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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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2-Deoxy-D-glucose


2-Deoxy-D-glucose
ChemSpider 2D Image | 2-Deoxy-D-glucose | C6H12O5
Deoxyglucose.png

2-Deoxy-D-glucose

  • Molecular FormulaC6H12O5
  • Average mass164.156 Da

2-Deoxy-D-glucose

(4R,5S,6R)-6-(Hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol(4R,5S,6R)-6-(Hydroxyméthyl)tétrahydro-2H-pyran-2,4,5-triol

154-17-6[RN]

  • 2-Deoxy-D-arabino-hexose
  • 2 DG
  • 2-Deoxy-D-glucose
  • 2-Deoxy-D-mannose
  • 2-Deoxyglucose
  • 2-Desoxy-D-glucose
  • Ba 2758
  • D-Glucose, 2-deoxy-
  • NSC 15193

2-Deoxy-D-arabino-hexopyranose2-deoxy-D-glucopyranose2-deoxyglucose
2-DGD-arabino-2-DesoxyhexoseD-arabino-Hexopyranose, 2-deoxy- [(4R,5S,6R)-6-(Hydroxymethyl)oxane-2,4,5-triol2-deoxyglucopyranose2-deoxymannopyranose2-dGlc

61-58-5 [RN]77252-38-1 [RN]

D-arabino-2-Deoxyhexoseglucitol, 2,5-anhydro-
2-Deoxy-D-glucose

CAS Registry Number: 154-17-6

CAS Name: 2-Deoxy-D-arabino-hexose

Additional Names: D-arabino-2-desoxyhexose; 2-deoxyglucose; 2-DGManufacturers’ Codes: Ba-2758Molecular Formula: C6H12O5Molecular Weight: 164.16Percent Composition: C 43.90%, H 7.37%, O 48.73%Literature References: Antimetabolite of glucose, q.v., with antiviral activity.


Synthesis: M. Bergmann et al.,Ber.55, 158 (1922); 56, 1052 (1923); J. C. Sowden, H. O. L. Fischer, J. Am. Chem. Soc.69, 1048 (1947); H. R. Bolliger, Helv. Chim. Acta34, 989 (1954); H. R. Bolliger, M. D. Schmid, ibid. 1597, 1671; H. R. Bolliger, “2-Deoxy-D-arabino-hexose (2-Deoxy-D-glucose)” in Methods in Carbohydrate Chemistryvol. I, R. L. Whistler, M. L. Wolfrom, Eds. (Academic Press, New York, 1962) pp 186-189.
Inhibition of influenza virus multiplication: E. D. Kilbourne, Nature183, 271 (1959).
Effects on herpes simplex virus: R. J. Courtney et al.,Virology52, 447 (1973). Mechanism of action studies: M. R. Steiner et al.,Biochem. Biophys. Res. Commun.61, 745 (1974); E. K. Ray et al.,Virology58, 118 (1978). Use in human genital herpes infections: H. A. Blough, R. L. Giuntoli, J. Am. Med. Assoc.241, 2798 (1979); L. Corey, K. K. Holmes, ibid.243, 29 (1980). Effect vs respiratory syncytial viral infections in calves: S. B. Mohanty et al.,Am. J. Vet. Res.42, 336 (1981).

Properties: Cryst from acetone or butanone, mp 142-144°. [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine).

Melting point: mp 142-144°

Optical Rotation: [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine) Derivative Type: a-Form

Properties: Cryst from isopropanol, mp 134-136°. [a]D26 +156° ® +103° (c = 0.9 in pyridine).Melting point: mp 134-136°Optical Rotation: [a]D26 +156° ® +103° (c = 0.9 in pyridine) Use: Exptlly as an antiviral agent.

Source Temperature: 210 °C
   Sample Temperature: 150 °C
   Direct, 75 eV
14.0       2.2
      15.0      11.5
      17.0       3.9
      18.0      19.4
      19.0      13.7
      26.0       2.5
      27.0      12.1
      28.0      21.9
      29.0      31.2
      30.0       4.6
      31.0      41.3
      32.0      12.4
      39.0       5.9
      40.0       2.1
      41.0      10.9
      42.0      12.4
      43.0      46.3
      44.0      31.5
      45.0      34.3
      46.0       2.8
      47.0       4.1
      53.0       1.5
      54.0       2.0
      55.0      14.4
      56.0      35.3
      57.0      55.7
      58.0      11.4
      59.0       2.0
      60.0     100.0
      61.0      31.1
      62.0       2.3
      68.0       4.6
      69.0      12.2
      70.0       3.0
      71.0      34.9
      72.0       7.0
      73.0      25.3
      74.0      46.6
      75.0       5.1
      81.0       1.5
      82.0       2.4
      83.0       1.3
      84.0       1.3
      85.0      18.1
      86.0      55.3
      87.0       4.6
      89.0       1.2
      91.0       1.5
      97.0       3.6
      98.0       2.9
      99.0       1.7
     100.0       3.5
     102.0       1.1
     103.0      19.8
     104.0       1.4
     111.0       1.6
     115.0      25.2
     116.0       3.0
     117.0       2.1
     120.0       3.3
     128.0       1.0
     129.0       2.5
     133.0       1.8
     147.0       2.2

1H NMR DMSO D6

1H NMR D20

IR NUJOL MULL

IR KBR

PAPERCollection of Czechoslovak Chemical Communications (1955), 20, 42-5. http://cccc.uochb.cas.cz/20/1/0042/

Preparation of 2-​deoxy-​D-​glucose

By: Stanek, Jaroslav; Schwarz, Vladimir

Triacetyl-​D-​glucal (I) adds (BzO)​2IAg and (BzO)​2BrAg, to give 1-​benzoyl-​3,​4,​6-​triacetyl-​2-​deoxy-​2-​iodo-​α-​D-​glucopyranose (II) and 1-​benzoyl-​3,​4,​6-​triacetyl-​2-​deoxy-​2-​bromo-​α-​D-​glucopyranose (III)​, resp.  Both halogen derivs. give 2-​deoxy-​D-​glucose (IV) by reduction.  Adding a C6H6 soln. of 16.7 g. iodine into a suspension of 33.6 g. dry BzOAg in 200 ml. C6H6, treating the mixt. with a soln. of 20 g. I in 200 ml. C6H6, heating the mixt. 7 hrs. on the steam bath, removing the AgI, evapg. the solvent, and crystg. the residue from EtOH gave 20.8 g. (54.7​%) II, m. 129-​30°, [α]​21D 21.7°.  Analogous procedure with 13.4 g. BzOAg, 4.6 g. Br, and 8 g. I gave 3.9 g. (33​%) III, m. 139-​40°, [α]​17D 33.5°.  The same compd. (3 g.)​, m. 140°, [α]​18D 33.6°, was obtained by adding 3.2 g. Br to a soln. of 5.44 g. I in 50 ml. CCl4, by refluxing the mixt. 2 hrs. with 6 g. BzOAg, filtering off the AgBr, and evapg. the solvent.  Reducing 8 g. II or an equiv. III in 150 ml. MeOH with 60 g. Zn activated by 1 hr. immersion in a soln. of 60 g. CuSO4 in 1500 ml. H2O, removing Zn after 8 hrs., evapg. the MeOH, and sapong. the residue with Ba(OH)​2 yielded 0.42 g. (20​%) IV, m. 145°, [α]​18D 46.1°.

Wavlen: 589.3 nm; Temp: 18 °C, +46.1 °  ORD

PATENT

https://patents.google.com/patent/WO2004058786A1/enThe present invention relates to a process for the synthesis of 2-deoxy-D-glucose. Background of the invention 2-deoxy-D-glucose is useful in control of respiratory infections and for application as an antiviral agent for treatment of human genital herpes.Prior art for preparation of 2-deoxy-D-glucose while operable, tend to be expensive and time consuming. Reference may be made to Bergmann, M., Schotte, H., Lechinsky, W., Ber, 55, 158 (1922) and Bergmann, M., Schotte, H., Lechinsky, W., Ber 56, 1052 (1923) which disclose the preparation of 2-deoxy-D-glucose in low yield by mineral acid catalyzed addition of water to D-glucal. Another method of producing 2-deoxy-D-glucose is from diethyldithioacetal derivative of D-glucose (Bolliger, H.R. Schmid, M.D., Helv. Chim. Ada 34, 989 (1951); Bolliger, H.R., Schmid, M.D., Helv. Chim. A a 34, 1597 (1951); Bolliger, H.R. Schmid, M.D., Helv. Chim. Ada 34, 1671 (1951) and from D-arabhiose by reaction with nitromethane followed by acetylation, reduction and hydrolysis (Sowden, J.C, Fisher, H.O.L., J. Am. Chem., 69, 1048 (1947). However these methods result in the formation of 2- deoxy-D-glucose in low yield and of inferior purity due to the formation of several byproducts and involve use of toxic reagents such as ethanethiol and nitromethane. As a result purification of 2-deoxy-D-glucose has to be done by recrystallisation which is tedious, time consuming and difficult.Accordingly it is important to develop a process for synthesis of 2-deoxy-D-glucose which obviates the drawbacks as detailed above and results in good yield and good purity. Objects of the inventionThe main object of the present invention is to provide a process for the synthesis of 2- deoxy-D-glucose resulting in good yield and with good purity.Another object of the invention is to provide an economical process for the synthesis of 2-deoxy-D-glucose. Summary of the inventionA process that would produce 2-deoxy-D-glucose economically and with desired purity, is a welcome contribution to the art. This invention fulfills this need efficiently.Accordingly the present invention relates to a process for the synthesis of 2-deoxy- D-glucose comprising haloalkoxylation of R-D-Glucal wherein R is selected from H and 3, 4, 6-tri-O-benzyl, to obtain alkyl 2-deoxy-2-halo-R-α/ -D-gluco/mannopyranoside, converting alkyl 2-deoxy-2-halo-R-α/β-D-gluco/mannopyranoside by reduction to alkyl 2- deoxy-α/β-D-glucopyranoside, hydrolysing alkyl 2-deoxy-α/β-D-glucopyranoside to 2- deoxy-D-glucose.In one embodiment of the invention, the alkyl 2-deoxy-α/β-D-glucopyranoside is obtained by (a) haloalkoxylating 3,4,6,-tri-O-benzyl-D-glucal to alkyl 2-deoxy-2-halo-3,4,6-tri-O- benzyl-α/β-D-gluco-/mannopyranoside; (b) subjecting alkyl 2-deoxy-2-halo-3,4,6-tri-O-benzyl-α/β-D-gluco/mannopyranoside to reductive dehalogenation and debenzylation to obtain alkyl 2-deoxy -α/β-D- glucopyranoside. In another embodiment of the invention, in step (a) haloalkoxylation of 3,4,6-tri-O- benzyl-D-glucal is carried out by reaction with a haloalkoxylating agent selected from a N- halosuccinimide and a N-haloacetamide, and alcohol.The reaction scheme for the reactions involved in the process of the invention are also given below:

Figure imgf000005_0001

in R’=CH3I R=C6H5CH2 H R=C6H5CH2, X=Br, R’=CH3 IV R=H V R=CH3, C2HSJ C6H5CH3, iPr, X=Br

Figure imgf000005_0002

Such overall synthesis may be depicted as follows where R=H, CH3, C2H5, (CH3)2CH, C6H5CH ; RX-CH3; X-CL, Br.Example 1 To a solution of 3,4,6-tri-O-benzyl-D-glucal (39 g, 0.09 mol) in dichloromethane (20ml) and methanol (100 ml) was added N-bromosuccinimide (18.7 g, 0.09 mil) during 10 min. at room temperature and stirred for 4 h. After completion of the reaction solvent was distilled off. The resultant residue extracted into carbon tetrachloride (2×100 ml) and organic phase concentrated to obtain methyl 2-bromo 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco- /mannopyranoside as a syrup. Quantity obtained 50 g. 1H NMR (200 MHz, CDC13) 3.40-4.00 (m, 7H, H-2,5,6,6′ and OCH3) 4.30-5.10 (m, 9H, H-1,3,4 and 3xPhCH2O), 7.10-7.60 (m, 15H, Ar-H). A solution of methyl 2-bromo-2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco- /mannopyranoside (50 g) in methanol (300) was charged into one litre autoclave along with Raney nickel (10 ml) Et3N (135 ml) and subjected to hydrogenation at 120 psi pressure at 50°C for 8 h. After completion of the reaction the catalyst was filtered off and the residue washed with methanol (25 ml). The filtrate was concentrate to obtain methyl 2-deoxy-3,4,6- tri-O-benzyl-α/β-D-glucopyranoside as a syrup (37.9 g, 89%). 1H NMR (200 MHz, CDC13): δ 1.50-2.40 (m,2H,H-2,2′)5 3.32, 3.51 (2s, 3H, OCH3) 3.55-4.00 (m, 5H, H-3,4,5,6,6′), 4.30-5.00 (m, 7H, 3xPhCH2, H-l), 7.10-7.45 (m, 15H, Ar-H). The syrup of methyl 2-deoxy-3,4,6- tri-O-benzyl-α/β-D-glucopyranoside (37.9g) was dissolved in methanol (200 ml). 1 g of 5%Pd/C was added and hydrogenated at 150 psi pressure at room temperature. After 5 hours catalyst was filtered off and solvent evaporated. Quantity of the methyl 2-deoxy-α/β-D- glucopyranoside obtained 10.5 g (70%). [ ]D + 25.7° (c 1.0, MeOH), 1H NMR (200 MHz, D2O); δ 1.45-2.40 (m, 2H, H-2,2′) 3.20-4.80, (m 9H, H- 1,3,4,5,6,6′ – OCH3).Example 2 To a solution of D-glucal (64.6g, 0.44 mol) in methanol (325 ml) at 10°C was addedN-bromosuccinimide (78.7 g, 0.44 mol) during 40 min. maintaining the temperature between 10-15°C during the addition. The reaction mixture was stirred at room temperature. After 5 hours solvent was evaporated to obtain a residue which was refluxed in ethyl acetate (100 ml). Ethyl acetate layer was discarded to leave a residue of methyl 2-bromo-2-deoxy-α/β-D- gluco/mannopyranoside (105 g) as a syrup. [α]D + 36° (c 1.0, MeOH). 1H NMR (200 MHz, D2O): δ 3.47, 3.67 (2s, 3H, OCH3), 3.70-4.05 (m, 6h, H-23,4,5,6,6′), 4.48-5.13 (2s, 1H, H-l). The syrupy methyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside was dissolved in methanol (400 ml), a slurry of 80 g Raney nickel (a 50% slurry in methanol), Et3N (30 ml) and hydrogenated in a Parr apparatus at 120 psi. After 8-9 hours, the reaction mixture was filtered through a Celite filter pad and washed with MeOH. The washings and filtrate were combined and triturated with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and traces of succinimide. The filtrate was concentrated to a residue. The isolated yield of methyl 2-deoxy-α/β-D-glucopyranoside was 89%. Ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside: When solvent was ethanol instead of methanol the compound obtained was ethyl 2- bromo-2-deoxy-α/β-D-gluco-/mannopyranoside. 1HNMR (200 MHz, D2O): δ 1.10-1.32 (m, 3H, CH3), 2.80 (s, 4H, -CO(CH2)2CO-NH-), 3.40-4.10 (m, 8H, H-2,3,4,5,6,6′, CH2), 4.40, 5.20 (2s 1H, H-l α/β).Isopropyl 2-bromo-2-deoxy- /β-D-gluco-/mannopyranoside: When isopropanol instead of methanol was used as a solvent the compound obtained was isopropyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside. 1H NMR (200 MHz, D2O): δ 1.10-1.30 (m, 6H, 2xCH3) 2.80 (s, 4H, -CO(CH2)2CO-NH-), 3.60-4.60 (m 8H,H- 2,3,4,5,6,6′, CH2) 4.40, 5.30 (2s, 1H, H-l, α/β).Example 3 A mixture of D-glucal (64.6 g), methanol (400 ml), N-bromosuccinimide (79 g) were stirred at 15 C for 6 h. The reaction mixture was hydrogenated in a Parr apparatus in presence of 60 g of Raney nickel catalyst (a 50% slurry in methanol) and triethylamine (62 ml). After 8-9 h, the reaction mixture was filtered on a Celite filter pad. The Celite pad was washed with methanol. The washings and filtrate were combined, concentrated to a thick heavy syrup, dissolve in chloroform (500 ml), pyridine (400 ml) and acetic anhydride (251 ml) was added while stirring, maintaining the temperature between 5-10°C. After 12 hours, the reaction mixture was diluted with CHC13 (500 ml) transferred to a separating funnel and organic phase was washed with water. The organic phase was separated, dried (Na2SO4) and concentrated to obtain methyl 2-deoxy-3,4,6-tri-O-acetyl-2 deoxy-α/β-D-glucopyranoside as a syrup (163.43 g, 87%). [α]D + 65.0° (c 1.0, CHC13) 1H NMR (200 MHz, CDC13): δ 1.55-1.90 (m, 2H, H-2,2′), 2.01, 2.04,2.11, 2.15, (4s, 9H, 3xOCOCH3), 2.18,3.40 (2s, 3H, OCH3), 3.45-50 (m, 3H, H-5, 6,6′) 4.80-5.40 (m, 3H,H-1,3,4). The syrup was dissolved in methanol (600 ml) IN NaOMe in methanol (25ml) was added and left at room temperature. After 6-10 h, dry CO2 gas was passed into the reaction mixture, solvent was evaporated to obtain a syrupy residue. The residue was once again extracted into dry methanol and concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside as syrup. Quantity obtained 81 g (92%).Example 4 A 500 ml round bottom flask equipped with magnetic stir bar was charged with a solution of D-glucal (32.3 g) in methanol (175 ml), cooled to 15°C, N-bromosucci-t imide (NBS) (39.4 g) was added and stirred for 6 hours at 15°C. The reaction mixture was concentrated to half the volume, cooled to 0°C and separated succinimide was removed by filtration. To the filtrate was added a slurry of 30 g Raney nickel (a 50% slurry in methanol) Et3N (32 ml) and hydrogenated in a Parr apparatus at 120 psi. After 7-8 hours, the reaction mixture was filtered through a Celite filter pad, and washed with MeOH. The washings and filtrate were combined and triturate with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and succinimide. The filtrate was concentrated to a residue, dissolved in methanol and triturated with hexane to remove most of the triethylamine hydrobromide and succinimide. The filtrate was concentrated to obtain methyl 2-deoxy-α/β- D-glucopyranoside (85%).Example 5 To a stirred solution of methyl 3,4,6-tri-O-acetyl-2-deoxy-α/β-D-glucopyranoside (47 g) (from example 3) in acetic acid (40 ml) and acetic anhydride (110 ml) was added concentrated sulphuric acid (0.94 ml) at 0°. The reaction mixture was brought to room temperature and stirred. After 2 hours the reaction mixture was diluted with water (50 ml) and extracted into CH2C12 (3×150 ml). The organic phase was separated, washed with saturated NaHCO3 solution, H2O dried over Na2SO and concentrated to obtain 2-deoxy- 1,3,4,6-tetra-O-acetyl-α/β-D-glucopyranoside as a crystalline compound, mp. 115-118°C. Quantity obtained 44.5 g (86%). [α]D + 21.5° (c 1.0, CHC13). 1H NMR (200 MHz, CDC13): δ 1.50-2.45 (m, 14H, H-2,2′, 4xOCOCH3), 3.85-5.40, (m, 5H, H-3,4,5,6,6′), 5.75-6.20 (m, 1H, H-l,α/ β). To a heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D- glucopyranoside (10 g) in water (100 ml) was added acetyl chloride (10 ml) and heated to 80°C. After 6 hours the reaction mixture was cooled to room temperature, neutralised with saturated aq. Ba(OH)2, concentrated to half the volume and filtered on a Celite pad. Filtrate was concentrated on a rotary evaporator and dried over anhydrous P2O5 to obtain a residue which was dissolved in hot isopropyl alcohol and filtered on a pad of Celite to obtain a clear filtrate. The filtrate was concentrated to a residue, dissolved in hot isopropyl alcohol (50 ml), acetone (75 ml) and seeded with a few crystals of 2-deoxy-D-glucose. After 15-18 hours at 5°C crystalline title product was filtered. Quantity obtained 3.21 g (64.9%) m.p. 148-149°C.Example 6 A heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (9 g) (from example 5), water (30 ml) and 11% aq. H2SO (0.3 ml) was stirred at 85°C for 7 h to obtain a homogenous solution. The reaction mixture was cooled, neutralised with aq. Ba(OH)2 solution and filtered. The filtrate obtained was concentrated to half the volume and solids separated were filtered. To the filtrate was added activated carbon (1 g) and filtered. The filtrate was concentrated on a rotary evaporator and dried over P2O5 to obtain 2-deoxy- D-glucose that was crystallized from methyl alcohol (27 ml) and acetone (54 ml). Quantity obtained 2.4 g. mp. 146-149°C.Example 7A heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside(25g) (from example 5), H2O (250 ml), toluene (250 ml) and glacial acetic acid (1.25 ml) was heated to reflux for 10-12 hours, while it was connected to a Dean- Stark azeotropic distillation apparatus. An azeotropic mixture of acetic acid, toluene was collected to remove acetic acid and every one hour fresh toluene (50 ml) was introduced. After completion of the reaction, toluene was removed by distillation from the reaction mixture to obtain a residue that was dissolved in methanol, treated with charcoal and filtered. The filtrate was separated, concentrated to a residue and crystallized from isopropyl alcohol and acetone to obtain 2- deoxy-D-glucose (7.33 g, 59%). mp. 148-151°C.Example 8 A heterogeneous mixture of l,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (lOg) (from example 5), H2O (200 ml) cone. HC1 (0.3 ml) and glacial acetic acid (0.5 ml) was heated to 85°C. After 6 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. Filtrate was separated, treated with charcoal and filtered. The filtrate was concentrated to a residue and crystallized from MeOH, acetone to obtain the product. Quantity obtained 2.75 g. mp. 147-148°C.Example 9 A heterogeneous mixture of l,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside(lOg) (from example 3) water (100 ml) and cone. HCI (0.5ml) was heated to 80°C. After 2-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. The filtrate was concentrated to a residue, dissolved in ethanol, treated with charcoal and filtered. The filtrate was concentrated to a solid residue andcrystallized from methanol-acetone to obtain the title product. Quantity obtained 3.15g mp. 148-151°C.Example 10A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30g) (from example 2) water(15 ml) and cone. HCI (1.5 ml) was heated to 80-85°C. After 3-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered to remove insoluble salts. The filtrate was concentrated to a residue, crystallized from MeOH, acetone and hexane to obtain 2-deoxy-D-glucose (11.77 g) mp. 149-151°C.Example 11A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30g) (from example 2) water (195 ml) and cone. H2SO (5.9 ml) was heated to 80°C. After 2-3 hours the reaction mixture was cooled, neutralized with aq. Ba(OH)2 and filtered. The filtrate was separated, treated with charcoal and filtrate. The Filtrate was concentrated to a residue and crystallized from isopropyl alcohol to obtain the title product. Quantity obtained 5.2 g. mp. 152-154°C.Example 12 A mixture of methyl 2-deoxy-α/β-D-glucopyranoside (24g) (from example 2) water(125 ml) and IR 120 H+ resin (7.5 ml) was heated to 90-95°C for 2h. The reaction mixture was cooled to room temperature, filtered and the resin was washed with water (20 ml). The filtrate was concentrated to residue and crystallized from ethanol to obtain 2-deoxy-D- glucose (8.8 g), mp. 150-152°C. The main advantages of the present invention are:-1). It does not involve the use of toxic mercaptans like ethane thiol. 2). This process does not involve reaction of D-glucal with mineral acid, thereby avoiding the formation of Ferrier by-products.

