AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Belinostat (PXD101), a novel HDAC inhibitor

 FDA 2014, Uncategorized  Comments Off on Belinostat (PXD101), a novel HDAC inhibitor
Jul 232016
 

File:Belinostat.svg

Belinostat (PXD101)

 FAST TRACK FDA , ORPHAN STATUS

PXD101;PX105684;PXD-101;PXD 101;PX-105684
UNII:F4H96P17NZ
N-Hydroxy-3-(3-phenylsulphamoylphenyl)acrylamide
N-HYDROXY-3-[3-[(PHENYLAMINO)SULFONYL]PHENYL]-2-PROPENAMIDE
NSC726630
(E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide
414864-00-9 [RN]
866323-14-0 [RN]
Beleodaq®

Approved by FDA……http://www.drugs.com/newdrugs/fda-approves-beleodaq-belinostat-peripheral-t-cell-lymphoma-4052.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+July+3%2C+2014

July 3, 2014 — The U.S. Food and Drug Administration today approved Beleodaq (belinostat) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The action was taken under the agency’s accelerated approval program.

Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM, with activity demonstrated in cisplatin-resistant tumors.

CLINICAL TRIALS…http://clinicaltrials.gov/search/intervention=Belinostat+OR+PXD101

MP 172–174 °C, (lit.(@) 172 °C). 1H NMR (400 MHz, DMSO-d6) δ = 10.75–10.42 (m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10–7.01 (m, 3H), 6.51 (d, J = 15.8 Hz, 1H). MS (ESI): m/z = 318.6 [M+H] +.

Finn, P. W.; Bandara, M.; Butcher, C.; Finn, A.; Hollinshead, R.; Khan, N.; Law, N.; Murthy, S.; Romero,R.; Watkins, C.; Andrianov, V.; Bokaldere, R. M.; Dikovska, K.; Gailite, V.; Loza, E.; Piskunova, I.;Starchenkov, I.; Vorona, M.; Kalvinsh, I. Helv. Chim. Acta 2005, 88, 1630, DOI: 10.1002/hlca.200590129

Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.

Belinostat was granted orphan drug status for the treatment of Peripheral T-cell lymphoma (PTCL) in the US in September 2009 and the EU in October 2012. In July 2015, an orphan drug designation has also been granted for malignant thymoma in the EU.

Belinostat received its first global approval in the US-FDA on 3 July 2014 for the intravenous (IV) treatment of relapsed or refractory PTCL in adults.

Belinostat was approved by the U.S. Food and Drug Administration (FDA) on July 3, 2014. It was originally developed by CuraGen Pharma,then developed by Spectrum Pharmaceuticals cooperating with Onxeo, then marketed as Beleodaq® by Spectrum.

Beleodaq is a pan-histone deacetylase (HDAC) inhibitor selectively causing the accumulation of acetylated histones and other proteinsin tumor cells. It is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

Beleodaq® is available as lyophilized powder for intravenous infusion, containing 500 mg of free Belinostat. The recommended dose is 1,000 mg/m2 once daily on days 1-5 of a 21-day cycle.

Index:

MW 318.07
MF C15H14N2O4S

414864-00-9  cas no

866323-14-0

(2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]acrylamide

A novel HDAC inhibitor

Chemical structure for belinostat
PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. In 2014, the National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die. PTCL represents about 10 to 15 percent of NHLs in North America.Belinostat inhibits the growth of tumor cells (A2780, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852) with IC50 from 0.2-0.66 μM. PD101 shows low activity in A2780/cp70 and 2780AD cells. Belinostat inhibits bladder cancer cell growth, especially in 5637 cells, which shows accumulation of G0-G1 phase, decrease in S phase, and increase in G2-M phase. Belinostat also shows enhanced tubulin acetylation in ovarian cancer cell lines. A recent study shows that Belinostat activates protein kinase A in a TGF-β signaling-dependent mechanism and decreases survivin mRNA.

Beleodaq works by stopping enzymes that contribute to T-cells, a type of immune cell, becoming cancerous. It is intended for patients whose disease returned after treatment (relapsed) or did not respond to previous treatment (refractory).

“This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval expands the number of treatment options available to patients with serious and life-threatening diseases.”

The FDA granted accelerated approval to Folotyn (pralatrexate) in 2009 for use in patients with relapsed or refractory PTCL and Istodax (romidepsin) in 2011 for the treatment of PTCL in patients who received at least one prior therapy.

The safety and effectiveness of Beleodaq was evaluated in a clinical study involving 129 participants with relapsed or refractory PTCL. All participants were treated with Beleodaq until their disease progressed or side effects became unacceptable. Results showed 25.8 percent of participants had their cancer disappear (complete response) or shrink (partial response) after treatment.

The most common side effects seen in Beleodaq-treated participants were nausea, fatigue, fever (pyrexia), low red blood cells (anemia), and vomiting.

The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs. Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit. Beleodaq also received orphan product designation by the FDA because it is intended to treat a rare disease or condition.

 

BELINOSTAT

Belinostat (trade name Beleodaq, previously known as PXD101) is a histone deacetylase inhibitor drug developed by TopoTargetfor the treatment of hematological malignancies and solid tumors.[2]

It was approved in July 2014 by the US FDA to treat peripheral T-cell lymphoma.[3]

In 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin andpaclitaxel for relapsed ovarian cancer.[4] Final results in late 2009 of a phase II trial for T-cell lymphoma were encouraging.[5]Belinostat has been granted orphan drug and fast track designation by the FDA,[6] and was approved in the US for the use againstperipheral T-cell lymphoma on 3 July 2014.[3] It is not approved in Europe as of August 2014.[7]

The approved pharmaceutical formulation is given intravenously.[8]:180 Belinostat is primarily metabolized by UGT1A1; the initial dose should be reduced if the recipient is known to be homozygous for the UGT1A1*28 allele.[8]:179 and 181

NCI: A novel hydroxamic acid-type histone deacetylase (HDAC) inhibitor with antineoplastic activity. Belinostat targets HDAC enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis. This agent may sensitize drug-resistant tumor cells to other antineoplastic agents, possibly through a mechanism involving the down-regulation of thymidylate synthase

 

The study of inhibitors of histone deacetylases indicates that these enzymes play an important role in cell proliferation and differentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al., 1990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida and Beppu, 1988), reverts the transformed phenotype of different cell lines, and induces differentiation of Friend leukaemia cells and others (Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent the formation of tumours in mice (Finnin et al., 1999).

Trichostatin A (TSA)

Figure imgf000005_0001

Suberoylanilide Hydroxamic Acid (SAHA)

Figure imgf000005_0002

Cell cycle arrest by TSA correlates with an increased expression of gelsolin (Hoshikawa et al., 1994), an actin regulatory protein that is down regulated in malignant breast cancer (Mielnicki et al., 1999). Similar effects on cell cycle and differentiation have been observed with a number of deacetylase inhibitors (Kim et al., 1999). Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts et al., 1998.

Recently, certain compounds that induce differentiation have been reported to inhibit histone deacetylases. Several experimental antitumour compounds, such as trichostatin A (TSA), trapoxin, suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have been reported to act, at least in part, by inhibiting histone deacetylase (see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al., 1993). Additionally, diallyl sulfide and related molecules (see, e.g., Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999), MS-27-275, a synthetic benzamide derivative (see, e.g., Saito et al., 1999; Suzuki et al., 1999; note that MS-27-275 was later re-named as MS-275), butyrate derivatives (see, e.g., Lea and Tulsyan, 1995), FR901228 (see, e.g., Nokajima et al., 1998), depudecin (see, e.g., Kwon et al., 1998), and m-carboxycinnamic acid bishydroxamide (see, e.g., Richon et al., 1998) have been reported to inhibit histone deacetylases. In vitro, some of these compounds are reported to inhibit the growth of fibroblast cells by causing cell cycle arrest in the G1 and G2 phases, and can lead to the terminal differentiation and loss of transforming potential of a variety of transformed cell lines (see, e.g., Richon et al, 1996; Kim et al., 1999; Yoshida et al., 1995; Yoshida & Beppu, 1988). In vivo, phenybutyrate is reported to be effective in the treatment of acute promyelocytic leukemia in conjunction with retinoic acid (see, e.g., Warrell et al., 1998). SAHA is reported to be effective in preventing the formation of mammary tumours in rats, and lung tumours in mice (see, e.g., Desai et al., 1999).

The clear involvement of HDACs in the control of cell proliferation and differentiation suggest that aberrant HDAC activity may play a role in cancer. The most direct demonstration that deacetylases contribute to cancer development comes from the analysis of different acute promyelocytic leukaemias (APL). In most APL patients, a translocation of chromosomes 15 and 17 (t(15;17)) results in the expression of a fusion protein containing the N-terminal portion of PML gene product linked to most of RARσ (retinoic acid receptor). In some cases, a different translocation (t(11 ;17)) causes the fusion between the zinc finger protein PLZF and RARα. In the absence of ligand, the wild type RARα represses target genes by tethering HDAC repressor complexes to the promoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARα and displaces the repressor complex, allowing expression of genes implicated in myeloid differentiation. The RARα fusion proteins occurring in APL patients are no longer responsive to physiological levels of RA and they interfere with the expression of the RA- inducible genes that promote myeloid differentiation. This results in a clonal expansion of promyelocytic cells and development of leukaemia. In vitro experiments have shown that TSA is capable of restoring RA-responsiveness to the fusion RARα proteins and of allowing myeloid differentiation. These results establish a link between HDACs and oncogenesis and suggest that HDACs are potential targets for pharmaceutical intervention in APL patients. (See, for example, Kitamura et al., 2000; David et al., 1998; Lin et al., 1998).

