxylate I- -7- phenoxy-1,2, 3,4-tetrahydro-isoquinoline (IV) (5. 9g, 20mmol) and dichloromethane 100mL, 0 ° C and under stirring added potassium carbonate (13. 8g, 0. lmol), p-toluenesulfonyl chloride (11. 4g, 60mmol), the addition was completed, the ice bath was removed and stirred at room temperature 3 hour. Water was added 30mL, after stirring standing layer, the organic phase was washed with dilute hydrochloric acid, water and saturated brine, and concentrated, the resulting product was added a 30% by weight sodium hydroxide solution (8. 0g, 60mmol) and dimethyl sulfoxide 60mL, gradually warming to 120-130 ° C, the reaction was stirred for 2-4 hours to complete the reaction by TLC. Cooled to room temperature, water was added lOOmL, extracted three times with ethyl acetate, the combined organic phase was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated, the resulting oil was treated with ethyl acetate and n-hexane (1: 3) recrystallization, vacuum dried to give an off-white solid 1-methyl-3-carboxylate 7-phenoxyheptanoic isoquinoline (V) 5. 25g, yield 89. 6%; EI-MS m / z: 294 [M + H] VH NMR (DMS0-d6) δ 2. 85 (s, 3H), 3 · 97 (s, 3H), 7 · 16-7. 24 (m, 3H), 7 · 49-7. 60 (m, 4Η), 8 · 35 (d, J = 9 · 0,1Η), 8 · 94 (s, 1Η).

Example five:

[0047] added 1-methyl-3-carboxylic acid methyl ester 7-phenoxyheptanoic isoquinoline (V) (2. 93g, IOmmol) and glacial acetic acid 50mL reaction flask, stirring solution of 30% by weight hydrogen peroxide 5mL, warmed to 60-70 ° C, was slowly added dropwise within 10 hours the percentage by weight of a mixture of 30% hydrogen peroxide 2mL and 12mL of glacial acetic acid, a dropping was completed, the reaction was continued for 20-24 hours. Concentrated under reduced pressure, ethanol was added, distillation is continued to be divisible remaining glacial acetic acid. The residue was dissolved with dichloromethane, washed with 5% by weight of sodium bicarbonate, the organic phase was separated, dried over anhydrous sodium sulfate. Filtered and the resulting solution was added p-toluenesulfonyl chloride (3. 8g, 20mmol), was heated to reflux, the reaction was stirred for 3-4 hours, TLC detection completion of the reaction. The solvent was distilled off under reduced pressure, cooled to room temperature, methanol was added, the precipitated solid, cooled to square ° C, allowed to stand overnight. Filtered, the filter cake washed twice with cold methanol and vacuum dried to give an off-white solid 1- methyl-3-methyl-4-hydroxy-phenoxy-isoquinoline -7- (VI) I. 86g, yield 60.2 %; EI-MS m / z:.. 310 [M + H] +, 1H NMR (DMS0-d6) δ 2.90 (s, 3H), 4.05 (s, 3H), 7 17-7 26 (m, 3H ), 7. 49-7. 61 (m, 4H), 8. 38 (d, J = 9. 0,1H), 11. 7 (s, 1H) 〇

Example VI:

in the reaction flask with magnetic stirring and pressure to join I- methyl-3-methyl-4-hydroxy-7-phenoxyheptanoate isoquinoline (VI) (1.55g, 5mmol), glycine (I. 13g, 15mmol) and sodium methoxide (3. 25g, 6mmol) in methanol (30mL).Sealed, slowly heated to 120 ° C, the reaction was stirred for 8-10 hours to complete the reaction by TLC. Cooled to room temperature, solid precipitated. Filtration, and the resulting solid was recrystallized from methanol, acetone and then beating the resulting solid was dried under vacuum to give a white solid Connaught orlistat 1.40g, yield 79.5%;

EI-MS m / z: 353 [M + H] +,

1H NMR (DMS0-d6) S2.72 (s, 3H), 3 · 99 (d, J = 6 · 0, 2H), 7 · 18-7. 28 (m, 3H), 7 · 49-7. 63 (m, 4H), 8 · 31 (d, J = 8 · 8,1H), 9 · 08 (s, lH), 13.41 (brs, lH).