2-Deoxy-d-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively inhibit the production of glucose-6-phosphate from glucose at the phosphoglucoisomerase level (step 2 of glycolysis).[2] In most cells, glucose hexokinase phosphorylates 2-deoxyglucose, trapping the product 2-deoxyglucose-6-phosphate intracellularly (with exception of liver and kidney)[; thus, labelled forms of 2-deoxyglucose serve as a good marker for tissue glucose uptake and hexokinase activity. Many cancers have elevated glucose uptake and hexokinase levels. 2-Deoxyglucose labeled with tritium or carbon-14 has been a popular ligand for laboratory research in animal models, where distribution is assessed by tissue-slicing followed by autoradiography, sometimes in tandem with either conventional or electron microscopy.

2-DG is uptaken by the glucose transporters of the cell. Therefore, cells with higher glucose uptake, for example tumor cells, have also a higher uptake of 2-DG. Since 2-DG hampers cell growth, its use as a tumor therapeutic has been suggested, and in fact, 2-DG is in clinical trials. [3] A recent clinical trial showed 2-DG can be tolerated at a dose of 63 mg/kg/day, however the observed cardiac side-effects (prolongation of the Q-T interval) at this dose and the fact that a majority of patients’ (66%) cancer progressed casts doubt on the feasibility of this reagent for further clinical use.[4] However, it is not completely clear how 2-DG inhibits cell growth. The fact that glycolysis is inhibited by 2-DG, seems not to be sufficient to explain why 2-DG treated cells stop growing.[5] Because of its structural similarity to mannose, 2DG has the potential to inhibit N-glycosylation in mammalian cells and other systems, and as such induces ER stress and the Unfolded Protein Response (UPR) pathway.[6][7][8]

Clinicians have noted that 2-DG is metabolised in the pentose phosphate pathway in red blood cells at least, although the significance of this for other cell types and for cancer treatment in general is unclear.

Work on the ketogenic diet as a treatment for epilepsy have investigated the role of glycolysis in the disease. 2-Deoxyglucose has been proposed by Garriga-Canut et al. as a mimic for the ketogenic diet, and shows great promise as a new anti-epileptic drug.[9][10] The authors suggest that 2-DG works, in part, by increasing the expression of Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Arc (protein) (ARC), and Basic fibroblast growth factor (FGF2).[11] Such uses are complicated by the fact that 2-deoxyglucose does have some toxicity.

A study found that by combining the sugar 2-deoxy-D-glucose (2-DG) with fenofibrate, a compound that has been safely used in humans for more than 40 years to lower cholesterol and triglycerides, an entire tumor could effectively be targeted without the use of toxic chemotherapy.[12][13]

2-DG has been used as a targeted optical imaging agent for fluorescent in vivo imaging.[14][15] In clinical medical imaging (PET scanning), fluorodeoxyglucose is used, where one of the 2-hydrogens of 2-deoxy-D-glucose is replaced with the positron-emitting isotope fluorine-18, which emits paired gamma rays, allowing distribution of the tracer to be imaged by external gamma camera(s). This is increasingly done in tandem with a CT function which is part of the same PET/CT machine, to allow better localization of small-volume tissue glucose-uptake differences.

Resistance to 2-DG has been reported in HeLa cells [16] and in yeast;[17][8] in the latter, it involves the detoxification of a metabolite derived from 2-DG (2DG-6-phosphate) by a phosphatase. Despite the existence of such a phosphatase in human (named HDHD1A) However it is unclear whether it contributes to the resistance of human cells to 2DG or affects FDG-based imaging.

SYN

Indian Pat. Appl., 2004DE02075,

SYN

CN 106496288,

STARTING MATERIAL CAS 69515-91-9

C14 H20 O9, 332.30

D-​arabino-​Hexopyranose, 2-​deoxy-​, 1,​3,​4,​6-​tetraacetate

SYN

Bioorganic & Medicinal Chemistry Letters, 22(10), 3540-3543; 2012

https://www.sciencedirect.com/science/article/abs/pii/S0960894X12004258

PATENT

https://patents.google.com/patent/US6933382B2/en2-deoxy-D-glucose is useful in control of respiratory infections and for application as an antiviral agent for treatment of human genital herpes.Prior art for preparation of 2-deoxy-D-glucose while operable, tend to be expensive and time consuming. Reference may be made to Bergmann M., Schotte, H., Lechinsky, W., Ber, 55, 158 (1922) and Bergmann, M., Schotte, H., Lechinsky, W., Ber 56, 1052 (1923) which disclose the preparation of 2-deoxy-D-glucose in low yield by mineral acid catalyzed addition of water to D-glucal. Another method of producing 2-deoxy-D-glucose is from diethyldithioacetal derivative of D-glucose (Bolliger, H. R. Schmid, M. D., Helv. Chim. Acta 34, 989 (1951); Bolliger, H. R., Schmid, M. D., Helv, Chim. Acta 34, 1597 (1951); Bolliger, H. R Schmid, M. D., Helv. Chim. Acta 34, 1671 (1951) and from D-arabinose by reaction with nitromethane followed by acetylation, reduction and hydrolysis (Sowden, J. C., Fisher, H. O. L., J. Am. Chem., 69, 1048 (1947). However these methods result in the formation of 2-deoxy-D-glucose in low yield and of inferior purity due to the formation of several by-products and involve use of toxic reagents such as ethanethiol and nitromethane. As a result purification of 2-deoxy-D-glucose has to be done by recrystallisation which is tedious, time consuming and difficult.

Figure US06933382-20050823-C00001

EXAMPLE 1To a solution of 3,4,6-tri-O-benzyl-D-glucal (39 g, 0.09 mmol) in dichloromethane (20 ml) and methanol (100 ml) was added N-bromosuccinimide (18.7 g, 0.09 mil) during 10 min. at room temperature and stirred for 4 h. After completion of the reaction solvent was distilled off. The resultant residue extracted into carbon tetrachloride (2×100 ml) and organic phase concentrated to obtain methyl 2-bromo 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco-/mannopyranoside as a syrup. Quantity obtained 50 g. 1H NMR (200 MHz, CDCl3) 3.40-4.00 (m, 7H, H-2,5,6,6′ and OCH3) 4.30-5.10 (m, 9H, H-1,3,4 and 3×PhCH2O), 7.10-7.60 (m 15H, Ar—H). A solution of methyl 2-bromo-2-deoxy-3,4,6-tri-O-benzyl/α/β-D-gluco-/mannopyranoside (50 g) in methanol (300) was charged into one liter autoclave along with Raney nickel (10 ml) Et3N (135 ml) and subjected to hydrogenation at 120 psi pressure at 50° C. for 8 h. After completion of the reaction the catalyst was filtered off and the residue washed with methanol (25 ml). The filtrate was concentrate to obtain methyl 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-glucopyranoside as a syrup (37.9 g, 89%). 1H NMR (200 MHz CDCl3): δ 1.50-2.40 (m,2H,H-2,2′), 3.32, 3.51 (2s, 3H, OCH3) 3.55-4.00 (m, 5, H-3,4,5,6,6′) 4.30-5.00 (M 7H, 3×PhCH2, H-1), 7.10-7.45 (m, 15H, Ar—H). The syrup of methyl 2-deoxy-3,4, 6-tri-O-benzyl-α/β-D-glucopyranoside (37.9 g) was dissolved in methanol (200 ml). 1 g of 5% Pd/C was added and hydrogenated at 150 psi pressure at room temperature. After 5 hours catalyst was filtered off and solvent evaporated. Quantity of the methyl 2-deoxy-α/β-D-glucopyranoside obtained 10.5 g (70%). [α]D+25.7° (c 1.0, MeOH), 1H NMR (200 MHz, D2O); δ 1.45-2.40 (m, 2H, H-2,2′) 3.20-4.80, (m 9H, H-1,3,4,5,6,6′—OCH3).EXAMPLE 2To a solution of D-glucal (64.6 g, 0.44 mmol) in methanol (325 ml) at 10° C. was added N-bromosuccinimide (78.7 g, 0.44 mol) during 40 min. maintaining the temperature between 10-15° C. during the addition. The reaction mixture was stirred at room temperature. After 5 hours solvent was evaporated to obtain a residue which was refluxed in ethyl acetate (100 ml). Ethyl acetate layer was discarded to leave a residue of methyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside (105 g) as a syrup. [α]D+36° (c 1.0, MeOH). 1H NMR (200 MHz, D2O): δ 3.47, 3.67 (2s, 3H, OCH3), 3.70-4.05 (m, 6h, H-2,3,4,5,6,6′), 4.48-5.13 (28, 1H, 1H, H-1). The syrupy methyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside was dissolved in methanol (400 ml), a slurry of 80 g Raney nickel (a 50% slurry in methanol), Et3N (30 ml) and hydrogenated in a Parr apparatus at 120 psi. After 8-9 hours, the reaction mixture was filtered through a Celite filter pad and washed with MeOH. The washings and filtrate were combined and triturated with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and traces of succinimide. The filtrate was concentrated to a residue. The isolated yield of methyl 2-deoxy-α/β-D-glucopyranoside was 89%.Ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside:When solvent was ethanol instead of methanol the compound obtained was ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside. 1H NMR (200 MHz, D2O): δ 1.10-1.32 (m, 3H, CH3), 2.80 (s, 4H, —CO(CH2)2CO—NH—), 3.40-4.10 (m, 8H, H-2,3,4,5,6,6′, CH2), 4.40, 5.20 (2s 1H, H-1, α/β).Isopropyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside:When isopropanol instead of methanol was used as a solvent the compound obtained was isopropyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside, 1H NMR (200 MHz, D2O): δ 1.10-1.30 (m, 6H, 2×CH3) 2.80 (s, 4H, —CO(CH2)2CO—NH—), 3.60-4.60 (m 8H,H-2,3,4,5,6,6′, CH2) 4.40, 5,30 (2s, 1H, H-1, α/β.EXAMPLE 3A mixture of D-glucal (64.6 g), methanol (400 ml), N-bromosuccinimide (79 g) were stirred at 15° C. for 6 h. The reaction mixture was hydrogenated in a Parr apparatus in presence of 60 g of Raney nickel catalyst (a 50% slurry in methanol) and triethylamine (62 ml). After 8-9 h, the reaction mixture was filtered on a Celite filter pad. The Celite pad was washed with methanol. The washings and filtrate were combined, concentrated to a thick heavy syrup, dissolve in chloroform (500 ml), pyridine (400 ml) and acetic anhydride (251 ml) was added while stirring, maintaining the temperature between 5-10° C. After 12 hours, the reaction mixture was diluted with CHCl(500 ml) transferred to a separating funnel and organic phase was washed with water. The organic phase was separated, dried (Na2SO4) and concentrated to obtain methyl 2-deoxy-3,4,6-tri-O-acetyl-2 deoxy-α/β-D-glucopyranoside as a syrup (163.43 g, 87%). [α]D+65.0° (c 1.0, CHCl31H NMR (200 MHz, CDCl3): δ 1.55-1.90 (m, 2H, H-22′), 2.01, 2.04, 2.11, 2.15, (4s, 9H, 3×OCOCH3), 2.18, 3.40 (2s, 3H, OCH3), 3.45-50 (m, 3H, H-5, 6,6′) 4.80-5.40 (m, 3H,H-1,3,4). The syrup was dissolved in methanol (600 ml) 1N NaOMe in methanol (25 ml) was added and left at room temperature. After 6-10 h, dry COgas was passed into the reaction mixture, solvent was evaporated to obtain a syrupy residue. The residue was once again extracted into dry methanol and concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside as syrup. Quantity obtained 81 g (92%).EXAMPLE 4A 500 ml round bottom flask equipped with magnetic stir bar was charged with a solution of D-glucal (323 g) in methanol (175 ml), cooled to 15° C., N-bromosuccinimide (NIBS) (39.4 g) was added and stirred or 6 hours at 15° C., The reaction mixture was concentrated to half the volume, cooled to 0° C. and separated succinimide, was removed by filtration. To the filtrate was added a slurry of 30 g Raney nickel (a 50% slurry in Methanol) Et3N (32 ml) and hydrogenated in a Parr apparatus at 120 psi. After 7-8 hours, the reaction mixture was filtered through a Celite filter pad, and washed with MeOH. The washings and filtrate were combined and triturate with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and succinimide. The filtrate was concentrated to a residue, dissolved in methanol and triturated with hexane to remove most of the triethylamine hydrobromide and succinimide. The filtrate was concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside (85%).EXAMPLE 5To a stirred solution of methyl 3,4,6-tri-O-acetyl-2-deoxy-α/β-D-glucopyranoside (47 g) (from example 3) in acetic acid (40 ml) and acetic anhydride (110 ml) was added concentrated sulphuric acid (0.94 ml) at 0°. The reaction mixture was brought to room temperature and stirred. After 2 hours the reaction mixture was diluted with water (50 ml) and extracted into CH2Cl(3×150 ml). The organic phase was separated, washed with saturated NaHCOsolution H2O dried over Na2SOand concentrated to obtain 2-deoxy-1,3,4,6-tetra-O-acetyl-α/β-D-glucopyranoside as a crystalline compound. mp. 115-118° C. Quantity obtained 44.5 g (86%). [α]D+21.5° (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ 1.50-2.45 (m, 14H, H-2,2′, 4×OCOCH3), 3.85-5.40, (m, 5H, H-3,4,5,6,6′), 5.75-6.20 (m, 1H, H-1, α/β). To a heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) in water (100 ml) was added acetyl chloride (10 ml) and heated to 80° C. After 6 hours the reaction mixture was cooled to room temperature, neutralised with saturated aq. Ba(OH)2, concentrated to half the volume and filtered on a Celite pad, Filtrate was concentrated on a rotary evaporator and dried over anhydrous P2Oto obtain a residue which was dissolved in hot isopropyl alcohol and filtered on a pad of Celite to obtain a clear filtrate. The filtrate was concentrated to a residue, dissolved in hot isopropyl alcohol (50 ml), acetone (75 ml) and seeded with a few crystals of 2-deoxy-D-glucose. After 15-18 hours at 5° C. crystalline title product was filtered. Quantity obtained 3.21 g (64.9%) m.p. 148-149° C.EXAMPLE 6A heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (9 g) (from example 5), water (30 ml) and 11% aq. H2SO(0.3 ml) was stirred at 85° C. for 7 h to obtain a homogenous solution. The reaction mixture was cooled, neutralised with aq. Ba(OH)solution and filtered. The filtrate obtained was concentrated to half the volume and solids separated were filtered. To the filtrate was added activated carbon (1 g) and filtered. The filtrate was concentrated on a rotary evaporator and dried over P2Oto obtain 2-deoxy-D-glucose that was crystallized from methyl alcohol (27 ml) and acetone (54 ml). Quantity obtained 2.4 g. mp. 146-149° C.,EXAMPLE 7A heterogeneous mixture of 1,3,4,tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (25 g) (from example 5), H2O (250 ml), toluene (250 ml) and glacial acetic acid (1.25 ml) was heated to reflux for 10-12 hours, while it was connected to a Dean-Stark azeotropic distillation apparatus. An azeotropic mixture of acetic acid, toluene was collected to remove acetic acid and every one hour fresh toluene (50 ml) was introduced. After completion of the reaction, toluene was removed by distillation from the reaction mixture to obtain a residue that was dissolved in methanol, treated with charcoal and filtered. Be filtrate was separated, concentrated to a residue and crystallized from isopropyl alcohol and acetone to obtain 2-deoxy-D-glucose (7.33 g, 59%). mp. 148-151° C.EXAMPLE 8A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (tom example 5), H2O (200 ml) conc. HCl (0.3 ml) and glacial acetic acid (0.5 ml) was heated to 85° C. After 6 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)and filtered on a pad of Celite. Filtrate was separated, treated with charcoal and filtered. The filtrate was concentrated to a residue and crystallized from MeOH, acetone to obtain the product. Quantity obtained 275 g. mp. 147-148° C.EXAMPLE 9A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (from example 3) water (100 ml) and conc. HCl (0.5 ml) was heated to 80° C. After 2-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)and filtered on a pad of Celite. The filtrate was concentrated to a residue, dissolved in ethanol, treated with charcoal and filtered. The filtrate was concentrated to a solid residue and crystallized from methanol-acetone to obtain the title product. Quantity obtained 3.15 g mp. 148-151° C.,EXAMPLE 10A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (from example 2) water (15 ml) and conc. HCl (1.5 ml) was heated to 80-85° C. After 3-5 hours the reaction mixture was cooled to room temperature, neutralize with aq. Ba(OH)and filtered to remove insoluble salts. The filtrate was concentrated to a residue, crystallized from MeOH, acetone and hexane to obtain 2-deoxy-D-glucose (11.77 g) mp. 149-151° C.EXAMPLE 11A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (form example 2) water (195 ml) and conc. H2SO(5.9 ml) was heated to 80° C. After 2-3 hours the reaction mixture was cooled, neutralized with aq. Ba(OH)and filtered. The filtrate was separated, treated with charcoal and filtrate. The Filtrate was concentrated to a residue and crystallized from isopropyl alcohol to obtain the title product. Quantity obtained 5.2 g. mp. 152-154° C.EXAMPLE 12A mixture of methyl 2-deoxy-α/β-D-glucopyranoside (24 g) (from example 2) water (125 ml) and IR 120H+resin (7.5 ml) was heated to 90-95° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and the resin was washed with water (20 ml). The filtrate was concentrated to residue and crystallized from ethanol to obtain 2-deoxy-D-glucose (8.8 g), mp. 150-152° C.CLIP