BELINOSTAT

Furthermore, different lines of evidence suggest that HDACs may be important therapeutic targets in other types of cancer. Cell lines derived from many different cancers (prostate, coloreetal, breast, neuronal, hepatic) are induced to differentiate by HDAC inhibitors (Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have been studied in animal models of cancer. They reduce tumour growth and prolong the lifespan of mice bearing different types of transplanted tumours, including melanoma, leukaemia, colon, lung and gastric carcinomas, etc. (Ueda et al., 1994; Kim et al., 1999).

Psoriasis is a common chronic disfiguring skin disease which is characterised by well-demarcated, red, hardened scaly plaques: these may be limited or widespread. The prevalence rate of psoriasis is approximately 2%, i.e., 12.5 million sufferers in the triad countries (US/Europe/Japan). While the disease is rarely fatal, it clearly has serious detrimental effects upon the quality of life of the patient: this is further compounded by the lack of effective therapies. Present treatments are either ineffective, cosmetically unacceptable, or possess undesired side effects. There is therefore a large unmet clinical need for effective and safe drugs for this condition. Psoriasis is a disease of complex etiology. Whilst there is clearly a genetic component, with a number of gene loci being involved, there are also undefined environmental triggers. Whatever the ultimate cause of psoriasis, at the cellular level, it is characterised by local T-cell mediated inflammation, by keratinocyte hyperproliferation, and by localised angiogenesis. These are all processes in which histone deacetylases have been implicated (see, e.g., Saunders et al., 1999; Bernhard et al, 1999; Takahashi et al, 1996; Kim et al , 2001 ). Therefore HDAC inhibitors may be of use in therapy for psoriasis. Candidate drugs may be screened, for example, using proliferation assays with T-cells and/or keratinocytes.

 CLIP

PXD101/Belinostat®

(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.

Figure US20100286279A1-20101111-C00001

PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.

Figure US20100286279A1-20101111-C00002
Figure US20100286279A1-20101111-C00003

PATENT

GENERAL SYNTHESIS

str1

WO2002030879A2

IGNORE 10

Figure imgf000060_0002

ENTRY 45 IS BELINOSTAT

Scheme 1

Figure imgf000101_0001

By using amines instead of aniline, the corresponding products may be obtained. The use of aniline, 4-methoxyaniline, 4-methylaniline, 4-bromoaniline, 4-chloroaniline, 4-benzylamine, and 4-phenethyamine, among others, is described in the Examples below.

In another method, a suitable amino acid (e.g., ω-amino acid) having a protected carboxylic acid (e.g., as an ester) and an unprotected amino group is reacted with a sulfonyl chloride compound (e.g., RSO2CI) to give the corresponding sulfonamide having a protected carboxylic acid. The protected carboxylic acid is then deprotected using base to give the free carboxylic acid, which is then reacted with, for example, hydroxylamine 2-chlorotrityl resin followed by acid (e.g., trifluoroacetic acid), to give the desired carbamic acid.

One example of this approach is illustrated below, in Scheme 2, wherein the reaction conditions are as follows: (i) RSO2CI, pyridine, DCM, room temperature, 12 hours; (ii) 1 M LiOH or 1 M NaOH, dioxane, room temperature, 3-48 hours; (iii) hydroxylamine 2-chlorotrityl resin, HOAt, HATU, DIPEA, DCM, room temperature, 16 hours; and (iv) TFA/DCM (5:95, v/v), room temperature, 1.5 hours.

Scheme 2

Figure imgf000102_0001

Additional methods for the synthesis of compounds of the present invention are illustrated below and are exemplified in the examples below.

Scheme 3A

Figure imgf000102_0002

Scheme 3B

Figure imgf000103_0001

Scheme 4

Figure imgf000104_0001
Figure imgf000105_0001

Scheme 8

Figure imgf000108_0002

Scheme 9

Figure imgf000109_0001

PATENT

SYNTHESIS

WO2002030879A2

Example 1

3-Formylbenzenesulfonic acid, sodium salt (1)

Figure imgf000123_0001

Oleum (5 ml) was placed in a reaction vessel and benzaldehyde (2.00 g, 18.84 mmol) was slowly added not exceeding the temperature of the reaction mixture more than 30°C. The obtained solution was stirred at 40°C for ten hours and at ambient temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The aqueous phase was treated with CaC03 until the evolution of C02 ceased (pH~6-7), then the precipitated CaSO4was filtered off and washed with water. The filtrate was treated with Na2CO3 until the pH of the reaction medium increased to pH 8, obtained CaCO3 was filtered off and water solution was evaporated in vacuum. The residue was washed with methanol, the washings were evaporated and the residue was dried in desiccator over P2Oβ affording the title compound (2.00 g, 51%). 1H NMR (D20), δ: 7.56-8.40 (4H, m); 10.04 ppm (1 H, s).

Example 2 3-(3-Sulfophenyl)acrylic acid methyl ester, sodium salt (2)

Figure imgf000124_0001

Sodium salt of 3-formylbenzenesulfonic acid (1) (1.00 g, 4.80 mmol), potassium carbonate (1.32 g, 9.56 mmol), trimethyl phosphonoacetate (1.05 g, 5.77 mmol) and water (2 ml) were stirred at ambient temperature for 30 min., precipitated solid was filtered and washed with methanol. The filtrate was evaporated and the title compound (2) was obtained as a white solid (0.70 g, 55%). 1H NMR (DMSO- dβl HMDSO), δ: 3.68 (3H, s); 6.51 (1 H, d, J=16.0 Hz); 7.30-7.88 (5H, m).

Example 3 3-(3-Chlorosulfonylphenyl)acrylic acid methyl ester (3)

Figure imgf000124_0002

To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2) (0.670 g, 2.53 mmol) benzene (2 ml), thionyl chloride (1.508 g, 0.9 ml, 12.67 mmol) and 3 drops of dimethylformamide were added and the resultant suspension was stirred at reflux for one hour. The reaction mixture was evaporated, the residue was dissolved in benzene (3 ml), filtered and the filtrate was evaporated to give the title compound (0.6’40 g, 97%).

Example 4 3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a)

Figure imgf000125_0001

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50°C for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCI. The organic layer was washed successively with water, saturated NaCl, and dried (Na2S0 ). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1 , v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). 1H NMR (CDCI3, HMDSO), δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1 H, br s); 6.92-7.89 (10H, m).

Example 5 3-(3-Phenylsulfamoylphenyl)acrylic acid (5a)

Figure imgf000125_0002

3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a) (0.220 g, 0.69 mmol) was dissolved in methanol (3 ml), 1N NaOH (2.08 ml, 2.08 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 10% HCI and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2Os to give the title compound as a white solid (0.173 g, 82%). Example 6 3-(3-Phenylsulfamoylphenyl)acryloyl chloride (6a)

Figure imgf000126_0001

To a suspension of 3-(3-phenylsulfamoylphenyl)acrylic acid (5a) (0.173 g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40°C for one hour and concentrated under reduced pressure to give crude title compound (0.185 g).

Example 7

N-Hydroxy-3-(3-phenylsulfamoylphenyl)acrylamide (7a) (PX105684) BELINOSTAT

Figure imgf000126_0002

To a suspension of hydroxylamine hydrochloride (0.200 g, 2.87 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCOβ solution (2.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a 3-(3-phenylsulfamoylphenyl)acryloyl chloride (6a) (0.185 g) solution in tetrahydrofuran (2.3 ml) was added and stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCI. The organic layer was washed successively with water and saturated NaCl, the solvent was removed and the residue was washed with acetonitrile and diethyl ether.

The title compound was obtained as a white solid (0.066 g, 36%), m.p. 172°C. BELINOSTAT

1H NMR (DMSO-d6, HMDSO), δ: 6.49 (1 H, d, J=16.0 Hz); 7.18-8.05 (10H, m); 9.16 (1 H, br s); 10.34 (1 H, s); 10.85 ppm (1 H, br s).

HPLC analysis on Symmetry C18column: impurities 4% (column size 3.9×150 mm; mobile phase acetonitrile – 0.1 M phosphate buffer (pH 2.5), 40:60; sample concentration 1 mg/ml; flow rate 0.8 ml/ min; detector UV 220 nm).

Anal. Calcd for C154N204S, %: C 56.59, H 4.43, N 8.80. Found, %: C 56.28, H 4.44, N 8.56.

PATENT

https://www.google.com/patents/CN102786448A?cl=en

Example: belinostat (compound of formula I) Preparation of

 

Figure CN102786448AD00092

Methods of operation:

The compound of formula II (4. Og) added to the reactor, was added methanol 30ml, and stirred to dissolve, was added IM aqueous sodium hydroxide solution (38mL), stirred at room temperature overnight, the reaction was completed, ethyl acetate was added (IOmL) ^ K (20mL), stirred for 5 minutes, phase separation, the ethyl acetate phase was discarded, the aqueous phase was acidified with 10% hydrochloric acid to pH2, stirred at room temperature for 30 minutes, filtered, washed with water, and dried to give hydrolyzate 3. lg, yield rate of 81.6%.