PATENT

WO 2014014835

Example 10. Preparation of Compound A

a) 5-Phenoxyphthalide

[0200] A reactor was charged with DMF (68 Kg), and stirring was initiated. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromophthalide (85 Kg), copper bromide (9 Kg), and potassium carbonate (77 Kg). The mixture was heated above 85 °C and maintained until reaction completion and then cooled. Water was added. Solid was filtered and washed with water. Solid was dissolved in dichloromethane, and washed with aqueous HCl and then with water. Solvent was removed under pressure and methanol was added. The mixture was stirred and filtered. Solid was washed with methanol and dried in an oven giving 5- phenoxyphthalide (Yield: 72%, HPLC: 99.6%). b) 2-Chloromethyl-4-phenoxybenzoic acid methyl ester

[0201] A reactor was charged with toluene (24 Kg), and stirring was initiated. The reactor was then charged with 5-phenoxyphthalide (56 Kg), thionyl chloride (41 Kg), trimethyl borate (1

Kg), dichlorotriphenylphosphorane (2.5 Kg), and potassium carbonate (77 Kg). The mixture was heated to reflux until reaction completion and solvent was removed leaving 2-chloromethyl-4- phenoxybenzoyl chloride. Methanol was charged and the mixture was heated above 50 °C until reaction completion. Solvent was removed and replaced with DMF. This solution of the product methyl 2-chloromethyl-4-phenoxybenzoic acid methyl ester in DMF was used directly in the next step (HPLC: 85%). c) 4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (la)

[0202] A reactor was charged with a solution of 2-chloromethyl-4-phenoxybenzoic acid methyl ester (~68 Kg) in DMF, and stirring was initiated. The reactor was then charged with p- toluenesulfonylglycine methyl ester (66 Kg), potassium carbonate (60 Kg), and sodium iodide (4 Kg). The mixture was heated to at least 50 °C until reaction completion. The mixture was cooled. Sodium methoxide in methanol was charged and the mixture was stirred until reaction completion. Acetic acid and water were added, and the mixture was stirred, filtered and washed with water. Solid was purified by acetone trituration and dried in an oven giving la (Yield from step b): 58%; HPLC: 99.4%). 1H NMR (200 MHz, DMSO-d6) δ 11.60 (s, 1 H), 8.74 (s, 1H),

8.32 (d, J = 9.0 Hz, 1 H), 7.60 (dd, J = 2.3 & 9.0 Hz, 1H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.96 (s, 3 H); MS-(+)-ion M+l = 296.09 d) Methyl l-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

(lb)

[0203] A flask was charged with la (29.5 g) and acetic acid (44.3 g ± 5%), and then stirred. Bis-dimethylaminomethane (12.8 g ± 2%) was slowly added. The mixture was heated to 55 ± 5 °C and maintained until reaction completion. The reaction product was evaluated by MS, HPLC and 1H NMR. 1H NMR (200 MHz, DMSO-d6) δ 11.7 (s, 1 H), 8.38 (d, J = 9.0 Hz, 1 H), 7.61 (dd, J = 9.0, 2.7 Hz, 1 H), 7.49 (m, 3 H), 7.21 (m, 3 H), 5.34 (s, 2 H), 3.97 (s, 3 H), 1.98 (s, 3 H); MS-(+)-ion M+l = 368.12. e) Methyl l-((acetoxy)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (lc)

[0204] The solution of lb from a) above was cooled below 25 °C, at which time acetic anhydride (28.6 g ± 3.5 %) was added to maintain temperature below 50 °C. The resulting mixture was heated to 100 ± 5 °C until reaction completion.

[0205] The solution of lc and Id from above was cooled to less than 65 ± 5 °C. Water (250 mL) was slowly added. The mixture was then cooled to below 20 ± 5 °C and filtered. The wet cake was washed with water (3 x 50 mL) and added to a new flask. Dichloromethane (90 mL) and water (30 mL) were added, and the resulting mixture was stirred. The dichloromethane layer was separated and evaluated by HPLC.

[0206] The organic layer was added to a flask and cooled 5 ± 5 °C. Morpholine was added and the mixture was stirred until reaction completion. Solvent was replaced with acetone/methanol mixture. After cooling, compound lc precipitated and was filtered, washed and dried in an oven (Yield: 81%, HPLC: >99.7%). 1H NMR (200 MHz, DMSO-d6) δ 11.6 (S, 1 H), 8.31 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.95 (s, 3 H), 3.68 (s, 2H), 2.08 (s, 6 H); MS-(+)-ion M+l = 357.17. f) Methyl 4-hydroxy-l-methyl-7-phenoxyisoquinoline-3-carboxylate (le)

[0207] A reactor was charged with lc (16.0 g), Pd/C (2.08 g), anhydrous Na₂C0₃ (2.56 g) and ethyl acetate (120 mL). The flask was vacuum-purged with nitrogen (3X) and vacuum-purged with hydrogen (3X). The flask was then pressurized with hydrogen and stirred at about 60 °C until completion of reaction. The flask was cooled to 20-25 °C, the pressure released to ambient, the head space purged with nitrogen three times and mixture was filtered. The filtrate was concentrated. Methanol was added. The mixture was stirred and then cooled. Product precipitated and was filtered and dried in an oven (Yield: 90%, HPLC: 99.7%). g) [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid

(Compound A)