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  15. ^ Cheng, Z., Levi, J., Xiong, Z., Gheysens, O., Keren, S., Chen, X., and Gambhir, S., Bioconjugate Chemistry, 17(3), (2006), 662-669
  16. ^ Barban, Stanley (December 1962). “Induced resistance to 2-deoxy-d-glucose in cell cultures”. Biochimica et Biophysica Acta65(2): 376–377. doi:10.1016/0006-3002(62)91065-xISSN 0006-3002PMID 13966473.
  17. ^ Sanz, Pascual; Randez-Gil, Francisca; Prieto, José Antonio (September 1994). “Molecular characterization of a gene that confers 2-deoxyglucose resistance in yeast”. Yeast10 (9): 1195–1202. doi:10.1002/yea.320100907ISSN 0749-503XPMID 7754708S2CID 9497505.

The Drugs Controller General of India (DCGI) has given permission for the emergency use of drug 2-deoxy-D-glucose (2-DG) as an adjunct therapy in moderate to severe Covid-19 cases, said Defence Research and Development Organisation on Saturday.

“Being a generic molecule and analogue of glucose, it can be easily produced and made available in plenty,” said the DRDO in a statement.

An adjunct therapy refers to an alternative treatment that is used together with the primary treatment. Its purpose is to assist the primary treatment.

“The drug has been developed by DRDO lab Institute of Nuclear Medicine and Allied Sciences in collaboration with Dr Reddy’s Laboratories. Clinical trial have shown that this molecule helps in faster recovery of hospitalized patients and reduces supplemental oxygen dependence,” the statement read.

According to DRDO, the patients treated with 2-DG showed faster symptomatic cure than Standard of Care (SoC) on various endpoints in the efficacy trends.

“A significantly favourable trend (2.5 days difference) was seen in terms of the median time to achieving normalization of specific vital signs parameters when compared to SOC,” it said.

The drug comes in powder form in sachets, which is taken orally by dissolving it in water.

“It accumulates in the virus-infected cells and prevents virus growth by stopping viral synthesis and energy production,” said the DRDO.

In April 2020, during the first wave of the Covid-19 pandemic, INMAS-DRDO scientists conducted laboratory experiments of 2-DG with the help of the Centre for Cellular and Molecular Biology (CCMB), Hyderabad.

They found that this molecule works effectively against the SARS-CoV-2 virus and inhibits viral growth.

Based on the results, the DCGI had in May 2020 permitted Phase-II clinical trial of 2-DG in Covid-19 patients.

In Phase-II trials (including dose-ranging) conducted from May to October 2020, the drug was found to be safe and showed significant improvement in the patients’ recovery.

“Phase IIa was conducted in 6 hospitals and Phase IIb (dose-ranging) clinical trial was conducted at 11 hospitals all over the country. Phase-II trial was conducted on 110 patients,” said the DRDO.

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Names
IUPAC name(4R,5S,6R)-6-(hydroxymethyl)oxane-2,4,5-triol
Other names2-Deoxyglucose
2-Deoxy-d-mannose
2-Deoxy-d-arabino-hexose
2-DG
Identifiers
CAS Number154-17-6 
3D model (JSmol)Interactive image
ChEMBLChEMBL2074932
ChemSpider388402 
EC Number205-823-0
IUPHAR/BPS4643
PubChem CID108223
UNII9G2MP84A8W 
showInChI
showSMILES
Properties
Chemical formulaC6H12O5
Molar mass164.16 g/mol
Melting point142 to 144 °C (288 to 291 °F; 415 to 417 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////2-Deoxy-D-glucose,  2 dg, 2-dg, 2 DEOXY D GLUCOSE, COVID 19, CORONA VIRUS, INDIA 2021, DCGI, DRDO, DR REDDYS

C(C=O)C(C(C(CO)O)O)O

Pegylated Interferon alpha-2b, (PegIFN), Virafin


DB00022 sequence CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMI QQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVR KYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE

CDLPQTHSLG SRRTLMLLAQ MRRISLFSCL KDRHDFGFPQ EEFGNQFQKA ETIPVLHEMI
QQIFNLFSTK DSSAAWDETL LDKFYTELYQ QLNDLEACVI QGVGVTETPL MKEDSILAVR
KYFQRITLYL KEKKYSPCAW EVVRAEIMRS FSLSTNLQES LRSKE

2D chemical structure of 215647-85-1
Chemical structure of peginterferon α-2a and α-2b. Abbreviations: PeG-IFN, peginterferon; IFN, interferon; Lys, lysine; His, histidine; Cys, cysteine; Ser, serine. 

Chemical structure of peginterferon α-2a and α-2b. Abbreviations: PeG-IFN, peginterferon; IFN, interferon; Lys, lysine; His, histidine; Cys, cysteine; Ser, serine.

Pegylated Interferon alpha-2b

(PegIFN), Virafin

Zydus seeks DCGI approval for the use of Pegylated Interferon alpha-2b in  treating COVID-19 - The Indian Practitioner
FormulaC860H1353N229O255S9
CAS99210-65-8, 98530-12-2, 215647-85-1
Mol weight19268.9111
  • Interferon α2b, pegylated
  • PegIFN a-2b
  • PegIFN a-2b (biologics)
  • PegIFN α-2b
  • PegIntron
  • Pegaferon
  • PegiHep
  • Peginterferon alfa-2b
  • Peginterferon α-2b
  • Pegylated interferon alfa-2b
  • Pegylated interferon α-2b
  • Pegylated interferons, PegIFN a-2b
  • Proteinaceous biopharmaceuticals, PegIFN a-2b
  • Sch 54031
  • Sylatron
  • ViraferonPeg

Active Moieties

NAMEKINDUNIICASINCHI KEY
Interferon alfa-2bunknown43K1W2T1M698530-12-2Not applicable
Clinical data
Trade namesPegIntron, Sylatron, ViraferonPeg, others
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa605030
License dataEU EMAby INN
Routes of
administration
Subcutaneous injection
ATC codeL03AB10 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]EU: Rx-only
Pharmacokinetic data
Elimination half-life22–60 hrs
Identifiers
showIUPAC name
CAS Number215647-85-1 
IUPHAR/BPS7462
DrugBankDB00022 
ChemSpidernone
UNIIG8RGG88B68
KEGGD02745 
ChEMBLChEMBL1201561 
ECHA InfoCard100.208.164 
Chemical and physical data
FormulaC860H1353N229O255S9
Molar mass19269.17 g·mol−1
wdt-19

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New Delhi: ,,,,,,https://www.ndtv.com/india-news/zydus-virafin-gets-emergency-use-approval-for-treating-moderate-covid-19-cases-2420358

Zydus Cadila received emergency use approval from the Drugs Controller General of India (DGCI) on Friday for the use of “Virafin”, Pegylated Interferon alpha-2b (PegIFN) in treating moderate COVID-19 infection in adults.

A single-dose subcutaneous regimen of the antiviral Virafin will make the treatment more convenient for the patients. When administered early on during COVID-19, Virafin will help patients recover faster and avoid much of the complications, the company said.

In a release, Cadila Health highlighted that “the drug has also shown efficacy against other viral infections.”

Speaking on the development, Dr Sharvil Patel, Managing Director, Cadila Healthcare Limited said, “The fact that we are able to offer a therapy which significantly reduces the viral load when given early on can help in better disease management. It comes at a much-needed time for patients and we will continue to provide them access to critical therapies in this battle against COVID-19.”

In its Phase III clinical trials, the therapy had shown better clinical improvement in the patients suffering from COVID-19. During the trials, a higher proportion of patients administered with PegIFN arm were RT-PCR negative by day 7. The drug ensures faster viral clearance and has several add-on advantages compared to other anti-viral agents, the release further reads.

The development and the nod from DGCI come at a time when India is combating the second wave of coronavirus.

The central government in one of its major announcements decided to administer COVID-19 vaccines to all age above 18 years.

India recorded 3,32,730 new COVID-19 cases in the last 24 hours, the highest single-day spike since the pandemic broke out last year. India has crossed the mark of 3 lakh COVID-19 cases for two consecutive days now. This has taken the cumulative count of the COVID infection in the country to 1,62,63,695.

2CommentsThe country has recorded 2,263 new deaths due to COVID-19 in the last 24 hours. As many as 1,86,920 people have succumbed to the viral infection in India so far. There are 24,28,616 active COVID-19 cases in the country now.

PATENT

https://patents.google.com/patent/EP1562634B1/en

  • Interferon alpha-2a plays an important role for the treatment of chronic hepatitis C, but it is limited in its efficacy by the short in vivo half-life. To improve the half-life and efficacy, interferon alpha-2a was conjugated with a polyethylene glycol moiety. Pegylation changes physicochemical and biological properties of the protein. One effect is the decrease of the proteolytic degradation and the renal clearance. This increases the half-life of the pegylated protein in blood. Another effect is the altered distribution in the body, depending on the size of the PEG moiety of the protein. Interferon alpha 2a pegylated with a large polyethylene glycol moiety (PEG moiety) such as a 40 kDa branched polyethylene moietywherein R and R’ are independently lower alkyl; n and n’ are integers having a sum of from 600 to 1500; and the average molecular weight of the polyethylene glycol units in said conjugate is from about 26,000 daltons to about 66,000 daltons;
    has an improved biological activity and exhibits sustained adsorption and reduced renal clearance, resulting in a strong antiviral pressure throughout a once-weekly dosing schedule, see Perry M. C., et al. Drugs, 2001,15,2263-2288 and Lamb M. W., et al. The Annals of Pharmacotherapy, 2002, 36, 933-938.
  • [0003]See also Monkarsh et al. Analytical Biochemistry, 1997, 247, 434- 440 (Positional Isomers of Mono-pegylated Interferon α-2a) and Bailon et al. Bioconjugate Chemistry, 2001, 12, 195-202 (Rational Design of a Potent, Long-Lasting Form of interferon).
  • [0004]The method for the pegylation of interferon alpha-2a is described in EP A 809 996. Since this pegylation is performed by reaction of PEG2-NHS of formulawith primary amino groups on for example lysine or to the N-terminus of the interferon alpha.one or more PEG moieties may be attached and form a mixture of unpegylated, mono- and multiple-pegylated interferon. Monopegylated interferon alpha can be isolated from the mixture by methods known in the art. Furthermore, since interferon alpha-2a molecule exhibits 12 sites for pegylation (11 lysines and the N-terminus) it is a mixture of positional isomers. From these possible twelve isomers, nine were isolated and characterized, each of these being conjugated to the branched polyethylene glycol chain at a specific lysine, namely,
    at Lys(31) to form interferon alpha 2a pegylated at Lys(31) [referred to as PEG-Lys(31)],
    at Lys(49) to form interferon.alpha 2a pegylated at Lys(49) [referred to as PEG-Lys(49)],
    at Lys(70) to form interferon alpha 2a pegylated at Lys(70) [referred to as PEG-Lys(70)],
    at Lys(83) to form interferon alpha 2a pegylated at Lys(83) [referred to as PEG-Lys(83)],
    at Lys(112) to form interferon alpha 2a pegylated at Lys(112) [referred to as PEG-Lys(112)],
    at Lys(121) to form interferon alpha 2a pegylated at Lys(121) [referred to as PEG-Lys(121)],
    at Lys(131) to form interferon alpha 2a pegylated at Lys(131) [referred to as PEG-Lys(131)],
    at Lys(134) to form interferon alpha 2a pegylated at Lys(134) [referred to as PEG-Lys(134)],
    at Lys(164) to form interferon alpha 2a pegylated at Lys(164) [referred to as PEG-Lys(164)].
  • [0005]It has been found that PEG-Lys(31) and PEG-Lys(134) have higher activities in an antiviral assay than the mixture, the activity of PEG-Lys(164) was equal to the mixture, whereas the activities of PEG-Lys(49), PEG-Lys(70), PEG-Lys(83), PEG-Lys(112), PEG-Lys(121) and PEG-Lys(131) were lower.
  • The following examples will further illustrate the invention