 The hydrolyzate (3. Og) added to the reactor, was added methylene chloride (53. 2g), dissolved with stirring, was added oxalyl chloride (2.8mL, 0.0032mol) at room temperature was added I drop DMF, reflux I hours, concentrated and the residue was dissolved in THF (30mL) alternate, the other to take a reaction flask was added hydroxylamine hydrochloride (3. 5g, 0.05mol), THF (50mL), saturated aqueous sodium bicarbonate (40mL), the mixture at room temperature under stirring for 10 minutes, then was added to spare, stirred at room temperature for I hour, the reaction was complete, at – at room temperature was added ethyl acetate (50mL), 2M hydrochloric acid (50mL), stirred for 5 minutes the phases were separated, the aqueous phase was discarded, the organic layer was washed with water, saturated brine, dried, filtered and concentrated to give crude product belinostat, recrystallized from ethyl acetate, 50 ° C and dried for 8 hours to give white crystals 2. 6g, yield 83.8%. .  1H-NMR (DMS0-d6, 400MHz) δ: 6 50 (1H, d, J = 16. OHz); 7 07 (d, J = 7. 8Hz, 2H); 7 16 (t.. , J = 7. 3Hz, 1H);. 7 25 (m, 2H);. 7 45 (t, J = 7. 8Hz, 1H);. 7 60 (d, J = 15. 9Hz, 1H); 7 . 62 (d, J = 7. 7Hz, 1H);. 7 75 (d, J = 7. 8Hz, 1H);. 7 88 (br s. ‘1H);. 9 17 (br s’ 1H); 10. 35 (s, 1H);. 10 82ppm (br s, 1H). ·

str1

 

Step a): Preparation of Compound III

 

Figure CN102786448AD00071

 The carboxy benzene sulfonate (224g, Imol), anhydrous methanol (2300g), concentrated hydrochloric acid (188. 6g) refluxing

3-5 hours, filtered and the filtrate was added anhydrous sodium bicarbonate powder (200g), stirred for I hour, filtered, the filter residue was discarded, the filtrate was concentrated. The concentrate was added methanol (2000g), stirred at room temperature for 30 minutes, filtered and the filtrate was concentrated to dryness, 80 ° C and dried for 4 hours to give a white solid compound III147g, yield 61.8%.

Step b): Preparation of Compound IV

 

Figure CN102786448AD00072

 Compound III (50g, 0. 21mol), phosphorus oxychloride (250mL) was refluxed for 2_6 hours, completion of the reaction, cooled to

0-5 ° C, was slowly added to ice water, stirred for 2 hours and filtered to give a brown solid compound IV40 g, due to the instability of Compound IV, directly into the next reaction without drying.

Preparation of Compound V: [0040] Step c)

 

Figure CN102786448AD00073

The aniline (5. 58g, 0. 06mol) and 30mL of toluene added to the reactor, stirred to dissolve, in step b) the resulting compound IV (7. 05g, O. 03mol) was dissolved in 60 ml of toluene, at room temperature dropwise added to the reactor, the addition was completed, stirring at room temperature for 1-2 hours, the reaction was completed, the filtered solid washed with water, and then recrystallized from toluene, 50 ° C and dried for 4 hours to obtain a white crystalline compound V6. Og, yield 73%. mp:.. 144 4-145 2. . .

 1H- bandit R (CDCl3, 400MHz) δ:…. 3 92 (s, 3H); 6 80 (. Br s, 1H); 7 06-7 09 (m, 2H); 7 11. . -7 15 (m, 1H);.. 7 22-7 26 (m, 2H);. 7 51 (t, J = 7. 8Hz, 1H);.. 7 90-7 93 (dt, J = . 1.2,7 8Hz, 1H); 8 18-8 21 (dt, J = I. 4, 7. 8Hz, 1H);… 8 48 (t, J = L 6Hz, 1H).

 IR v ™ r: 3243,3198,3081,2953,1705,1438,1345,766,702,681cm-1.

 Step d): Preparation of Compound VI

 

Figure CN102786448AD00081

 The anhydrous lithium chloride 2. 32g, potassium borohydride 2. 96g, THF50mL added to the reactor, stirring evenly, Compound V (8g, 0. 027mol) was dissolved in 7mL of tetrahydrofuran, was slowly dropped into the reactor was heated under reflux for 5 hours, the reaction was completed, the force mouth 40mL water and ethyl acetate 40mL, stirred for half an hour, allowed to stand for separation, the organic layer was washed with 40mL water, concentrated under reduced pressure to give the crude product, the crude product was recrystallized from toluene, solid 50 V dried for 4 hours to give a white crystalline compound VI6. 82g, yield 90. O%. mp:.. 98 2-98 6. . .

1H-NMR (DMS0-d6, 400ΜΗζ) δ:….. 4 53 (s, 2H); 5 39 (s, 1H); 6 99-7 03 (m, 1H); 7 08- 7. ll (m, 2H);.. 7 19-7 24 (m, 2H);.. 7 45-7 52 (m, 2H);.. 7 61-7 63 (dt, J = I. 8 , 7 4Hz, 1H);.. 7 79 (br s, 1H);. 10. 26 (s, 1H).

IRv =: 3453,3130,2964,1488,1151,1031, 757,688cm_10

Step e): Preparation of Compound VII

Figure CN102786448AD00082

After Compound VI (7.5g, 0.028mol) dissolved in acetone was added 7ml, dichloromethane was added 60mL, supported on silica gel was added PCC at room temperature 20g, stirred at room temperature for 12-24 hours, the reaction was complete, filtered and the filtrate was purified The layers were separated and the aqueous layer was discarded after the organic phase is washed 30mL5% aqueous sodium bicarbonate, evaporated to dryness under reduced pressure to give the crude product, the crude product was recrystallized from toluene, 50 ° C and dried for 8 hours to give white crystalline compound VII4. 7g, yield 62.7%. mp:.. 128 1-128 5 ° C.

 1H- bandit R (CDCl3,400MHz) δ:…. 7 08-7 15 (m, 4Η); 7 · 23-7 27 (m, 2H); 7 · 60-7 64 (t, J = 7 7Hz, 1Η);.. 8 00 (d, J = 7. 6Hz, 1Η);. 8 04 (d, J = 7. 6Hz, 1Η);. 8 30 (br s’ 1Η).; 10. 00 (S, 1Η).

 IR ν ™ Γ: 3213,3059,2964,2829,1687,1480,1348,1159,1082,758,679cm_10

Preparation of compounds of formula II: [0055] Step f)

 

Figure CN102786448AD00091

 phosphoryl trimethylorthoacetate (2. 93g, 0. 0161mol) added to the reaction vessel, THF30mL, stirring to dissolve, cooled to -5-0 ° C, was added sodium hydride (O. 8g, content 80%) , the addition was completed, stirring for 10-20 minutes, was added dropwise the compound VII (4g, O. 0156mol) and THF (20mL) solution, stirred for 1_4 hours at room temperature, the reaction was complete, 10% aqueous ammonium chloride solution was added dropwise 50mL, and then After addition of 50mL of ethyl acetate, stirred 30min rested stratification, the aqueous layer was discarded, the organic phase was concentrated under reduced pressure to give the crude product, the crude product was recrystallized from methanol 60mL, 50 ° C and dried for 8 hours to give white crystalline compound 113. 6g, yield 75%. mp:.. 152 0-152 5 ° C.

 1H-Nmr (Cdci3JOOmHz) δ:…. 3 81 (s, 3H); 6 40 (d, J = 16. 0Hz, 1H); 6 79 (. Br s, 1H); 7 08 ( d, J = 7. 8Hz, 2H);. 7 14 (t, J = 7. 3Hz, 1H);. 7 24 (m, 2H);. 7 46 (t, J = 7. 8Hz, 1H); 7. 61 (d, J = 16. ΟΗζ, ΙΗ);. 7 64 (d, J = 7. 6Hz, 1H);. 7 75 (d, J = 7. 8Hz, 1H);. 7 89 (br . s, 1H).

IR v ^ :: 3172,3081,2954,2849,1698,1475,1345,1157,773,714,677cm-1.

 

PATENT

SYNTHESIS

US20100286279

Figure US20100286279A1-20101111-C00034

CLIP

SYNTHESIS AND SPECTRAL DATA

Journal of Medicinal Chemistry, 2011 ,  vol. 54,  13  pg. 4694 – 4720

(E)-N-Hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (28, belinostat, PXD101).

http://pubs.acs.org/doi/full/10.1021/jm2003552

 http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf

The methyl ester (27) (8.0 g) was prepared according to reported synthetic route,

(Watkins, C. J.; Romero-Martin, M.-R.; Moore, K. G.; Ritchie, J.; Finn, P. W.; Kalvinsh, I.;
Loza, E.; Dikvoska, K.; Gailite, V.; Vorona, M.; Piskunova, I.; Starchenkov, I.; Harris, C. J.;
Duffy, J. E. S. Carbamic acid compounds comprising a sulfonamide linkage as HDAC
inhibitors. PCT Int. Appl. WO200230879A2, April 18, 2002.)
but using procedure D (Experimental Section) or method described for 26 to convert the methyl ester to crude
hydroxamic acid which was further purified by chromatography (silica, MeOH/DCM = 1:10) to
afford 28 (PXD101) as off-white or pale yellow powder (2.5 g, 31%).

LC–MS m/z 319.0 ([M +H]+).

1H NMR (DMSO-d6)  12–9 (very broad, 2H), 7.90 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.70 (d, J

= 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.08 (d,J = 7.8 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H);

13C NMR (DMSO-d6)  162.1, 140.6, 138.0, 136.5, 135.9, 131.8, 130.0, 129.2, 127.1, 124.8, 124.1, 121.3, 120.4.