[0208] A pressure flask was charged with le (30.92 g), glycine (22.52 g), methanol (155 mL), sodium methoxide solution (64.81 g) and sealed (as an alternative, sodium glycinate was used in place of glycine and sodium methoxide). The reaction was heated to about 110 °C until reaction was complete. The mixture was cooled, filtered, washed with methanol, dried under vacuum, dissolved in water and washed with ethyl acetate. The ethyl acetate was removed and to the resulting aqueous layer an acetic acid (18.0 g) solution was added. The suspension was stirred at room temperature, filtered, and the solid washed with water (3 x 30 mL), cold acetone (5-10 °C, 2 x 20 mL), and dried under vacuum to obtain Compound A (Yield: 86.1%, HPLC: 99.8%). Example 11. Biological Testing

[0209] The solid forms provided herein can be used for inhibiting HIF hydroxylase activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF), and can be used to treat and prevent HIF-associated conditions and disorders (see, e.g., U.S. Patent No. 7,323,475, U.S. Patent Application Publication No. 2007/0004627, U.S. Patent Application Publication No. 2006/0276477, and U.S. Patent Application Publication No. 2007/0259960, incorporated by reference herein).

SYNTHESIS……..

http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8

FG-4592 - zliming2004 - zliming2004的博客

Condensation of 5-bromophthalide (I) with phenol (II) in the presence of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (III), which upon lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene yields 2-chloromethyl-4-phenoxybenzoyl chloride (IV). Esterification of acid chloride (IV) with MeOH at 50 °C furnishes the methyl ester (V), which is then condensed with methyl N-tosylglycinate (VI) in the presence of K2CO3 and NaI in DMF at 50 °C to afford N-substituted aminoester (VII). Cyclization of the intermediate diester (VII) using NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (VIII), which is submitted to Mannich reaction with bis-dimethylaminomethane (IX) in the presence of AcOH at 57 °C to provide the dimethylaminomethyl compound (X). Treatment of amine (X) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-acetoxymethyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XI). Hydrogenolysis of the benzylic acetate (XII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XII), which finally couples with glycine (XIII) in the presence of NaOMe in MeOH at 110 °C to afford the target roxadustat (1-3).

FG-4592 - zliming2004 - zliming2004的博客

Cyclization of 4-phenoxyphthalic acid (I) with glycine (II) at 215 °C gives the phthalimide (III), which upon esterification with MeOH and H2SO4 at reflux yields methyl ester (IV). Subsequent rearrangement of phthalimidoacetate (IV) by means of Na in BuOH at 97 °C, followed by flash chromatography provides the isoquinoline-2-carboxylate (V). Bromination of intermediate (V) using POBr3 and NaHCO3 in acetonitrile leads to butyl 8-bromo-3-hydroxy-6-phenoxy-isoquinoline-2-carboxylate (VI), which upon hydrolysis with NaOH in refluxing H2O/EtOH furnishes carboxylic acid (VII). Substitution of bromine in intermediate (VII) using MeI and BuLi in THF at -78 °C, followed by alkylation with PhCH2Br in the presence of K2CO3 in refluxing acetone affords the 2-methyl isoquinoline (VIII). Ester hydrolysis in intermediate (VIII) using KOH in MeOH gives the corresponding carboxylic acid (IX), which is then activated with i-BuOCOCl and Et3N in CH2Cl2, followed by coupling with benzyl glycinate hydrochloride (X) to yield benzylated roxadustat (XI). Finally, debenzylation of intermediate (XI) with H2 over Pd/C in EtOAc/MeOH provides the title compound (1).

FG-4592 - zliming2004 - zliming2004的博客

Condensation of 4-nitro-ortho-phthalonitrile (I) with phenol (II) in the presence of K2CO3 in DMSO gives 4-phenoxy-ortho-phthalonitrile (III) (1), which upon hydrolysis with NaOH (1) or KOH (2) in refluxing MeOH yields 4-phenoxyphthalic acid (IV) (1,2). Dehydration of dicarboxylic acid (IV) using Ac2O and AcOH at reflux furnishes the phthalic anhydride (V), which is then condensed with methyl 2-isocyanoacetate (VI) using DBU in THF to provide oxazole derivative (VII). Rearrangement of intermediate (VII) with HCl in MeOH at 60 °C leads to isoquinoline derivative (VIII), which is partially chlorinated by means of POCl3 at 70 °C to afford 1-chloro-isoquinoline derivative (IX). Substitution of chlorine in intermediate (IX) using Me3B, Pd(PPh3)4 and K2CO3 in refluxing dioxane gives methyl 4-hydroxy-1-methyl-7-phenoxy-3-carboxylate (X), which is then hydrolyzed with aqueous NaOH in refluxing EtOH to yield the carboxylic acid (XI). Coupling of carboxylic acid (XI) with methyl glycinate hydrochloride (XII) by means of PyBOP, (i-Pr)2NH and Et3N in CH2Cl2 yields roxadustat methyl ester (XII), which is finally hydrolyzed with aqueous NaOH in THF to afford the target roxadustat (1).

