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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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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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Roxadustat, ASP 1517, FG 4592


STR1

ROXADUSTAT

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

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

Fibrogen, Inc.

THERAPEUTIC CLAIM, Treatment of anemia

Roxadustat nonproprietary drug name

CHEMICAL NAMES

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

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

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

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

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

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

Most Recent Events

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

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

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

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

STR1

PATENT

CN 104892509

MACHINE TRANSLATED

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

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

Figure CN104892509AD00031

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

Figure CN104892509AD00032

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

Figure CN104892509AD00041

n PhO. eight XOOH

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

Figure CN104892509AD00042

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

Figure CN104892509AD00052

Example One:

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

Example Two:

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

 Example Three:

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

 Example Four:

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

Example five:

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

 Example VI:

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

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

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

PATENT

WO 2014014835

Example 10. Preparation of Compound A

a) 5-Phenoxyphthalide

Figure imgf000056_0001

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

Figure imgf000056_0002

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

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

Figure imgf000057_0001

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

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

(lb)

Figure imgf000057_0002

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

Figure imgf000058_0001

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

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

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

Figure imgf000058_0002

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

(Compound A)

Figure imgf000059_0001

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

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

SYNTHESIS……..

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

FG-4592 - zliming2004 - zliming2004的博客

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

FG-4592 - zliming2004 - zliming2004的博客

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

FG-4592 - zliming2004 - zliming2004的博客

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

CLIPS

SAN FRANCISCO, Nov 12, 2013 (BUSINESS WIRE) — FibroGen, Inc. (FibroGen), today announced that data from a China-based Phase 2 study of roxadustat (FG-4592), a first-in-class oral compound in late stage development for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), were presented in an oral session at the 2013 American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia.
Roxadustat is an orally administered, small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. HIF is a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced and iron is incorporated into hemoglobin (Hb).
The randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of roxadustat in the correction of anemia in patients (N=91) with chronic kidney disease who had not received dialysis treatment, were not receiving erythropoiesis-stimulating agents (ESAs), and had Hb levels less than 10 g/dL. The correction study randomized patients 2:1 between roxadustat and placebo for 8 weeks of dosing, and included a low-dose cohort (n=30) and high-dose cohort (n=31). Intravenous (IV) iron was not allowed. The study also evaluated iron utilization, changes in serum lipids, and other biomarkers during treatment with roxadustat.
Data from this study suggest that roxadustat effectively corrected hemoglobin levels in anemic CKD patients in a dose-dependent manner as compared to placebo, and did so in the absence of IV iron supplementation regardless of degree of iron repletion at baseline. At the end of the 8-week treatment period, subjects showed mean maximum Hb increases from baseline of 2.6 g/dL in the high dose cohort and 1.8 g/dL in the low dose cohort, as compared to 0.7 g/dL in the placebo group (p < 0.0001) from mean baseline Hb of 8.8 g/dL, 8.8 g/dL, and 8.9 g/dL in the high dose, low dose, and placebo groups, respectively. 87% of patients in the high-dose cohort, 80% of patients in the low-dose cohort, and 23% of patients in the placebo group experienced a hemoglobin increase of 1 g/dL or greater from baseline (p < 0.0001). Similarly, 71% of patients in the high-dose cohort, 50% of patients in the low-dose cohort, and 3% of patients in the placebo group achieved target hemoglobin of 11 g/dL or greater (p < 0.0001). Serum iron levels remained stable in subjects randomized to roxadustat while the subjects underwent brisk erythropoiesis.
Study data also suggest that roxadustat may lower cholesterol. Dyslipidemia is highly prevalent in chronic kidney disease patients and a major cardiovascular risk factor in this population. Patients treated with roxadustat experienced a statistically significant reduction in total cholesterol (p <0.0001) and low-density lipoprotein (LDL) cholesterol (p <0.0001) at the end of the treatment period. The relative proportion of high density lipoprotein (HDL) cholesterol to LDL cholesterol increased significantly (p <0.02). Overall LDL cholesterol levels declined by a mean of 26% and median of 23% from a mean baseline value of 103 mg/dL.
Roxadustat was well tolerated by patients in the study with incidence of adverse events similar across all groups. In contrast to the exacerbation of hypertension observed in studies in which patients received currently available ESA therapies, subjects who received roxadustat in the present study showed small decreases in blood pressure that were similar to blood pressure changes in the placebo group. No cardiovascular serious adverse events were reported in patients treated with roxadustat.
The efficacy and safety of roxadustat are currently being investigated in a global pivotal Phase 3 development program.
“There is a global need for effective, safe, and accessible anemia therapies,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “Side effects associated with current treatments include exposure to supra-physiological levels of erythropoietin and depletion of iron stores. Preliminary clinical findings show that oral administration of roxadustat (FG-4592) is able to correct anemia and maintain hemoglobin levels in patients with chronic kidney disease, to do so with peak erythropoietin levels within physiological range, and to achieve these effects without the administration of intravenous iron. These results suggest roxadustat, as an oral agent, has the potential to overcome the treatment barriers and inconveniences of current ESA therapies, including administration by injection and IV iron supplementation, in treating anemia in CKD patients.”
About Chronic Kidney Disease (CKD) and Anemia
Diabetes, high blood pressure, and other conditions can cause significant damage to the kidneys. If left untreated, those can result in chronic kidney disease and progress to kidney failure. Such deterioration can lead to patients needing a kidney transplant or being placed on dialysis to remove excess fluid and toxins that build up in the body. The progression of CKD also increases the prevalence of anemia, a condition associated with having fewer of the red blood cells that carry oxygen through the body, and/or lower levels of hemoglobin, the protein that enables red blood cells to carry oxygen. As hemoglobin falls, the lower oxygen-carrying capacity of an anemic patients’ blood results in various symptoms including fatigue, loss of energy, breathlessness, and angina. Anemia in CKD patients has been associated with increased hospitalization rates, increased mortality, and reduced quality of life.
Chronic kidney disease is a worldwide critical healthcare problem that affects millions of people and drives significant healthcare cost. In the US, prevalence of CKD has increased dramatically in the past 20 years, from 10 percent of the adult population (or approximately 20 million U.S. adults) as stated in the National Health and Nutrition Evaluation Survey (NHANES) 1988-1994, to 15 percent (or approximately 30 million U.S. adults) in NHANES 2003-2006. In 2009, total Medicare costs for CKD patients were $34 billion. China has an estimated 145 million CKD patients, or approximately five times the number of CKD patients in the U.S. (Lancet April 2012).
About Roxadustat / FG-4592
Roxadustat (FG-4592) is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity, in development for the treatment of anemia in patients with chronic kidney disease (CKD). HIF is a protein transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis (the process by which red blood cells are produced) and other protective pathways. Roxadustat has been shown to correct anemia and maintain hemoglobin levels without the need for supplementation with intravenous iron in CKD patients not yet receiving dialysis and in end-stage renal disease patients receiving dialysis. An Independent Data Monitoring Committee has found no signals or trends to date to suggest that treatment with roxadustat is associated with increased risk of cardiovascular events, thrombosis, or increases in blood pressure requiring initiation or intensification of antihypertensive medications.
About FibroGen
FibroGen is a privately-held biotechnology company focused on the discovery, development, and commercialization of therapeutic agents for treatment of fibrosis, anemia, cancer, and other serious unmet medical needs. FibroGen’s FG-3019 monoclonal antibody is in clinical development for treatment of idiopathic pulmonary fibrosis and other proliferative diseases, including pancreatic cancer and liver fibrosis. Roxadustat (FG-4592), FibroGen’s small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, is currently in clinical development for the treatment of anemia. FibroGen is also currently pursuing the use of proprietary recombinant human type III collagens in synthetic corneas for treatment of corneal blindness. For more information please visit: www.fibrogen.com .

References

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

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

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

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

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

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

//////////ASP1517,  ASP 1517,  ASP-1517,  FG-4592,  FG 4592,  FG4592,  Roxadustat, PHASE 3, ASTELLAS, FibroGen, 808118-40-3
O=C(O)CNC(C1=C(O)C2=C(C(C)=N1)C=C(OC3=CC=CC=C3)C=C2)=O

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

FG-4592

FG-4592 - zliming2004 - zliming2004的博客

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

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

Phase Organization ConditionPhase IIIAstellas Pharma
AstraZeneca
FibroGenAnemia, renal failure

FG-4592 - zliming2004 - zliming2004的博客

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

FG-4592 - zliming2004 - zliming2004的博客

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

FG-4592 - zliming2004 - zliming2004的博客

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

EP 1644336
US 8278325
JP 2006527200
JP 2010111697
CN 102977015
US 2014343094
CN 102977016
US 7323475
US 8765956
US 2013310565
CN 103145616
US 2013178417
CN 102718708
WO 2004108681
US 2004254215
JP 2011148810
EP 2357175
US 8017625
US 2012029011
US 8916585

Drug Substances
WO 2013013609
EP 2734504
CN 104024227
US 2015031721
FG-4592 - zliming2004 - zliming2004的博客

Polymorphs
Drug Substances
WO 2014014834
CN 103435546

Synthesis
Synthesis Intermediates
CN 103539735
US 2014024676
WO 2014014835
US 2014303202
US 2015038529
EP 2872488

Drug Substances
Polymorphs
US 2014024675
US 8883823
KR 2015058147
US 2015175550

Polymorphs
Drug Substances
EP 1644336
US 8278325
JP 2006527200
JP 2010111697
CN 102977015
US 2014343094
CN 102977016
US 7323475
US 8765956
US 2013310565
CN 103145616
US 2013178417
CN 102718708
WO 2004108681
US 2004254215
JP 2011148810
EP 2357175
US 8017625
US 2012029011
US 8916585

Product patent

WO 2004108681

https://patents.google.com/patent/WO2004108681A1/pt

WO 2013013609

https://patents.google.com/patent/WO2013013609A1

polymorph scan

[(4-Hydroxy- 1 -methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino] -acetic acid (hereinafter, Compound A) is a potent inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase, as described in U.S. Patent No. 7,323,475. HIF prolyl hydroxylase inhibitors are useful for increasing the stability and/or activity of HIF, and useful for, inter alia, treating and preventing disorders associated with HIF, including anemia, ischemia, and hypoxia.

Innovator

WO2004108681

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004108681

Example D-81
e) [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid

[0604] Synthesized from [(4-benzyloxy- l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid benzyl ester in analogy to Example D-78 d); MS-(-)-ion: M-l = 351.1.

Example D-78
d) [(4-Hydroxy-l-methoxymethyl-isoquinoline-3-carbonyl)-amino]-acetic acid [0590] A mixture of [(4-benzyloxy- 1 -methoxymethyl-isoquinoline-3 -carbonyl)-amino] -acetic acid benzyl ester (134 mg, 0.285 mmol), Pd/C (100 mg, 10 wt% Pd), EtOAc (10 ml) and MeOH (50 ml) was stirred under a Hj-atmosphere at ambient pressure and temperature for 18 h. Then the mixture was filtered through a pad of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a tan solid (74 mg); MS-(-)-ion: M-l = 289.2

WO 2014014835

https://patents.google.com/patent/WO2014014835A2

Fibrogen, Inc.

Figure imgf000009_0001

Compound A.

In one embodiment, the pharmaceutical composition comprises a compound selected from the group consisting of: Compound A Form A, Compound A Form B, Compound A Form C, Compound A Form D, Compound A sodium salt, Compound A L-arginine salt, Compound A L-lysine salt, Compound A ethanolamine salt, Compound A diethanolamine salt, Compound A tromethamine salt, amorphous Compound A, and Compound A potassium salt, as described generally above, and at least one pharmaceutically acceptable excipient.

Solid Forms of Compound A

[0073] As described generally above, the present disclosure provides solid forms of [(4- hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino] -acetic acid (Compound A).

[0074] Compound A Form A is characterized by its X-ray powder diffractogram that comprises peaks at 8.5, 16.2, and 27.4 °2Θ ± 0.2 °2Θ. The diffractogram comprises additional peaks at 12.8, 21.6, and 22.9 °2Θ ± 0.2 °2Θ. Form A also is characterized by its full X-ray powder diffractogram as substantially shown in Figure 1.

[0075] In some embodiments, Form A is characterized by its differential scanning calorimetry (DSC) curve that comprises an endotherm at about 223 °C. Form A also is characterized by its full DSC curve as substantially as shown in Figure 2.

[0076] Compound A Form B is characterized by its X-ray powder diffractogram that comprises peaks at 4.2, 8.3, and 16.6 °2Θ ± 0.2 °2Θ. The diffractogram comprises additional peaks at 12.5, 14.1, and 17.4 °2Θ ± 0.2 °2Θ. Form B also is characterized by its full X-ray powder

diffractogram as substantially shown in Figure 3.

[0077] In some embodiments, Form B is characterized by its differential scanning calorimetry (DSC) curve that comprises an endotherm at about 222 °C. Form B also is characterized by its full DSC curve as substantially as shown in Figure 4.

[0078] Compound A Form C is characterized by its X-ray powder diffractogram that comprises peaks at 4.5, 13.7, and 16.4 °2Θ ± 0.2 °2Θ. The diffractogram comprises additional peaks at 15.4, 15.5, and 20.6 °2Θ ± 0.2 °2Θ. Form C also is characterized by its full X-ray powder diffractogram as substantially shown in Figure 5.

[0079] In some embodiments, Form C is characterized by its differential scanning calorimetry (DSC) curve that comprises an endotherm at about 222 °C. Form C also is characterized by its full DSC curve as substantially as shown in Figure 6.