Anal.
(C15H14N2O4S) C, H, N

str1

 

 

PATENT

SYNTHESIS

str1

WO2009040517A2

PXDIOI / Belinostat®

(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.

Figure imgf000003_0001

PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.

Scheme 1

Not isolated

Figure imgf000003_0002

ed on (A)

on (D)

Figure imgf000003_0003

d on (H)

Figure imgf000004_0001

There is a need for alternative methods for the synthesis of PXD101 and related compounds for example, methods which are simpler and/or employ fewer steps and/or permit higher yields and/or higher purity product.

Scheme 5

Figure imgf000052_0001

DMAP, toluene

Figure imgf000052_0003
Figure imgf000052_0002
Figure imgf000052_0004

Synthesis 1 3-Bromo-N-phenyl-benzenesulfonamide (3)

Figure imgf000052_0005

To a 30 gallon (-136 L) reactor was charged aniline (2) (4.01 kg; 93.13 g/mol; 43 mol), toluene (25 L), and 4-(dimethylamino)pyridine (DMAP) (12 g), and the mixture was heated to 50-600C. 3-Bromobenzenesulfonyl chloride (1) (5 kg; 255.52 g/mol; 19.6 mol) was charged into the reactor over 30 minutes at 50-600C and progress of the reaction was monitored by HPLC. After 19 hours, toluene (5 L) was added due to losses overnight through the vent line and the reaction was deemed to be complete with no compound (1) being detected by HPLC. The reaction mixture was diluted with toluene (10 L) and then quenched with 2 M aqueous hydrochloric acid (20 L). The organic and aqueous layers were separated, the aqueous layer was discarded, and the organic layer was washed with water (20 L), and then 5% (w/w) sodium bicarbonate solution (20 L), while maintaining the batch temperature at 45-55°C. The batch was then used in the next synthesis.

Synthesis 2 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrylic acid ethyl ester (5)

Figure imgf000053_0001

To the batch containing 3-bromo-N-phenyl-benzenesulfonamide (3) (the treated organic layer obtained in the previous synthesis) was added triethylamine (2.97 kg; 101.19 g/mol; 29.4 mol), tri(o-tolyl)phosphine (119 g; 304.37 g/mol; 0.4 mol), and palladium (II) acetate (44 g; 224.51 g/mol; 0.2 mol), and the resulting mixture was degassed four times with a vacuum/nitrogen purge at 45-55°C. Catalytic palladium (0) was formed in situ. The batch was then heated to 80-900C and ethyl acrylate (4) (2.16 kg; 100.12 g/mol; 21.6 mol) was slowly added over 2.75 hours. The batch was sampled after a further 2 hours and was deemed to be complete with no compound (3) being detected by HPLC. The batch was cooled to 45-55°C and for convenience was left at this temperature overnight.

The batch was then reduced in volume under vacuum to 20-25 L, at a batch temperature of 45-55°C, and ethyl acetate (20 L) was added. The batch was filtered and the residue washed with ethyl acetate (3.5 L). The residue was discarded and the filtrates were sent to a 100 gallon (-454 L) reactor, which had been pre-heated to 600C. The 30 gallon (-136 L) reactor was then cleaned to remove any residual Pd, while the batch in the 100 gallon (-454 L) reactor was washed with 2 M aqueous hydrochloric acid and water at 45-55°C. Once the washes were complete and the 30 gallon (-136 L) reactor was clean, the batch was transferred from the 100 gallon (-454 L) reactor back to the 30 gallon (-136 L) reactor and the solvent was swapped under vacuum from ethyl acetate/toluene to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it. The batch was then cooled to 0-100C and held at this temperature over the weekend in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). A sample of the wet-cake was taken for Pd analysis. The Pd content of the crude product (5) was determined to be 12.9 ppm.

The wet-cake was then charged back into the 30 gallon (-136 L) reactor along with ethyl acetate (50 L) and heated to 40-500C in order to obtain a solution. A sparkler filter loaded with 12 impregnated Darco G60® carbon pads was then connected to the reactor and the solution was pumped around in a loop through the sparkler filter. After 1 hour, a sample was taken and evaporated to dryness and analysed for Pd content. The amount of Pd was found to be 1.4 ppm. A second sample was taken after 2 hours and evaporated to dryness and analysed for Pd content. The amount of Pd had been reduced to 0.6 ppm. The batch was blown back into the reactor and held at 40-500C overnight before the solvent was swapped under vacuum from ethyl acetate to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it and the batch was cooled to 0-100C and held at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum for 25 hours. A first lot of the title compound (5) was obtained as an off-white solid (4.48 kg, 69% overall yield from 3-bromobenzenesulfonyl chloride (1)) with a Pd content of 0.4 ppm and a purity of 99.22% (AUC) by HPLC.

Synthesis 3 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrvlic acid (6)

Figure imgf000054_0001

To the 30 gallon (-136 L) reactor was charged the (E)-3-(3-phenylsulfamoyl-phenyl)- acrylic acid ethyl ester (5) (4.48 kg; 331.39 g/mol; 13.5 mol) along with 2 M aqueous sodium hydroxide (17.76 L; -35 mol). The mixture was heated to 40-50°C and held at this temperature for 2 hours before sampling, at which point the reaction was deemed to be complete with no compound (5) being detected by HPLC. The batch was adjusted to pH 2.2 using 1 M aqueous hydrochloric acid while maintaining the batch temperature between 40-500C. The product had precipitated and the batch was cooled to 20-300C and held at this temperature for 1 hour before filtering and washing the cake with water (8.9 L). The filtrate was discarded. The batch was allowed to condition on the filter overnight before being charged back into the reactor and slurried in water (44.4 L) at 40-500C for 2 hours. The batch was cooled to 15-20°C, held for 1 hour, and then filtered and the residue washed with water (8.9 L). The filtrate was discarded. The crude title compound (6) was transferred to an oven for drying at 45-55°C under vacuum with a slight nitrogen bleed for 5 days (this was done for convenience) to give a white solid (3.93 kg, 97% yield). The moisture content of the crude material was measured using Karl Fischer (KF) titration and found to be <0.1% (w/w). To the 30 gallon (-136 L) reactor was charged the crude compound (6) along with acetonitrile (47.2 L). The batch was heated to reflux (about 80°C) and held at reflux for 2 hours before cooling to 0-10°C and holding at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with cold acetonitrile (7.9 L). The filtrate was discarded and the residue was dried under vacuum at 45-55°C for 21.5 hours. The title compound (6) was obtained as a fluffy white solid (3.37 kg, 84% yield with respect to compound (5)) with a purity of 99.89% (AUC) by HPLC.

Synthesis 4 (E)-N-Hvdroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (PXD101) BELINOSTAT

Figure imgf000055_0001

To the 30 gallon (-136 L) reactor was charged (E)-3-(3-phenylsulfamoyl-phenyl)-acrylic acid (6) (3.37 kg; 303.34 g/mol; 11.1 mol) and a pre-mixed solution of 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in isopropyl acetate (IPAc) (27 g in 30 L; 152.24 g/mol; 0.18 mol). The slurry was stirred and thionyl chloride (SOCI2) (960 mL; density ~1.631 g/mL; 118.97 g/mol; -13 mol) was added to the reaction mixture and the batch was stirred at 20-300C overnight. After 18.5 hours, the batch was sampled and deemed to be complete with no compound (6) being detected by HPLC. The resulting solution was transferred to a 100 L Schott reactor for temporary storage while the

30 gallon (-136 L) reactor was rinsed with isopropyl acetate (IPAc) and water. Deionized water (28.9 L) was then added to the 30 gallon (-136 L) reactor followed by 50% (w/w) hydroxylamine (6.57 L; -1.078 g/mL; 33.03 g/mol; -214 mol) and another charge of deionized water (1.66 L) to rinse the lines free of hydroxylamine to make a 10% (w/w) hydroxylamine solution. Tetrahydrofuran (THF) (6.64 L) was then charged to the

30 gallon (-136 L) reactor and the mixture was stirred and cooled to 0-100C. The acid chloride solution (from the 100 L Schott reactor) was then slowly charged into the hydroxylamine solution over 1 hour maintaining a batch temperature of 0-10°C during the addition. The batch was then allowed to warm to 20-300C. The aqueous layer was separated and discarded. The organic layer was then reduced in volume under vacuum while maintaining a batch temperature of less than 300C. The intention was to distill out 10-13 L of solvent, but this level was overshot. A larger volume of isopropyl acetate (IPAc) (16.6 L) was added and about 6 L of solvent was distilled out. The batch had precipitated and heptanes (24.9 L) were added and the batch was held at 20-30°C overnight. The batch was filtered and the residue was washed with heptanes (6.64 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum with a slight nitrogen bleed over the weekend. The title compound (PXD101) was obtained as a light orange solid (3.11 kg, 89% yield with respect to compound (6)) with a purity of 99.25% (AUC) by HPLC.

The title compound (PXD101) (1.2 kg, 3.77 mol) was dissolved in 8 volumes of 1:1 (EtOH/water) at 600C. Sodium bicarbonate (15.8 g, 5 mol%) was added to the solution. Water (HPLC grade) was then added at a rate of 65 mL/min while keeping the internal temperature >57°C. After water (6.6 L) had been added, crystals started to form and the water addition was stopped. The reaction mixture was then cooled at a rate of 10°C/90 min to a temperature of 0-10cC and then stirred at ambient temperature overnight. The crystals were then filtered and collected. The filter cake was washed by slurrying in water (2 x 1.2 L) and then dried in an oven at 45°C for 60 hours with a slight nitrogen bleed. 1.048 kg (87% recovery) of a light orange solid was recovered. Microscopy and XRPD data showed a conglomerate of irregularly shaped birefringant crystalline particles. The compound was found to contain 0.02% water.