CLIPS

SAN FRANCISCO, Nov 12, 2013 (BUSINESS WIRE) — FibroGen, Inc. (FibroGen), today announced that data from a China-based Phase 2 study of roxadustat (FG-4592), a first-in-class oral compound in late stage development for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), were presented in an oral session at the 2013 American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia.

Roxadustat is an orally administered, small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. HIF is a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced and iron is incorporated into hemoglobin (Hb).

The randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of roxadustat in the correction of anemia in patients (N=91) with chronic kidney disease who had not received dialysis treatment, were not receiving erythropoiesis-stimulating agents (ESAs), and had Hb levels less than 10 g/dL. The correction study randomized patients 2:1 between roxadustat and placebo for 8 weeks of dosing, and included a low-dose cohort (n=30) and high-dose cohort (n=31). Intravenous (IV) iron was not allowed. The study also evaluated iron utilization, changes in serum lipids, and other biomarkers during treatment with roxadustat.

Data from this study suggest that roxadustat effectively corrected hemoglobin levels in anemic CKD patients in a dose-dependent manner as compared to placebo, and did so in the absence of IV iron supplementation regardless of degree of iron repletion at baseline. At the end of the 8-week treatment period, subjects showed mean maximum Hb increases from baseline of 2.6 g/dL in the high dose cohort and 1.8 g/dL in the low dose cohort, as compared to 0.7 g/dL in the placebo group (p < 0.0001) from mean baseline Hb of 8.8 g/dL, 8.8 g/dL, and 8.9 g/dL in the high dose, low dose, and placebo groups, respectively. 87% of patients in the high-dose cohort, 80% of patients in the low-dose cohort, and 23% of patients in the placebo group experienced a hemoglobin increase of 1 g/dL or greater from baseline (p < 0.0001). Similarly, 71% of patients in the high-dose cohort, 50% of patients in the low-dose cohort, and 3% of patients in the placebo group achieved target hemoglobin of 11 g/dL or greater (p < 0.0001). Serum iron levels remained stable in subjects randomized to roxadustat while the subjects underwent brisk erythropoiesis.

Study data also suggest that roxadustat may lower cholesterol. Dyslipidemia is highly prevalent in chronic kidney disease patients and a major cardiovascular risk factor in this population. Patients treated with roxadustat experienced a statistically significant reduction in total cholesterol (p <0.0001) and low-density lipoprotein (LDL) cholesterol (p <0.0001) at the end of the treatment period. The relative proportion of high density lipoprotein (HDL) cholesterol to LDL cholesterol increased significantly (p <0.02). Overall LDL cholesterol levels declined by a mean of 26% and median of 23% from a mean baseline value of 103 mg/dL.

Roxadustat was well tolerated by patients in the study with incidence of adverse events similar across all groups. In contrast to the exacerbation of hypertension observed in studies in which patients received currently available ESA therapies, subjects who received roxadustat in the present study showed small decreases in blood pressure that were similar to blood pressure changes in the placebo group. No cardiovascular serious adverse events were reported in patients treated with roxadustat.

The efficacy and safety of roxadustat are currently being investigated in a global pivotal Phase 3 development program.

“There is a global need for effective, safe, and accessible anemia therapies,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “Side effects associated with current treatments include exposure to supra-physiological levels of erythropoietin and depletion of iron stores. Preliminary clinical findings show that oral administration of roxadustat (FG-4592) is able to correct anemia and maintain hemoglobin levels in patients with chronic kidney disease, to do so with peak erythropoietin levels within physiological range, and to achieve these effects without the administration of intravenous iron. These results suggest roxadustat, as an oral agent, has the potential to overcome the treatment barriers and inconveniences of current ESA therapies, including administration by injection and IV iron supplementation, in treating anemia in CKD patients.”

About Chronic Kidney Disease (CKD) and Anemia

Diabetes, high blood pressure, and other conditions can cause significant damage to the kidneys. If left untreated, those can result in chronic kidney disease and progress to kidney failure. Such deterioration can lead to patients needing a kidney transplant or being placed on dialysis to remove excess fluid and toxins that build up in the body. The progression of CKD also increases the prevalence of anemia, a condition associated with having fewer of the red blood cells that carry oxygen through the body, and/or lower levels of hemoglobin, the protein that enables red blood cells to carry oxygen. As hemoglobin falls, the lower oxygen-carrying capacity of an anemic patients’ blood results in various symptoms including fatigue, loss of energy, breathlessness, and angina. Anemia in CKD patients has been associated with increased hospitalization rates, increased mortality, and reduced quality of life.

Chronic kidney disease is a worldwide critical healthcare problem that affects millions of people and drives significant healthcare cost. In the US, prevalence of CKD has increased dramatically in the past 20 years, from 10 percent of the adult population (or approximately 20 million U.S. adults) as stated in the National Health and Nutrition Evaluation Survey (NHANES) 1988-1994, to 15 percent (or approximately 30 million U.S. adults) in NHANES 2003-2006. In 2009, total Medicare costs for CKD patients were $34 billion. China has an estimated 145 million CKD patients, or approximately five times the number of CKD patients in the U.S. (Lancet April 2012).