[0080] Compound A Form D is characterized by its X-ray powder diffractogram that comprises peaks at 8.4, 8.5, and 16.8 °2Θ ± 0.2 °2Θ. The diffractogram comprises additional peaks at 4.2, 12.6, and 28.4 °2Θ ± 0.2 °2Θ. Form D also is characterized by its full X-ray powder diffractogram as substantially shown in Figure 7. [0081] In some embodiments, Form D is characterized by its differential scanning calorimetry (DSC) curve that comprises an endotherm at about 222 °C. Form D also is characterized by its full DSC curve as substantially as shown in Figure 8.

Example 10. Preparation of Compound A

a) 5-Phenoxyphthalide

Figure imgf000056_0001

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

Figure imgf000056_0002

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

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

Figure imgf000057_0001

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

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

(lb)

Figure imgf000057_0002

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

Figure imgf000058_0001

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

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

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

Figure imgf000058_0002

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

(Compound A)

Figure imgf000059_0001

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

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

[0210] The biological activity of the solid forms provided herein may be assessed using any conventionally known method. In particular embodiments, cells derived from animal tissues, preferably human tissues, capable of expressing erythropoietin when stimulated by compounds of the invention are cultured for the in vitro production of endogenous proteins. Cells contemplated for use in such methods include, but are not limited to, cells derived from hepatic, hematopoietic, renal, and neural tissues.

[0211] Cell culture techniques are generally available in the art and include any method that maintains cell viability and facilitates expression of endogenous proteins. Cells are typically cultured in a growth medium optimized for cell growth, viability, and protein production. Cells may be in suspension or attached to a substrate, and medium may be supplied in batch feed or continuous flow-through regimens. Compounds of the invention are added to the culture medium at levels that stimulate erythropoietin production without compromising cell viability. Erythropoietin produced by the cells is secreted into the culture medium. The medium is then collected and the erythropoietin is purified using methods known to those of skill in the art. (See, e.g., Lai et al. (1987) U.S. Pat. No. 4,667,016; and Egrie (1985) U.S. Pat. No. 4,558,006.)

PATENT

https://patents.google.com/patent/CN104892509A/en

Connaught orlistat (Roxadustat, I) has the chemical name: N_ [(4- hydroxy-l-methyl-3-isoquinolinyl) carbonyl] glycine, having the formula:

[0004]

Figure CN104892509AD00031

[0005] The originator’s International Patent W02004108681 provides a Connaught orlistat prepared from the intermediates and orlistat Connaught intermediate synthetic route:

[0006]

Figure CN104892509AD00032

[0007] Zhejiang International Patent W02013013609 Beida’s preparation and acylation of the intermediate core is further optimized, which is a synthetic route:

[0008]

Figure CN104892509AD00041

n PhO. eight XOOH

[0009] The originator’s International Patent W02014014834 and W02014014835 also provides another synthetic route Division Connaught his prepared:

[0010]

Figure CN104892509AD00042

[0011] 

Figure CN104892509AD00052

PATENT

https://patents.google.com/patent/US9617218B2/en

PATENT

WO 2013013609

https://patents.google.com/patent/WO2013013609A1

Zhejiang Beta Pharma Incorporation

The present invention relates to approximately pure crystalline polymorphs, wherein these polymorphs are the polymorphs of the compound of Formula I, and/or a hydrate thereof, and/or a solvate thereof.

Figure imgf000003_0001

Formula I .

The compound of Formula I of the present invention exists in one or more crystal forms. The inventors designated these crystal forms Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII.

Figure imgf000028_0001

8,                                                                                  9,                                                                                                                  10

Synthesis of Compound 1

Under inert gas (N?), 4~Mtro~o~phth.ak>nitrile (9.2 g), phenol (5.0 g), .2CO3 (7.3 g) and DMSO (40 mL) were added into a flask, and were stirred and reacted at room temperature for 48 hrs., then heated to 60 °C and reacted for 2 hrs. After cooled down, the reaction mixture was filtered and the resulted yellow solid was dried to obtain 11.6 g of Compound 1.

Synthesis of Compound 2

50 % of NaOH solution (25 mL) was added into the methanol solution of Compound 1 (11.3 g). The solution was heated to reflux for 48 hr until the reaction was complete. Concentrated HCl was then added to adjust the pH value to 3. The precipitate was filtered and dried to obtain 10.5 g of Compound 2.

Synthesis of Compound 3

Compound 2 (6.0 g) was dissolved in glacial acetic acid (60 mL) and acetic anhydride (60 mL) and heated to reflux for 3 hrs. The solvent was removed on a rotary evaporator to obtain Compound

3.

Synthesis of Compound 4

Compounds 3 (6.0 g) and methyl isocyanoacetate (2.65 g) were dissolved in THF (60 mL). 3.54 g of DBU (CAS No. 6674-22-2) was added in drop-wise at room temperature and stirred for 1 hr. at room temperature. After extracted with ethyl acetate under alkaline conditions to remove the impurities, the pH value of the aqueous phase was adjusted to 3 with diluted HCL Extracted with ethyl acetate, washed with water and dried with anhydrous Na2S04 and fi ltered, the resulting organic phase was distilled on a rotary evaporator to obtain 9.0g of Compound 4. Synthesis of Compound 5

Compound 4 (9.0 g) in CH3OH was added in concentrated HC1 and heated to 60 °C for 4 hrs. The resulted precipitation was filtered to obtain 5.8 g of crude product. The product was further purified by chromatography to obtain 1.85 g of Compound 5.

Synthesis of Compound 6

Compound 5 (1.77 g) in POCI3 (10 mL) was heated to about 70 and reacted for 3 hrs., then cooled dow and poured into ice. After POCU was completely decomposed, the resulting precipitate was filtered and washed with water, to obtain 1.45 g of Compound 6.

Synthesis of Compound 7

Under N2 atmosphere, Compound 6 (1 .41 g), dioxane (20 mL), rdj Pii ).Π )φ (0.49 g), .2CO3 (1.78 g) and trimethyl borane (0.54 g) were stirred mixed and heated to reflux for 3 hrs., then stirred at room temperature for 48 hrs. After concentration, the resulting mixture was extracted with ethyl acetate, washed with water, dried and filtered, then distilled on a rotary evaporator, followed by further purification through chromatography, to obtain 0.42 g of Compound 7.

Synthesis of Compound 8

Compound 7 (1.02 g) was added into the mixture of etiianol (10 mL) and 2N of NaOH (10 mL), and refluxed for 1.5 hrs. After removing the impurities by filtration, the resulting mixture was distilled to remove ethanol on a rotary evaporator. The resulting pale yellow precipitate was then filtered, washed with water, and dried to obtain 0.5 g of Compound 8.

Synthesis of Compound 9

Compound 8 (0.37 g), glycine methyl ester hydrochloride (0.44 g) and 1.00 g of PyBOP (CAS No. 128625-52-5) were added into dichloromethane (15 mL). and then added triethyiamine (0.74 mL) and bis(isopropyl)eth.y I amine ( 1.0 mL), stirred and reacted at room temperature for 3 hrs. After filtration, the organic phase was washed with water, dried and filtered, followed by a rotary evaporation, and further purification by a silica gel column, to obtain 0.29 g of Compound 9.

Synthesis of Compound 10, the compound of Formula I

Compound 9 (0.28 g) in THF was added in 1 NaOH (5 mL) and stirred and reacted for 1 hr. at room temperature. After remo ving THF by a rotary evaporation, the pFi value of the residue was adjusted to about 3 by diluted HQ, washed further by ethyl acetate, filtered and dried, to obtain 0.21 g of Compound 10, the compound of Formula I. Example 2

Preparation of Crystalline Form I of the compound of Formula I

The compound of Formula I prepared from the method disclosed in Example 1 above, was dissolved in the mixed solvent of methanol/MTBE (methyl tertbutyl ether) at room temperature, followed by a spontaneous precipitation to obtain the desired Polymorph Form I, with the melting point of 174-177 °C.

 Example 2

Preparation of Crystalline Form I of the compound of Formula I

The compound of Formula I prepared from the method disclosed in Example 1 above, was dissolved in the mixed solvent of methanol/MTBE (methyl tertbutyl ether) at room temperature, followed by a spontaneous precipitation to obtain the desired Polymorph Form I, with the melting point of 174-177 °C.

Example 3

Preparation of Crystalline Form II of the compound of Formula I

A slurry suspension of excess amount of the compound of Formula I prepared from the method disclosed in Example 1 above, was stirred in the mixed solvent of H20/acetonitrile (3: 1) or H20/ethanol at room temperature or 50°C at least 48 hrs., or in the mixed solvent of methanol/H20 at room temperature over 48 hr, to obtain the desired Crystalline Form II, with the melting point of 209-212 °C .

Example 4

Preparation of Crystalline Form III of the compound of Formula I

The compound of Formula I prepared from the method disclosed in Example 1 above, was dissolved in the mixed solvent of methanol/acetonitrile at room temperature, followed by a spontaneous precipitation to obtain the desired Crystalline Form III.

Or, a slurry suspension of excess amount of the compound of Formula I prepared from the method disclosed in Example 1 above, was stirred in H20, CH2C12, isopropyl acetate (IPAc), ethyl acetate (EtOAc), or the mixed solvent of IPAc/heptane or H20/acetone at 50 °C over 48 hrs., to obtain the desired Crystalline Form III, with the melting point of 198-200 °C ..

Example 5

Preparation of Crystalline Form IV of the compound of Formula I

A slurry suspension of excess amount of the compound of Formula I prepared from the method disclosed in Example 1 above, was stirred in MTBE, or the mixed solvent of MTBE/heptane, IPAc/heptane, ethyl acetate/heptane or H20/acetone at room temperature over 48 hrs., to obtain the desired Crystalline Form IV.

Or, a slurry suspension of excess amount of the compound of Formula I prepared from the method disclosed in Example 1 above, was stirred in the mixed solvent of ethyl acetate/heptane at 50 °C over 48 hrs., to obtain the desired Ciystalline Form IV.

Or, a slurry suspension of excess amount of the Crystalline Form III as prepared in Example 4 was stirred in the mixed solvent of FFiO/acetone at 50°C for 12-14 days, to obtain the desired Crystalline Form IV, with the melting point of 204-207 °C .

Example 6

Preparation of Crystalline Form V of the compound of Formula I

A slurry suspension of excess amount of the compound of Formula I prepared from the method disclosed in Example 1 above, was stirred in the mixed solvent of MTBE/heptane at 50 C over 48 hr, to obtain she desired Crystalline Form V; or, water was added as anti-solvent into the methanol solution of the compound of Formula I, to obtain the desired Ciystalline Form V, with the melting point of 190-193 °C .

Example 7

Preparation of Crystalline Form VI of the compound of Formula I

A slurry suspension of excess amount of the compound of Formula I prepared from the method disclosed in Example 1 above, was stirred in the mixed solvent of acetonitrile/FFiO (1 : 1) or THF/H2O at room temperature over 48 hrs, to obtain she desired Crystalline Form VI.

Or, the compound of Formula I prepared from the method disclosed in Example 1 above, was dissolved in the mixed solvent of methanol/ethy! acetate at room temperature, followed by a spontaneous precipitation using Ciystalline Form IV as prepared in Example 5 as crystal seeds to obtain the desired Crystalline Form VI, with the melting point of 200-203 °C =

Example 8

Preparation of Crystalline Form VH of the compound of Formula I

Ciystalline Form V prepared from the method of Example 6 was heated to 180 °C, to obtain the desired Crystalline Form VH.

PATENT

IN 201641016266

REDDYS AMORPHOUS FORM

The US patent number 7323475 B2, Example D-81 (e), by referring Example D-78 (d), discloses a process for isolation of roxadustat by concentration of organic phases (EtOAc/Methanol) in vacuo.

The US patent number 8883823 B2 discloses amorphous, different polymorphic Forms, solvates and salts of roxadustat.

The US patent number 9206134 B2 discloses different crystalline Forms of roxadustat.

PATENT

CN 106187888

PATENT

US 2014024675

PATENT

https://patents.google.com/patent/US9206134B2/en

BEIJING BETTA PHARMACEUTICALS CO. 

The present invention relates to approximately pure crystalline polymorphs, wherein these polymorphs are the polymorphs of the compound of Formula and/or a hydrate thereof, and/or a solvate thereof.

Figure US09206134-20151208-C00002

The compound of Formula I of the present invention exists in one or more crystal forms. The inventors designated these crystal forms Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII.

CN104892509A *2015-06-042015-09-09苏州明锐医药科技有限公司Preparation method of Roxadustat
US9340511B22012-07-162016-05-17Fibrogen, Inc.Process for making isoquinoline compounds
US9617218B22012-07-162017-04-11Fibrogen, Inc.Crystalline forms of a prolyl hydroxylase inhibitor
Family To Family Citations
CN102272117B2008-11-142015-06-17菲布罗根有限公司Thiochromene derivatives as hip hydroxylase inhibitors
WO2012106472A12011-02-022012-08-09Fibrogen, Inc.Naphthyridine derivatives as inhibitors of hypoxia inducible factor (hif) hydroxylase
US8883823B22012-07-162014-11-11Fibrogen, Inc.Crystalline forms of a prolyl hydroxylase inhibitor
CN103694172A *2013-12-262014-04-02辽宁亿灵科创生物医药科技有限公司Derivative of aza-aryl compound
WO2017143131A1 *2016-02-192017-08-24Cornell UniversityHif-stabilization and prevention of hyperoxia-induced neonatal lung disease
CN106187888A *2016-07-182016-12-07江苏德源药业股份有限公司FG-4592 single crystal and preparation method thereof

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

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Roxadustat


STR1

ROXADUSTAT

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

Fibrogen, Inc.