As discussed above: the yield of compound (5) with respect to compound (1) was 69%. the yield of compound (6) with respect to compound (5) was 84%. the yield of PXD101 with respect to compound (6) was 89%.

 

PAPER

Synthetic Commun. 2010, 40, 2520-2524.

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PATENT

FORMULATION

WO2006120456A1

Formulation Studies

These studies demonstrate a substantial enhancement of HDACi solubility (on the order of a 500-fold increase for PXD-101) using one or more of: cyclodextrin, arginine, and meglumine. The resulting compositions are stable and can be diluted to the desired target concentration without the risk of precipitation. Furthermore, the compositions have a pH that, while higher than ideal, is acceptable for use.

Figure imgf000047_0001

UV Absorbance

The ultraviolet (UV absorbance E\ value for PXD-101 was determined by plotting a calibration curve of PXD-101 concentration in 50:50 methanol/water at the λmax for the material, 269 nm. Using this method, the E1i value was determined as 715.7.

Methanol/water was selected as the subsequent diluting medium for solubility studies rather than neat methanol (or other organic solvent) to reduce the risk of precipitation of the cyclodextrin.

Solubility in Demineralised Water

The solubility of PXD-101 was determined to be 0.14 mg/mL for demineralised water. Solubility Enhancement with Cvclodextrins

Saturated samples of PXD-101 were prepared in aqueous solutions of two natural cyclodextrins (α-CD and γ-CD) and hydroxypropyl derivatives of the α, β and Y cyclodextrins (HP-α-CD, HP-β-CD and HP-γ-CD). All experiments were completed with cyclodextrin concentrations of 250 mg/mL, except for α-CD, where the solubility of the cyclodextrin was not sufficient to achieve this concentration. The data are summarised in the following table. HP-β-CD offers the best solubility enhancement for PXD-101.

Figure imgf000048_0001

Phase Solubility Determination of HP-β-CD

The phase solubility diagram for HP-β-CD was prepared for concentrations of cyclodextrin between 50 and 500 mg/mL (5-50% w/v). The calculated saturated solubilities of the complexed HDACi were plotted against the concentration of cyclodextrin. See Figure 1.

 

Links

 

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SPECTRUM

Tiny Biotech With Three Cancer Drugs Is More Alluring Takeover Bet Now
Forbes
The drug is one of Spectrum’s two drugs undergoing phase 3 clinical trials. Allergan paid Spectrum $41.5 million and will make additional payments of up to $304 million based on achieving certain milestones. So far, Raj Shrotriya, Spectrum’s chairman, 

http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/

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Copenhagen, December 10, 2013
Topotarget announces the submission of a New Drug Application (NDA) for belinostat for the treatment of relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) to the US Food and Drug Administration (FDA). The NDA has been filed for Accelerated Approval with a request for Priority Review. Response from the FDA regarding acceptance to file is expected within 60 days from the FDA receipt date.
read all this here

PAPER

The Development of an Effective Synthetic Route of Belinostat

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00170
Publication Date (Web): July 12, 2016
Copyright © 2016 American Chemical Society
Abstract Image

A practical synthetic route of belinostat is reported. Belinostat was obtained via a five-step process starting from benzaldehyde and including addition reaction with sodium bisulfite, sulfochlorination with chlorosulfonic acid, sulfonamidation with aniline, Knoevenagel condensation, and the final amidation with hydroxylamine. Key to the strategy is the preparation of 3-formylbenzenesulfonyl chloride using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and acceptable overall yield. The scale-up experiment was carried out to provide 169 g of belinostat with 99.6% purity in 33% total yield.

(E)-N-Hydroxy-3-((phenylamino)sulfonyl)phenyl)acrylamide (Belinostat, 1)

1

mp 172–174 °C, (lit.(@) 172 °C). 1H NMR (400 MHz, DMSO-d6) δ = 10.75–10.42 (m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10–7.01 (m, 3H), 6.51 (d, J = 15.8 Hz, 1H). MS (ESI): m/z = 318.6 [M+H] +.

Finn, P. W.; Bandara, M.; Butcher, C.; Finn, A.; Hollinshead, R.; Khan, N.; Law, N.; Murthy, S.; Romero,R.; Watkins, C.; Andrianov, V.; Bokaldere, R. M.; Dikovska, K.; Gailite, V.; Loza, E.; Piskunova, I.;Starchenkov, I.; Vorona, M.; Kalvinsh, I. Helv. Chim. Acta 2005, 88, 1630, DOI: 10.1002/hlca.200590129

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Belinostat (Beleodaq),

Belinostat is a drug which was developed by Spectrum Pharmaceuticals and is currently marketed by Onxeo as Beleodaq. The
drug, which received fast track designation by the United States Food and Drug Administration (US FDA) and was approved for
the treatment of hematological malignancies and solid tumors associated with peripheral T-cell lymphoma (PTCL) in 2014,58 is a histone deacetylase (HDAC) inhibitor and is the third such treatment to receive accelerated approval for PTCL, the others being
vorinostat (Zolinza) and pralatrexate (Folotyn).58 Although belinostat was not yet approved in Europe as of August 2014,58 the
compound exhibits a safety profile considered to be acceptable for HDAC inhibitors–less than 25% of patients reported adverse
effects and these most frequently were nausea, fatigue, pyrexia,anemia, and emesis.58 While several different synthetic approaches
have been reported for the preparation of belinostat and related HDAC inhibitors,59–62 the most likely process-scale approach has
been described in a patent application filed by Reisch and co-workers at Topotarget UK, which exemplifies the synthesis described in
Scheme 8 on kilogram scale.63

Commercially available 3-bromobenzenesulfonyl chloride (41) was reacted with aniline in the presence of aqueous sodium carbonate
to deliver sulfonamide 42 in 94% yield. Next, this aryl bromide was subjected to a Heck reaction involving ethyl acrylate to
give rise to cinnamate ester 43, which was immediately saponified under basic conditions and acidic workup to furnish the corresponding acid 44. This acid was activated as the corresponding acid chloride prior to subjection to hydroxylamine under basic conditions to form the hydroxamic acid, which was then recrystallized from an 8:1 ethanol/water mixture in the presence of a catalytic
amount of sodium bicarbonate to furnish crystalline belinostat (VI) in 87% overall yield from acid 44.61

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Lee, H. Z.; Kwitkowski, V. E.; Del Valle, P. L.; Ricci, M. S.; Saber, H.;Habtemariam, B. A.; Bullock, J.; Bloomquist, E.; Li Shen, Y.; Chen, X. H.;Brown, J.; Mehrotra, N.; Dorff, S.; Charlab, R.; Kane, R. C.; Kaminskas, E.;Justice, R.; Farrell, A. T.; Pazdur, R. Clin. Cancer Res. 2015, 21, 2666.
59. Qian, J.; Zhang, G.; Qin, H.; Zhu, Y.; Xiao, Y. CN Patent 102786448A, 2012.
60. Wang, H.; Yu, N.; Chen, D.; Lee, K. C.; Lye, P. L.; Chang, J. W.; Deng, W.; Ng, M.C.; Lu, T.; Khoo, M. L.; Poulsen, A.; ngthongpitag, K.; Wu, X.; Hu, C.; Goh, K.C.; Wang, X.; Fang, L.; Goh, K. L.; Khng, H. H.; Goh, S. K.; Yeo, P.; Liu, X.; Bonday, Z.; Wood, J. M.; Dymock, B. W.; Kantharaj, E.; Sun, E. T. J. Med. Chem.2011, 54, 4694.
61. Yang, L.; Xue, X.; Zhang, Y. Synth. Comm. 2010, 40, 2520.

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Let’s Research !!!!!

 
 Helv Chim Acta 2005, 88(7), 1630-1657: It is first reported synthesis for Belinostat and many other derivatives. The procedure uses oleum, thionyl chloride (SOCl2) as well as oxalyl chloride (COCl)2, no wonder better procedures were derived from it. ABOVE
Synth Comm 2010, 40(17), 2520–2524: The synthesis avoids the use of the extremely corrosive oleum and thionyl chloride (SOCl2) and therefore is possibly better for scaled-up production. Second, synthetic steps do not involve tedious separations and give a better overall yield.  BELOWIdentifications:
1H NMR (Estimated) for Belinostat

Experimental: 1H NMR (300 MHz, DMSO-d6): δ 6.52 (d, J=15.9 Hz, 1H), 6.81–7.12 (m, 6H), 7.33 (d, J=15.9 Hz, 1H), 7.47–7.67 (m, 3 H), 7.87 (s, 1H), 9.00–11.20 (br, 3H).

 SEE COMPILATION ON SIMILAR COMPOUNDS AT …………..http://drugsynthesisint.blogspot.in/p/nostat-series.html

 

HPLC

ANALYTICAL HPLC TEST METHOD

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HPLC spectrum of Belinostat.