Example 1A Separation of the positional isomers

  • [0035]A two-step isolation and purification scheme was used to prepare the monopegylated isoforms of PEG-interferon alpha 2a.
  • a) The first step was a separation of the positional isomers on a preparative low pressure liquid chromatography column with a weak-cation exchange matrix (TOSOH-BIOSEP, Toyopearl CM-650S, e.g. Resin Batch no. 82A the diameter of the column being 16 mm, the length 120 cm). A linear pH-gradient of increasing sodium acetate concentration (25 mM, pH 4.0 up 75 mM to pH 7.8) was applied at a flow rate of 0.7 mL/min. Detection was at 280 nm. With this chromatographic step species 1, 2, 5,6 and a mixture of 3, 4, 4a, 7 and 8 could be collected, see Table 1.
  • b) The fractions were further separated and purified in the second preparation step. A preparative column with the same matrix as the analytical strong-cation exchange column (Resin Batch no. 82A having a ion exchange capacity of 123 mEq/ml) as described above but larger dimensions (30 mm i.d. and 70 mm length), further a higher flow rate and an extended run time was used. As for the analytical method the column was pre-equilibrated with 3.4 mM sodium acetate, 10% ethanol and 1% diethylene glycol, adjusted to pH 4.4 (buffer A). After loading the PEG-IFN samples, the column was washed with buffer A, followed by an ascending linear gradient to 10 mM dibasic potassium phosphate, 10% ethanol and 1% diethylene glycol, adjusted to pH 6.6 (buffer B). The flow rate was 1.0 mL/min and the detection at 218 nm.
  • [0036]The protein concentration of the PEG-IFN alpha 2a isomer was determined by spectrophotometry, based on the 280 nm absorption of the.protein moiety of the PEG-IFN alpha 2a.
  • [0037]An analytical elution profile of 180 µg of PEG-IFN alpha 2a is shown in Figure 1. The result of this method is a separation into 8 peaks, 2 peaks with baseline separation and 6 with partial separation. The decrease of the baseline absorption towards the end of the chromatogram suggests that there were no other monopegylated species of IFN alpha 2a eluting at higher retention time.
  • [0038]In addition, looking carefully at the IEC-chromatogram a further peak close to the detection limit is visible between peaks 2 and 3 indicating the presence of additional positional isomers that should also contribute to the specific activity of the PEG-IFN alpha 2a mixture. Additional species were expected as the interferon alpha-2a molecule exhibits 12 sites for pegylation (11 lysines and the N-terminus). However, given the low abundance of the these species, they were not isolated and characterised.
  • [0039]Isomer samples derived from IEC optimisation runs were investigated directly after the isolation (t = 0) and after 2 of weeks of storage at 5°C (data not shown). No significant differences were observed for the protein derived from IEC-peaks with regard to the protein content as determined by spectrometric methods; nor were any changes to be detected in the monopegylation site, the content of oligo-PEG-IFN alpha 2a, the amount of aggregates and the bioassay activity. Taking into account the relative abundance of the individual isomers – as determined by the IEC method – as well as the specific activities – as determined in the anti-viral assay – almost the total specific bioactivity of the PEG-IFN alpha 2a mixture used for their isolation is recovered (approximately 93%).
  • [0040]The analytical IE-HPLC was used to check the purity of the individual isomers with respect to contamination with other positional isomers in the IEC fractions. The peaks 2, 3, 4, 4a, 5 and 7 had more than 98%, the peaks 1 and 8 had 93% and peak 6 had 88 % purity. Table 1:PEG-peptides identified by comparison of the Lys-C digest spectra of the isomers and the reference standard.Identified PEG Sites in the separated PEG-IFN SpeciesPeakmissing peaks in peptide mapPEG-IFNPEG siteMr (DA)SequencePeak 1K31A,E24-49Peak 2K134I, I’134-164Peak 3K131C122-131aPeak 4K121B, C113-131Peak 4aK164b134-164a,bPeak 5K70D, F50-83Peak 6K83D, H71-112Peak 7K49E, F32-70Peak 8K112B, H84-121a132-133 too small to detect.a,b RP-HPLC.
  • [0041]The fractions were characterised by the methods described in examples 2 to 6.

Example 1B Analytical separation of positional isomers of mono-pegylated interferon alpha 2a

  • [0042]HPLC Equipment:HP1100Column:SP-NPR, TosoH Bioscience, Particle size: 2.5µm, nonporous, Order#: 13076Injection:5-10 µg monopegylated IFNmobile Phase:Buffer A:  10% v/vEthanol 1% v/vDiethylenglycol 2.3 mMNa-Acetat 5.2 mMAcetic acid, in purified water, no pH adjustment Buffer B:  10% v/vEthanol 1% v/vDiethylenglycol 16.4 mMKH2PO4 4.4 mMK2HPO4, in purified water, no pH adjustmentGradient:0 Min40 %B 2 Min40 %B 2.1 Min48 %B 25 Min68 %B 27 Min75 %B 30 Min75 %B 34 Min40 %B 40 Min40 %BFlow:1.0 ml/min Column Temperature:25°C Detection:218 nm a typical Chromatogram is given in Figure 8.

Example 2 Analysis of the fractions by mass spectrometry peptide mapping

  • [0043]Mass spectra were recorded on a MALDI-TOF MS instrument (PerSeptive Biosystems Voyager-DE STR with delayed extraction). Each IEC fraction (Ion Exchange Chromatography) was desalted by dialysis, reduced with 0.02 M 1,4-dithio-DL-threitol (DTT) and alkylated with 0.2 M 4-vinyl pyridine. Then the proteins were digested with endoproteinase Lys-C (Wako Biochemicals) in 0.25 M Tris (tris(hydroxymethyl)-aminoethane) at pH 8.5 with an approximate enzyme to protein ratio of 1:30. The reaction was carried out over night at 37 °C.
  • [0044]A solution of 20 mg/ml α-cyano-4-hydroxycinnamic acid and 12 mg/ml nitrocellulose in acetone/isopropanol 40/60 (v/v) was used as matrix (thick-layer application). First, 0.5 µL of matrix was placed on the target and allowed to dry. Then, 1.0 µL of sample was added. The spectra were obtained in linear positive ionisation mode with an accelerating voltage of 20.000 V and a grid voltage of 95 %. At least 190 laser shots covering the complete spot were accumulated for each spectrum. Des-Arg1-bradykinin and bovine insulin were used for internal calibration.

Example 3 high-performance liquid chromatography (RP-HPLC) Peptide Mapping

  • [0045]The peptides were characterized by reverse-phase high-performance liquid chromatography (RP-HPLC) Peptide Mapping. The IEC fractions were reduced, alkylated and digested with endoproteinase Lys-C as described for the MALDI-TOF MS peptide mapping. The analysis of the digested isomers was carried out on a Waters Alliance HPLC system with a Vydac RP-C18 analytical column (5 µm, 2.1 × 250 mm) and a precolumn with the same packing material. Elution was performed with an acetonitrile gradient from 1 % to 95 % for 105 min in water with a flow rate of 0.2 mL/min. Both solvents contained 0.1 % (v/v) TFA. 100 µL of each digested sample were injected and monitored at 215 nm.

Example 4 MALDI-TOF spectra of undigested protein

  • [0046]An 18 mg/ml solution of trans-3-indoleacrylic acid in acetonitrile/0.1 % trifluoroacetic acid 70/30 (v/v) was premixed with the same volume of sample solution. Then 1.0 µL of the mixture was applied to the target surface. Typically 150 – 200 laser shots were averaged in linear positive ionisation mode. The accelerating voltage was set to 25.000 V and the grid voltage to 90 %. Bovine albumin M+ and M2+ were used for external calibration.

Example 5 SE-HPLC (size exclusion HPLC)

  • [0047]SE-HPLC was performed with a Waters Alliance 2690 HPLC system equipped with a TosoHaas TSK gel G 4000 SWXL column (7.8 × 300 mm). Proteins were eluted using a mobile phase containing 0.02 M NaH2PO4, 0.15 M NaCl, 1% (v/v) diethylene glycol and 10 % (v/v) ethanol (pH 6.8) at a flow rate of 0.4 mL/min and detected at 210 nm. The injection amounts were 20 µg of each isomers.
  • [0048]Size Exclusion HPLC and SDS-PAGE were used to determine the amount of oligo-PEG-IFN alpha 2a forms and aggregates in the different IEC fractions. The reference material contains 2.3 % aggregates and 2.2 % oligomers (Figure 4).
  • [0049]Peaks 1, 4, 4a, 5, 6 and 8 contain < 0.7 % of the oligopegylated IFN alpha 2a forms, whereas in,peaks 2, 3, and 7 the percentage of the oligopegylated IFN alpha 2a forms are under the detection limit (< 0.2 %). In the case of the aggregates a different trend could be seen. In all peaks the amount of aggregates is below 0.9 %.

Example 6 SDS-PAGE

  • [0050]SDS-PAGE was carried out both under non-reducing and under reducing conditions using Tris-Glycine gels of 16 % (1.5 mm, 10 well). Novex Mark 12 molecular weight markers with a mass range from 2.5 to 200 kDa were used for calibration, bovine serum albumin (BSA) was used as sensitivity standard (2 ng). Approximately 1 µg of all the samples and 0.5 µg of standard were applied to the gel. The running conditions were 125 V and 6 W for 120 min. The proteins were fixed and stained using the silver staining kit SilverXpress from Novex.
  • [0051]The gels that were recorded under non-reducing conditions for the IEC fractions 1- 8 (Figure 2) show a pattern that is comparable to that of the PEG-IFN alpha 2a reference standard.
  • [0052]Under reducing conditions, the gels show an increase in intensity of the minor bands at about 90 kDa as compared to the standard. Between 6 and 10 kDa protein fragments appear for peaks 6, 7 and 8 (Figure 3). Both bands together correspond to approximately 1 % of clipped material. In the lanes of isomer 1, 5, 6, 7, 8 additional bands with more than 100 kDa can be seen which are also present in the standard. These can be assigned to oligomers. Thus SDS-PAGE confirms the results of the SE-HPLC analysis.
  • [0053]Overall, RP-HPLC and SDS-PAGE experiments indicate that the purity of the IEC fractions can be considered comparable to the PEG-IFN alpha 2a reference standard.
  • [0054]The structure of the PEG-IFN alpha 2a species derived from the 9 IEC-fractions were identified based on the results of the methods described above using the strategy mentioned above.

Example 7 The antiviral activity (AVA)

  • [0055]The antiviral activity was estimated by its protective effect on Madin-Darby bovine kidney (MDBK) cells against the infection by vesticular stomatitis virus (VSV) and compared with a PEG-IFN alpha 2a standard. Samples and reference standard were diluted in Eagle’s Minimum Essential Medium (MEM) containing 10 % fetal bovine serum to a final concentration of 10 ng/mL (assay starting concentration). Each sample was assayed in quadruplicate.
  • [0056]The antiviral protection of Madin-Darby bovine kidney cells (MDBK) with vesicular stomatitis virus was tested according to the method described in Virol. 1981, 37, 755-758. All isomers induced an activity in the anti-viral assay as presented in Table 2. The activities range between 1061 and 339 U/µg, indicating that the difference in specific activities of the protein in the positional isomers is significant. The know-how and the results generated so far will allow the initiation of further investigations to establish this structure-function relationship between the positional isomers and the IFN alpha receptors. Table 2:In Vitro Antiviral Activities of PEG-IFN alpha 2a and individual PEG-IFN alpha 2a isomers. The Antiviral activity was determined in MDBK cells infected with vesicular stomatitis virus. The results present the averages of three assays performed independently.Antiviral Assay of PEG-IFNPeakU/µgPEG-IFN1061 ± 50Peak 11818 ± 127Peak 21358 ± 46Peak 3761197Peak 4339 ± 33Peak 4a966 ± 107Peak 5600 ± 27Peak 6463 ± 25Peak7513 ± 20Peak 8468 ± 23
  • [0057]The results are further illustrated by the following figures
  • Figure 1: Analytical IEC-HPLC of 180µg of PEG-IFN alpha 2a. An analytical strong-cation exchange column was used to check the purity of the separated positional isomers from each purification step (TOSOH-BIOSEP, SP-SPW,10 µm particle size, 7.5 mm diameter, 7.5 cm length).
  • Figure 2: A/B: SDS-PAGE analysis with Tris-glycine (16%), the samples were electrophoresed under non-reduced conditions. The gels were stained for protein with Silver Stain. Lanes: M, molecular weight marker proteins/ 2, Peak 1/ 3, Peak 2/ 4, Peak 3/ 5, Peak 4/ 6, Peak 4a/ 7, Peak 5/ 8, Peak 6/ 9, Peak 7/10, Peak 8/ 11, Ix PEG-IFN standard/ 12, 1.5x PEG-IFN standard/ C1, IFN standard.
  • Figure 3: A/B: SDS-PAGE analysis with Tris-glycine (16%), the samples were electrophoresed under reduced conditions. The gels were stained for protein with Silver Stain. Lanes: M, molecular weight marker proteins/ 2, Peak 1/ 3, Peak 2/ 4, Peak 3/ 5, Peak 4/ 6, Peak 4a/ 7, Peak 5/ 8, Peak 6/ 9, Peak 7/ 10, Peak 8/ 11, 1x PEG-IFN standard/ 12, 1.5x PEG-IFN standard/ C1, IFN standard.
  • Figure 4: Size Exclusion (SE-) HPLC was used to determine the amount of oligo PEG-IFN forms and aggregates in the different IEC fractions. SE-HPLC was performed with a TosoHaas TSK gel G 4000 SWXL column (7.8 × 300 mm).
  • Figure 5: MALDI-TOF spectrometry was used to determine the molecular weight of each isomer in order to ensure that the PEG-IFN molecules were still intact after IEC chromatography and to confirm the monopegylation.
  • Figure 6: MALDI-TOF Lys-C peptide maps of the PEG-IFN reference standard and the peaks 1, 2, 3, 4, 4a, 5, 6, 7, 8. Missing peaks compared to the standard are indicated by arrows.
  • Figure 7: RP-HPLC chromatograms of the Lys-C digests of the PEG-IFN reference and peak 4a
  • Figure 8: Analytical HPLC of 5-10µg of PEG-IFN alpha 2a mixture of positional isomers on a column charged with SP-NPR, TosoH Bioscience, Particle size: 2.5µm, nonporous as described in Example 1B..
  • Figure 9: Ribbon structure of interferon alpha-2a showing the pegylation sites. This is the high resolution structure of human interferon alpha-2a determined with NMR spectroscopy see JMol. Biol. 1997, 274, 661-675. The pegylation sites of pegylated interferon alpha-2a are coloured red and labelled with residue type and residue number.

Pegylated interferon alfa-2b, sold under the brand name PegIntron among others, is a medication used to treat hepatitis C and melanoma.[3] For hepatitis C it is typically used with ribavirin and cure rates are between 33 and 82%.[3][4] For melanoma it is used in addition to surgery.[3] It is given by injection under the skin.[3]

Side effects are common.[5] They may include headache, feeling tired, mood changes, trouble sleeping, hair loss, nausea, pain at the site of injection, and fever.[3] Severe side effects may include psychosisliver problemsblood clotsinfections, or an irregular heartbeat.[3] Use with ribavirin is not recommended during pregnancy.[3] Pegylated interferon alfa-2b is in the alpha interferon family of medications.[3] It is pegylated to protect the molecule from breakdown.[5]

Pegylated interferon alfa-2b was approved for medical use in the United States in 2001.[3] It is on the World Health Organization’s List of Essential Medicines.[6]

Peginterferon alfa-2b is a form of recombinant interferon used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients 3. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) resulting in less use of Peginterferon alfa-2b. Peginterferon alfa-2b is derived from the alfa-2b moeity of recombinant human interferon and acts by binding to human type 1 interferon receptors. Activation and dimerization of this receptor induces the body’s innate antiviral response by activating the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Use of Peginterferon alfa-2b is associated with a wide range of severe adverse effects including the aggravation and development of endocrine and autoimmune disorders, retinopathies, cardiovascular and neuropsychiatric complications, and increased risk of hepatic decompensation in patients with cirrhosis. The use of Peginterferon alfa-2b has largely declined since newer interferon-free antiviral therapies have been developed.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) no longer recommend Peginterferon alfa-2b for the treatment of Hepatitis C 2. Peginterferon alfa-2b was used alongside Ribavirin(https://go.drugbank.com/drugs/DB00811) with the intent to cure, or achieve a sustained virologic response (SVR), after 48 weeks of therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality 1.

Peginterferon alfa-2b is available as a variable dose injectable product (tradename Pegintron) used for the treatment of chronic Hepatitis C. Approved in 2001 by the FDA, Pegintron is indicated for the treatment of HCV with Ribavirin or other antiviral drugs Label. When combined together, Peginterferon alfa-2b and Ribavirin have been shown to achieve a SVR between 41% for genotype 1 and 75% for genotypes 2-6 after 48 weeks of treatment.