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

THERAPEUTIC CLAIM
Treatment of anemia

Roxadustat nonproprietary drug name

CHEMICAL NAMES

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

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

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

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

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

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

Most Recent Events

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

 

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

 

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

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

STR1

PATENT

CN 104892509

MACHINE TRANSLATED

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

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

Figure CN104892509AD00031

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

Figure CN104892509AD00032

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

Figure CN104892509AD00041

n PhO. eight XOOH

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

Figure CN104892509AD00042

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

Figure CN104892509AD00052

Example One:

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

Example Two:

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

 Example Three:

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

 Example Four:

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

Example five:

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

 Example VI:

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

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

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

PATENT

WO 2014014835

Example 10. Preparation of Compound A

a) 5-Phenoxyphthalide

Figure imgf000056_0001

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

Figure imgf000056_0002

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

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

Figure imgf000057_0001

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

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

(lb)

Figure imgf000057_0002

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

Figure imgf000058_0001

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

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

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

Figure imgf000058_0002

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

(Compound A)

Figure imgf000059_0001

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

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

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

FG-4592 - zliming2004 - zliming2004的博客

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

FG-4592 - zliming2004 - zliming2004的博客

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

FG-4592 - zliming2004 - zliming2004的博客

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

CLIPS

SAN FRANCISCO, Nov 12, 2013 (BUSINESS WIRE) — FibroGen, Inc. (FibroGen), today announced that data from a China-based Phase 2 study of roxadustat (FG-4592), a first-in-class oral compound in late stage development for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), were presented in an oral session at the 2013 American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia.
Roxadustat is an orally administered, small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. HIF is a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced and iron is incorporated into hemoglobin (Hb).
The randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of roxadustat in the correction of anemia in patients (N=91) with chronic kidney disease who had not received dialysis treatment, were not receiving erythropoiesis-stimulating agents (ESAs), and had Hb levels less than 10 g/dL. The correction study randomized patients 2:1 between roxadustat and placebo for 8 weeks of dosing, and included a low-dose cohort (n=30) and high-dose cohort (n=31). Intravenous (IV) iron was not allowed. The study also evaluated iron utilization, changes in serum lipids, and other biomarkers during treatment with roxadustat.
Data from this study suggest that roxadustat effectively corrected hemoglobin levels in anemic CKD patients in a dose-dependent manner as compared to placebo, and did so in the absence of IV iron supplementation regardless of degree of iron repletion at baseline. At the end of the 8-week treatment period, subjects showed mean maximum Hb increases from baseline of 2.6 g/dL in the high dose cohort and 1.8 g/dL in the low dose cohort, as compared to 0.7 g/dL in the placebo group (p < 0.0001) from mean baseline Hb of 8.8 g/dL, 8.8 g/dL, and 8.9 g/dL in the high dose, low dose, and placebo groups, respectively. 87% of patients in the high-dose cohort, 80% of patients in the low-dose cohort, and 23% of patients in the placebo group experienced a hemoglobin increase of 1 g/dL or greater from baseline (p < 0.0001). Similarly, 71% of patients in the high-dose cohort, 50% of patients in the low-dose cohort, and 3% of patients in the placebo group achieved target hemoglobin of 11 g/dL or greater (p < 0.0001). Serum iron levels remained stable in subjects randomized to roxadustat while the subjects underwent brisk erythropoiesis.
Study data also suggest that roxadustat may lower cholesterol. Dyslipidemia is highly prevalent in chronic kidney disease patients and a major cardiovascular risk factor in this population. Patients treated with roxadustat experienced a statistically significant reduction in total cholesterol (p <0.0001) and low-density lipoprotein (LDL) cholesterol (p <0.0001) at the end of the treatment period. The relative proportion of high density lipoprotein (HDL) cholesterol to LDL cholesterol increased significantly (p <0.02). Overall LDL cholesterol levels declined by a mean of 26% and median of 23% from a mean baseline value of 103 mg/dL.
Roxadustat was well tolerated by patients in the study with incidence of adverse events similar across all groups. In contrast to the exacerbation of hypertension observed in studies in which patients received currently available ESA therapies, subjects who received roxadustat in the present study showed small decreases in blood pressure that were similar to blood pressure changes in the placebo group. No cardiovascular serious adverse events were reported in patients treated with roxadustat.
The efficacy and safety of roxadustat are currently being investigated in a global pivotal Phase 3 development program.
“There is a global need for effective, safe, and accessible anemia therapies,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “Side effects associated with current treatments include exposure to supra-physiological levels of erythropoietin and depletion of iron stores. Preliminary clinical findings show that oral administration of roxadustat (FG-4592) is able to correct anemia and maintain hemoglobin levels in patients with chronic kidney disease, to do so with peak erythropoietin levels within physiological range, and to achieve these effects without the administration of intravenous iron. These results suggest roxadustat, as an oral agent, has the potential to overcome the treatment barriers and inconveniences of current ESA therapies, including administration by injection and IV iron supplementation, in treating anemia in CKD patients.”
About Chronic Kidney Disease (CKD) and Anemia
Diabetes, high blood pressure, and other conditions can cause significant damage to the kidneys. If left untreated, those can result in chronic kidney disease and progress to kidney failure. Such deterioration can lead to patients needing a kidney transplant or being placed on dialysis to remove excess fluid and toxins that build up in the body. The progression of CKD also increases the prevalence of anemia, a condition associated with having fewer of the red blood cells that carry oxygen through the body, and/or lower levels of hemoglobin, the protein that enables red blood cells to carry oxygen. As hemoglobin falls, the lower oxygen-carrying capacity of an anemic patients’ blood results in various symptoms including fatigue, loss of energy, breathlessness, and angina. Anemia in CKD patients has been associated with increased hospitalization rates, increased mortality, and reduced quality of life.
Chronic kidney disease is a worldwide critical healthcare problem that affects millions of people and drives significant healthcare cost. In the US, prevalence of CKD has increased dramatically in the past 20 years, from 10 percent of the adult population (or approximately 20 million U.S. adults) as stated in the National Health and Nutrition Evaluation Survey (NHANES) 1988-1994, to 15 percent (or approximately 30 million U.S. adults) in NHANES 2003-2006. In 2009, total Medicare costs for CKD patients were $34 billion. China has an estimated 145 million CKD patients, or approximately five times the number of CKD patients in the U.S. (Lancet April 2012).
About Roxadustat / FG-4592
Roxadustat (FG-4592) is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity, in development for the treatment of anemia in patients with chronic kidney disease (CKD). HIF is a protein transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis (the process by which red blood cells are produced) and other protective pathways. Roxadustat has been shown to correct anemia and maintain hemoglobin levels without the need for supplementation with intravenous iron in CKD patients not yet receiving dialysis and in end-stage renal disease patients receiving dialysis. An Independent Data Monitoring Committee has found no signals or trends to date to suggest that treatment with roxadustat is associated with increased risk of cardiovascular events, thrombosis, or increases in blood pressure requiring initiation or intensification of antihypertensive medications.
About FibroGen
FibroGen is a privately-held biotechnology company focused on the discovery, development, and commercialization of therapeutic agents for treatment of fibrosis, anemia, cancer, and other serious unmet medical needs. FibroGen’s FG-3019 monoclonal antibody is in clinical development for treatment of idiopathic pulmonary fibrosis and other proliferative diseases, including pancreatic cancer and liver fibrosis. Roxadustat (FG-4592), FibroGen’s small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, is currently in clinical development for the treatment of anemia. FibroGen is also currently pursuing the use of proprietary recombinant human type III collagens in synthetic corneas for treatment of corneal blindness. For more information please visit: www.fibrogen.com .

References

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

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

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

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

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

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

//////////ASP1517,  ASP 1517,  ASP-1517,  FG-4592,  FG 4592,  FG4592,  Roxadustat, PHASE 3, ASTELLAS, FibroGen, 808118-40-3
O=C(O)CNC(C1=C(O)C2=C(C(C)=N1)C=C(OC3=CC=CC=C3)C=C2)=O

UCT Drug Discovery and Development Centre, H3D, pioneers world-class drug discovery in Africa.


H3D

UCT’s H3D is a center of excellence for research and innovation with an already strong track record in malaria drug  discovery. The vision of H3D is to be the leading organization for integrated drug discovery and development on the African continent.

ABOUT H3D

H3D is Africa’s first integrated drug discovery and development centre. The Centre was founded at the University of Cape Town in April 2011 and pioneers world-class drug discovery in Africa.

Our Vision

To be the leading organisation for integrated drug discovery and development from Africa, addressing global unmet medical needs.

Our Mission

To discover and develop innovative medicines for unmet medical needs on the African continent and beyond, by performing state-of-the-art research and development and bridging the gap between basic science and clinical studies.

We embrace partnerships with local and international governments, pharmaceutical companies, academia, and the private sector, as well as not-for-profit and philanthropic organisations, while  training scientists to be world experts in the field.

The H3D collaboration with the Medicines for Malaria Venture (MMV) focuses on delivering potential agents against malaria that will be affordable and safe to use. In line with the global aim to eradicate malaria, projects are pursued that not only eliminates blood-stage Plasmodium falciparum and Plasmodium vivax infection, but also acts against liver stages and blocks transmission of the infection. The projects embrace multidisciplinary activities to optimise hit compounds from screening libraries through the drug discovery pipeline and deliver clinical candidates.

Merck Serono Announces Recipients of the Second Annual €1 Million Grant for Multiple Sclerosis Innovation

Darmstadt, Germany, September 12, 2014 – Merck Serono, the biopharmaceutical division of Merck, today announced the recipients of the second annual Grant for Multiple Sclerosis Innovation (GMSI) at MS Boston 2014, the joint meeting of the Americas Committee for Treatment and Research in MS (ACTRIMS) and European Committee for Treatment and Research in MS (ECTRIMS), taking place September 10-13 in Boston, U.S.A.

Merck signed a research agreement with the University of Cape Town (UCT), South Africa, to co-develop a new R&D platform. It aims at identifying new lead programs for potential treatments against malaria, with the potential to expand it to other tropical diseases. It combines Merck’s R&D expertise and the drug discovery capabilities of the UCT Drug Discovery and Development Centre, H3D.
UCT’s H3D is a center of excellence for research and innovation with an already strong track record in malaria drug  discovery. The vision of H3D is to be the leading organization for integrated drug discovery and development on the African continent. They say that working with partners like Merck is critical to build up a comprehensive pipeline to tackle malaria and related infectious diseases.

Journal Publications:

  1. Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization C. Soares de Melo, T-S. Feng, R. van der Westhuyzen, R.K. Gessner, L. Street, G. Morgans, D. Warner, A. Moosa, K. Naran, N. Lawrence, H. Boshoff, C. Barry, C. Harris, R. Gordon, K. Chibale. Biorg. Med. Chem. 2015, 23, 7240-7250.
  2. A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum- Infected Mouse Models from Structure−Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines. C. Le Manach, T. Paquet, C. Brunschwig, M. Njoroge, Z. Han, D. Gonzàlez Cabrera, S. Bashyam, R. Dhinakaran, D. Taylor, J. Reader, M. Botha, A. Churchyard, S. Lauterbach, T. Coetzer, L-M. Birkholtz, S. Meister, E. Winzeler, D. Waterson, M. Witty, S. Wittlin, M-B. Jiménez-Díaz, M. Santos Martínez, S. Ferrer, I. Angulo-Barturen, L. Street, and K. Chibale, J. Med. Chem. 2015, XX, XXXX
  3. Structure−Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines. D. Gonzàlez Cabrera, F. Douelle, C. Le Manach, Z. Han, T. Paquet, D. Taylor, M. Njoroge, N. Lawrence, L. Wiesner, D. Waterson, M. Witty, S. Wittlin, L. Street and K. Chibale. J Med Chem. 2015, 58, 7572-7579.
  4. Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2. Le Manach, T. Paquet, D. Gonzalez Cabrera, Y. Younis, D. Taylor, L. Wiesner, N. Lawrence, S. Schwager, D. Waterson, M.J. Witty, S. Wittlin, L. Street, and K. Chibale. J. Med. Chem. 2014, 57, 8839−8848.
  5. Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1. Le Manach, D. González Cabrera, F. Douelle, A.T. Nchinda, Y. Younis, D. Taylor, L. Wiesner, K. White, E. Ryan, C. March, S. Duffy, V. Avery, D. Waterson, M. J. Witty, S. Wittlin; S. Charman, L. Street, and K. Chibale. J. Med. Chem. 2014, 57, 2789-2798.
  6. 2,4-Diamino-thienopyrimidines as Orally Active Antimalarial Agents. D. González Cabrera, C. Le Manach, F. Douelle, Y. Younis, T.-S. Feng, T. Paquet, A.T. Nchinda, L.J. Street, D. Taylor, C. de Kock, L. Wiesner, S. Duffy, K.L. White, K.M. Zabiulla, Y. Sambandan, S. Bashyam, D. Waterson, M.J. Witty, A. Charman, V.M. Avery, S. Wittlin, and K. Chibale. J. Med. Chem. 2014,57, 1014-1022.
  7. Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension. Burger, T.L. Reudelhuber, A. Mahajan, K. Chibale,E.D. Sturrock, R.M. Touyz. Clin. Sci. (Lond). 2014, 127(1), 57-63.
  8. Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor. Denti, S.K. Sharp, W.L. Kröger, S.L. Schwager, A. Mahajan, M. Njoroge, L. Gibhard, I. Smit, K. Chibale, L. Wiesner, E.D. Sturrock, N.H. Davies. Eur. J. Pharm. Sci.2014, 56, 113-119.
  9. Fragment-based design for the development of N-domain-selective angiotensin-1-converting enzyme inhibitors. R.G. Douglas, R.K. Sharma, G. Masuyer, L. Lubbe, I. Zamora, K.R. Acharya, K. Chibale, E.D. Sturrock. Sci. (Lond). 2014, 126(4),305-313.
  10. Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. Le Manach, C. Scheurer, S. Sax, S. Schleiferböck, D. González Cabrera, Y. Younis, T. Paquet, L. Street, P.J. Smith, X. Ding, D. Waterson, M.J. Witty, D. Leroy, K. Chibale and S. Wittlin*. Malaria Journal, 2013, 12, 424.
  11. Structure-Activity-Relationship Studies Around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in vivo Activity. Y. Younis, F. Douelle, González Cabrera, C. Le Manach, A.T. Nchinda, T. Paquet, L.J. Street, K.L. White, K. M. Zabiulla, J.T. Joseph,  S. Bashyam, D. Waterson, M.J. Witty, S. Wittlin, S.A. Charman, and K. Chibale*   J. Med. Chem. 2013, 56, 8860−8871.
  12. Cell-based Medicinal Chemistry Optimization of High Throughput Screening (HTS) Hits for Orally Active Antimalarials-Part 2: Hits from SoftFocus Kinase and other Libraries. Y. Younis, L. J. Street, D. Waterson, M.J. Witty, and K. Chibale. J. Med. Chem. 2013, 56, 7750−7754.
  13. Structure-Activity Relationship Studies of Orally active Antimalarial 3,5-Substituted 2-Aminopyridines. D. González Cabrera, F. Douelle, Y. Younis, T.-S. Feng, C. Le Manach, A.T. Nchinda, L.J. Street, C. Scheurer, J. Kamber, K. White, O. Montagnat, E. Ryan, K. Katneni, K.M. Zabiulla, J. Joseph, S. Bashyam, D. Waterson, M.J. Witty, S. Charman, S. Wittlin, and K. Chibale* J. Med. Chem. 2012, 55, 11022– 11030.
  14. 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential. Y. Younis, F. Douelle, T.-S. Feng, D. González Cabrera, C. Le Manach, A.T. Nchinda, S. Duffy, K.L. White, M. Shackleford,  J. Morizzi, J. Mannila, K. Katneni, R. Bhamidipati, K. M. Zabiulla, J.T. Joseph,  S. Bashyam, D. Waterson, M.J. Witty, D. Hardick, S. Wittlin, V. Avery, S.A. Charman, and K. Chibale*.  J. Med. Chem.  2012, 55, 3479−3487.
  15. Novel Orally Active Antimalarial Thiazoles. D. González Cabrera, F. Douelle, T.-S Feng, A.T. Nchinda, Y. Younis, K.L. White, Wu,E. Ryan, J.N. Burrows,D. Waterson, M.J. Witty,S. Wittlin,S.A. Charman and K. Chibale.  J. Med. Chem. 2011, 54, 7713–7719.
  16. Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme. A.T. Nchinda, K. Chibale, P. Redelinghuys and E.D. Sturrock. Med. Chem. Lett. 2006, 16(17), 4616-4619.

Patents

  1. Anti-Malarial Agents. Y. Younis, K. Chibale, M.J. Witty, D. Waterson. (2016) US9266842 B2.
  2. New Anti-Malarial Agents. D. Waterson, M.J. Witty, K. Chibale, L. Street, D. González Cabrera, T. Paquet. EP patent application (2015), No. 15 176 514.6.
  3. Preparation of aminopyrazine compounds as antimalarial agents for treatment of malaria. Y. Younis, K. Chibale, M.J. Witty, D. Waterson. PCT Int Appl. (2013), WO 2013121387 A1 20130822.
  4. Preparation of peptides as angiotensin I-converting enzyme (ACE) inhibitors. E.D. Sturrock, A.T. Nchinda, K. Chibale. PCT Int. ppl. (2006), WO 2006126087 A2 20061130.
  5. Preparation of peptides as angiotensin I-converting enzyme (ACE) inhibitors, E.D. Sturrock, A.T. Nchinda, K. Chibale. PCT Int. ppl. (2006), WO 2006126086 A2 20061130.

Head Office, Medicinal Chemistry Unit

Physical Address:
Department of Chemistry
7.32 H3D Lab Suite, PD Hahn Building, Level 7
North Lane off Ring Road
Upper Campus, University of Cape Town
Rondebosch, 7700, South Africa

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Postal Address:
University of Cape Town
Private Bag X3
Rondebosch 7701
South Africa

P. D. Hahn Bldg, Rondebosch, Cape Town,
Map of P. D. Hahn Bldg, Rondebosch, Cape Town, 7700, South Africa
P. D. Hahn Bldg, Rondebosch, Cape Town, 7700, South Africa

//////H3D, Africa,  integrated drug discovery and development centre,  University of Cape Town 

(±)-Integrifolin, Compound from plants keeps human cancer cells from multipying


STR1

CAS 89647-87-0

MFC15 H18 O4, MW 262.30
Azuleno[4,5-b]furan-2(3H)-one, decahydro-4,8-dihydroxy-3,6,9-tris(methylene)-, (3aR,4R,6aR,8S,9aR,9bR)-
  • Azuleno[4,5-b]furan-2(3H)-one, decahydro-4,8-dihydroxy-3,6,9-tris(methylene)-, [3aR-(3aα,4β,6aα,8β,9aα,9bβ)]-
  • (3aR,4R,6aR,8S,9aR,9bR)-Decahydro-4,8-dihydroxy-3,6,9-tris(methylene)azuleno[4,5-b]furan-2(3H)-one
  • 8-epi-Deacylcynaropicrin
  • 8β-Hydroxyzaluzanin C
  • Integrifolin (guaianolide)

STR1Integrifolin

STR1

STR1

STR1

STR1

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PATENT

WO 2011085979

Paper

Two New Amino Acid-Sesquiterpene Lactone Conjugates from Ixeris dentata

BLOG POST FROM CHEMISTRY VIEWS, WILEY

thumbnail image: Total Synthesis of (±)-IntegrifolinSTR1STR1STR1

(±)-Integrifolin

Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Total Synthesis of (±)-Integrifolin

Compound from plants keeps human cancer cells from multipying

Read more at Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Weight control is an important concern of human beings, both for medical (pharmaceutical and/or nutraceutical) as well as non-therapeutic, e.g. cosmetic, reasons. More importantly, excessive accumulation of body fat (i.e. obesity (= adiposity), especially with excessive fat in the ventral region and surrounding the viscera) can be dangerous and has been linked to health problems such as type II diabetes, hypertension, heart disease, atherosclerosis (where more than two of the preceding disorders are present, the condition is often called “Metabolic Syndrome” or “syndrome X”), hyperlipidemia, coronary heart disease, stroke, breast and colon cancer, sleep apnoea, gallbladder disease, reproductive disorders such as polycystic ovarian syndrome, gastroesophageal reflux disease, increased incidence of complications of general anesthesia, fatty liver, gout or thromboembolism (see, e.g., Kopelman, Nature 404: 635-43 (2000)). Obesity reduces life-span and carries a serious risk of the co-morbidities listed above, as well disorders such as infections, varicose veins,

acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al, Br. Med. J. 301 : 835-7 (1990)). Obesity is one of the main factors in the development of cardiovascular diseases. As a side effect the levels of cholesterol, blood pressure, blood sugar and uric acid in obese people are usually higher than those of persons of normal weight. The morbidity from coronary heart disease among the overweight people is increased as well. Among the people aged 40-50, mortality will rise about 1% when body weight increases by 0.5 kg and the death rate will increase 74% when body weight exceeds 25% of the standard. The prevalence of obesity in the United States has more than doubled since the turn of the last century (whole population) and more than tripled within the last 30 years among children aged from 6 to 11. This problem more and more becomes a disease risk also in Europe. In Germany, particularly many people have been found to suffer from overweight recently, already 25% of the young people, children and adolescents there are affected by obesity and related disorders. Furthermore, being overweight is considered by the majority of the Western population as unattractive.

Overweight and obesity result from an imbalance between the calories consumed and the calories used by the body. When the calories consumed exceed the calories burned, the body is in positive energy balance and over time weight gain will occur. The excess calories are stored in the fat cells. When the calories burned exceed the calories consumed, the body is in negative energy balance and over time weight loss will occur.

Determinants of obesity include social factors, psychological factors, genetic factors, developmental factors and decreased physical activity. Some components of a comprehensive weight loss programs include medical assessment, behavioural and dietary modification, nutrition education, mental and cognitive restructuring, increased physical activity, and long term follow-up.

An increasing interest by consumers in the maintenance or reduction of their body weight can be found. This leads to a demand for products useful for these purposes. Preferred are such food products which can conveniently be consumed as part of the daily diet, for example meal replacer products, such as meal replacer bars and beverages. These are usually designed for use as a single-serving food product to replace one or two meals a day.

An issue is that often a saturating effect is missed when such products are consumed, resulting in hunger feelings only a relatively short time after consummation or even in the lack of a saturation feeling already directly after consummation.

Summing up, there remains a need for new safe and effective compositions for promoting weight loss and/or loss of body fat in subjects such as humans. The problem to be solved by the present invention is therefore to find compositions or compounds useful in the treatment of obesity; and/or for improving the total cholesterol HDIJLDL ratio.

Phytochemistry provides a large pool of compounds and compositions to be looked at whether they are able to solve this problem.

The present invention provides methods and compositions useful in the control, treatment and prevention of obesity and obesity-related conditions, disorders, and diseases; and/or and/or for improving the total cholesterol HDL/LDL ratio.

Rosinski, G., et al., Endocrinological Frontiers in Phyiological Insect Ecology, Wroclow Technical University Press, Wroclow 1989, describe that certain tricyclic sequiterpene lactones, such as grossheimin and repin, showed inhibition of larval growth and antifeeding activity in Mealworm (Tenebrio σιοΐϊίοή. Grossheimin shows no anti-feeding but little decrease of absorption of digested food constituents and a little decrease in efficiency in digesting. Repin exhibit low effects at all. Both compounds show no effect on lipid levels in blood.

Shimoda, H., et al, Bioinorganic & Medicinal Chemistry Letters 13 (2003), 223-228, describe that methanolic extracts from Artichoke (Cynara sclolymus L.) with cynaropicrin, aguerin B and grossheimin as components and certain sesquiterpene glycosides suppress serum triglyceride elevation in olive oil-loaded mice. Some of these compounds exhibit a moderate short term (2 hours after olive oil administration) anti-hyperlipidemic activity presented as a lowering of the serum triglyceride (serum TG) concentrations, the long term (6 hours) show in the case of cynaropicrin and aguerine B an increase of the serum TG. Furthermore the authors present data of the gastric emptying (GE) of a methanolic ectract of artichoke. They determine a significantly inhibited GE. However, as shown below, this mechanism is not an explanation for the anti obesity effect shown in the present invention (see Example 1 ).

Fritzsche, J., et al., Eur. Food Res. Technol. 215, 149-157 (2002) describe the effect of certain isolated artichoke leaflet extract components with cholesterol lowering potential. Ahn, E.M-., et al, Arch Pharm. res. 29(1 1 ), 937-941 , 2006, shows ACAT inhibitory activity for two sesquiterpene lactones. KR 20040070985 also shows an effect of certain sesquiterpene lactone derivatives on cholesterol biosynthesis involved enzymes. Gebhard, R., Phytother. Res. 16, 368-372 (2002) and J. Pharmacol. Exp. Ther. 286(3), 1 122-1 128 (1998), shows

enforcement of cholesterol biosynthesis inhibition in HepG2 cells by artichoke extracts. WO 2007/006391 also claims reduction in cholesterol by certain Cynara scolymus variety extracts.

Other reported activities of tricyclic sesquiterpene lactones are antioxidant activity (European Food Research & Technology (2002), 215(2): 149-157), inhibitors of NF kb (Food Style 21 (2007), 1 1 (6): 54-56; JP 2006-206532), serum triglyceride increase-inhibitory effect (Kagaku Kogyo (2006), 57(10): 740-745), hypoglycaemic effect (J. Trad. Med. (2003), 20(2): 57-61), bitter taste (DE 2654184). Any beneficial effects are included in this invention by reference.