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PATENT

http://www.google.si/patents/CN102531972A?cl=en

Belinostat synthesis process related to the first report of the literature of W002 / 30879 A2, including preparation for Belinostat described as follows:

Figure CN102531972AD00031

Example 3:

3- (3-sulfonate-yl) phenyl – acrylate preparation:

First, 3-bromophenyl sulfonate 37. Ig (257. 90g / mol, 0. 1439mol) was dissolved with stirring in 260mL toluene IL reactor was then added triethylamine 36. 5g (101. 19g / mol, 0. 3604mol), tri (o-methylphenyl) phosphine 0. 875g (304. 37g / mol, 0. 002874mol), palladium acetate 0. 324g (224. 51g, 0. 001441mol), the reaction mixture was heated to 45- 55 ° C with nitrogen pumping ventilation four, this time in the reaction system to generate the catalytically active 1 ^ (0). The temperature of the reaction system was raised to 80-90 ° C, within 2. 75h dropwise methacrylate 13. 6g (86. 04g / mol, 0. 1586mol), the reaction was continued after the cell by HPLC 3- bromophenyl sulfonyl chloride was completion of the reaction. The temperature of the reaction system was reduced to 45-55 ° C.

[0021] In at 45-55 ° C, the reaction mixture was concentrated under reduced pressure, ethyl acetate and n-heptane and recrystallized to give the product 29. 4g, 83% yield.

[0022] The spectral data:

1HNMR (DMS0-d6, HMDS0), δ (ppm): 3. 65 (3H, S, H-1); 6. 47 (1H, d, J = 16 0 Hz, H-2.); 7. 30 -8 00 (5H, m, H-3, H_4, H_5, H_6, H_7) m / e:. 264. 23

Figure CN102531972AD00061

Links

References

    1.  “Beleodaq (belinostat) For Injection, For Intravenous Administration. Full Prescribing Information” (PDF). Spectrum Pharmaceuticals, Inc. Irvine, CA 92618. Retrieved 21 November2015.
    2. Plumb JA; Finn PW; Williams RJ; et al. (2003). “Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101”. Molecular Cancer Therapeutics 2 (8): 721–728.PMID 12939461.
    3.  “FDA approves Beleodaq to treat rare, aggressive form of non-Hodgkin lymphoma”. FDA. 3 July 2014.
    4.  “CuraGen Corporation (CRGN) and TopoTarget A/S Announce Presentation of Belinostat Clinical Trial Results at AACR-NCI-EORTC International Conference”. October 2007.
    5.  Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma, December 2009
    6.  “Spectrum adds to cancer pipeline with $350M deal.”. February 2010.
    7.  H. Spreitzer (4 August 2014). “Neue Wirkstoffe – Belinostat”.Österreichische Apothekerzeitung (in German) (16/2014): 27.
    8.  Lexicomp, (corporate author) (2016). Bragalone, DL, ed.Drug Information Handbook for Oncology (14th ed.). Wolters Kluwer. ISBN 9781591953517.
  1. Helvetica Chimica Acta, 2005 ,  vol. 88,  7  PG. 1630 – 1657, MP 172
  2. WO2009/40517 A2, ….
  3. WO2006/120456 A1, …..
  4. Synthetic Communications, 2010 ,  vol. 40,  17  PG. 2520 – 2524, MP 172
  5. Journal of Medicinal Chemistry, 2011 ,  vol. 54,   13  PG. 4694 – 4720, NMR IN SUP INFO

Drug@FDA, NDA206256 Pharmacology Review(s).

 Biochem. J. 2008, 409, 581-589.

J. Transl. Med. 2007, 5, 1-12.

Mol. Cancer Ther. 2006, 5, 2086-2095.

Int. J. Cancer 2008, 122, 1400-1410.

. PLoS One 2013, 8, e54522.

Synthetic Commun. 2010, 40, 2520-2524.

CN101868446A * Sep 23, 2008 Oct 20, 2010 托波塔吉特英国有限公司 Methods of synthesis of certain hydroxamic acid compounds
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EP2093292A2 * Mar 26, 2001 Aug 26, 2009 Methylgene, Inc. Inhibition of specific histone deacetylase isoforms
GB2378179A * Title not available
WO2002030879A2 * Sep 27, 2001 Apr 18, 2002 Prolifix Limited Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors
WO2008068170A1 * Nov 27, 2007 Jun 12, 2008 William Paul Jackson Hdac inhibitors
WO2009146871A1 * Jun 1, 2009 Dec 10, 2009 William Paul Jackson 5-lipoxygenase inhibitors
Citing Patent Filing date Publication date Applicant Title
CN104478769A * Dec 22, 2014 Apr 1, 2015 深圳万乐药业有限公司 Belinostatsynthesis method suitable for industrial production
CN104478769B * Dec 22, 2014 Jan 6, 2016 深圳万乐药业有限公司 一种适合工业化生产的贝利司他合成方法
CN104610100A * Jan 9, 2015 May 13, 2015 华东理工大学 Nitrogen-chlorine type chlorination agent
US2008274120 11-7-2008 Histone Deacetylase (Hdac) Inhibitors (Pxd101) for the Treatment of Cancer Alone or in Combination With Chemotherapeutic Agent
US2008227845 9-19-2008 CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION
US2008213399 9-5-2008 Combination Therapies Using Hdac Inhibitors
US2008194690 8-15-2008 Pharmaceutical Formulations Of Hdac Inhibitors
US7407988 8-6-2008 Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
US7402603 7-23-2008 Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination
US7183298 2-28-2007 Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
US2005107445 5-20-2005 Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
US6888027 5-4-2005 Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors
WO2002030879A2 Sep 27, 2001 Apr 18, 2002 Prolifix Ltd Carbamic acid compounds comprising asulfonamide linkage as hdac inhibitors
US7973181 7-6-2011 HYDROXAMIC ACID DERIVATIVES AS INHIBITORS OF HDAC ENZYMATIC ACTIVITY
US7928081 4-20-2011 Combined Use of Prame Inhibitors and Hdac Inhibitors
US2011077305 3-32-2011 5-LIPOXYGENASE INHIBITORS
US2011003777 1-7-2011 Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat
US2010286279 11-12-2010 Methods of Synthesis of Certain Hydroxamic Acid Compounds
US2010190694 7-30-2010 Methods for identifying patients who will respond well to cancer treatment
US2010010010 1-15-2010 HDAC INHIBITORS
US2009312311 12-18-2009 COMBINATION OF ORGANIC COMPOUNDS
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US7557140 7-8-2009 CARBAMIC ACID COMPOUNDS COMPRISING A SULFONAMIDE LINKAGE AS HDAC INHIBITORS
WO1998038859A1 * Mar 4, 1998 Sep 11, 1998 Thomas E Barta Sulfonyl divalent aryl or heteroaryl hydroxamic acid compounds
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WO2000056704A1 * Mar 22, 2000 Sep 28, 2000 Duncan Batty Hydroxamic and carboxylic acid derivatives
WO2000069819A1 * May 12, 2000 Nov 23, 2000 Thomas E Barta Hydroxamic acid derivatives as matrix metalloprotease inhibitors
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US4642316 May 20, 1985 Feb 10, 1987 Warner-Lambert Company Parenteral phenytoin preparations
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Belinostat
Belinostat.svg
Systematic (IUPAC) name
(2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide
Clinical data
Trade names Beleodaq
AHFS/Drugs.com beleodaq
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
Intravenous (IV)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding 92.9–95.8%[1]
Metabolism UGT1A1
Excretion Urine
Identifiers
CAS Number 866323-14-0 
ATC code L01XX49 (WHO)
PubChem CID 6918638
ChemSpider 5293831 Yes
UNII F4H96P17NZ Yes
ChEBI CHEBI:61076 Yes
ChEMBL CHEMBL408513 Yes
Synonyms PXD101
Chemical data
Formula C15H14N2O4S
Molar mass 318.348 g/mol
////////////Belinostat, PXD101, novel HDAC inhibitor, Beleodaq, Folotyn, Spectrum Pharmaceuticals, Inc., Henderson, Nevada, Istodax, Celgene Corporation,  Summit, New Jersey,  CuraGen Pharma, FDA 2014
O=S(=O)(Nc1ccccc1)c2cc(\C=C\C(=O)NO)ccc2
 SEE COMPILATION ON SIMILAR COMPOUNDS AT …………..http://drugsynthesisint.blogspot.in/p/nostat-series.html
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Lobeglitazone sulfate (Duvie)

 FDA 2014, Uncategorized  Comments Off on Lobeglitazone sulfate (Duvie)
Jul 212016
 

 

 

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Lobeglitazone.svg

Lobeglitazone Sulfate, CKD-501, IDR-105

(Duvie®)Approved KOREA

Chong Kun Dang (Originator)

Adjunct to diet and exercise to improve glycemic control in adults with type 2 Diabetes mellitus

A dual PPARα and PPARγ agonist used to treat type 2 diabetes.

Trade Name:Duvie®MOA:Dual PPARα and PPARγ agonistIndication:Type 2 diabetes

CAS No. 607723-33-1(FREE)

CAS 763108-62-9(Lobeglitazone Sulfate)

2,4-Thiazolidinedione, 5-((4-(2-((6-(4-methoxyphenoxy)-4- pyrimidinyl)methylamino)ethoxy)phenyl)methyl)-, sulfate (1:1);

Duvie Tab.