About Roxadustat / FG-4592

Roxadustat (FG-4592) is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity, in development for the treatment of anemia in patients with chronic kidney disease (CKD). HIF is a protein transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis (the process by which red blood cells are produced) and other protective pathways. Roxadustat has been shown to correct anemia and maintain hemoglobin levels without the need for supplementation with intravenous iron in CKD patients not yet receiving dialysis and in end-stage renal disease patients receiving dialysis. An Independent Data Monitoring Committee has found no signals or trends to date to suggest that treatment with roxadustat is associated with increased risk of cardiovascular events, thrombosis, or increases in blood pressure requiring initiation or intensification of antihypertensive medications.

About FibroGen

FibroGen is a privately-held biotechnology company focused on the discovery, development, and commercialization of therapeutic agents for treatment of fibrosis, anemia, cancer, and other serious unmet medical needs. FibroGen’s FG-3019 monoclonal antibody is in clinical development for treatment of idiopathic pulmonary fibrosis and other proliferative diseases, including pancreatic cancer and liver fibrosis. Roxadustat (FG-4592), FibroGen’s small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, is currently in clinical development for the treatment of anemia. FibroGen is also currently pursuing the use of proprietary recombinant human type III collagens in synthetic corneas for treatment of corneal blindness. For more information please visit: www.fibrogen.com .

References

1: Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, Leong R, Hemmerich S, Yu KH, Neff TB. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015 Oct;30(10):1665-73. doi: 10.1093/ndt/gfv302. Epub 2015 Aug 3. PubMed PMID: 26238121; PubMed Central PMCID: PMC4569392.

2: Forristal CE, Levesque JP. Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl Med. 2014 Feb;3(2):135-40. doi: 10.5966/sctm.2013-0134. Epub 2013 Dec 26. PubMed PMID: 24371328; PubMed Central PMCID: PMC3925058.

3: Bouchie A. First-in-class anemia drug takes aim at Amgen’s dominion. Nat Biotechnol. 2013 Nov;31(11):948-9. doi: 10.1038/nbt1113-948b. PubMed PMID: 24213751.

4: Flight MH. Deal watch: AstraZeneca bets on FibroGen’s anaemia drug. Nat Rev Drug Discov. 2013 Oct;12(10):730. doi: 10.1038/nrd4135. PubMed PMID: 24080688.

5: Beuck S, Schänzer W, Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Test Anal. 2012 Nov;4(11):830-45. doi: 10.1002/dta.390. Epub 2012 Feb 24. Review. PubMed PMID: 22362605.

6: Cases A. The latest advances in kidney diseases and related disorders. Drug News Perspect. 2007 Dec;20(10):647-54. PubMed PMID: 18301799.

//////////ASP1517, ASP 1517, ASP-1517, FG-4592, FG 4592, FG4592, Roxadustat, PHASE 3, ASTELLAS, FibroGen, 808118-40-3

O=C(O)CNC(C1=C(O)C2=C(C(C)=N1)C=C(OC3=CC=CC=C3)C=C2)=O

Racecadotril, acetorphan

Uncategorized Comments Off

Jun 212016

Racecadotril;

CAS 81110-73-8;

Acetorphan; Benzyl 2-(3-(acetylthio)-2-benzylpropanamido)acetate; Tiorfan; CADOTRIL;

benzyl 2-[[2-(acetylsulfanylmethyl)-3-phenylpropanoyl]amino]acetate

Molecular Formula:	C₂₁H₂₃NO₄S
Molecular Weight:	385.47662 g/mol

LAUNCHED 1993 BIOPROJET IN FRANCE

2010 IN CHINA

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor.^[2] Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into the intestine.^[3] It is available in France (where it was first introduced in ~1990) and other European countries (including Germany, Italy, the UK and Spain) as well as most of South America and some South East Asian countries (including China, India and Thailand), but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan.^[4] In Italy it is sold under the tradename Tiorfix.^[4]

Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinase.^[5]

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. Unlike other medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into the intestine. It is available in India (It was first introduced in 1993 and is widely used in France) and other European countries, as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan. In Italy it is sold under the tradename Tiorfix.

In india trade names REDOTTIL, ZEDOTT .

A small randomized controlled trial found racecadotril to significantly reduce the duration and volume of watery diarrhea in children when given as an adjunct to oral rehydration therapy.

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. Unlike other medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into the intestine. It is available in India (It was first introduced in 1993 and is widely used in France) and other European countries, as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan. In Italy it is sold under the tradename Tiorfix.

In india trade names REDOTTIL, ZEDOTT .

A small randomized controlled trial found racecadotril to significantly reduce the duration and volume of watery diarrhea in children when given as an adjunct to oral rehydration therapy.

Indication & Dosage

Acute diarrhoea

Adult: 100 mg tid, up to 7 days.

Administration – May be taken with or without food.