Medical uses

It is used to treat hepatitis C and melanoma. For hepatitis C it is typically used with ribavirin. For melanoma it is used in addition to surgery.[3]

For hepatitis C it may also be used with boceprevirtelaprevirsimeprevir, or sofosbuvir.[5]

In India, in 2021, DGCI approved emergency use of Zydus Cadila‘s Virafin in treating moderate COVID-19 infection.[7]

Host genetic factors

For genotype 1 hepatitis C treated with pegylated interferon-alfa-2a or pegylated interferon-alfa-2b combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature,[8] showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more likely to achieve sustained virological response after the treatment than others. A later report from Nature[9] demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

Side effects

Common side effects include headache, feeling tired, mood changes, trouble sleeping, hair loss, nausea, pain at the site of injection, and fever. Severe side effects may include psychosisliver problemsblood clotsinfections, or an irregular heartbeat.[3] Use with ribavirin is not recommended during pregnancy.[3]

Mechanism of action

One of the major mechanisms of PEG-interferon alpha-2b utilizes the JAK-STAT signaling pathway. The basic mechanism works such that PEG-interferon alpha-2b will bind to its receptor, interferon-alpha receptor 1 and 2 (IFNAR1/2). Upon ligand binding the Tyk2 protein associated with IFNAR1 is phosphorylated which in turn phosphorylates Jak1 associated with IFNAR2. This kinase continues its signal transduction by phosphorylation of signal transducer and activator of transcription (STAT) 1 and 2 via Jak 1 and Tyk2 respectively. The phosphorylated STATs then dissociate from the receptor heterodimer and form an interferon transcription factor with p48 and IRF9 to form the interferon stimulate transcription factor-3 (ISGF3). This transcription factor then translocates to the nucleus where it will transcribe several genes involved in cell cycle control, cell differentiation, apoptosis, and immune response.[10][11]

PEG-interferon alpha-2b acts as a multifunctional immunoregulatory cytokine by transcribing several genes, including interleukin 4 (IL4). This cytokine is responsible for inducing T helper cells to become type 2 helper T cells. This ultimately results in the stimulation of B cells to proliferate and increase their antibody production. This ultimately allows for an immune response, as the B cells will help to signal the immune system that a foreign antigen is present.[12]

Another major mechanism of type I interferon alpha (IFNα) is to stimulate apoptosis in malignant cell lines. Previous studies have shown that IFNα can cause cell cycle arrest in U266, Daudi, and Rhek-1 cell lines.[13]

A follow-up study researched to determine if the caspases were involved in the apoptosis seen in the previous study as well as to determine the role of mitochondrial cytochrome c release. The study confirmed that there was cleavage of caspase-3, -8, and -9. All three of these cysteine proteases play an important role in the initiation and activation of the apoptotic cascade. Furthermore, it was shown that IFNα induced a loss in the mitochondrial membrane potential which resulted in the release of cytochrome c from the mitochondria. Follow-up research is currently being conducted to determine the upstream activators of the apoptotic pathway that are induced by IFNα.[14]

History

It was developed by Schering-Plough. Merck studied it for melanoma under the brand name Sylatron. It was approved for this use in April 2011.

References

  1. ^ “PegIntron- peginterferon alfa-2b injection, powder, lyophilized, for solution PegIntron- peginterferon alfa-2b kit”DailyMed. Retrieved 28 September 2020.
  2. ^ “Sylatron- peginterferon alfa-2b kit”DailyMed. 28 August 2019. Retrieved 28 September 2020.
  3. Jump up to:a b c d e f g h i j k l “Peginterferon Alfa-2b (Professional Patient Advice) – Drugs.com”http://www.drugs.comArchived from the original on 16 January 2017. Retrieved 12 January 2017.
  4. ^ “ViraferonPeg Pen 50, 80, 100, 120 or 150 micrograms powder and solvent for solution for injection in pre-filled pen CLEAR CLICK – Summary of Product Characteristics (SPC) – (eMC)”http://www.medicines.org.uk. Archived from the original on 13 January 2017. Retrieved 12 January 2017.
  5. Jump up to:a b c “Peginterferon alfa-2b (PegIntron)”Hepatitis C OnlineArchived from the original on 23 December 2016. Retrieved 12 January 2017.
  6. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ https://www.aninews.in/news/national/general-news/dgci-approves-emergency-use-of-zyduss-virafin-in-treating-moderate-covid-19-infection20210423163622/
  8. ^ Ge D, Fellay J, Thompson AJ, et al. (2009). “Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance”. Nature461 (7262): 399–401. Bibcode:2009Natur.461..399Gdoi:10.1038/nature08309PMID 19684573S2CID 1707096.
  9. ^ Thomas DL, Thio CL, Martin MP, et al. (2009). “Genetic variation in IL28B and spontaneous clearance of hepatitis C virus”Nature461 (7265): 798–801. Bibcode:2009Natur.461..798Tdoi:10.1038/nature08463PMC 3172006PMID 19759533.
  10. ^ Ward AC, Touw I, Yoshimura A (January 2000). “The JAK-STAT pathway in normal and perturbed hematopoiesis”Blood95 (1): 19–29. doi:10.1182/blood.V95.1.19PMID 10607680. Archived from the original on 2014-04-26.
  11. ^ PATHWAYS :: IFN alpha[permanent dead link]
  12. ^ Thomas H, Foster G, Platis D (February 2004). “Corrigendum toMechanisms of action of interferon and nucleoside analogues J Hepatol 39 (2003) S93–8″J Hepatol40 (2): 364. doi:10.1016/j.jhep.2003.12.003.
  13. ^ Sangfelt O, Erickson S, Castro J, Heiden T, Einhorn S, Grandér D (March 1997). “Induction of apoptosis and inhibition of cell growth are independent responses to interferon-alpha in hematopoietic cell lines”Cell Growth Differ8 (3): 343–52. PMID 9056677Archived from the original on 2014-04-26.
  14. ^ Thyrell L, Erickson S, Zhivotovsky B, et al. (February 2002). “Mechanisms of Interferon-alpha induced apoptosis in malignant cells”Oncogene21 (8): 1251–62. doi:10.1038/sj.onc.1205179PMID 11850845.

External links

///////////Pegylated Interferon alpha-2b,  PegIFN, Virafin, COVID 19, CORONA VIRUS, INDIA 2021, APPROVALS 2021

COVAXIN, BBV 152


covid vaccine india, corona vaccine, corona virus vaccine, first covid vaccine in inida

COVAXIN

CAS 2501889-19-4

  • Whole-Virion Inactivated SARS-CoV-2 Vaccine
  • UNII76JZE5DSN6
  • BBV 152
  • A whole virion inactivated COVID-19 vaccine candidate derived from SARS-CoV-2 strain NIV-2020-770

REF

medRxiv (2020), 1-21.

bioRxiv (2020), 1-32.

BBV152 (also known as Covaxin) is an inactivated virus-based COVID-19 vaccine being developed by Bharat Biotech in collaboration with the Indian Council of Medical Research.

BBV152 is a vaccine candidate created by the Indian Council of Medical Research (ICMR). The candidate, a whole virion inactivated SARS-CoV-2 vaccine, was developed from a well-known SARS-CoV-2 strain and a vero cell platform (CCL-81) with adjuncts of either aluminum hydroxide gel (Algel) or a novel TLR7/8 agonist adsorbed gel. The components of the vaccine include BBV152A, BBV152B, and BBV152C. Animal studies in mice, rats, and rabbits reported BBV152 immunogenicity at two separate antigen concentrations with both types of adjuvants. The formulation with the TLR7/8 adjuvant specifically induced significant Th1 biased antibody responses and increased SARS-CoV-2 lymphocyte responses. Thus, as of July 2020, BBV152 is in Phase 1/2 clinical trials assessing safety and immunogenicity in humans (NCT04471519).

Clinical research

Phase I and II trials

In May 2020, Indian Council of Medical Research’s (ICMR‘s) National Institute of Virology approved and provided the virus strains for developing a fully indigenous COVID-19 vaccine.[1][2] In June 2020, the company got permission to conduct Phase I and Phase II human trials of a developmental COVID-19 vaccine named Covaxin, from the Drugs Controller General of India (DCGI), Government of India.[3] A total of 12 sites were selected by the Indian Council for Medical Research for Phase I and II randomised, double-blind and placebo-controlled clinical trials of vaccine candidate.[4][5][6]

In December 2020, the company announced the report for Phase I trials and presented the results through medRxiv preprint;[7][8] the report was later published in the The Lancet.[9]

On March 8, 2021, Phase II results were published in The Lancet. The study showed that Phase II trials had a higher immune response and induced T-cell response due to the difference in dosing regime from Phase I. The doses in Phase II were given at 4 weeks interval as opposed to 2 weeks in Phase I. Neutralization response of the vaccine were found significantly higher in Phase II.[10]

Phase III trials[edit]

In November 2020, Covaxin received the approval to conduct Phase III human trials[11] after completion of Phase I and II.[12] The trial involves a randomised, double-blinded, placebo-controlled study among volunteers of age group 18 and above and started on 25 November.[13] The Phase III trials involved around 26,000 volunteers from across India.[14] The phase III trials covered a total of 22 sites consisting several states in the country, including DelhiKarnataka and West Bengal.[15] Refusal rate for Phase III trials was much higher than that for Phase I and Phase II. As a result only 13,000 volunteers had been recruited by 22 December with the number increasing to 23,000 by 5 January. [16][17]

As on March 2021, the stated interim efficacy rate for phase III trial is 81%.[18][10]

B.1.1.7 (United Kingdom) variant

In December 2020, a new SARS‑CoV‑2 variantB.1.1.7, was identified in the UK.[19] A study on this variant was carried and preliminary results presented in biorxiv have shown Covaxin to be effective in neutralizing this strain.[20]

Manufacturing

The vaccine candidate is produced with Bharat Biotech’s in-house vero cell manufacturing platform[21] that has the capacity to deliver about 300 million doses.[22] The company is in the process of setting up a second plant at its Genome Valley facility in Hyderabad to make Covaxin. The firm is in talks with other state governments like Odisha[23] for another site in the country to make the vaccine. Beside this, they are also exploring global tie-ups for Covaxin manufacturing.[24]

In December 2020, Ocugen Inc entered a partnership with Bharat Biotech to co-develop Covaxin for the U.S. market.[25][26] In January 2021, Precisa Med entered an agreement with Bharat Biotech to supply Covaxin in Brazil[27]

Emergency use authorisation

 
show  Full authorizationshow  Emergency authorization

See also: COVID-19 vaccine § Trial and authorization status

Bharat Biotech has applied to the Drugs Controller General of India (DCGI), Government of India seeking an emergency use authorisation (EUA).[31] It was the third firm after Serum Institute of India and Pfizer to apply for emergency use approval.[32]

On 2 January 2021, the Central Drugs Standard Control Organisation (CDSCO) recommended permission for EUA,[33] which was granted on 3 January.[34] The emergency approval was given before Phase III trial data was published. This was criticized in some sections of the media.[35][36]

The vaccine was also approved for Emergency Use in Iran and Zimbabwe.[30][29]

References

  1. ^ “ICMR teams up with Bharat Biotech to develop Covid-19 vaccine”Livemint. 9 May 2020.
  2. ^ Chakrabarti A (10 May 2020). “India to develop ‘fully indigenous’ Covid vaccine as ICMR partners with Bharat Biotech”ThePrint.
  3. ^ “India’s First COVID-19 Vaccine Candidate Approved for Human Trials”The New York Times. 29 June 2020.
  4. ^ “Human clinical trials of potential Covid-19 vaccine ‘COVAXIN’ started at AIIMS”DD News. Prasar Bharati, Ministry of I & B, Government of India. 25 July 2020.
  5. ^ Press, Associated (25 July 2020). “Asia Today: Amid new surge, India tests potential vaccine”Washington Post. Retrieved 17 December 2020.
  6. ^ “Delhi: 30-year-old is first to get dose of trial drug Covaxin”The Indian Express. 25 July 2020.
  7. ^ Perappadan, Bindu Shajan (16 December 2020). “Coronavirus | Covaxin phase-1 trial results show promising results”The Hindu. Retrieved 17 December 2020.
  8. ^ Sabarwal, Harshit (16 December 2020). “Covaxin’s phase 1 trial result shows robust immune response, mild adverse events”Hindustan Times. Retrieved 17 December 2020.
  9. ^ Ella, Raches; Vadrevu, Krishna Mohan; Jogdand, Harsh; Prasad, Sai; Reddy, Siddharth; Sarangi, Vamshi; Ganneru, Brunda; Sapkal, Gajanan; Yadav, Pragya; Abraham, Priya; Panda, Samiran; Gupta, Nivedita; Reddy, Prabhakar; Verma, Savita; Rai, Sanjay Kumar; Singh, Chandramani; Redkar, Sagar Vivek; Gillurkar, Chandra Sekhar; Kushwaha, Jitendra Singh; Mohapatra, Satyajit; Rao, Venkat; Guleria, Randeep; Ella, Krishna; Bhargava, Balram (21 January 2021). “Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial”The Lancet Infectious Diseasesdoi:10.1016/S1473-3099(20)30942-7PMC 7825810PMID 33485468.
  10. Jump up to:a b Ella, Raches; Reddy, Siddhart; Jogdand, Harsh; Sarangi, Vamsi; Ganneru, Brunda; Prasad, Sai; Das, Dipankar; Dugyala, Raju; Praturi, Usha; Sakpal, Gajanan; Yadav, Pragya; Reddy, Prabhakar; Verma, Savita; Singh, Chandramani; Redkar, Sagar Vivek; Singh, Chandramani; Gillurkar, Chandra Sekhar; Kushwaha, Jitendra Singh; Mohapatra, Satyajit; Mohapatra, Satyajit; Bhate, Amit; Rai, Sanjay; Panda, Samiran; Abraham, Priya; Gupta, Nivedita; Ella, Krishna; Bhargav, Balram; Vadrevu, Krishna Mohan (8 March 2021). “Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial”The Lancet Infectious Diseasesdoi:10.1016/S1473-3099(21)00070-0.
  11. ^ “Coronavirus | Covaxin Phase III trial from November”The Hindu. 23 October 2020.
  12. ^ Ganneru B, Jogdand H, Daram VK, Molugu NR, Prasad SD, Kannappa SV, et al. (9 September 2020). “Evaluation of Safety and Immunogenicity of an Adjuvanted, TH-1 Skewed, Whole Virion InactivatedSARS-CoV-2 Vaccine – BBV152”. doi:10.1101/2020.09.09.285445S2CID 221635203.
  13. ^ “An Efficacy and Safety Clinical Trial of an Investigational COVID-19 Vaccine (BBV152) in Adult Volunteers”clinicaltrials.gov(Registry). United States National Library of Medicine. NCT04641481. Retrieved 26 November 2020.
  14. ^ “Bharat Biotech begins Covaxin Phase III trials”The Indian Express. 18 November 2020.
  15. ^ Sen M (2 December 2020). “List of states that have started phase 3 trials of India’s first Covid vaccine”mint.
  16. ^ “70%-80% Drop In Participation For Phase 3 Trials Of Covaxin: Official”NDTV. 17 December 2020.
  17. ^ “Bharat Biotech’s Covaxin given conditional nod based on incomplete Phase 3 trial results data”The Print. 3 January 2021.
  18. ^ Kumar, N. Ravi (3 March 2021). “Bharat Biotech says COVID-19 vaccine Covaxin shows 81% efficacy in Phase 3 clinical trials”The Hindu.
  19. ^ “Inside the B.1.1.7 Coronavirus Variant”The New York Times. 18 January 2021. Retrieved 29 January 2021.
  20. ^ Sapkal, Gajanan N.; Yadav, Pragya D.; Ella, Raches; Deshpande, Gururaj R.; Sahay, Rima R.; Gupta, Nivedita; Mohan, V. Krishna; Abraham, Priya; Panda, Samiran; Bhargava, Balram (27 January 2021). “Neutralization of UK-variant VUI-202012/01 with COVAXIN vaccinated human serum”bioRxiv: 2021.01.26.426986. doi:10.1101/2021.01.26.426986S2CID 231777157.
  21. ^ Hoeksema F, Karpilow J, Luitjens A, Lagerwerf F, Havenga M, Groothuizen M, et al. (April 2018). “Enhancing viral vaccine production using engineered knockout vero cell lines – A second look”Vaccine36 (16): 2093–2103. doi:10.1016/j.vaccine.2018.03.010PMC 5890396PMID 29555218.
  22. ^ “Coronavirus vaccine update: Bharat Biotech’s Covaxin launch likely in Q2 of 2021, no word on pricing yet”http://www.businesstoday.in. India Today Group. Retrieved 13 December2020.
  23. ^ “Odisha fast tracks coronavirus vaccine manufacturing unit”The New Indian Express. 7 November 2020.
  24. ^ Raghavan P (24 September 2020). “Bharat Biotech exploring global tie-ups for Covaxin manufacturing”The Indian Express.
  25. ^ Reuters Staff (22 December 2020). “Ocugen to co-develop Bharat Biotech’s COVID-19 vaccine candidate for U.S.” Reuters. Retrieved 5 January 2021.
  26. ^ “Bharat Biotech, Ocugen to co-develop Covaxin for US market”The Economic Times. Retrieved 5 January 2021.
  27. ^ “Bharat Biotech inks pact with Precisa Med to supply Covaxin to Brazil”mint. 12 January 2021.
  28. ^ Schmall E, Yasir S (3 January 2021). “India Approves Oxford-AstraZeneca Covid-19 Vaccine and 1 Other”The New York Times. Retrieved 3 January 2021.
  29. Jump up to:a b “Iran issues permit for emergency use for three other COVID-19 vaccines: Official”IRNA English. 17 February 2021.
  30. Jump up to:a b Manral, Karan (4 March 2021). “Zimbabwe approves Covaxin, first in Africa to okay India-made Covid-19 vaccine”Hindustan Times. Retrieved 6 March 2021.
  31. ^ Ghosh N (7 December 2020). “Bharat Biotech seeks emergency use authorization for Covid-19 vaccine”Hindustan Times.
  32. ^ “Coronavirus | After SII, Bharat Biotech seeks DCGI approval for Covaxin”The Hindu. 7 December 2020.
  33. ^ “Expert panel recommends granting approval for restricted emergency use of Bharat Biotech’s Covaxin”The Indian Express. 2 January 2021.
  34. ^ “Coronavirus: India approves vaccines from Bharat Biotech and Oxford/AstraZeneca”BBC News. 3 January 2021. Retrieved 3 January 2021.
  35. ^ “Disputes Mount, but Heedless Govt Intent on Rolling Vaccine Candidates Out”The Wire. 12 January 2021.
  36. ^ “AIPSN urges govt to reconsider emergency approval for Covaxin till Phase 3 data is published – Health News , Firstpost”Firstpost. 8 January 2021.

External links

Scholia has a profile for Covaxin / BBV152 (Q98703813).

COVAXIN®, Indias indigenous COVID-19 vaccine by Bharat Biotech is developed in collaboration with the Indian Council of Medical Research (ICMR) – National Institute of Virology (NIV).