  • Developer Chong Kun Dang; EQUIS & ZAROO
  • Class Antihyperglycaemics; Pyrimidines; Small molecules; Thiazolidinediones
  • Mechanism of Action Peroxisome proliferator-activated receptor alpha agonists; Peroxisome proliferator-activated receptor gamma agonists
  • MarketedType 2 diabetes mellitus
  • Most Recent Events

    • 01 May 2016Chong Kun Dang Pharmaceutical completes two phase I drug-interaction trials in Healthy volunteers in South Korea (PO) (NCT02824874; NCT02827890)
    • 01 Apr 2016Chong Kun Dang Pharmaceutical initiates two phase I drug-interaction trials in Healthy volunteers in South Korea (PO) (NCT02824874; NCT02827890)
    • 01 Mar 2016Chong Kun Dang completes a phase I pharmacokinetic trial in Impaired hepatic function in Healthy volunteers in South Korea, NCT02007941)
    • Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie® by Chong Kun Dang Corporation.Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.Duvie® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

 

 

Lobeglitazone sulfate.png

Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.[3]

Chong Kun Dang

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Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie® by Chong Kun Dang Corporation.

Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Duvie® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC50:  0.02 μM, PPARγ EC50:  0.018 μM, rosiglitazone; PPARα EC50:  >10 μM, PPARγ EC50:  0.02 μM, pioglitazone PPARα EC50:  >10 μM, PPARγ EC50:  0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKAy mice than rosiglitazone and pioglitazone.17 Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.

Medical uses

Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.[4]

Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.[4][5]

SYNTHESIS

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Chong Kun Dang’s Modcol Flu Dry Syrup is released in four different versions: All-Day, Night, Nose and Cough. [CHONG KUN DANG]

 

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PAPER

Org. Process Res. Dev. 2007, 11, 190-199.

Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)

Process Research and Development Laboratory, Chemical Research Group, Chong Kun Dang Pharmaceutical Cooperation, Cheonan P. O. Box 74, Cheonan 330-831, South Korea, and Department of Chemistry, Korea University, 5-1-2, Anam-Dong, Seoul 136-701, Korea
Org. Process Res. Dev., 2007, 11 (2), pp 190–199
DOI: 10.1021/op060087u

http://pubs.acs.org/doi/abs/10.1021/op060087u

Abstract Image

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

Silica gel TLC Rf = 0.35 (detection:  iodine char chamber, ninhydrin solution, developing solvents:  CH2Cl2/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm-1;

1H NMR (400 MHz, CDCl3) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH);

13C NMR (100 MHz, CDCl3) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5;

MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C24H26N4O9S2:  C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found:  C, 49.85; H, 4.57; N, 9.75; S, 11.15.

PATENT

WO03080605A1.

 

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Lobeglitazone sulfate (Duvie) Lobeglitazone sulfate, an oral peroxisome proliferator-activated receptor (PPARa/c) dual agonist with IC50 = 20 and 18 nM respectively, was developed by Chong Kun Dang Pharmaceutical in Korea for the treatment of diabetes.135 This drug is differentiated from two other PPAR agonists available—pioglitazone and rosiglitazone —which lack PPARa activity.135 The most likely processscale preparation of lobeglitazone sulfate follows the route described in a process communication from Chong Kun Dang Pharmaceutical.136

Commercially available 4,6-dichloropyrimidine (152) was treated with a stoichiometric equivalent of p-methoxyphenol (153) in the presence of KF in warm DMF (Scheme 24). Upon completion of this reaction, 2-methylaminoethanol was added to the mixture to provide pyrimidine 154 in high yield.137

Next, alcohol 154 underwent a substitution reaction with p-fluorobenzaldehyde (155) under basic conditions to provide alkoxy benzaldehyde 156 which was converted to the benzylidene thiazolidindione 158 upon subjection to Knoevenagel conditions with 2,4-thiazolidinedione (157) in 90% yield.

Finally, reduction of olefin 158 was facilitated by treatment with the Hantzsch ester (159) in the presence of silica gel followed by treatment with methanolic sulfuric acid (96%) at low temperature to ultimately furnish lobeglitazone sulfate in 90% yield.

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135. Jin, S. M.; Park, C. Y.; Cho, Y. M.; Ku, B. J.; Ahn, C. W.; Cha, B.-S.; Min, K. W.;Sung, Y. A.; Baik, S. H.; Lee, K. W.; Yoon, K.-H.; Lee, M.-K.; Park, S. W. Diab.Obes. Metab. 2015, 17, 599.
136. Lee, H. W.; Ahn, J. B.; Kang, S. K.; Ahn, S. K.; Ha, D.-C. Org. Process Res. Dev.2007, 11, 190.
137. Lee, H. W.; Kim, B. Y.; Ahn, J. B.; Kang, S. K.; Lee, J. H.; Shin, J. S.; Ahn, S. K.; Lee,S. J.; Yoon, S. S. Eur. J. Med. Chem. 2005, 40, 862.

 

References

  1. Lee JH, Noh CK, Yim CS, Jeong YS, Ahn SH, Lee W, Kim DD, Chung SJ. (2015). “Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.”.Journal of Pharmaceutical sciences 104 (9): 3049–3059.doi:10.1002/jps.24378. PMID 25648999.
  2.  Kim JW, Kim JR, Yi S, Shin KH, Shin HS, Yoon SH, Cho JY, Kim DH, Shin SG, Jang IJ, Yu KS. (2011). “Tolerability and pharmacokinetics of lobeglitazone (CKD-501), a peroxisome proliferator-activated receptor-γ agonist: a single- and multiple-dose, double-blind, randomized control study in healthy male Korean subjects.”. Clinical therapeutics 33 (11): 1819–1830.doi:10.1016/j.clinthera.2011.09.023. PMID 22047812.
  3.  Lee JH, Woo YA, Hwang IC, Kim CY, Kim DD, Shim CK, Chung SJ. (2009). “Quantification of CKD-501, lobeglitazone, in rat plasma using a liquid-chromatography/tandem mass spectrometry method and its applications to pharmacokinetic studies.”. Journal of Pharmaceutical and Biomedical Analysis 50 (5): 872–877.doi:10.1016/j.jpba.2009.06.003. PMID 19577404.
  4.  “MFDS permission information of Duvie Tablet 0.5mg”(Release of Information). Ministry of Food and Drug Safety. Retrieved2014-10-23.
  5.  “국내개발 20번째 신약‘듀비에정’허가(20th new drug developed in Korea ‘Duvie Tablet’ was approved)”. Chong Kun Dang press release. 2013-07-04. Retrieved 2014-10-23.
Lobeglitazone
Lobeglitazone.svg
Systematic (IUPAC) name
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Trade names Duvie
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%[1]
Metabolism liver (CYP2C9, 2C19, and 1A2)[1]
Biological half-life 7.8–9.8 hours[2]
Identifiers
CAS Number 607723-33-1
PubChem CID 9826451
DrugBank DB09198 Yes
ChemSpider 8002194
Synonyms CKD-501
Chemical data
Formula C24H24N4O5S
Molar mass 480.53616 g/mol

Identifications:

1H NMR (Estimated) for Lobeglitazone

Experimental: 1H NMR (400 MHz, CDCl3) δ 3.12 (m, 4H), 3.45 (m, 1H), 3.83 (s, 3H), 4.00 (m, 2H), 4.16 (m, 2H), 4.50 (m, 1H), 5.84 (bs, 1H), 6.83 (m, 2H), 7.06 (m, 2H), 7.15 (m, 2H), 8.31 (s, 1H), 8.89 (bs, NH).

///Lobeglitazone Sulfate, CKD-501, Duvie®,  Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes, CKD 501, 763108-62-9, 607723-33-1, IDR-105

CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O

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Eliglustat tartrate (Cerdelga) エリグルスタット酒石酸塩 依利格鲁司特 エリグルスタット,サーデルガ

 FDA 2014, Uncategorized  Comments Off on Eliglustat tartrate (Cerdelga) エリグルスタット酒石酸塩 依利格鲁司特 エリグルスタット,サーデルガ
Jul 192016
 

Eliglustat tartrate (Cerdelga) エリグルスタット酒石酸塩

依利格鲁司特

エリグルスタット,サーデルガ

FOR TREATMENT OF GAUCHERS DISEASE

ELIGLUSTAT; Cerdelga; Genz 99067; Genz-99067; UNII-DR40J4WA67; GENZ-112638;

CAS 491833-29-5 FREE FORM

Molecular Formula: C23H36N2O4
Molecular Weight: 404.54294 g/mol

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide;(2R,3R)-2,3-dihydroxybutanedioic acid
Mechanism of Action: glucosylceramide synthase inhibitor
Indication: Type I Gaucher Disease
Date of Approval: August 19, 2014 (US)

US patent number:US6916802 , US7196205 , US7615573
Patent Expiration Date: Apr 29, 2022 (US6916802, US7196205, US7615573)
Exclusivity Expiration Date:Aug 19, 2019(NCE), Aug 19, 2021 (ODE)
Originator:University of Michigan
Developer: Genzyme, a unit of Sanofi

Eliglustat, marketed by Genzyme as CERDELGA, is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease. Patients selected for treatment with Eliglustat undergo an FDA approved genotype test to establish if they are CYP2D6 EM (extensive metabolizers), IM (intermediate metabolizers), or PM (poor metabolizers), as the results of this test dictate the dosage of Eliglustat recommended. Eliglustat was approved for use by the FDA in August 2014.