Special Precautions – Renal insufficiency, pregnancy, lactation.

Adverse Drug Reactions – Vomiting, nausea, constipation, abdominal pain, thirst, vertigo and headache.

Mechanism of Action

Racecadotril increases the availability of endogenous opioids (enkephalins) by inhibiting the membrane-bound enkephalinase. These enkephalins activate δ-opioid receptors in the GI tract. This leads to a reduction in cAMP mucosal levels, resulting in a reducted secretion of water and electrolytes in the intestinal lumen. Onset: Within 30 min.

Foreign Names

Racecadotrilum (Latin)

Racecadotril (German)

Racécadotril (French)

Racecadotrilo (Spanish)

Brand Names

AD – Hetero, India

Aquasec – Micro Nova, India

Cadotril – Medifarma, Peru

Diarfix – CristerS, France

Dirasec – Abbott, India

Du La Bao – Baili Pharmaceutical, China

Enuff – Hetero, India

Feng Hai Ting – Zhengda Fenghai Pharmaceutical, China

Hidrasec – Abbott, China; Abbott, Philippines; Bagó, Ecuador; Ferrer, Costa Rica; Ferrer, Dominican Republic; Ferrer, Guatemala; Ferrer, Honduras; Ferrer, Mexico; Ferrer, Nicaragua; Ferrer, Panama; Ferrer, El Salvador; Fournier, Bulgaria; Fournier, Romania; Galenica, Greece; Laboratoire Sophartex, Vietnam; Leti, Venezuela; Silesia, Chile;

Solvay, Thailand

Hidrasec Children (pediatric) – Fournier, Bulgaria

Hidrasec Infants (pediatric)-Fournier, Bulgaria

Hydral – Alembic, India

Lomorest – Zuventus, India

Mo Ni Ka – Hailing, China

Mold – Aversi, Georgia

Pedidot – Elder, India

Racaril -East West, India

Racedot – Macleods, Georgia

Race-F – Bestochem, India

Racotil – Cipla, India

Racy – Abbott, India

Redotil – Dr. Reddy’s, India

Resorcal Lactantes/Ninos (pediatric) – Andromaco, Chile

Resorcal – Andromaco, Chile

Tiorfan – Abbott, Germany; Bago, Brazil; Bioproject, Tunisia; Bioprojet, France; CPH, Portugal; Ferrer, Peru; Ferrer Farma, Spain

Tiorfan Infantil – CPH, Portugal

Tiorfan Niños (pediatric) – Ferrer, Peru

Tiorfan nourrissons (pediatric) – Bioproject, Tunisia

Tiorfanor – Bioprojet, France

Tiorfast – Bioprojet, France

Tiorfix – Costanzafarma, Italy

Zomatril – FDC, India

European Patent No. EP 0501870B 1 discloses a process for the preparation of racec

Racecadotril

The use of coupling agents like hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) generally induces the formation of side products such as dicyclohexylurea. These side products do lead to major problems, wherein purification by chromatography may be contemplated, but the side products are extremely difficult to remove on an industrial scale.

Consequently, efforts have been made to replace the peptidic coupling step

so as to avoid the formation of side products associated with the use of the coupling agents. Thus, it appears that, even if the preparation of N-(mercaptoacyl)amino acid derivatives from .alpha.-substituted acrylic acids by Michael addition of a thio acid and conversion of acid to acid chloride by using thionyl chloride and then coupling of an amino ester may be advantageous on a laboratory scale, such reactions are difficult to adapt on an industrial use.

The aforementioned processes described above involves expensive reagents such as hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) and hazardous reagent like thionyl chloride thus rendering the processes expensive and not feasible on industrial scale.

SYNTHESIS BY WORLDDRUGTRACKER

Patent

https://www.google.com/patents/WO2013098826A1?cl=en

EXAMPLES

Example-1: Preparation of Racecadotril (I):

Step A) Preparation of 2-acetyIsulfanyI methyI-3-phenyI propionic acid (IV)

16.2 g of 2-benzylacrylic acid and 12.3 ml of thioacetic acid were were charged into a clean and dry R.B.flask and stirred at about 30°C for about 1 hour. The reaction mixture was heated to about 60°C and stirred for about 4 hours.The excess of thioacetic acid was distilled off completely to afford the title compound as residue. Yield: 23.8 g. Step B) Preparation of Racecadotril crude (la)

23.8 g. of 2-acetyl sulfanylmethyl-3-phenyl-propionic acid (IV), 200ml of methylene chloride and 16.7 ml of triethylamine were charged into a clean and dry R.B.flask. 10. 5 ml of ethylchloroformate was added at about -5°C. The resultant reaction mixture was stirred at about 0°C for about 30 min. 33.7 g of glycine benzyl ester p-tosyalte (II), 14 ml of triethylamine and 100ml of methylene chloride was added as a mixture to the reaction mass at about 0°C. Then the resultant reaction mixture was stirred at about 0°C for about 1 hr. followed by at about 30°C for about 30 min. After completion of the reaction as determined by TLC, the reaction mass was washed with 65 ml of distilled water, 65 ml 4% sodium bicarbonate solution and followed by 65 ml distilled water. The organic and aqueous phases were separated and the solvent was distilled completely, 2 x 50 ml Isopropyl alcohol was charged and again distilled off the solvent completely to give residue. The residue

obtained was triturated with a mixture of isopropyl alcohol 4 ml) and n-hexane (94 ml) at about 5°C to the title compound as crude. Yield: 34 g.