The indigenous, inactivated vaccine is developed and manufactured in Bharat Biotech’s BSL-3 (Bio-Safety Level 3) high containment facility.

The vaccine is developed using Whole-Virion Inactivated Vero Cell derived platform technology. Inactivated vaccines do not replicate and are therefore unlikely to revert and cause pathological effects. They contain dead virus, incapable of infecting people but still able to instruct the immune system to mount a defensive reaction against an infection.

Why develop Inactivated Vaccine? Conventionally, inactivated vaccines have been around for decades. Numerous vaccines for diseases such as Seasonal Influenza, Polio, Pertussis, Rabies, and Japanese Encephalitis use the same technology to develop inactivated vaccines with a safe track record of >300 million doses of supplies to date. It is the well-established, and time-tested platform in the world of vaccine technology.

Key Attributes:

  • COVAXIN® is included along with immune-potentiators, also known as vaccine adjuvants, which are added to the vaccine to increase and boost its immunogenicity.
  • It is a 2-dose vaccination regimen given 28 days apart.
  • It is a vaccine with no sub-zero storage, no reconstitution requirement, and ready to use liquid presentation in multi-dose vials, stable at 2-8oC.
  • Pre-clinical studies: Demonstrated strong immunogenicity and protective efficacy in animal challenge studies conducted in hamsters & non-human primates. For more information about our animal study, please visit our blog page on Non-Human Primates.
  • The vaccine received DCGI approval for Phase I & II Human Clinical Trials in July, 2020.
  • A total of 375 subjects have been enrolled in the Phase 1 study and generated excellent safety data without any reactogenicity. Vaccine-induced neutralizing antibody titers were observed with two divergent SARS-CoV-2 strains. Percentage of all the side-effects combined was only 15% in vaccine recipients. For further information, visit our blog page on phase 1 study.
  • In Phase 2 study, 380 participants of 12-65 years were enrolled. COVAXIN® led to tolerable safety outcomes and enhanced humoral and cell-mediated immune responses. Know more about our phase 2 study.
Covaxin phase 3 trials
  • A total of 25,800 subjects have been enrolled and randomized in a 1:1 ratio to receive the vaccine and control in a Event-Driven, randomized, double-blind, placebo-controlled, multicentre phase 3 study.

The purpose of this study is to evaluate the efficacy, safety, and immunogenicity of COVAXIN® in volunteers aged ≥18 years.

Of the 25,800 participants, >2400 volunteers were above 60 years of age and >4500 with comorbid conditions.

COVAXIN® demonstrated 81% interim efficacy in preventing COVID-19 in those without prior infection after the second dose.

COVAXIN® effective against UK variant strain:

Analysis from the National Institute of Virology indicates that vaccine-induced antibodies can neutralize the UK variant strains and other heterologous strains.

Global Acceptance of COVAXIN®:

Bharat biotech has been approached by several countries across the world for the procurement of COVAXIN®.

  • Clinical trials in other countries to commence soon.
  • Supplies from government to government in the following countries to take place: Mongolia, Myanmar, Sri Lanka, Philippines, Bahrain, Oman, Maldives and Mauritius.
Covaxin world map
A person holding a vial of the Covaxin vaccine
Vaccine description
TargetSARS-CoV-2
Vaccine typeInactivated
Clinical data
Trade namesCovaxin
Routes of
administration
Intramuscular
ATC codeNone
Legal status
Legal statusEUA : INDIRNZBW
Identifiers
DrugBankDB15847
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COVID-19 pandemic
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////////COVAXIN, BBV152, BBV 152, INDIA 2021, APPROVALS 2021, COVID 19, CORONA VIRUS, bharat biotech

#COVAXIN, #BBV152, #BBV 152, #INDIA 2021, #APPROVALS 2021, #COVID 19, #CORONA VIRUS, #bharat biotech

TRIENTINE HYDROCHLORIDE, 塩酸トリエンチン , 曲恩汀


Skeletal formula of triethylenetetramine

TRIENTINE

  • Molecular Formula C6H18N4
  • Average mass 146.234 Da

112-24-3 CAS

曲恩汀, KD-034, MK-0681, MK-681, TECZA, TETA, TJA-250

1,2-Ethanediamine, N1,N2-bis(2-aminoethyl)-
1,8-diamino-3,6-diazaoctane
Image result for TRIENTINE

TRIENTINE HYDROCHLORIDE

  • Molecular Formula C6H19ClN4
  • Average mass 182.695 Da

38260-01-4 CAS

Launched – 1986 VALEANT, WILSONS DISEASE

Image result for MSD

Image result for VALEANT

塩酸トリエンチン
Trientine Hydrochloride

C6H18N4▪2HCl : 219.16
[38260-01-4]

UPDATE CDSCO INDIA Trientine 08.06.2021 APPROVED

Trientine Tetrahydrochloride bulk and
Trientine Tetrahydrochloride capsules 333 mg
(Each capsule contains Trientine
tetrahydrochloride 333mg equivalent to
Trientine 167mg base)

For the treatment of Wilson’s disease
(hepatolenticular degeneration) in patients
intolerant to Penicillamine. It should be
used when continued treatment with
Penicillamine is no longer possible because
of intolerable or life endangering side
effects.

Aton Pharma, a subsidiary of Valeant Pharmaceuticals, has developed and launched Syprine, a capsule formulation of trientine hydrochloride, for treating Wilson disease.

Image result for TRIENTINE

Triethylenetetramine, abbreviated TETA and trien and also called trientine (INN), is an organic compound with the formula [CH2NHCH2CH2NH2]2. This oily liquid is colorless but, like many amines, assumes a yellowish color due to impurities resulting from air-oxidation. It is soluble in polar solvents. The branched isomer tris(2-aminoethyl)amine and piperazine derivatives may also be present in commercial samples of TETA.[1]

Trientine hydrochloride is a metal antagonist that was first launched by Merck, Sharp & Dohme in the U.S. in 1986 under the brand name Syprine for the oral treatment of Wilson’s disease.

Orphan drug designation has also been assigned in the U.S. for the treatment of patients with Wilson’s disease who are intolerant or inadequately responsive to penicillamine and in the E.U. by Univar for the treatment of Wilson’s disease

 Trientine hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=90373

By condensation of ethylenediamine (I) with 1,2-dichloroethane (II)

Trientine hydrochloride is N,N’-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether.

The empirical formula is C6H18N4·2HCI with a molecular weight of 219.2. The structural formula is:

NH2(CH2)2NH(CH2)2NH(CH2)2NH2•2HCI

Trientine hydrochloride is a chelating compound for removal of excess copper from the body. SYPRINE (Trientine Hydrochloride) is available as 250 mg capsules for oral administration. Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.

Image result for TRIENTINE

Production

TETA is prepared by heating ethylenediamine or ethanolamine/ammonia mixtures over an oxide catalyst. This process gives a variety of amines, which are separated by distillation and sublimation.[2]

Uses

The reactivity and uses of TETA are similar to those for the related polyamines ethylenediamine and diethylenetriamine. It was primarily used as a crosslinker (“hardener”) in epoxy curing.[2]

The hydrochloride salt of TETA, referred to as trientine hydrochloride, is a chelating agent that is used to bind and remove copper in the body to treat Wilson’s disease, particularly in those who are intolerant to penicillamine. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.[3]

Coordination chemistry

TETA is a tetradentate ligand in coordination chemistry, where it is referred to as trien.[4] Octahedral complexes of the type M(trien)Cl3 can adopt several diastereomeric structures, most of which are chiral.[5]

Trientine, chemically known as triethylenetetramine or N,N’-bis(2-aminoethyl)-l,2-ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson’s disease.

Image result for TRIENTINE

Trientine dihydrochloride (1)

Trientine dihydrochloride formulation, developed by Aton with the proprietary name SYPRINE, was approved by USFDA on November 8, 1985 for the treatment of patients with Wilson’s disease, who are intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer’s disease and cancer.

Various synthetic methods for preparation of triethylenetetramine (TETA) and the corresponding dihydrochloride salt have been disclosed in the prior art.

U.S. 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using Titania supported phosphorous catalyst while U.S. 4,550,209 and U.S. 5,225,599 disclose catalytic condensation of ethylenediamine and ethylene glycol for the synthesis of linear triethylenetetramine using catalysts like zirconium trimethylene diphosphonate, or metatungstate composites of titanium dioxide and zirconium dioxide.

U.S. 4,503,253 discloses the preparation of triethylenetetramine by reaction of an alkanolamine compound with ammonia and an alkyleneamine having two primary amino groups in the presence of a catalyst, such as supported phosphoric acid wherein the support is comprised of silica, alumina or carbon.

The methods described above for preparation of triethylenetetramine require high temperatures and pressure. Further, due to the various possible side reactions and consequent associated impurities, it is difficult to control the purity of the desired amine.

CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of Ν,Ν’-dibenzyl-,N,N’-bis[2-(l,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N’-dibenzyl-,N,N’-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N’-dibenzyl-,N,N’-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.

CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetrahydrochlonde salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetrahydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetrahydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.

The process is quite circuitous and cumbersome, requiring use of strong bases, filtration of sodium chloride and results in yields as low as 60%.

US 8,394,992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetrahydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetrahydrochloride salt with a strong base like sodium alkoxide to produce the amine free base (TETA) and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether (TBME), followed by removal of sodium chloride salt and finally the amine free base TETA is treated with hydrochloric acid in solvent ethanol to give trientine hydrochloride salt.

PATENT

WO-2017046695

str1

EXAMPLES

Example 1: Preparation of 2-([2-[cyanomethyl]-t-butyloxycarbonylamino]ethyl- 1-butyloxy carbonylamino)acetonitrile (5)

Potassium carbonate (481.9 g) was added to a stirred mixture of ethylenediamine (100.0 g) in acetonitrile (800 ml) and cooled to around 10°C. Chloroacetonitrile (263.8 g) was gradually added at same temperature and stirred at 25-30°C, till completion of the reaction, as monitored by HPLC. The mixture was cooled to 5-15°C and Boc-anhydride (762. lg) was added to it, followed by stirring at the same temperature. The temperature was raised to 25-30°C and the mass was stirred till completion of the reaction, as monitored by HPLC.

The reaction mass was filtered and the filtrate was concentrated. Toluene was added to the residue, and the mixture was heated to around 70°C followed by cooling and filtration to give 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino) acetonitrile (5).

Yield: 506.8 g

% Yield: 89.9 %

Example 2: Preparation of t-butyl( N-2-aminoethyl)N-([2-[(2-aminoethyl)t-butyloxy)carbonylamino] ethyl) carbamate (6)

Raney nickel (120.0 g) in isopropanol (100 ml) was charged into an autoclave, followed by a mixture of Compound 5 (200 g) in isopropanol (400 ml). Cooled ammonia solution prepared by purging ammonia gas in 1400 ml isopropanol, equivalent to 125 g ammonia was gradually charged to the autoclave and the reaction was carried out around 15-25°C under hydrogen pressure of 2-5 Kg/cm2.

After completion of the reaction, as monitored by HPLC, the mass was filtered, concentrated, and methyl tertiary butyl ether was added to the residue. The mixture was heated to around 50°C, followed by cooling of the mass, stirring, optional seeding with compound 6 and filtration to give tertiary butyl-(N-2-aminoethyl)N-([2-[(2-aminoethyl)-(tert-butyloxy) carbonylamino] ethyl) carbamate.

Yield: 174 g

%Yield: 85 %

Example 3: Preparation of triethylenetetramine dihydrochloride (1)

Concentrated hydrochloric acid (121.5 g) was gradually added to a stirred mixture of tertiary-butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy) carbonyl] amino] ethyl} carbamate (Compound 6, 200.0 g) and water (1400 ml) at 20-30°C. The reaction mixture was heated in the temperature range of 100-105°C till completion of the reaction, as monitored by HPLC, with optionally distilling out water, if so required.

The reaction mass was concentrated and ethanol (600 ml) was added to the residue, followed by heating till a clear solution was obtained. The reaction mixture was gradually cooled with stirring, filtered and dried to provide triethylenetetramine dihydrochloride (1).

Yield: 88.9 g, (70 %)

Purity : > 99%

Patent

https://www.google.com/patents/US8394992

Trientine was said to be used in the synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine in French Patent No. FR2810035 to Guilard et al. Cetinkaya, E., et al., “Synthesis and characterization of unusual tetraminoalkenes,” J. Chem. Soc. 5:561-7 (1992), is said to be directed to synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine from trientine, as is Araki T., et al., “Site-selective derivatization of oligoethyleneimines using five-membered-ring protection method,” Macromol., 21:1995-2001 (1988). Triethylenetetramine may reportedly also be used in the synthesis of N-methylated triethylenetetramine, as reported in U.S. Pat. No. 2,390,766, to Zellhoefer et al.

Synthesis of polyethylenepolyamines, including triethylenetetramines, from ethylenediamine and monoethanolamine using pelleted group IVb metal oxide-phosphate type catalysts was reported by Vanderpool et al. in U.S. Pat. No. 4,806,517. Synthesis of triethylenetetramine from ethylenediamine and ethanolamine was also proposed in U.S. Pat. No. 4,550,209, to Unvert et al. U.S. Pat. No. 5,225,599, to King et al. is said to be directed to the synthesis of linear triethylene tetramine by condensation of ethylenediamine and ethylene glycol in the presence of a catalyst. Joint production of triethylenetetramine and 1-(2-aminoethyl)-aminoethyl-piperazine was proposed by Borisenko et al. in U.S.S.R. Patent No. SU1541204. U.S. Pat. No. 4,766,247 and European Patent No. EP262562, both to Ford et al., reported the preparation of triethylenetetramine by reaction of an alkanolamine compound, an alkaline amine and optionally either a primary or secondary amine in the presence of a phosphorous containing catalyst, for example phosphoric acid on silica-alumina or Group IIIB metal acid phosphate, at a temperature from about 175° C. to 400° C. under pressure. These patents indicate that the synthetic method used therein was as set forth in U.S. Pat. No. 4,463,193, to Johnson. The Ford et al. ‘247 patent is also said to be directed to color reduction of polyamines by reaction at elevated temperature and pressure in the presence of a hydrogenation catalyst and a hydrogen atmosphere. European Patent No. EP450709 to King et al. is said to be directed to a process for the preparation of triethylenetetramine and N-(2-aminoethyl)ethanolamine by condensation of an alkylenamine and an alkylene glycol in the presence of a condensation catalyst and a catalyst promoter at a temperature in excess of 260° C.

Russian Patent No. RU2186761, to Zagidullin, proposed synthesis of diethylenetriamine by reaction of dichloroethane with ethylenediamine. Ethylenediamine has previously been said to have been used in the synthesis of N-carboxylic acid esters as reported in U.S. Pat. No. 1,527,868, to Hartmann et al.

Japanese Patent No. 06065161 to Hara et al. is said to be directed to the synthesis of polyethylenepolyamines by reacting ethylenediamine with ethanolamine in the presence of silica-treated Nb205 supported on a carrier. Japanese Patent No. JP03047154 to Watanabe et al., is said to be directed to production of noncyclic polyethylenepolyamines by reaction of ammonia with monoethanolamine and ethylenediamine. Production of non-cyclic polyethylenepolyamines by reaction of ethylenediamine and monoethanolamine in the presence of hydrogen or a phosphorous-containing substance was said to be reported in Japanese Patent No. JP03048644. Regenerative preparation of linear polyethylenepolyamines using a phosphorous-bonded catalyst was proposed in European Patent No. EP115,138, to Larkin et al.

A process for preparation of alkyleneamines in the presence of a niobium catalyst was said to be provided in European Patent No. 256,516, to Tsutsumi et al. U.S. Pat. No. 4,584,405, to Vanderpool, reported the continuous synthesis of essentially noncyclic polyethylenepolyamines by reaction of monoethanolamine with ethylenediamine in the presence of an activated carbon catalyst under a pressure between about 500 to about 3000 psig., and at a temperature of between about 200° C. to about 400° C. Templeton, et al., reported on the preparation of linear polyethylenepolyamides asserted to result from reactions employing silica-alumina catalysts in European Patent No. EP150,558.

Production of triethylenetetramine dihydrochloride was said to have been reported in Kuhr et al., Czech Patent No. 197,093, via conversion of triethylenetetramine to crystalline tetrahydrochloride and subsequently to triethylenetetramine dihydrochloride. “A study of efficient preparation of triethylenetetramine dihydrochloride for the treatment of Wilson’s disease and hygroscopicity of its capsule,” Fujito, et al., Yakuzaigaku, 50:402-8 (1990), is also said to be directed to production of triethylenetetramine.

Preparation of triethylenetetramine salts used for the treatment of Wilson’s disease was said to be reported in “Treatment of Wilson’s Disease with Triethylene Tetramine Hydrochloride (Trientine),” Dubois, et al., J. Pediatric Gastro. & Nutrition, 10:77-81 (1990); “Preparation of Triethylenetetramine Dihydrochloride for the Treatment of Wilson’s Disease,” Dixon, et al., Lancet, 1(1775):853 (1972); “Determination of Triethylenetetramine in Plasma of Patients by High-Performance Liquid Chromatography,” Miyazaki, et al., Chem. Pharm. Bull., 38(4):1035-1038 (1990); “Preparation of and Clinical Experiences with Trien for the Treatment of Wilson’s Disease in Absolute Intolerance of D-penicillamine,” Harders, et al., Proc. Roy. Soc. Med., 70:10-12 (1977); “Tetramine cupruretic agents: A comparison in dogs,” Allen, et al., Am. J. Vet. Res., 48(1):28-30 (1987); and “Potentiometric and Spectroscopic Study of the Equilibria in the Aqueous Copper(II)-3,6-Diazaoctane-1,8-diamine System,” Laurie, et al., J.C.S. Dalton, 1882 (1976).