None of the documents suggest that a control and treatment of obesity and body fat in warmblooded animals might be possible.

http://www.chemistryviews.org/details/ezine/9412451/Total_Synthesis_of_-Integrifolin.html?elq_mid=10181&elq_cid=1558306

Cynaropicrin, a tricyclic sesquiterpene lactone causes in vivo a strong weight loss. More surprisingly it was found that this effect is not correlated to a decrease in food intake. The weight balance is not affected by reduction of assimilation efficiency; the decrease of body fat and body weight is presumably caused by effects on energy metabolism. Surprisingly, it was found in addition that cynaropicrin also allows for improving the total cholesterol HDL7LDL ratio

Tricyclic sequiterpene lactones or known ingredients of plants of the subclass Asterides, especially from the family of Asteraceae, more specifically from species of the genera of the list consisting of Achilea, Acroptilon, Agranthus, Ainsliaea, Ajania, Amberboa, Andryala, Artemisia, Aster, Bisphopanthus, Brachylaena, Calea, Calycocorsus, Cartolepsis, Centaurea, Cheirolophus, Chrysanthemum, Cousinia, Crepis, Cynara, Eupatorium, Greenmaniella, Grossheimia, Hemistaptia, Ixeris, Jurinea, Lapsana, Lasiolaena, Liatris, Lychnophora, Macroclinidium, Mikania, Otanthus, Pleiotaxis, Prenanthes, Pseudostifftia, Ptilostemon,

Rhaponticum, Santolina, Saussurea, Serratula, Sonchus, Stevia, Taeckholmia, Tanacetum, Tricholepis, Vernonia, Volutarella, Zaluzania; even more specifically from species of the list consisting of Achillea clypeolata, Achillea collina, Acroptilon repens, Agrianthus pungens, Ainsliaea fragrans, Ajania fastigiata, Ajania fruticulosa, Amberboa lippi, Amberboa muricata, Amberboa ramose**, Amberboa tubuliflora and other Amberboa spp.*, Andryala integrifolia, Andryala pinnatifida, Artemisia absinthium, Artemisia cana, Artemisia douglasiana, Artemisia fastigiata, Artemisia franserioides, Artemisia montana, Artemisia sylvatica, Artemisia

tripartita, Aster auriculatus, Bishopanthus soliceps, Brachylaena nereifolia, Brachylaena perrieri, Calea jamaicensis, Calea solidaginea, Calycocorsus stipitatus, Cartolepsis intermedia, Centaurea babylonica, Centaurea bella, Centaurea canariensis*, Centaurea clementei, Centaurea conicum, Centaurea dealbata, Centaurea declinata, Centaurea glastifolia, Centaurea hermanii, Centaurea hyrcanica, Centaurea intermedia, Centaurea janeri, Centaurea kalscyi, Centaurea kandavanensis, Centaurea kotschyi, Centaurea linifolia, Centaurea macrocephala, Centaurea musimomum, Centaurea nicolai, Centaurea pabotii, Centaurea pseudosinaica, Centaurea repens, Centaurea salonitana, Centaurea scoparia, Centaurea sinaica, Centaurea solstitialis, Centaurea tweediei and other Centaurea spp. *, Cheirolophus uliginosus, Chrysanthemum boreale, Cousin ia canescens, Cousinia conifera, Cousinia picheriana, Cousinia piptocephala, Crepis capillaris, Crepis conyzifolia, Crepis crocea, Crepis japonica, Crepis pyrenaica, Crepis tectorum, Crepis virens, Crepis zacintha, Cynara alba, Cynara algarbiensis, Cynara auranitica, Cynara baetica, Cynara cardunculus, Cynara cornigera, Cynara cyrenaica, Cynara humilis, Cynara hystrix, Cynara syriaca, Cynara scolymus**, Cynara sibthorpiana and other Cynara spp.*, Eupatorium anomalum,

Eupatorium chinense, Eupatorium lindleyanum, Eupatorium mohrii, Eupatorium

rotundifolium, Eupatorium semialatum, Greenmaniella resinosa, Grossheimia

macrocephala** and other Grossheimia spp. *, Hemisteptia lyrata, Ixeris chinensis, Ixeris debilis, Ixeris dentata, Ixeris repens, Ixeris stolonifera, Jurinea carduiformis, Jurinea derderioides, Jurinea maxima, Lapsana capillaris, Lapsana communis, Lasiolaena morii, Lasiolaena santosii, Liatris chapmanii, Liatris gracilis, Liatris pycnostachya, Lychnophora blanchetii, Macroclinidium trilobum, Mikania hoehnei, Otanthus maritimus, Pleiotaxis rugosa, Prenanthes acerifolia, Pseudostifftia kingii, Ptilostemon diacanthus, Ptilostemon

gnaphaloides, Rhaponticum serratuloides, Santolina jamaicensis, Saussurea affinis,

Saussurea elegans, Saussurea involucrata, Saussurea laniceps, Saussurea neopulchella** and other Sauusurea spp. *, Serratula strangulata, Sonchus arborea, Stevia sanguinea, Taeckholmia arborea, Taeckholmia pinnata, Tanacetum fruticulosum, Tanacetum

parthenium, Tricholepis glaberrima** and other Tricholepsis spp. *, Vernonia arkansana, Vernonia nitidula, Vernonia noveboracensis, Vernonia profuga, Vernonia sublutea,

Volutarella divaricata, Zaiuzania resinosa; and can potentially be isolated from any part of the plants. Those genera and/or species marked with an asterisk (*) and especially those species marked with two asterisks (**) are especially preferred.

Appropriate plant material can be obtained from various sources, e.g. from:

Alfred Galke GmbH, Gittelde/Harz, Germany; Miiggenburg Pflanzliche Rohstoffe, Bad Bramstedt, Germany; Friedrich Nature Discovery, Euskirchen, Germany; VitaPlant AG, Uttwil, Switzerland; Amoros Nature SL, Hostalric, Spain.

(±)-Integrifolin

Banksia integrifolia

Coast Banksia

Family: Proteaceae

Banksia integrifolia is a tall shrub or small tree 6 – 16m tall. It is common in sandy coastal areas, but also grows in the forests of tablelands. The light grey bark is hard and rough.

Mature leaves 5 -10 cm long, are stiff, entire (untoothed), dull dark green above and hairy-white underneath. They are generally lanceolate. Younger leaves are irregularly toothed and shorter than the mature leaves. The species name ‘integrifolia’ means whole-leaved.

The pale yellow flower spikes of Banksia integrifolia range from 7-14cm long and 7cm wide. The bent styles emerge from individual flowers on the spike, straightening and spreading.

A short time after flowering, the seed pods protrude cleanly from the woody cone and open to shed black, papery, winged seeds.

Banksia integrifolia flowers from January to June.

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https://www.jstage.jst.go.jp/article/cpb1958/33/8/33_8_3361/_pdf

PAPER

http://onlinelibrary.wiley.com/doi/10.1002/chem.201601275/abstract

Total Synthesis of (±)-Integrifolin

  • DOI: 10.1002/chem.201601275

///////(±)-Integrifolin,  human cancer cells,  multipying

C=C1C(=O)O[C@@H]2[C@H]3C(=C)[C@@H](O)C[C@H]3C(=C)C[C@@H](O)[C@@H]12

Novartis, Torrent drug for diabetes, NVP-LBX192, LBX-192


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Figure US07750020-20100706-C00023

 

CHEMBL573983.png

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

(3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide)

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

cas 866772-52-3

Novartis Ag

NVP-LBX192

LBX-192

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R(−) 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

R(−)17c BELOW

Abstract Image
Inventors Gregory Raymond Bebernitz, Ramesh Chandra Gupta, Vikrant Vijaykumar Jagtap, Appaji Baburao Mandhare, Davinder Tuli,
Original Assignee Novartis Ag

 

Molecular Formula: C26H33N5O4S2
Molecular Weight: 543.70132 g/mol

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LBX192, also known as NVP-LBX192, is a Liver Targeted Glucokinase Activator. LBX192 activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice. A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen.

SYNTHESIS BY WORLDDRUGTRACKER

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54 Discovery and Evaluation of NVP-LBX192, a Liver Targeted Glucokinase Activator

Thursday, October 8, 2009: 10:30 AM
Nathan Hale North (Hilton Third Floor)
Gregory R. Bebernitz, PhD , Global Discovery Chemistry, Novartis Institute for Biomedical Research, Cambridge, MA
Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching clinical evaluation.  A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen.  We will describe our efforts to generate liver selective GK activators which culminated in the discovery of NVP-LBX192 (3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide).  This compound activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice.

https://acs.confex.com/acs/nerm09/webprogram/Paper75087.html

Sulfonamide-Thiazolpyridine Derivatives,  Glucokinase Activators, Treatment Of Type 2 Diabetes

2009 52 (19) 6142 – 6152
Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes
Journal of Medicinal Chemistry
Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao JP, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang JS, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, Denny IS, Taslimi PM, Vash B, Caplan SL

2010 240th (August 22) Medi-198
Glucokinase activators with improved physicochemicalproperties and off target effects
American Chemical Society National Meeting and Exposition
Kirman LC, Schuster HF, Grondine MS et al

2010 240th (August 22) Medi-197
Investigation of functionally liver selective glucokinase activators
American Chemical Society National Meeting and Exposition
Schuster HF, Kirman LC, Bebernitz GC et al

PATENT

http://www.google.com/patents/US7750020

EXAMPLE 1 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A. Phenylacetic Acid Ethyl Ester

A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) is treated with catalytic amount of sulfuric acid (4 mL). The reaction mixture is refluxed for 4 h. The reaction is then concentrated in vacuo. The residue is dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100 mL). The organic layer dried over sodium sulfate filtered and concentrated in vacuo to give phenylacetic acid ethyl ester as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.2 (t, J=7.2, 3H), 3.6 (s, 2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]+.

B. (4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester

To a cooled chlorosulfonic acid (83.83 g, 48 mL, 0.71 mol) under nitrogen is added the title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol) over a period of 1 h. Reaction temperature is brought to RT (28° C.), then heated to 70° C., maintaining it at this temperature for 1 h while stirring. Reaction is cooled to RT and poured over saturated aqueous sodium chloride solution (200 mL) followed by extraction with DCM (2×200 mL). The organic layer is washed with water (5×100 mL), followed by saturated aqueous sodium chloride solution (1×150 mL). The organic layer dried over sodium sulfate, filtered and concentrated in vacuo to give crude (4-chlorosulfonyl-phenyl)acetic acid ethyl ester. Further column chromatography over silica gel (60-120 mesh), using 100% hexane afforded pure (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester as a colorless oil.

C. [4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester

A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]+.

D. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester

A solution of the title C compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (15 g, 0.046 mol) in a mixture of THF (60 mL) and DMTP (10 mL) is cooled to −78° C. under nitrogen. The resulting solution is stirred at −78° C. for 45 min and to this is added LDA (25.6 mL, 6.40 g, 0.059 mol, 25% solution in THF/Hexane). A solution of iodomethylcyclopentane (11.60 g, 0.055 mol) in a mixture of DMTP (12 mL) and THF (20 mL) is added over a period of 15 min at −78° C. and reaction mixture stirred at −78° C. for 3 h further, followed by stirring at 25° C. for 12 h. The reaction mixture is then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) and is concentrated in vacuo. The residue is diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic solution is washed with a saturated aqueous sodium chloride (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography over silica gel (60-120 mesh), using 50% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 1.2 (t, J=7.1, 3H), 2.3 (s, 3H), 2.5 (br s, 4H), 3.0 (br s, 4H), 3.6 (m, 1H), 4.1 (q, J=7.1, 2H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H); MS 409 [M+1]+.

E. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid

A solution of the title D compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester (14 g, 0.034 mol) in methanol:water (30 mL:10 mL) and sodium hydroxide (4.11 g, 0.10 mol) is stirred at 60° C. for 8 h in an oil bath. The methanol is then removed in vacuo at 45-50° C. The residue is diluted with water (25 mL) and extracted with ether (1×40 mL). The aqueous layer is acidified to pH 5 with 3 N aqueous hydrochloric acid solution. The precipitated solid is collected by vacuum filtration, washed with water (20 mL), followed by isopropyl alcohol (20 mL). Finally, solid cake is washed with 100 mL of hexane and dried under vacuum at 40° C. for 6 h to give 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.1-2.0 (m, 11H), 2.4 (s, 3H), 2.7 (br s, 4H), 3.1 (br s, 4H), 3.6 (m, 1H), 7.5 (d, J=8.3, 2H), 7.6 (d, J=8.3, 2H); MS 381 [M+l]+.

F. 5-Methoxy-thiazolo[5,4-b]pyridin-2-ylamine

A solution of 6-methoxy-pyridin-3-ylamine (5.0 g, 0.0403 mol) in 10 mL of acetic acid is added slowly to a solution of potassium thiocyanate (20 g, 0.205 mol) in 100 mL of acetic acid at 0° C. followed by a solution of bromine (2.5 mL, 0.0488 mol) in 5 mL of acetic acid. The reaction is stirred for 2 h at 0° C. and then allowed to warm to RT. The resulting solid is collected by filtration and washed with acetic acid, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The insoluble material is removed by filtration and the organic layer is evaporated and dried to afford 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a tan solid.

G. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A solution of the title E compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (5 g, 0.013 mol) in DCM (250 mL) is cooled to 0° C. and then charged HOBt hydrate (2.66 g, 0.019 mol), followed by EDCI hydrochloride (6 g, 0.031 mol). The reaction mixture is stirred at 0° C. for 5 h. After that the solution of the title F compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.36 g, 0.013 mol) and D1EA (8 mL, 0.046 mol) in a mixture of DCM (60 mL) and DMF (20 mL) is added dropwise over 30 min. Reaction temperature is maintained at 0° C. for 3 h, then at RT (28° C.) for 3 days. Reaction is diluted with (60 mL) of water and the organic layer is separated and washed with saturated sodium bicarbonate solution (2×50 mL) followed by water washing (2×50 mL) and saturated sodium chloride aqueous solution (1×150 mL). Finally the organic layer is dried over sodium sulfate, filtered, and evaporated under vacuo. The crude product is purified using column chromatography over silica gel (60-120 mesh), using 40% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 2.2 (s, 3H), 2.5 (br s, 4H), 3.1 (br s, 4H), 3.7 (m, 1H), 4.0 (s, 3H), 6.8 (d, J=8.8, 1H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H), 7.8 (d, J=8.8, 1H), 8.6 (s, 1H); MS 617 [M+1]+.

H. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride

The title G compound, 3-cyclopentyl-2-(4-methyl piperazinyl sulfonyl)phenyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)propionamide (2.8 g, 0.0051 mol) is added to a cooled solution of 10% hydrochloric acid in isopropanol (3.75 mL). The reaction mixture is stirred at 0° C. for 1 h and then at RT for 2 h. The solid is separated, triturated with 10 mL of isopropanol and collected by vacuum filtration and washed with 50 mL of hexane. The solid is dried at 70° C. for 48 h to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride as an off white solid.

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4° C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.

EXAMPLE 3 (S)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is prepared analogously to Example 2.

J MED CHEM 2009, 52, 6142-52

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139
Torrent Research Centre, Village Bhat, Gujarat, India
J. Med. Chem., 2009, 52 (19), pp 6142–6152
DOI: 10.1021/jm900839k

http://pubs.acs.org/doi/abs/10.1021/jm900839k

Abstract Image

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10−15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the β-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (αKa = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

STR3

STR3

PATENT

EP-1735322-B1

Example 2(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Image loading...

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4°C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250 x 20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min / %B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.

REFERENCES

US 7750020

WO-2005095418-A1

US-20080103167-A1

1 to 2 of 2
Patent ID Date Patent Title
US2015218151 2015-08-06 NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020 2010-07-06 Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

 

 PAPER

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139
Torrent Research Centre, Village Bhat, Gujarat, India
J. Med. Chem., 2009, 52 (19), pp 6142–6152
DOI: 10.1021/jm900839k
Publication Date (Web): September 11, 2009
Copyright © 2009 American Chemical Society
*To whom correspondence should be addressed. Phone: (617) 871 7302. Fax: (617) 871 7042. E-mail: greg.bebernitz@novartis.com.

Abstract Image

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10−15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the β-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (αKa = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

str1

https://www.google.com/patents/US7750020

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4° C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.
Patent ID Date Patent Title
US2015218151 2015-08-06 NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020 2010-07-06 Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

 

Torrent Research Centre, Village Bhat, Gujarat, India

Mr. Samir Mehta, 52, is the Vice Chairman of the USD 2.75 billion Torrent Group and Chairman of Torrent Pharma

Mr. Sudhir Mehta - Executive Chairman

 

 

 

 

 

 

 

 

 

Shri Sudhir Mehta – Chairman Emeritus ::

Dr. Chaitanya Dutt – Director (Research & Development) ::
Dr. Chaitanya Dutt - Director (R&D)Born in the year 1950, Dr. Chaitanya Dutt holds an MD in Medicine. He practiced as a consulting physician before joining the company in 1982. Since then he has been associated with the Company. His rich experience spans in the areas of Pharma R&D, clinical research, manufacturing, quality assurance, etc. He is one of the key professionals in the top management team of the Company. He has been instrumental in setting up the Torrent Research Centre (TRC), the research wing of the Company. Under his prudent guidance and leadership, TRC has achieved tremendous progress in the areas of discovery research as well as development work on formulations. He does not hold any directorship in any other company.

 

 

 

///NOVARTIS, DIABETES, Sulfonamide-Thiazolpyridine Derivatives,  Glucokinase Activators, Treatment Of Type 2 Diabetes, 866772-52-3, Novartis Molecule, functionally liver selective glucokinase activators, treatment of type 2 diabetes , NVP-LBX192, LBX-192

c1(sc2nc(ccc2n1)OC)NC(C(c3ccc(cc3)S(=O)(=O)N4CCN(CC4)C)CC5CCCC5)=O

Therapeutic Effect of Amaranthus hybridus on Diabetic Nephropathy


Diabetes Nephropathy, a chronic metabolic complication of diabetes mellitus, is characterized by elevated levels of serum glucose,creatinine, urea and uric acid in addition to abnormal histopathological changes in kidney. In the recent past, many antidiabetic agents are introduced; still the diabetes and the related nephropathy complication continue to be a major medical problem, not only in developed countries but also in developing countries. Not with standing much research work, the diabetic kidney damages are increasing rapidly and patients with diabetes kidney failure undergo either painful dialysis or kidney transplantation [1] which is both costly and harmful. More and more interest is now growing about plant use as an alternative therapy for protecting kidney damage in patients with diabetes mellitus. Reactive oxygen species (ROS) have been widely implicated in the pathogenicity of diabetes mellitus and its nephropathy. A number of clinical studies suggest that the antioxidants in medicinal plants are key factors in reducing the incidence of diabetic nephropathy. Traditional medicines and extracts from medicinal plants with antioxidant potential have been extensively used as alternative medicine for better control and management of diabetes nephropathy [2]. However, searching for new antidiabetic drugs with nephroprotective properties from natural plants is currently very important.
Amaranthus hybridus L. (Amaranthaceae) commonly known as ‘Cheera’ in Malayalam, is an erect branched annual herb distributed throughout tropical and temperate regions of India as a common weed in the agricultural fields and wastelands. In traditional medicinal system different parts of the plant Amaranthus hybridus (A. hybridus) have been mentioned to be useful in a variety of diseases. Traditionally, the plant has been used in treating dysentery, diarrhoea, ulcers and hemorrhage of the bowel due to its astringent property [35]. In southern India, the leaves are used in folk medicine for the treatment of diabetes. Leaves possess antibacterial effect, cleansing effect and also help to reduce tissue swelling [5]. In Nigeria, A. hybridus leaves combined with condiments are used to prepare soup [68]. In Congo, their leaves are eaten as spinach or green vegetables [6,9]. These leaves boiled and mixed with a groundnut sauce are eaten as salad in Mozambique and in West Africa [10,11]. The Amaranthus species contains amaranthine, quercetin, and kaempferol glycosides [12].A. hybridus leaves are used as an antidote for snake and scorpion bite [13,14].
Amaranthus species were of great importance in pre-Colombian American people’s diets [15] and A. cruentus and A. hybridus have a high nutritional value [16] (Fernand et al.). The consumption of A. cruentus products is advised for patients with celiac disease and, therefore, also for diabetic persons [17]. A. hybridus has been used traditionally for the treatment of liver infections and knee pain and for its laxative, diuretic, and cicatrisation properties [16].
Furthermore, recent studies established theantihyperglycemic activities of other species of Amaranthus genus as A. spinosus [18] and A. viridis [19,20]. However, based on the literature survey, there is no scientific report proving the anti-hyperglycemic efficacy of this particular species. Therefore, the current study was designed to evaluate the nephroprotective activity of Amaranthus hybridus in STZ induced diabetic rats.

Therapeutic Effect of Amaranthus hybridus on Diabetic Nephropathy

Balasubramanian T* and Karthikeyan M
Department of Pharmacology, Al Shifa College of Pharmacy, Kerala, India
Corresponding Author : Dr. Thirumalaiswamy Balasubramanian
Department of Pharmacology
Al Shifa College of Pharmacy
Poonthavanam Post, Kizhattur Village
Perinthalmanna, Malappuram Dist
Kerala-679 325, India
Tel: +919544496752
E-mail: tbaluanandhi@gmail.com
Received December 29, 2015; Accepted January 07, 2016; Published January 14, 2016
Citation: Balasubramanian T and Karthikeyan M (2016) Therapeutic Effect of Amaranthus hybridus on Diabetic Nephropathy. J Develop Drugs 5:147.doi:10.4172/2329-6631.1000147

SEE

http://www.omicsgroup.org/journals/therapeutic-effect-of-amaranthus-hybridus-on-diabetic-nephropathy-2329-6631-1000147.php?aid=67002

balasubramanian.jpg

Dr. T. Balasubramanian

Karthikeyan M

http://alshifacollegeofpharmacy.com/teaching-faculty.html

Map of Kizhattur Village Perinthalmanna

////////Therapeutic Effect, Amaranthus hybridus,  Diabetic Nephropathy, AYURVEDA

Final WHO Guidance Document on Good Data and Record Management Practices


DRUG REGULATORY AFFAIRS INTERNATIONAL

The WHO has just released the  the final version of the important guideline “Good Data and Record Management Practices“.

http://www.gmp-compliance.org/enews_05418_Final-WHO-Guidance-Document-on-Good-Data-and-Record-Management-Practices_15488,15637,Z-COVM_n.html

We recently informed you about the WHO Draft Guidance on Good Data and Record Management Practices. Now, the WHO has just released the  the final version of this important guideline “Good Data and Record Management Practices”.

The final version is sectioned rather similar to the draft version:

– Introduction
– Aims and objectives of this guidance
– Glossary
– Principles
– Quality risk management to ensure good data management
– Management governance and quality audits
– Contracted organizations, suppliers and service providers
– Training in good data and record management
– Good documentation practices
– Designing and validation systems to assure data quality and reliability
– Managing data and records throughout  the data lifecycle
– Addressing data reliability issues
– References and further reading

Although the individual chapters were…

View original post 208 more words

Revision of the general Chapter on Pharmaceutical Water in the US Pharmacopoeia


DRUG REGULATORY AFFAIRS INTERNATIONAL

The 2nd supplement of USP39 NF34 comprises the revised version of the chapter on pharmaceutical water of the US Pharmacopoeia <1231> Water for pharmaceutical purposes.

http://www.gmp-compliance.org/enews_05410_Revision-of-the-general-Chapter-on-Pharmaceutical-Water-in-the-US-Pharmacopoeia_15160,15266,15221,15612,Z-PEM_n.html

The 2nd supplement of USP39 NF34 comprises the revised version of the chapter on pharmaceutical water of the US Pharmacopoeia <1231> Water for pharmaceutical purposes. The first draft version had already been published in September 2015 in the USP Pharmacopeial Forum 41(5).

First of all: there are no new or revised specifications of individual test parameters or new requirements. But the chapter has been revised structurally to ensure better readability. In addition there are now also details regarding feed water as well as for the validation and on action and warning limits. With a chapter number greater than 1000 the Chapter <1231> is not binding, but has a recommending character. The recommended temperature for hot sanitising was changed. So far temperatures of 80…

View original post 85 more words

Indian API Manufacturers remain in the Focus of European GMP Inspectors


DRUG REGULATORY AFFAIRS INTERNATIONAL

Some time ago three Non-Compliance Reports have been published in quick succession in the EudraGMDP database. Those reports deal with inspections performed at pharmaceutical APIs production sites located in India. Read more about the fundamental violations of the requirements for GMP-compliant API manufacturing in those facilities.

http://www.gmp-compliance.org/enews_05414_Indian-API-Manufacturers-remain-in-the-Focus-of-European-GMP-Inspectors_15339,15332,S-WKS_n.html

The EudraGMDP database contains more and more frequently Non-Compliance Reports of API facilities located in India. Three of these reports were published in April and May this year. The companies inspected (Krebs Biochemicals & Industries Ltd, J P Laboratories Private Ltd and Dhanuka Laboratories Ltd) were accused of major violations of the GMP rules (in one case even a critical violation was observed). All in all, the GMP inspectors came to the conclusion that – in their current states – those facilities are not able to manufacture APIs in a GMP-compliant way.

At all three companies, deficiencies against the fundamental requirements for GMP-compliant…

View original post 199 more words

Recilisib Sodium, EX-RAD


Recilisib Sodium

Phase I

C16H12ClNaO4S
Molecular Weight: 358.771849 g/mol

Recilisib sodium.png

A protein kinase inhibitor potentially for the treatment of acute radiation syndrome.

sodium;4-[(E)-2-[(4-chlorophenyl)methylsulfonyl]ethenyl]benzoate

Onc-01210; ON-01210.Na, Ex-RAD; ON 01210.Na; ON-01210; ON-01210-Na; Recilisib

CAS No. 334969-03-8(free)

CAS 922139-31-9(Recilisib sodium)

Benzoic acid, 4-[(1E)-2-[[(4-chlorophenyl)methyl]sulfonyl]ethenyl]-, sodium salt (1:1)

Onconova Therapeutics Inc, Univ Temple INNOVATOR

Stephen C Cosenza, Lawrence Helson,Premkumar E Reddy, Ramana M V Reddy  INVENTORS

Company Onconova Therapeutics Inc.
Description Synthetic, low molecular weight radioprotectant that modulates DNA repair pathways
Molecular Target DNA
Mechanism of Action Radioprotectant
Therapeutic Modality Small molecule
Latest Stage of Development Phase I
Standard Indication Poisoning
Indication Details Prevent radiation poisoning; Provide radation protection; Treat and prevent acute radiation syndrome (ARS)
  • Originator Onconova Therapeutics
  • Class Radioprotectives; Small molecules; Sulfonamides
  • Mechanism of Action Apoptosis inhibitors; Protein kinase inhibitors
  • Orphan Drug Status Yes – Acute radiation syndrome
  • Phase I Acute radiation syndrome

Most Recent Events

  • 22 Apr 2016 Phase I development is ongoing in the US (PO & SC)
  • 20 Mar 2014 Recilisib receives Orphan Drug status for Acute radiation syndrome in USA
  • 03 Oct 2012 Phase-I clinical trials in Acute radiation syndrome in USA (PO)