ExampIe-2: Purification of Racecadotril (Crude):

34 g. of crude Racecadotril and 35 ml of 20 % v/v aqueous .methanol were charged in a clean and dry R.B.flask and heated to about 65°C. 3g. of SP.carbon was charged and stirred at about 65°C for about 10 min. The reaction suspension was stirred at about 65°C for about 10 min. The reaction suspension was filtered on hyflow bed (diatomous earth) and washed the hyflow bed with 30 ml of aqueous methanol. The filtrate obtained was cooled to about 0°C for about 30 min. The solid separated was filtered and the solid obtained washed with 60 ml of precooled aqueous methanol to afford the pure racecadotril (I).

Yield: 29 g.; Purity by HPLC: 99.5 area %; The overall yield is 75.3%.

PATENT

https://www.google.com/patents/CN104356036A?cl=en

Example 1

The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

Clips

US 20020055645

PATENT

CN 104356036 A

Racecadotril, chemical name N_ [(R, S) -3- acetyl-mercapto-2-benzyl-propionyl)] glycine benzyl ester, is a neprilysin inhibitor, selectively, reversible inhibition of neprilysin, so that the inner protection from degradation of endogenous enkephalins, prolong the physiological activity of endogenous enkephalins in the digestive tract, mainly used in clinical treatment of children and adults with acute diarrhea. Its structural formula is as follows:

Racecadotril as enkephalinase inhibitors, developed in France in 1993 Bioprojet listed acute diarrhea treatment, trade name Tiorfan.

In W02011116490A1, US5945548 and CN101768095A and other documents, documented racecadotril the synthesis process, but did not report the crystal form; therefore the present inventors have not reported Racecadotril crystalline polymorph conduct further

Example 1

[0032] The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

[0033] reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

research.

References

1 “SPC-DOC_PL 39418-0003.PDF” (PDF). Medicines and Healthcare Products Regulatory Agency. Bioprojet Europe Ltd. 26 December 2012. Retrieved 7 May 2014.
2Matheson AJ, Noble S (April 2000). “Racecadotril”. Drugs 59 (4): 829–35; discussion 836–7. doi:10.2165/00003495-200059040-00010. PMID 10804038.
3Matheson, AJ; Noble, S (April 2000). “Racecadotril.”. Drugs 59 (4): 829–35; discussion 836–7. doi:10.2165/00003495-200059040-00010. PMID 10804038.
4Brayfield, A, ed. (13 December 2013). “Racecadotril”. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 May 2014.
5Spillantini MG, Geppetti P, Fanciullacci M, Michelacci S, Lecomte JM, Sicuteri F (June 1986). “In vivo ‘enkephalinase’ inhibition by acetorphan in human plasma and CSF”. European Journal of Pharmacology 125 (1): 147–50. doi:10.1016/0014-2999(86)90094-4. PMID 3015640.
6 http://www.ingentaconnect.com/content/govi/pharmaz/2006/00000061/00000012/art00005?crawler=true

CN101103960A *	Jul 14, 2006	Jan 16, 2008	海南盛科生命科学研究院	Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A *	Dec 26, 2008	Jul 7, 2010	山东齐都药业有限公司	Preparation method of racecadotril
WO2001097803A1 *	Jun 20, 2001	Dec 27, 2001	Laboratoire Glaxosmithkline	Pharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 *	Dec 26, 2011	Jul 4, 2013	Symed Labs Limited	“a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”

Reference

Reference
CN101103960A *	Jul 14, 2006	Jan 16, 2008	海南盛科生命科学研究院	Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A *	Dec 26, 2008	Jul 7, 2010	山东齐都药业有限公司	Preparation method of racecadotril
WO2001097803A1 *	Jun 20, 2001	Dec 27, 2001	Laboratoire Glaxosmithkline	Pharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 *	Dec 26, 2011	Jul 4, 2013	Symed Labs Limited	“a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”
1	*	金庆平等: “神经内肽酶抑制剂消旋卡多曲(Racecadotril)的合成工艺研究“, 《中国现代应用药学杂志》, vol. 20, no. 7, 31 August 2003 (2003-08-31)