Preparation of Triethylenetetramine Salts by Reaction of Alcohol Solutions of Amines and acids was said to be reported in Polish Patent No. 105793, to Witek. Preparation of triethylenetetramine salts was also asserted in “Polycondensation of polyethylene polyamines with aliphatic dicarboxylic acids,” Witek, et al., Polimery, 20(3):118-119 (1975).

Baganz, H., and Peissker, H., Chem. Ber., 1957; 90:2944-2949; Haydock, D. B., and Mulholland, T. P. C., J. Chem. Soc., 1971; 2389-2395; and Rehse, K., et al., Arch. Pharm., 1994; 393-398, report on Strecker syntheses. Use of Boc and other protecting groups has been described. See, for example, Spicer, J. A. et al., Bioorganic & Medicinal Chemistry, 2002; 10: 19-29; Klenke, B. and Gilbert, I. H., J. Org. Chem., 2001; 66: 2480-2483.

FIG. 6 shows an 1H-NMR spectrum of a triethylenetetramine hydrochloride salt in D2O, as synthesized in Example 3. NMR values include a frequency of 400.13 Mhz, a 1H nucleus, number of transients is 16, points count of 32768, pulse sequence of zg30, and sweep width of 8278.15 H

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CLIP

Click to access JP17e_1.pdf

Method of purification: Dissolve Trientine Hydrochloride in water while warming, and recrystallize by addition of ethanol (99.5). Or dissolve Trientine Hydrochloride in water while warming, allow to stand after addition of activated charcoal in a cool and dark place for one night, and filter. To the filtrate add ethanol (99.5), allow to stand in a cool and dark place, and recrystallize. Dry the crystals under reduced pressure not exceeding 0.67 kPa at 409C until ethanol odor disappears.

References

  1.  “Ethyleneamines” (PDF). Huntsman. 2007.
  2. ^ Jump up to:a b Eller, K.; Henkes, E.; Rossbacher, R.; Höke, H. (2005). “Amines, Aliphatic”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001.
  3. Jump up^ Roberts, E. A.; Schilsky, M. L. (2003). “A practice guideline on Wilson disease” (pdf). Hepatology. 37 (6): 1475–1492. doi:10.1053/jhep.2003.50252. PMID 12774027.
  4. Jump up^ von Zelewsky, A. (1995). Stereochemistry of Coordination Compounds. Chichester: John Wiley. ISBN 047195599X.
  5.  Utsuno, S.; Sakai, Y.; Yoshikawa, Y.; Yamatera, H. (1985). “Three Isomers of the Trans-Diammine-[N,N′-bis(2-Aminoethyl)-1,2-Ethanediamine]-Cobalt(III) Complex Cation”. Inorganic Syntheses. 23: 79–82. doi:10.1002/9780470132548.ch16.
Triethylenetetramine
Skeletal formula of triethylenetetramine
Ball and stick model of triethylenetetramine
Spacefill model of triethylenetetramine
Names
Other names

N,N’-Bis(2-aminoethyl)ethane-1,2-diamine; TETA; Trien; Trientine (INN); Syprine (brand name)
Identifiers
3D model (Jmol)
605448
ChEBI
ChemSpider
ECHA InfoCard 100.003.591
EC Number 203-950-6
27008
KEGG
MeSH Trientine
RTECS number YE6650000
UNII
UN number 2259
Properties
C6H18N4
Molar mass 146.24 g·mol−1
Appearance Colorless liquid
Odor Fishy, ammoniacal
Density 982 mg mL−1
Melting point −34.6 °C; −30.4 °F; 238.5 K
Boiling point 266.6 °C; 511.8 °F; 539.7 K
Miscible
log P 1.985
Vapor pressure <1 Pa (at 20 °C)
1.496
Thermochemistry
376 J K−1 mol−1 (at 60 °C)
Pharmacology
A16AX12 (WHO)
Hazards
GHS pictograms The corrosion pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) The exclamation-mark pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
GHS signal word DANGER
H312, H314, H317, H412
P273, P280, P305+351+338, P310
Corrosive C
R-phrases R21, R34, R43, R52/53
S-phrases (S1/2), S26, S36/37/39, S45
Flash point 129 °C (264 °F; 402 K)
Lethal dose or concentration (LD, LC):
  • 550 mg kg−1 (dermal, rabbit)
  • 2.5 g kg−1 (oral, rat)
Related compounds
Related amines
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////////TRIENTINE, 112-24-3, 曲恩汀 , KD-034 , MK-0681, MK-681, TECZA, TETA, TJA-250, Orphan drug

NCCNCCNCCN

Cetilistat, セチリスタット


Cetilistat.svg

ChemSpider 2D Image | Cetilistat | C25H39NO3

Cetilistat, セチリスタット

  • Molecular FormulaC25H39NO3
  • Average mass401.582 Da
CAS 282526-98-1
2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one
282526-98-1 [RN]
2-Hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one
2-hexadecyl-oxy-6-methyl-4H-3,1-benzoxazin-4-one
4H-3,1-Benzoxazin-4-one, 2-(hexadecyloxy)-6-methyl
[282526-98-1]
2-(Hexadecycloxy)-6-methyl-4H-3,1-benzoxazin-4-one
ATL-962; ATL962;ATL 962
Trade Name:Oblean®
MOA:Pancreatic lipase inhibitor
Indication:Obesity
Status:Approved, 2013-09-20 JAPAN,  Japan PMDA.
Company:Norgine (Originator) , Takeda
Image result for Cetilistat
UPDATE 09.07.2021 INDIA CDSCO For the treatment of Obseity (limited to
patients with both type 2 diabetes mellitus
and dyslipidaemia, and with a BMI ≥ 25
kg/m2 inspite of dietary treatment and /or
excersise therapy)…………Cetilistat bulk and Cetilistat 120 mg tablets 

Cetilistat was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on September 20, 2013. It was developed by Norgine and Takeda, then marketed as Oblean® by Takeda in Japan.

Cetilistat is a pancreatic lipase inhibitor, and it acts in the same way as the older drug orlistat (Xenical) by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. It is usually used for the treatment of obesity (limited to patients with both type 2 diabetes mellitus and dyslipidemia, and with a BMI≥25 kg/m2 in spite of dietary treatment and/or exercise therapy).

Oblean® is available as tablet for oral use, containing 120 mg of free Cetilistat. The recommended dose is 120 mg three times a day immediately after each meal.

Cetilistat is a drug designed to treat obesity. It acts in the same way as the older drug orlistat (Xenical) by inhibitingpancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.[1]

In human trials, cetilistat was shown to produce similar weight loss to orlistat, but also produced similar side effects such as oily, loose stools, fecal incontinence, frequent bowel movements, and flatulence.[2][3] It is likely that the same precautions would apply in that absorption of fat-soluble vitamins and other fat-soluble nutrients may be inhibited, requiring vitamin supplements to be used to avoid deficiencies.

Central obesity have an important impact on the development of risk factors for coronary heart disease, including dislipidemia, glucose intolerance, insulin resistance and hypertension. These factors contribute to building cardiovascular (CV) disease as a major cause of death. The approach to obesity therapy should be designed to reduce CV risk and mortality. Diet and lifestyle changes remain the cornerstones of therapy for obesity, but the resultant weight loss is often small and long-term success is uncommon and disappointing. Drug therapy is considered for individuals with a body mass index greater than 30 kg/m2 or ranging from 25 to 30 kg/m2 if they have comorbid conditions. Antiobesity agents can be helpful to some patients in achieving and maintaining meaningful weight loss, but yet our pharmaceutical tools are of limited effectiveness considering the magnitude of the problem. At the present, only two drugs, orlistat and sibutramine, are approved for long-term treatment of obesity and promote no more than 5 to 10% of weight loss.

Rimonabant, a cannabinoid-1 receptor antagonist, was withdrawn from the market because of concerns about its safety, including risk of suicidal and seizures, although very effective in promoting clinically meaningful weight loss, reduction in waist circumference, and improvements in several metabolic risk factors, rimonabant, a cannabinoid-1 receptor antagonist was withdrawn from the market because it concerns about its safety, including risk of suicidal and seizures. Fortunately, recent fundamental insights into the neuroendocrine mechanisms regulating body weight provide an expanding list of molecular targets for novel, rationally designed antiobesity drugs. In this review, the therapeutic potential of some antiobesity molecules in the development will be analyzed based on an understanding of energy homeostasis.

Image result for CetilistatImage result for Cetilistat

Cetilistat has completed Phase 1 and 2 trials in the West and is currently in Phase 3 trials in Japan where it is partnered with Takeda.[4] Norgina BV has now acquired the full global rights to cetilistat from Alizyme after the latter went into administration.[5]

A published phase 2 trial found cetilistat significantly reduced weight with and was better tolerated than orlistat.[6

Image result for Cetilistat

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CLIP

Cetilistat (Oblean®)
Cetilistat is a selective pancreatic lipase inhibitor which was approved in Japan in September 2013
for the treatment of obesity. The drug was discovered by Alizyme PLC and later co-developed with
Takeda. Cetilistat demonstrated a lower incidence of adverse gastrointestinal events during a 12 week clinical trial, and the degree of weight loss associated with cetilistat is comparable to that of other approved antiobesity therapies.30 The most likely process-scale preparation of cetilistat is described below in Scheme. 4.31
Commercially available hexadecanol (21) was treated with phosgene in THF/toluene to give the
corresponding chloroformate (22), which was immediately subjected to commercial 2-amino-5-
methylbenzoic acid (23) in pyridine. Subsequent slow addition of methyl chloroformate at room
temperature resulted in the formation of cetilistat (IV), which was produced in 31% overall yield from
hexadecanol.31

REF FOR ABOVE ONLY

30  Kopelman, P.; Groot, G. d. H.; Rissanen, A.; Rossner, S.; Toubro, S.; Palmer, R.; Hallam, R.;
Bryson, A.; Hickling, R. I. Obesity 2010, 18, 108.
31. Hodson, H. F.; Downham, R.; Mitchell, T. J.; Carr, B. J.; Dunk, C. R.; Palmer, R. M. J. US
Patent 20030027821A1, 2003.

SYNTHESIS

Route 1

WO2000040569

AND

http://www.google.co.in/patents/US6624161

WO0040569A1 / US6656934B2.2. WO0040247A1 / US6624161B2.

Route 2

http://www.google.co.in/patents/US7396952

Carbamic ester derivatives of the general formula (1) and especially (2-carboxy-4-methylphenyl)carbamic esters of the general formula (1′)

Figure US07396952-20080708-C00004

are suitable intermediates for active pharmaceutical ingredients.

Thus, for example, hexadecyl (2-carboxy-4-methylphenyl)carbamate as compound of the formula (1′) with R═C16H33 is disclosed as an intermediate in the preparation of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one of the formula (3)

Figure US07396952-20080708-C00005

from the originally published version of WO-A 00/40569.

2-Hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one of the formula (3) is described therein as potential active ingredient for the treatment of obesity and type II diabetes.

In this originally published version of WO-A 00/40569, two synthetic routes 1 and 2 are described for preparing 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (3), each of which starts from the 5-methyl-substituted anthranilic acid (4).

In the two-stage synthetic route 1, the 5-methyl-substituted anthranilic acid (4) is reacted with hexadecyl chloroformate (5) and subsequently with methyl chloroformate to give 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (3), although the overall yield obtained is only 31%.

The one-stage synthetic route 2 with an excess of pyridine affords 2-hexadecyl-oxy-6-methyl-4H-3,1-benzoxazin-4-one (3) in an even lower yield of 15%.

Figure US07396952-20080708-C00006

The starting compound which is required for both the synthetic routes 1 and 2, the 5-methyl-substituted anthranilic acid (4), is not easily obtainable, however.

It is prepared by the method described in J. Org. Chem. 1952, 17, 141. This starts from p-toluidine, which is reacted with chloral hydrate and hydroxylamine hydrochloride. The resulting oxime is cyclized with acid catalysis, and subsequently the ring is cleaved again by oxidation under basic conditions.

Figure US07396952-20080708-C00007

The disadvantages of this synthesis are the low yields and the fact that only very low concentrations can be used. For this reason, this synthetic route is unattractive for an industrial reaction.

Further alternative routes known in principle for obtaining anthranilic acids are as follows:

J. Org. Chem. 1978, 43, 220 and Chem. Ber. 1909, 42, 430 disclose initial nitration of 3-cyanotoluene, then reduction of the nitro group and subsequent hydrolysis of the nitrile to the carboxylic acid.

Figure US07396952-20080708-C00008
A disadvantage of this synthesis is that the nitration of 3-cyanotoluene does not proceed selectively and therefore a further purification step is necessary. This requires additional effort and reduces the yield.
The synthesis which is described in J. Chem. Soc. Perkin I, 1973, 2940 and which starts from 3-toluic acid with subsequent nitration and reduction of the nitro group also has the same disadvantage.
The synthesis which is disclosed in Monatsh. Chem. 1920, 41, 155 and starts from 2,4-dimethyl-1-nitrobenzene is likewise unsuitable because oxidation of the methyl group next to the nitro group does not proceed selectively and therefore an elaborate separation of isomers is necessary.
Figure US07396952-20080708-C00009
EP-A 0 034 292 discloses a process for preparing optionally substituted anthranilic acids which includes a transition metal-catalysed carbonylation reaction with carbon monoxide to give an anthranilic acid derivative. This carbonylation reaction takes place in an aqueous reaction medium containing a trialkylamine and a catalyst formed from palladium and a tertiary phosphine. The anthranilic acid derivatives can be obtained by eliminating the protective group. The precursors employed for the carbonylation are obtained starting from optionally substituted anilines as shown in principle in the reaction scheme below:
Figure US07396952-20080708-C00010
EP-A 0 034 292 describes this reaction sequence of acetylation (a), halogenation (b), carbonylation (c) and subsequent elimination of the acetyl group (d) as affording the optionally substituted anthranilic acids in good yields (>80%). However, the introduction of the acetyl group is a disadvantage. This is necessary because the free anilines give only poor yields in transition metal-catalysed carbonylation reactions because of pronounced complexation [J. Org. Chem. 1981, 46, 4614-4617].
WO-A 97/28118 discloses a comparable process.

Because of the diverse difficulties, described above, associated with the known processes for preparing optionally substituted anthranilic acids and the yields, which are only unsatisfactory and thus limiting for the overall process, of the subsequent synthetic routes 1 and 2, the object of the present invention was to provide an improved process for preparing carbamic ester derivatives of the general formula (1).

US7396952B2.

EXAMPLES Example 1 Synthesis of hexadecyl 4-methylphenylcarbamate

Figure US07396952-20080708-C00027

91 g (375 mmol) of 1-hexadecanol were added to a solution of 50 g (375 mmol) of p-tolyl isocyanate in 50 ml of toluene, and the resulting solution was heated under reflux for 8 h. After cooling to room temperature and stirring at this temperature for 12 h, the precipitated solid was filtered off. The colourless solid was washed twice with 10 ml of toluene each time and then dried in vacuo. 80 g (213 mmol, 57%) of the desired carbamate were obtained in the form of a colourless solid with a melting point of 75° C. The melting point agreed with literature data (75-76° C., Microchem J. 1962, 6, 179).

1H-NMR (CDCl3, 400 MHz): δ=0.88 ppm (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 26 H), 1.66 (sext, J=6.9 Hz, 2H), 2.30 (s, 3H), 4.14 (t, J=6.9 Hz, 2H), 6.53 (br, 1 H), 7.10 (d, J=7.8 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H). Elemental Analysis Showed: Calculated: C 76.8%, H 11.0%, N 3.7% Found: C 76.9%, H 11.2%, N 3.7%.

Example 2 Synthesis of hexadecyl (2-bromo-4-methylphenyl)carbamate

Figure US07396952-20080708-C00028

19 g (119 mmol) of bromine were added dropwise to a solution of 45 g (119 mmol) of the carbamate in 225 ml (235 g) of glacial acetic acid at room temperature over the course of 1 h, and then the resulting solution was stirred at room temperature for 1 h. After addition of a further 25 ml (26 g, 437 mmol) of glacial acetic acid, the reaction mixture was stirred at 40° C. for 5 h and then cooled to room temperature. The precipitated solid was filtered off and washed with 20 ml of glacial acetic acid. Drying in vacuo resulted in 40 g (88 mmol, 74%) of the desired bromo compound in the form of a colourless solid with a melting point of 57° C.

1H-NMR (CDCl3, 400 MHz): δ=0.93 ppm (t, J=6.6 Hz, 3H), 1.25-1.43 (m, 26 H), 1.73 (sext, J=6.8 Hz, 2H), 2.33 (s, 3H), 4.21 (t, J=6.7 Hz, 2H), 7.04 (br, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 8.02 (d, J=8.3 Hz, 1H). 13C-NMR (CDCl3, 100 MHz): δ=14.2 ppm, 20.4, 22.7. 25.9, 29.0, 29.3, 29.4, 29.6 (2C), 29.7 (2C), 29.8 (4C), 32.0, 65.7, 112.5, 120.3, 129.0, 132.5, 133.5, 134.1, 153.5. Elemental Analysis Showed: Calculated: C 63.4%, H 8.9%, N 3.1% Found: C 63.6%, H 8.9%, N 3.1%.

Example 3 Synthesis of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid

Figure US07396952-20080708-C00029

217.5 g (478.5 mmol) of hexadecyl (2-bromo-4-methylphenyl)carbamate, 0.5 g (0.7 mmol) of bis(triphenylphosphine)palladium dichloride and 2.5 g (9.3 mmol) of triphenylphosphine were introduced into an autoclave. The autoclave was closed, flushed with nitrogen and an oxygen-free solution of 78.1 g (565.3 mmol) of potassium carbonate in 400 ml of water is added. The autoclave is evacuated and then 2 bar of carbon monoxide are injected and heated to 115° C. The pressure is subsequently adjusted to 8 bar. After CO uptake ceases, the mixture is cooled to RT and 200 ml of toluene are added. The pH is adjusted to 2 with 2M aqueous HCl solution, and the organic phase is separated off. The aqueous phase is extracted anew with 100 ml of toluene, the organic phase is separated off, and the two toluene extracts are combined. Removal of the solvent in vacuo results in 154.9 g (369.2 mmol, 77%) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid in the form of a pale yellow-coloured solid.