Ex-Rad (or Ex-RAD), also known by the code name ON 01210.Na, or recilisib sodium (INN, USAN) is a drug developed by Onconova Therapeutics and the U.S. Department of Defense.[1][2] This newly developed compound is said to be a potent radiation protection agent.  Chemically, it is the sodium salt of 4-carboxystyryl-4-chlorobenzylsulfone.[3]

Clinical trials

The results of two Phase I clinical studies in healthy human volunteers indicate that subcutaneously injected Ex-Rad is safe and well tolerated, with “no evidence of systemic side effects”.[4] A study in mice demonstrated the efficacy of Ex-Rad by increasing the survival rate of mice exposed to typically lethal whole-body irradiation. The study tested oral and parenteral administration of Ex-Rad for both pre- and post-exposure radiomitigation.[1]

Research on Ex-Rad has involved collaboration with the Armed Forces Radiobiology Research Institute (AFRRI), the Department of Biochemistry and Molecular & Cellular Biology at Georgetown University, Long Island University‘s Arnold & Marie Schwartz College of Pharmacy, and the Department of Oncological Sciences at the Mt. Sinai School of Medicine.[1]

Mechanism of action

Onconova suggests that Ex-Rad protects cells exposed to radiation against DNA damage, and that the drug’s mechanism of action does not involve scavenging free radicals or arresting the cell cycle. Instead, they claim it employs a “novel mechanism” involving “intracellular signaling, damage sensing, and DNA repair pathways”.[4] Ex-RAD is a chlorobenzylsulfone derivative that works after free radicals have damaged DNA. Onconova CEO Ramesh Kumar believes this is a better approach than trying to scavenge free radicals. “Free radicals are very short-lived, and so the window of opportunity to give a drug is very narrow,” he says. In cell and animal models, Ex-RAD protects hematopoieticand gastrointestinal tissues from radiation injury when given either before or after exposure.[5]

While anti-radiation suits or other protective gear may be effective at reducing radiation exposure, such gear is expensive, unwieldy, and generally not available to public. Moreover, radioprotective gear will not protect normal tissue adjacent to a tumor from stray radiation exposure during radiotherapy. Pharmaceutical radioprotectants offer a cost-efficient, effective and easily available alternative to radioprotective gear. However, previous attempts at radioprotection of normal cells with pharmaceutical compositions have not been entirely successful. For example, cytokines directed at mobilizing the peripheral blood progenitor cells confer a myeloprotective effect when given prior to radiation (Neta et al., Semin. Radiat. Oncol. 6:306-320, 1996), but do not confer systemic protection. Other chemical radioprotectors administered alone or in combination with biologic response modifiers have shown minor protective effects in mice, but application of these compounds to large mammals was less successful, and it was questioned whether chemical radioprotection was of any value (Maisin, J. R., Bacq and Alexander Award Lecture. “Chemical radioprotection: past, present, and future prospects”, Int J. Radiat Biol. 73:443-50, 1998). Pharmaceutical radiation sensitizers, which are known to preferentially enhance the effects of radiation in cancerous tissues, are clearly unsuited for the general systemic protection of normal tissues from exposure to ionizing radiation.

The major biological effects of radiation exposure are the destruction of bone marrow cells, gastrointestinal (GI) damage, lung pneumonitis, and central nervous system (CNS) damage. The long-term effects of radiation exposure include an increase in cancer rates. It has been estimated that the exposure of 100 rems (roentgen equivalent man: a measurement used to quantify the amount of radiation that would produce harmful biological effects) would produce ARS symptoms. Exposure levels above 300 rems would result in the death of approximately 50% of the exposed population.

The α,β-unsaturated aryl sulfones, in particular benzyl styryl sulfones, provide significant and selective systemic protection of normal cells from radiation-induced damage in animals. When used in radiotherapy techniques, these compounds also exhibit independent toxicity to cancer cells. These α,β-unsaturated aryl sulfones, in particular benzyl styryl sulfones, are described in U.S. Pat. Nos. 6,656,973 and 6,667,346, which are particularly incorporated herein by reference in their entirety. Although these compounds are stable in solid state their aqueous formulations for parenteral administration are pH sensitive and pose challenging hurdles to overcome physical stability. The most likely causative factor may be attributed to the reactive styryl sulfone conjugated double bond, which is prone to Michael addition by nucleophiles and eventual fallout of the conjugated addition product.

U.S. Patent No. 6,656,973, describes in vitro pharmacological effects of DMSO solubilization of a benzyl styryl sulfone (e.g. ON 01210.NA) but fails to disclose a composition comprising ON 01210. NA formulation and specifically, a shelf stable formulation which is suitable for administration to humans.

PCT Application WO 2007/016201 describes pharmaceutical solution compositions for parenteral administration for reducing toxic effects of ionizing radiation in a subject, comprising an effective amount of at least one radioprotective α,β-Unsaturated aryl sulfone, and at least one component selected from the group consisting of a) a water soluble polymer in an amount between about 0.5% and about 90% w/v, b) at least one chemically modified cyclodextrin in an amount between about 20% and about 60% w/v, and c) DMA in an amount between 10% and about 50% w/v.

U.S. Patent Application 20090247624, and corresponding PCT Application WO 2008/105808, are directed to aqueous solutions, which comprise between about 20 mg/ml to about 100 mg/ml of at least one α,β-unsaturated aryl sulfone (e.g., the compound ON 01210. Na ((E)-4-Carboxystyryl-4-chlorobenzylsulfone sodium salt, a cosolvent in an amount between about 25% and about 90% w/v (e.g., about 50% PEG 400), wherein the composition is buffered and exists within the range of about pH 7.0 to about pHIO (e.g., 0.2M Tris-EDTA, pH about 8.5). The aforementioned solution formulations have exhibited a sub-optimal shelf life and lack a preferred degree of solubility and/or stability. These formulations evolved progressively as a result of addressing the most challenging aspects in the formulation and drug development field, namely, solubility and stability parameters that defined the long term viability of these formulations. There seems to be a delicate balance between pH, solubility and stability of the active moiety in aqueous milieu, wherein achieving such balance and development of a shelf stable aqueous formulation has presented a formidable challenge. Therefore, a shelf stable effective solution formulation that prevents the breakdown of the therapeutically active entity and keeps the drug in the solution at the desired pH was most desired and significant effort was directed towards this goal.

What is needed therefore, is a shelf stable effective solution formulation of radioprotective α,β-unsaturated aryl sulfones that prevents the breakdown of the therapeutically active entity and keeps the drug in the solution at the desired pH. This invention solves these and other long felt needs by providing improved solution formulation of radioprotective α,β- unsaturated aryl sulfones having improved physical and chemical stability and enhanced shelf life.

SYNTHESIS BY WORLDDRUGTRACKER

STR1

PATENT

WO 2011119863

An exemplary species of a radioprotective α,β-unsaturated aryl sulfone is ON 01210.Na. ON 01210.Na is a derivative of chlorobenzylsulfone. This compound is described in U.S. Pat. Nos. 6,656,973 and 6,667,346 as exhibiting valuable prophylactic properties which mitigate the effects of accidental and intentional exposure to life-threatening levels of irradiation. Hence, a systematic development of this compound is described with the objective of developing a shelf stable formulation.

Table 1 describes the general physical properties of ON. 1210. Na. The exemplary compound is a sodium salt of (E)-4-Carboxystyryl-4-chlorobenzylsulfone.

TABLE 1

Physical Properties of ON.1210.Na

Chemical Structure

Figure imgf000018_0001

Chemical Name (E)-4-Carboxystyryl-4-chlorobenzylsulfone,

Sodium Salt

Empirical Formula C16H12ClNa04S

Molecular Weight 358.79

Physical Nature White crystalline flakes

Melting Point 354-356° C.

Solubility Soluble in water at 8-10 mg/ml

The compound ON 01210. Na appears to form at least one polymorph. X-ray diffraction pattern, for example, of precipitated ON 01210. Na is different from that of the originally synthesized compound. Polymorphs of ON 01210.Na are intended to be within the scope of the claims appended hereto.

EXAMPLE 1

Preparation of ON 01210. Na

4-Chlorobenzyl-4-carboxystyryl sulfone (ON 01210) (49 g; 0.145 mol) was taken in a one-liter conical flask and 500 ml of distilled water was added. Sodium hydroxide solution (16 ml: 10 M stock) (0.150 mol.) was added to the conical flask. The contents of the flask were then boiled with stirring till ON 01210 was completely dissolved. The solution was then cooled to room temperature and shining crystals separated were filtered through a fluted filter paper. The crystalline material was dried under vacuum to yield (48 g) (92% yield) of pure ON 1210. Na.

EXAMPLE II

Preparation of ON 01210. Na Formulation A (Without Vitamin E TPGS)

TRIS (968.0 mg), EDTA (233.8 mg), and deionized (DI) water (24 ml) were combined in a beaker equipped with a Teflon coated stirring bar. The mixture was stirred until complete dissolution occurred, and the resulting solution was covered with aluminum foil and allowed to stir gently overnight at room temperature. The following morning, PEG 400 NF (40.0 ml) was added to the TRIS/EDTA aqueous solution with continued stirring. The vessel containing PEG 400 NF was rinsed with DI water (2 x 3.2 ml), and the rinsate added to the formulation mixture. After stirring the mixture to homogeneity (approx. 10 minutes), the pH was measured to be 9.46 using a calibrated electronic pH meter. The pH was adjusted to 8.37 (target pH = 8.40) by the careful addition of 98 pipet drops of 1.0 M HCl (aq) with stirring and allowed to fully equilibrate over a 10-15 minute period. Once the pH steadied at 8.37, ON 01210. Na (4.0 g) was added to the stirring formulation mixture. Complete dissolution required vigorous stirring and brief periodic sonication to break up ON 01210.Na clumps over a two hour period. After complete dissolution of ON 01210. Na, DI water (approx. 5 ml) was added to bring the final volume to approximately 80 milliliters. The pH of the resulting solution was determined to be 8.31, and thus 20 pipet drops of 1.0N NaOH(aq) were added to adjust the final formulation batch (defined as ON 01210.Na Formulation A) pH to 8.41-8.42. Formulation A was 0.22 micron filtered using a 100 ml Gastight Syringe equipped with a Millex®GP filter unit (Millipore Express® PES Membrane; Lot No R8KN13888).

PATENT

WO 2008105808

PATENT

WO 2007016201 

PATENT

WO 2002069892

The α,β unsaturated aryl sulfones are characterized by cis-trans isomerism resulting from the presence of one or more double bonds. The compounds are named according to the Cahn-Ingold-Prelog system, the IUPAC 1974 Recommendations, Section E: Stereochemistry, in Nomenclature of Organic Chemistry, John Wiley & Sons, Inc., New York, NY, 4th ed., 1992, p.

127-138. Stearic relations around a double bond are designated as “Z” or “E”.

(E)-α,β unsaturated aryl sulfones may be prepared by Knoevenagel condensation of aromatic aldehydes with benzylsulfonyl acetic acids or arylsulfonyl acetic acids. The procedure is described by Reddy et al, Ada. Chim. Hung. 115:269-71 (1984); Reddy et al, Sulfur Letters 13:83-90 (1991); Reddy et al, Synthesis No. 4, 322-23 (1984); and Reddy et al, Sulfur Letters 7:43-48 (1987), the entire disclosures of which are incorporated herein by reference.
According to the Scheme 1 below, Ra and Rb each represent from zero to five substituents on the depicted aromatic nucleus. For purposes of illustration, and not limitation, the aryl groups are represented as phenyl groups, that is, the synthesis is exemplified by the preparation of styryl benzylsulfones. Accordingly, the benzyl thioacetic acid B is formed by the reaction of sodium thioglycollate and a benzyl chloride A. The benzyl thioacetic acid B is then oxidized with 30% hydrogen peroxide to give a corresponding benzylsulfonyl acetic acid C. Condensation of the benzylsulfonyl acetic acid C with an aromatic aldehyde D via a Knoevenagel reaction in the presence of benzylamine and glacial acetic acid yields the desired (E)-styryl benzylsulfone E.

Scheme 1

The following is a more detailed two-part synthesis procedure for preparing (E)-styryl benzylsulfones according to the above scheme.

General Procedure 1: Synthesis (E)-Styryl Benzylsulfones
Part A. To a solution of (8g, 0.2 mol) sodium hydroxide in methanol (200 ml), thioglycollic acid (0.1 mol) is added slowly and the precipitate formed is dissolved by stirring the contents of the flask. Then an appropriately substituted benzyl chloride (0.1 mol) is added stepwise and the reaction mixture is refluxed for 2-3 hours. The cooled contents are poured onto crushed ice and neutralized with dilute hydrochloric acid (200 ml). The resulting corresponding benzylthioacetic acid (0.1 mol) is subjected to oxidation with 30% hydrogen peroxide (0.12 mol) in glacial acetic acid (125 ml) by refluxing for 1 hour. The contents are cooled and poured onto crushed ice. The separated solid is recrystalized from hot water to give the corresponding pure benzylsulfonylacetic acid.
Part B. A mixture of the benzylsulfonyl acetic acid (10 mmol), an appropriately substituted aromatic aldehyde (10 mmol), and benzylamine (0.2 ml) in glacial acetic acid (12 ml) is refluxed for 2-3 hours. The contents are cooled and treated with cold ether (50 ml). Any product precipitated out is separated by filtration. The filtrate is diluted with more ether and washed successively with a saturated solution of sodium bicarbonate (20 ml), sodium bisulfite (20 ml), dilute hydrochloric acid (20 ml) and finally with water (35 ml). Evaporation of the dried ethereal layer yields styryl benzylsulfones as a solid material.