Reference
US6013829 *	Feb 4, 1997	Jan 11, 2000	Societe Civile Bioprojet	Process for the asymmetric synthesis of S-acyl derivatives of 2-mercaptomethyl -3- phenyl propanoic acid, application to the synthesis of N-(mercaptoacyl) amino acid derivatives
US20040009956 *	Apr 29, 2003	Jan 15, 2004	Dehua Pei	Inhibition of protein tyrosine phosphatases and SH2 domains by a neutral phosphotyrosine mimetic
1	*	MOHAMED A.O. ET AL.: ‘Stability-indicating methods for the determination of racecadotril in the presence of its degradation products‘ BIOSCIENCE TRENDS vol. 3, no. 6, 2009, pages 247 – 252, XP055074337
Citing Patent	Filing date	Publication date	Applicant	Title
CN104356036A *	Nov 7, 2014	Feb 18, 2015	山东齐都药业有限公司	Alpha crystal form of racecadotril and preparation method of alpha crystal form

Racecadotril
Systematic (IUPAC) name

(RS)-Benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate
Clinical data
Trade names	Hidrasec, Tiorfan
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only)
Pharmacokinetic data
Protein binding	90% (active thiorphan metabolite)^[1]
Metabolism	Liver-mediated^[1]
Biological half-life	3 hours^[1]
Excretion	Urine (81.4%), feces (8%)^[1]
Identifiers
CAS Number	81110-73-8
ATC code	A07XA04 (WHO)
PubChem	CID 107751
ChemSpider	96913
UNII	76K53XP4TO
ChEMBL	CHEMBL2103772
Synonyms	Benzyl 2-[3-(acetylthio)-2-benzylpropanamido]acetate
Chemical data
Formula	C₂₁H₂₃NO₄S
Molar mass	385.47662 g/mol
Chirality	Racemic mixture

/////////Racecadotril, acetorphan, antidiarrheal drug

CC(=O)SCC(CC1=CC=CC=C1)C(=O)NCC(=O)OCC2=CC=CC=C2

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AUTHOR OF THIS BLOG

Medical uses

Mechanism of action

History

Clinical trials

Approval

Ataluren trial success: trial aborted.

07 September 2011 – Pharma……..http://chem.vander-lingen.nl/info/item/September_2011/id/190/mid/140

References

External links

ERROR IN STRUCTURE

November 2005: China declared IND

November 2006: eligible for Phase I clinical documents of approval

November 2006: completion of the International Patent Licensing, China entered the international fray original new drug development

May 2008: completed Phase I clinical, showing international mechanism similar drugs have the potential to become the best

February 2009: eligible lymphoma indications II / III of this document

March 2009: Start of the Phase II clinical trial for the NDA to ①CTCL goal of clinical trials and ②PTCL

March 2009: IND by the FDA application is eligible to start Phase I clinical in the United States

July 2009: eligible for non-small cell lung cancer, breast cancer and prostate cancer clinical documents of approval

December 2010: of PTCL by a conventional phase II directly into Phase II clinical trial registered drug trial center and by recognition

March 2011: combination chemotherapy for non-small cell lung cancer clinical trials enter phase Ib

September 2012: of PTCL indication test deadline

December 2012: of PTCL clinical summary will be held

January 2013: Chidamide declare China NDA

December 2014: the State Food and Drug Administration (CFDA) approved the listing

In China, for the effective treatment of patients with relapsed or refractory PTCL has undertaken urgent clinical need

Chidamide is a completely independent intellectual property rights China originator of innovative medicines

Chidamide (Chidamide) has been multi-national invention patents

In October 2006, the US HUYA biological microchip company formally signed the International Patent Chidamide licensing and international clinical cooperative development agreement; the United States in the ongoing Phase I clinical

WRONG COMPD

Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment

GNT Biotech and Medicals Corporation Licenses Novel Cancer Molecule from Shenzhen Chipscreen Biosciences Ltd.

References

Overview

References

Continuous Processing

Semi-continuous processes

History

Shut-downs

Safety

Continuous processor (equipment)

EXAMPLE…………….

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

EXAMPLE…………….

NEXT EXAMPLE…………….

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al2O3 by a Continuous Process

NEXT EXAMPLE…………….

Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

NEXT EXAMPLE…………….

Multi-step Continuous Flow Pyrazole Synthesis via a Metal-free Amine-redox Process

NEXT EXAMPLE…………….

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

NEXT EXAMPLE…………….

Examples………..

Examples………..

Multikilogram Synthesis of 4-d-Erythronolactone via Batch andContinuous Processing

Examples………..

Continuous Biocatalytic Processes

PICS…………..

References

Sources and further reading

Synthesis

An Improved Synthesis of Antiulcerative Drug: Tenatoprazole

PATENT

CLIPS

References

Neelam Vaidya

ACS National Fall Symposium, 2015, Boston, MA (August 16-18, 2015)

Most Recent Events

PATENT

SYNTHESIS……..

References

See also

European Patent No. EP 0501870B 1 discloses a process for the preparation of racec

SYNTHESIS BY WORLDDRUGTRACKER

PATENT

References

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al₂O₃ by a Continuous Process