1H-NMR (CDCl3, 400 MHz): δ=0.88 ppm (t, J=6.7 Hz, 3H), 1.24-1.40 (m, 26 H), 1.70 (sext, J=6.8 Hz, 2H), 2.33 (s, 3H), 4.17 (t, J=6.8 Hz, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.90 (s, 1H), 8.35 (d, J=8.6 Hz, 1H). Signal of the NH proton not identifiable.13C-NMR (CDCl3, 100 MHz): δ=14.1 ppm, 20.5, 22.7. 25.9, 29.0, 29.3, 29.4, 29.6 (2 C), 29.7 (6 C), 32.0, 65.5, 113.6, 119.0, 131.1, 131.8, 136.3, 140.1, 153.9, 172.5.

Example 4 Synthesis of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one

Figure US07396952-20080708-C00030

4.0 g (10.0 mmol) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid are introduced into 20 ml of pyridine at 0° C. under a nitrogen atmosphere, and 4.93 g (45.4 mmol) of ethyl chloroformate are added dropwise to the resulting solution at 0° C. over the course of 20 min. After the reaction mixture has been stirred at 0° C. for 1 h and at room temperature for 2 h it is added to 30 ml of ice-water. The solid is filtered off and dried in vacuo. 3.3 g (8.2 mmol, 82%) of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one are obtained in the form of a pale yellow coloured solid with a melting point of 67° C. (literature: 72-73° C., WO 00/40569).

1H-NMR (CDCl3, 400 MHz): δ=0.86 ppm (t, J=6.6 Hz, 3H), 1.24-1.42 (m, 26 H), 1.75-1.82 (m, 2H), 2.40 (s, 3H), 4.41 (t, J=6.8 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.2, 1.9 Hz, 1H), 7.90 (d, J=0.9 Hz, 1H).

The 1H-NMR data agree with the literature data from WO-A 00/40569.

Patent

https://www.google.com/patents/CN104341370A?cl=en

cetirizine orlistat (2-methyl-6-firing sixteen -4H-3, 1- benzo ah winded -4- Korea, cetilistat) is a long-acting Alizyme developed and potent specific gastrointestinal lipase inhibitor, with the active serine site of the gastric and intestinal lumen gastric lipase and lipase membrane forms a covalent bond to inactivate the enzyme, and to reduce calorie intake, weight control therapeutic effect. The biggest advantage of the drug is not acting on the nervous system, does not affect other activity in the gastrointestinal tract, it is more secure than existing similar drugs orlistat. Its structural formula is as follows:

Figure CN104341370AD00061

West Division for the benefit of his synthesis and intermediates have been described in U.S. Patent US2007232825 and US2003027821, domestic literature orlistat no cetirizine synthesis of relevant reports.

U.S. Patent US2007232825 2-amino-5-methyl-benzoic acid starting material, direct and vilify chloroformate cetyl alcohol vinegar into the ring, get cetirizine orlistat. The reaction byproducts and more difficult W purification needs over baby gel column, resulting in a low yield, suitable for mass industrialization. Directions are as follows:

Figure CN104341370AD00062

Patent US2003027821 W toluene different acid vinegar as raw material to produce amino acid vinegar intermediate chloroformate, cetyl alcohol and vinegar reaction, after the desert generation essays glycosylation chloroformate caprolactone ring closure to give cetirizine orlistat. This method requires a great deal of glacial acetic acid, the presence of H waste discharge more harsh reaction conditions, equipment requirements, is not conducive to industrial production and other defects.

Figure CN104341370AD00063

The present invention is a W under the technical program realization:

Figure CN104341370AD00064
Figure CN104341370AD00065
Figure CN104341370AD00066
Figure CN104341370AD00071

Figure CN104341370AD00072

Figure CN104341370AD00091

Figure CN104341370AD00116

The following combination of embodiments of the present invention will be further described below.

(Sixteen essays firing oxygen-amino) -5- Preparation of 2-methyl benzoate desert vinegar; [0041] Example 1

Figure CN104341370AD00101

4. 9g H phosgene will be added to 50 blood dichloromethane firing, the temperature was lowered to OC, a solution of 2-amino-5 Desert benzoic acid methyl ester (5g) and H hexylamine (13.8 blood) dichloro A firing (20 blood) solution, the addition was complete OC to maintain 15min, warmed to room temperature the reaction mix of football.

Figure CN104341370AD00102

[0042] The 5. 26g cetyl alcohol was added to the reaction solution at room temperature the reaction of. After completion of the reaction, filtered and the filtrate was concentrated in vacuo spin dry, dry methanol residue fight starched coating, filtration, the filter cake is dried to constant weight. To give a white solid powder 9. Ig, namely 2- (sixteen essays firing oxygen-ylamino) -5-benzoic acid methyl ester desert; Yield; 85%.

2- (grilled oxygen sixteen essays) -5-methyl-benzoic acid methyl ester prepared; [0043] Example 2

Figure CN104341370AD00111

Under nitrogen blanket IOg 2- (sixteen grilled oxygen essays) -5- desert benzoic acid methyl ester was dissolved in 1,4-dioxane (50mL) and water Qiao blood), and Ilg anhydrous carbonate Bell, 1.44g methacrylic acid test, 0. 731g Pd (dppf) 2Cl2, the mixture at 105C for 3 hours. Completion of the reaction, cool down, filtered and the filtrate spin dry, the residue of anhydrous methanol wash coating, the filter cake dried to give a gray solid 6. 5g, is 2- (xvi grilled oxygen essays) -5-methyl benzoic acid methyl ester in 75% yield.

2- (grilled oxygen sixteen essays) -5-methyl-benzoic acid; [0044] Example 3

Figure CN104341370AD00112

The 7g 2- (sixteen grilled oxygen essays) -5-methyl-benzoic acid methyl ester was added to 35mL tetraammine clever furans and 7mL water mixture, adding ammonia oxidation in 20. Ig, 6 (TC reaction of the reaction is completed, the reaction mixture was concentrated, the residue was added 70mL of ice water, 6M hydrochloric suppression of 7, the filter cake was dried to constant weight to give a gray solid 6. 2g, namely 2- (sixteen firing oxygen-ylamino essays ) -5-methyl-benzoic acid, yield 92%.

Preparation of 2-methyl-6-firing sixteen -4H-3, 1- benzo Lai ah winded -4- (cetirizine Division him); 4 [0045] Example

Figure CN104341370AD00113

The 66g 2- (XVI essays firing oxo-ylamino) -5-methylbenzoic acid in 330mL of information coincidence floating in an ice bath, was slowly added dropwise 45mL chloroformate caprolactone, after the addition was complete, naturally rise to room temperature The reaction of. After completion of the reaction, the reaction solution was poured into 700mL ice water, filtered, and the filter cake was dried to constant weight to give a gray solid 56g, that is, sixteen firing-6-methyl-2- -4H-3, 1- benzo Lai ah winded -4- (cetirizine orlistat), a yield of 85%. Mass spectrum shown in Figure 2, ESI-MS〇b / z): 402 [M + Tin +; X- ray diffraction as shown in (3 consistent with the data reported in FIG patent US2012101090), analyzed as shown in Table 1, Figure 1 FIG. 2 W and W Table 1 confirm that the product was obtained as cetirizine orlistat.

[0046] Table 1

Figure CN104341370AD00114
Figure CN104341370AD00115
Figure CN104341370AD00116
Figure CN104341370AD00117
Figure CN104341370AD00118
Figure CN104341370AD00121
CLIP
CJPH  2015, Vol. 46 Issue (09): 946-947    DOI: 10.16522/j.cnki.cjph.2015.09.003
Synthesis of Cetilistat
1. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050; 2. Beijing Union Pharmaceutical Factory, Beijing 102600
Cetilistat was synthesized from 2-amino-5-methylbenzoic acid and cetyl chloroformate via acylation to give 2-[[(hexadecyloxy)carbonyl]amino]-5-methylbenzoic acid, which was subjected to intramolecular dehydrationcyclization in the presence of POCl3 with an overall yield of 90% and purity over 99%. This one-pot method was simple and suitable for large-scale application.

CLIP

http://amogsobgy.com/downloads/AkumentisChechwt/CurrOpinInvestigDrugs.pdf

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Cetilistat, a new lipase inhibitor for the treatment of obesity – AMOGS

amogsobgy.com/downloads/AkumentisChechwt/CurrOpinInvestigDrugs.pdf

by R Padwal – ‎Cited by 26 – ‎Related articles

clinical trials, and the above-mentioned lipase inhibitor cetilistat, which is the focus of this review.Synthesis and SAR. Cetilistat (2-hexadecyloxy-6-methyl-4H-3 …

PATENT

SEE

http://www.google.co.in/patents/WO1999016758A1?cl=en

CLIP

Taken from Ayurajan

str1

https://ayurajan.blogspot.in/2016_01_01_archive.html

Cetilistat | Inhibitor of Gastrointestinal Lipases | Inhibitor of Pancreatic Lipases | Anti-Obesity Drug

Cetilistat [2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one] is a novel highly lipophilic benzoxazinone that inhibits gastrointestinal (GI) and pancreatic lipases, and is chemically distinct from Orlistat [1].

 
Cetilistat: 2D and 3D Structure

Pancreatic lipase is the enzyme that breaks down triglycerides in the intestine. Inhibition of this enzyme ensures that triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.

In Phase I clinical trials in healthy volunteers, Cetilistat increased faecal fat excretion and was well tolerated. Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that Cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

The NDA submission is based on the results of three Phase 3 clinical trials in obese patients with type 2 diabetes and dyslipidemia: a 52-week placebo-controlled, double-blind study to evaluate the efficacy and safety, and two open-label studies to evaluate safety, 24-week and 52-week respectively. The results of the 52-week placebo-controlled, double-blind study demonstrate that Cetilistat 120mg three times daily is superior to placebo in the primary endpoint, with a mean reduction in body weight from baseline of -2.776% with Cetilistat versus -1.103% with placebo (p=0.0020). Greater reduction in HbA1c and low-density lipoprotein cholesterol were also observed in patients treated with Cetilistat, compared to placebo. In all these three studies, Cetilistat showed a good safety profile and was well tolerated.

Cetilistat was approved in Japan in September 2013 for the treatment of obesity. Cetilistat (Tradename: Oblean) is approved for a dosage of 120 mg three times a day for the treatment of obesity with complications.

The drug was discovered by UK based Alizyme PLC and in 2003 Takeda acquired the rights for development and commercialisation for Japan. Norgine acquired all rights to the product from Alizyme in October 2009 [3].

Cetilistat Synthesis

US20030027821A1: It appears to be the industrial process. The yields are in the range of 30-35%.

Identification:

 
1H NMR (Estimated) for Cetilistat

Experimental: 1H-NMR δH (400 MHz, CDCl3) 0.87 (3H, t, J 6.8, CH2CH3), 1.24-1.45 (26H, m, 13×CH2), 1.75-1.83 (2H, m, OCH2CH2), 2.41 (3H, s, ArCH3), 4.41 (2H, t, J 6.7, OCH2), 7.3 (1H, d, J 8.3, ArH), 7.51 (1H, dd, J 8.5, 2.0, ArH), 7.90 (1H, d, J 1.1, ArH); m/z (ES+) 402 (MH+); M Pt. 72-73° C.

Sideeffects: The most frequently experienced adverse events were those involving the gastrointestinal (GI) tract. The proportion of patients and the total number of GI adverse events reported in each of the active treatment groups were higher compared to the placebo group. However, GI adverse events were predominantly mild to moderate in intensity, with no evidence of a dose relationship.

The most frequently reported GI-related adverse events included increased defecation, soft stools, abdominal pain, flatulence and fatty/oily stool, which were all reported more frequently in the treatment arms compared to the placebo arm.

Faecal incontinence, flatus with discharge, oily evacuation and oily spotting occurred in only 1.8-2.8% of subjects in the active treatment arms and was not dose-related. Adverse events generally occurred on only one occasion and resolved rapidly.

Serum vitamin D, vitamin E and β-carotene levels were decreased significantly in the Cetilistat treatment arms. Generally, these reductions in vitamin levels did not take the levels outside the normal range and none required the use of vitamin supplements.

References FOR ABOVE ONLY

  1. Kopelman, P.; et. al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes (Lond) 2007, 31(3), 494-499.
  2. Hodson, H.; et. al. 2-Oxy-benzoxazinone derivatives for the treatment of obesity.US20030027821A1
  3. Cetilistat Approval (here).

Image result for Cetilistat

CN1359378A * Jan 6, 2000 Jul 17, 2002 阿利茨默治疗学有限公司 2-oxy-benzoxazine derivatives for the treatment of obesity
CN1785967A * Dec 12, 2005 Jun 14, 2006 兰爱克谢斯德国有限责任公司 Process for the preparation of carbamic acid derivatives
CN103936687A * Mar 24, 2014 Jul 23, 2014 重庆东得医药科技有限公司 Method for preparing cetilistat
WO2013166037A1 * Apr 30, 2013 Nov 7, 2013 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of eye disorders
PATENT 
Cited Patent Filing date Publication date Applicant Title
US20030013707 6 Jul 2001 16 Jan 2003 Hodson Harold Francis 2-amino-benzoxazinone derivatives for the treatment of obesity
EP0034292A2 31 Jan 1981 26 Aug 1981 F. HOFFMANN-LA ROCHE &amp; CO. Aktiengesellschaft Process for the preparation of anthranilic acid derivatives
WO1997028118A1 30 Jan 1997 7 Aug 1997 Hoechst Celanese Corporation Process for preparing anthranilic acids
Reference
1 Chem. Ber. 1909, 42, 430.
2 J. Chem. Soc. Perkin I, 1973, 2940; Peter H. Gore et al. Friedel-Crafts Reactions, Part XXV.<SUP>1 </SUP>Acetylation and Benzoylation of Iodobenzene and of o-, m-, and p- Iodotoluenes.
3 J. Org. Chem. 1952, 17, 141 B. R. Baker et al.; “An Antimalarial Alkaloid From Hydrangea, XIV, Synthesis of 5- ,6-,7-, and 8-Monosubstituted Derivatives“.
4 J. Org. Chem. 1978, vol. 43, No. 2, 220 T.H. Fisher et al.; “Kinetic Study of the N-Bromosuccin-imide Bromination of Some 4-Substituted 3-Cyanotoluenes“.
5 J. Org. Chem. 1981, 46, 4614-4617 Donald Valentine, Jr. et al; “Practical, Catalytic Synthesis of Anthranilic Acids“.
6 Monatsch. Chem. 1920, 41, 155.
7 Thomas G. Back et al.: “Conjugate Additions of o-Iodoanilines and Methyl Anthranilates to Acetylenic Sulfones. A New Route to Quinolones Including First Syntheses of Two Alkaloids from the Medical Herb Ruta chalepensis” Journal of Organic Chemistry., Bd. 68, 2003, Seiten 2223-2233, XP002371555 USAmerican Chemical Society, Easton. Seite 2227, Spalte 1, Reaktionsschema 4 und Spalte 2, Zeile 8-Zeile 9; Seite 2231, Spalte 2, Zeile 43-Zeile 54.
8 * Yadav et al., New Journal of Chemistry (2000), 24(8), 571-573.
Citing Patent Filing date Publication date Applicant Title
US8883780 22 Apr 2010 11 Nov 2014 Norgine B.V. Crystal of a benzoxazinone compound

References

  1.  Yamada Y, Kato T, Ogino H, Ashina S, Kato K (2008). “Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats”. Hormone and Metabolic Research. 40 (8): 539–43. doi:10.1055/s-2008-1076699. PMID 18500680.
  2.  Kopelman, P; Bryson, A; Hickling, R; Rissanen, A; Rossner, S; Toubro, S; Valensi, P (2007). “Cetilistat (ATL-962), a novel lipase inhibitor: A 12-week randomized, placebo-controlled study of weight reduction in obese patients”. International journal of obesity (2005). 31 (3): 494–9. doi:10.1038/sj.ijo.0803446. PMID 16953261.
  3.  Padwal, R (2008). “Cetilistat, a new lipase inhibitor for the treatment of obesity”. Current opinion in investigational drugs (London, England : 2000). 9 (4): 414–21. PMID 18393108.
  4.  http://www.alizyme.com/alizyme/products/cetilistat/ Archived January 7, 2009, at the Wayback Machine.
  5.  Norgine acquires cetilistat
  6.  “Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical).”. Obesity. 18: 108–15. Jan 2010. doi:10.1038/oby.2009.155. PMID 19461584.
  7. Japan PMDA.

セチリスタット
Cetilistat

C25H39NO3 : 401.58
[282526-98-1]

Cetilistat
Cetilistat.svg
Systematic (IUPAC) name
2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one
Identifiers
CAS Number 282526-98-1 Yes
ATC code none
PubChem CID 9952916
ChemSpider 8128526 
UNII LC5G1JUA39 Yes
KEGG D09208 Yes
ChEMBL CHEMBL2103825 
Chemical data
Formula C25H39NO3
Molar mass 401.582 g/mol

///////////////Cetilistat, ATL-962, ATL962, ATL 962, 2013-09-20, JAPAN, APPROVED,  Japan PMDA, 282526-98-1, セチリスタット

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Annual Reports in Medicinal Chemistry

2014 – ‎Science

… versus vehicle-treated mice.34Noteworthy in the multistep synthesis of canagliflozin is …CETILISTAT (ANTIOBESITY)43–52 Class: Pancreatic lipase inhibitor …

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