According to an alternative to Part A, the appropriate benzylsulfonylacetic acids may be generated by substituting a thioglycollate

HSCH2COOR for thioglycollic acid, where R is an alkyl group, typically C1-C6 alkyl. This leads to the formation of the alkylbenzylthioacetate intermediate (F),

which is then converted to the corresponding benzyl thioacetic acid B by alkaline or acid hydrolysis.

(E)-styryl phenyl sulfones (formula I: n=zero; Qls Q2 = substituted or unsubstituted phenyl) are prepared according to the method of General Procedure 1, replacing the benzylsulfonyl acetic acid in Part B with the appropriate substituted or unsubstituted phenylsulfonyl acetic acid.

(Z)-Styryl benzylsulfones are prepared by the nucleophilic addition of the appropriate thiols to substituted phenylacetylene with subsequent oxidation of the resulting sulfide by hydrogen peroxide to yield the (Z)-styryl benzylsulfone. The procedure is generally described by Reddy et al., Sulfur Letters 13:83-90 (1991), the entire disclosure of which is incorporated herein as a reference.
In the first step of the (Z)-styryl benzylsulfones synthesis, the sodium salt of benzyl mercaptan or the appropriate substituted benzyl mercaptan is allowed to react with phenylacetylene or the appropriate substituted phenylacetylene forming the pure (Z)-isomer of the corresponding styryl benzylsulfide in good yield.
In the second step of the synthesis, the (Z)-styryl benzylsulfide intermediate is oxidized to the corresponding sulfone in the pure (Z)-isomeric form by treatment with hydrogen peroxide.
The following is a more detailed two-part synthesis procedure for preparing (Z)-styryl benzylsulfones:

Procedure 2: Synthesis of (Z)-Styryl Benzylsulfones
Part A. To a refluxing methanolic solution of substituted or unsubstituted sodium benzylthiolate prepared from 460 mg (0.02g atom) of (i) sodium, (ii) substituted or unsubstituted benzyl mercaptan (0.02 mol) and (iii) 80 ml of absolute methanol, is added freshly distilled substituted or unsubstituted phenylacetylene. The mixture is refluxed for 20 hours, cooled and then poured on crushed ice. The crude product is filtered, dried and recrystalized from methanol or aqueous methanol to yield a pure (Z)- styryl benzylsulfide.
Part B. An ice cold solution of the (Z)- styryl benzylsulfide (3.0g) in 30 ml of glacial acetic acid is treated with 7.5 ml of 30% hydrogen peroxide. The reaction mixture is refluxed for 1 hour and then poured on crushed ice. The separated solid is filtered, dried, and recrystalized from 2-propanol to yield the pure (Z)-styryl benzylsulfone. The purity of the compounds is ascertained by thin layer chromatography and geometrical configuration is assigned by analysis of infrared and nuclear magnetic resonance spectral data.

The bis(styryl) sulfones of formula IN are prepared according to Procedure 3:
Procedure 3
Synthesis of (E)(E)- and (E)(Z)-bis(Styryl) Sulfones
To freshly distilled phenyl acetylene (51.07 g, 0.5 mol) is added sodium thioglycollate prepared from thioglycollic acid (46 g, 0.5 mol) and sodium hydroxide (40 g, 1 mol) in methanol (250 ml). The mixture is refluxed for 24 hours and poured onto crushed ice (500 ml) after cooling. The styrylthioacetic acid, formed after neutralization with dilute hydrochloric acid (250 ml), is filtered and dried; yield 88 g (90%); m.p. 84-86°C.
The styrylthioacetic acid is then oxidized to styrylsulfonylacetic acid as follows. A mixture of styrylthioacetic acid (5 g, 25 mmol) in glacial acetic acid (35 ml) and 30% hydrogen peroxide (15 ml) is heated under reflux for 60 minutes and the mixture is poured onto crushed ice (200 ml) after cooling. The compound separated is filtered and recrystalized from hot water to give white crystalline flakes of (Z)-styrylsulfonylacetic acid; yield 2.4 g (41%); m.p. 150-51°C.
A solution of (Z)-styrylsulfonylacetic acid (2.263 g, 10 m mol) in glacial acetic acid (6 ml) is mixed with an aromatic aldehyde (10 mmol) and benzylamine (0.2 ml) and refluxed for 3 hours. The reaction mixture is cooled, treated with dry ether (50 ml), and any product separated is collected by filtration. The filtrate is diluted with more ether and washed successively with a saturated solution of sodium hydrogen carbonate (15 ml), sodium bisulfite (15 ml), dilute hydrochloric acid (20 ml) and finally with water (30 ml). Evaporation of the dried ethereal layer yields (E)(Z)-bis(styryl)sulfones.
(E),(E)-bis(styryl)sulfones are prepared following the same procedure as described above with exception that sulfonyldiacetic acid is used in place of (Z)-styrylsulfonylacetic acid, and twice the amount of aromatic aldehyde (20 mmol) is used.

The styryl sulfones of formula N, which are systematically identified as 2-(phenylsulfonyl)-l-phenyl-3-phenyl-2-propen-l-ones, may be prepared according to either Method A or Method B of Procedure 4:

Procedure 4
Synthesis of 2-(Phenylsulfonyl)-l-phenyl-3-phenyl-2-propen-l-ones
These compounds are synthesized by two methods which employ different reaction conditions, solvents and catalysts.
Method A: Phenacyl aryl sulfones are made by refluxing α-bromoacetophenones (0.05 mol) and sodium arylsulfinates (0.05 mol) in absolute ethanol (200 ml) for 6-8 hours. The product which separates on cooling is filtered and washed several times with water to remove sodium bromide. The product is then recrystalized from ethanol: phenacyl-phenyl sulfone, m.p. 90-91°C; phenacyl-p-fluorophenyl sulfone, m.p. 148-149°C; phenacyl-p-bromophenyl sulfone, m.p. 121-122°C; phenacyl-p-methoxyphenyl sulfone, m.p. 104-105°C; p-nitrophenacyl-phenyl sulfone, m.p. 136-137°C.
A solution of phenacyl aryl sulfone (0.01 mol) in acetic acid (10 ml) is mixed with an araldehyde (0.01 mol) and benzylamine (0.02 ml) and refluxed for 3 hours. The solution is cooled and dry ether (50 ml) is added. The ethereal solution is washed successively with dilute hydrochloric acid, aqueous 10% NaOH, saturated NaHSO3 solution and water. Evaporation of the dried ethereal layer gives a solid product which is purified by recrystallization.

Method B: Dry tetrahydrofuran (200 ml) is taken in a 500 ml conical flask flushed with nitrogen. To this, a solution of titanium (IN) chloride (11 ml, 0.01 mol) in absolute carbon tetrachloride is added dropwise with continuous stirring. The contents of the flask are maintained at -20°C throughout the course of the addition. A mixture of phenacyl aryl sulfone (0.01 mol) and aromatic aldehyde (0.01 mol) is added to the reaction mixture and pyridine (4 ml, 0.04 mol) in tetrahydrofuran (8 ml) is added slowly over a period of 1 hour. The contents are stirred for 10-12 hours, treated with water (50 ml) and then ether (50 ml) is added. The ethereal layer is separated and washed with 15 ml of saturated solutions of 10% sodium hydroxide, sodium bisulfite and brine. The evaporation of the dried ethereal layer yields 2-(phenylsulfonyl)-l-phenyl-3-phenyl-2 propen-l-ones.

PATENT

https://www.google.com/patents/CN104817488A?cl=en

The structure of this medicine formula (I) shown below,

Figure CN104817488AD00031

Wherein, R1 is absent or is halogen, C1-3 alkyl, alkoxy and -CF3; R2 is absent or is halogen, C1-3 alkyl, alkoxy and -cf3; structural formula (I) The method for the preparation of compounds as follows:

Figure CN104817488AD00041
WO2007016201A2 Jul 28, 2006 Feb 8, 2007 Onconova Therapeutics, Inc. FORMULATION OF RADIOPROTECTIVE α, β UNSATURATED ARYL SULFONES
WO2008105808A2 Jul 27, 2007 Sep 4, 2008 Onconova Therapeutics, Inc. FORMULATIONS OF RADIOPROTECTIVE α, β UNSATURATED ARYL SULFONES
US6656973 Nov 27, 2002 Dec 2, 2003 Temple University – Of The Commonwealth System Of Higher Education (E)-4-carboxystyrl-4-chlorobenzyl sulfone and pharmaceutical compositions thereof
US6667346 Feb 28, 2002 Dec 23, 2003 Temple University – Of The Commonwealth System Of Higher Education Method for protecting cells and tissues from ionizing radiation toxicity with α, β unsaturated aryl sulfones
US6982282 * May 17, 2002 Jan 3, 2006 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US20090247624 Jul 27, 2007 Oct 1, 2009 Onconova Therapeutics Inc. Formulations of radioprotective alpha beta unsaturated aryl sulfones

References

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  3.  Ghosh, Sanchita P.; Perkins, Michael W.; Hieber, Kevin; Kulkarni, Shilpa; Kao, Tzu-Cheg; Reddy, E. Premkumar; Reddy, M. V Ramana; Maniar, Manoj; Seed, Thomas; Kumar, K. Sree (2009). “Radiation Protection by a New Chemical Entity, Ex-Rad™: Efficacy and Mechanisms”. Radiation Research 171 (2): 173–9. doi:10.1667/RR1367.1. PMID 19267542.
  4.  “Ex-RAD® for Protection from Radiation Injury”. Onconova Therapeutics. 2009. Archived from the original on 2011-03-22. Retrieved 2011-03-22.
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  6.  Kouvaris, J. R.; Kouloulias, V. E.; Vlahos, L. J. (2007). “Amifostine: The First Selective-Target and Broad-Spectrum Radioprotector”. The Oncologist 12 (6): 738–47.doi:10.1634/theoncologist.12-6-738. PMID 17602063.
  7.  http://www.news-medical.net/news/20110323/Cellerant-commences-CLT-008-Phase-III-trial-in-patients-with-leukemia.aspx
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  9. Mansour, Heba H.; Hafez, Hafez F.; Fahmy, Nadia M.; Hanafi, Nemat (2008). “Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats”.Biochemical Pharmacology 75 (3): 773–80. doi:10.1016/j.bcp.2007.09.018. PMID 18028880.
  10.  Demirel, C; Kilçiksiz, S; Ay, OI; Gürgül, S; Ay, ME; Erdal, N (2009). “Effect of N-acetylcysteine on radiation-induced genotoxicity and cytotoxicity in rat bone marrow”. Journal of radiation research 50 (1): 43–50. doi:10.1269/jrr.08066. PMID 19218780.
  11.  Demirel, C; Kilciksiz, S; Evirgen-Ayhan, S; Gurgul, S; Erdal, N (2010). “The preventive effect of N-acetylcysteine on radiation-induced dermatitis in a rat model”. Journal of the Balkan Union of Oncology 15 (3): 577–82. PMID 20941831.
  12. Geiger, Hartmut; Pawar, Snehalata A; Kerschen, Edward J; Nattamai, Kalpana J; Hernandez, Irene; Liang, Hai Po H; Fernández, Jose Á; Cancelas, Jose A; Ryan, Marnie A; Kustikova, Olga; Schambach, Axel; Fu, Qiang; Wang, Junru; Fink, Louis M; Petersen, Karl-Uwe; Zhou, Daohong; Griffin, John H; Baum, Christopher; Weiler, Hartmut; Hauer-Jensen, Martin (2012).“Pharmacological targeting of the thrombomodulin–activated protein C pathway mitigates radiation toxicity”. Nature Medicine 18 (7): 1123–9. doi:10.1038/nm.2813. PMC 3491776.PMID 22729286.

External links

Patent ID Date Patent Title
US2015265549 2015-09-24 STABLE AQUEOUS FORMULATION OF (E)-4-CARBOXYSTYRYL-4-CHLOROBENZYL SULFONE
US2015238448 2015-08-27 FORMULATION OF RADIOPROTECTIVE ALPHA, BETA UNSATURATED ARYL SULFONES
US2013012588 2013-01-10 COMPOSITIONS AND METHODS FOR PREVENTION AND TREATEMENT OF WOUNDS
US2013012589 2013-01-10 STABLE AQUEOUS FORMULATION OF (E)-4-CARBOXYSTYRYL-4-CHLOROBENZYL SULFONE
US2011250184 2011-10-13 METHODS FOR DETERMINING EFFICACY OF A THERAPEUTIC REGIMEN AGAINST DELETERIOUS EFFECTS OF CYTOTOXIC AGENTS IN HUMAN
US2011028504 2011-02-03 Formulation of radioprotective alpha beta unsaturated aryl sulfones
US2009247624 2009-10-01 FORMULATIONS OF RADIOPROTECTIVE ALPHA BETA UNSATURATED ARYL SULFONES
Ex-Rad
Ex-rad.png
Identifiers
922139-31-9 Yes
PubChem 23668369
Properties
C16H12ClNaO4S
Molar mass 358.77 g·mol−1

//////////Onc-01210,  ON-01210.Na, 334969-03-8,  922139-31-9, Recilisib Sodium, Phase I , A protein kinase inhibitor,   treatment of acute radiation syndrome, Orphan Drug Status, Ex-RAD

C1=CC(=CC=C1CS(=O)(=O)C=CC2=CC=C(C=C2)C(=O)[O-])Cl.[Na+]

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