Eliglustat (INN, USAN;[1] trade name Cerdelga) is a treatment for Gaucher’s disease developed by Genzyme Corp that was approved by the FDA August 2014.[2] Commonly used as the tartrate salt, the compound is believed to work by inhibition ofglucosylceramide synthase.[3][4] According to an article in Journal of the American Medical Association the oral substrate reduction therapy resulted in “significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count” in untreated adults with Gaucher disease Type 1.[5]

Cerdelga, capsule, 84 mg/1, oralGenzyme Corporation, 2014-09-03, Us

ELIGLUSTAT.pngELIGLUSTAT

ChemSpider 2D Image | Eliglustat tartrate | C50H78N4O14

Eliglustat tartrate

  • Molecular FormulaC50H78N4O14
  • Average mass959.173 Da
  • UNII-N0493335P3
  • Butanedioic acid, 2,3-dihydroxy-, (2R,3R)-, compd. with N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-pyrrolidinylmethyl)ethyl]octanamide (1:2)
  •  eliglustat hemitartrate
  •  eliglustat L-tartrate

CAS 928659-70-5

 

CERDELGA (eliglustat) capsules contain eliglustat tartrate, which is a small molecule inhibitor of glucosylceramide synthase that resembles the ceramide substrate for the enzyme, with the chemical name N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate. Its molecular weight is 479.59, and the empirical formula is C23H36N2O4+½(C4H6O6) with the following chemical structure:

 

CERDELGA (eliglustat) Structural Formula Illustration

Each capsule of CERDELGA for oral use contains 84 mg of eliglustat, equivalent to 100 mg of eliglustat tartrate (hemitartrate salt). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2.

Cost

In 2014, the annual cost of Cerdelga hard gelatin capsules taken orally twice a day was $310,250. Genzyme’s flagship Imiglucerase(brand name Cerezyme) cost about $300,000 for the infusions if taken twice a month.[6] Manufacturing costs for Cerdelga are slightly lower than for Cerezyme. Genzyme’s maintains higher prices for orphan drugs—most often paid for by insurers— in order to remain financially sustainable.[6]

Chemically Eliglustat is named N-[(1 R,2R)-2-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-hydroxy-1 -(1 -pyrrolidinylmethyl)ethyl]-Octanamide(2R!3R)-2,3-dihydroxybutanedioate and the hemitartarate salt of eliglustat has the structural formula as shown in Formula I.

Formula I

Eliglustat hemitartrate (Genz-1 12638), currently under development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase, and is currently under development by Genzyme.

U.S. patent No. 7,196,205 discloses a process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 discloses process for preparation of Eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of Eliglustat, (ii) a hemitartrate salt of Eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailablity patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. For some therapeutic indications one bioavailabihty pattern may be favoured over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.

 

CLIP

Eliglustat tartrate, developed and marketed by Genzyme Corporation (a subsidiary of Sanofi), was approved by the US FDA in August 2014 for the treatment of nonneuropathic (type 1) Gaucher disease (GD1) in both treatment-naïve and treatment-experienced adult patients.98

It is the first oral treatment to be approved for first-line use in patients with Gaucher disease type 1, which is a rare lysosomal storage disease characterized by accumulation of lipid glucosylceramide (GL-1) due to insufficient production of the enzyme glucosylceramidase.99,100

Clinical complications include hepatosplenomegaly, anemia, thrombocytopenia, and bone involvement.101 Eliglustat is a specific inhibitor of glucosylceramide synthase with an IC50 of 10 ng/mL and acts as substrate reduction therapy for GD1;102 it has demonstrated non-inferiority to enzyme replacement therapy, which is the current standard of care, in Phase III trials.99

While the process-scale route has not yet been disclosed,103 the largest scale route to eliglustat tartrate reported to date is described in Scheme 15.104

Condensation of commercially available S-(+)-2-phenyl glycinol (87) with phenyl bromoacetate (88) in acetonitrile in the presence of N,N-diisopropylethylamine (DIPEA) provided morpholin-2-one 89 upon treatment with HCl.Neutralization with NaHCO3 followed by coupling with aldehyde 90 in refluxing EtOAc/toluene yielded oxazine adduct 91, which was isolated as a precipitate from methyl-tert-butyl ether (MTBE).

The stereochemistry of the three new stereocenters in 91 can be rationalized through the cycloaddition of an ylide intermediate in the sterically-preferred S-configuration (generated by the reaction of the morpholinone 89 with aldehyde 90) with a second equivalent of the aldehyde. With the morpholinone in a chair conformation in which the phenyl group is equatorial, endo axial approach of the dipolarophile to the less-hindered face of the ylide and subsequent ring flip of the morpholinone ring to a boat conformation positions all exocyclic aryl substituents in a pseudoequatorial configuration. 105

Opening of oxazine 91 with pyrrolidine in refluxing THF followed by addition of HCl in refluxing MeOH gave amide 92, which was reduced to amine 93 using LiAlH4 in refluxing THF.

Subsequent hydrogenation with Pd(OH)2 in EtOH cleaved the phenylethanol group to give the free amine, which was converted to dioxalate salt 94 by treatment with oxalic acid in methyl isobutylketone (MIBK). Subjection of aminoethanol 94 to aqueous sodium hydroxide followed by coupling with palmitic acid Nhydroxysuccinimide (NHS)-ester (95) gave eliglustat as the corresponding freebase (96) in 9.5% overall yield from 87.

Salt formation with L-tartaric acid (0.5 equiv) then provided eliglustat tartrate (XII).106

STR1

STR1

98. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410585.htm.
99. Poole, R. M. Drugs 2014, 74, 1829.
100. Kaplan, P. Res. Rep. Endocr. Disord. 2014, 4, 1.
101. Pastores, G. M.; Hughes, D. Clin. Invest. 2014, 4, 45.
102. Shayman, J. A. Drugs Future 2010, 35, 613.
103. Javed, I.; Dahanukar, V. H.; Oruganti, S.; Kandagatla, B. WO Patent2,015,059,679, 2015.
104. Hirth, B.; Siegel, C. WO Patent 2,003,008,399, 2003.
105. Anslow, A. S.; Harwood, L. M.; Phillips, H.; Watkin, D.; Wong, L. F. Tetrahedron:Asymmetry 1991, 2, 1343.
106. Liu, H.; Willis, C.; Bhardwaj, R.; Copeland, D.; Harianawala, A.; Skell, J.;Marshall, J.; Kochling, J.; Palace, G.; Peterschmitt, J.; Siegel, C.; Cheng, S. WO Patent 2,011,066,352, 2011.

CLIP

TAKEN FROM

http://www.xinbiaopin.com/a/zuixindongtai/huaxuepinshuju/2015/0310/2383.html

str1

Nmr predict

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide H-NMR spectrum

13 C NMR

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide C-NMR spectrum

CAS NO. 491833-29-5, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide

C-NMR spectral analysis

 

str1

 

str1

PATENT

http://www.google.com/patents/WO2013059119A1?cl=en

Figure imgf000024_0001

http://www.google.com/patents/US7196205

Compound 7

(1R,2R)-Nonanoic acid[2-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide

Figure US07196205-20070327-C00026

This compound was prepared by the method described for Compound 6 using Nonanoic acid N-hydroxysuccinimide ester. Analytical HPLC showed this material to be 98.4% pure. mp 74–75° C.

1H NMR (CDCl3) δ 6.86–6.76 (m, 3H), 5.83 (d, J=7.3 Hz, 1H), 4.90 (d, J=3.3 Hz, 1H), 4.24 (s, 4H), 4.24–4.18 (m, 1H), 2.85–2.75 (m, 2H), 2.69–2.62 (m, 4H), 2.10 (t, J=7.3 Hz, 2H), 1.55–1.45 (m, 2H), 1.70–1.85 (m, 4H), 1.30–1.15 (m, 10H), 0.87 (t, J=6.9 Hz, 3H) ppm.

Intermediate 4(1R,2R)-2-Amino-1-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-3-pyrrolidin-1-yl-propan-1-ol

Figure US07196205-20070327-C00023

Intermediate 3 (5.3 g, 13.3 mmol) was dissolved in methanol (60 mL). Water (6 mL) and trifluoroacetic acid (2.05 m/L, 26.6 mmol, 2 equivalents) were added. After being placed under nitrogen, 20% Palladium hydroxide on carbon (Pearlman’s catalysis, Lancaster or Aldrich, 5.3 g) was added. The mixture was placed in a Parr Pressure Reactor Apparatus with glass insert. The apparatus was placed under nitrogen and then under hydrogen pressure 110–120 psi. The mixture was stirred for 2–3 days at room temperature under hydrogen pressure 100–120 psi. The reaction was placed under nitrogen and filtered through a pad of celite. The celite pad was washed with methanol (100 mL) and water (100 mL). The methanol was removed by rotoevaporation. The aqueous layer was washed with ethyl acetate three times (100, 50, 50 mL). A 10 M NaOH solution (10 mL) was added to the aqueous layer (pH=12–14). The product was extracted from the aqueous layer three times with methylene chloride (100, 100, 50 mL). The combined organic layers were dried with Na2SO4, filtered and rotoevaporated to a colorless oil. The foamy oil was vacuum dried for 2 h. Intermediate 4 was obtained in 90% yield (3.34 g).

Intermediate 3(1R,2R,1″S)-1-(2′,3′-Dihydro-benzo[1,4]dioxin-6′-yl)-2-(2″-hydroxy -1′-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol

Figure US07196205-20070327-C00022

To a 3-neck flask equipped with a dropping funnel and condenser was added LiAlH4 (Aldrich, 1.2 g, 31.7 mmol, 2.5 equivalents) and anhydrous THF (20 mL) under nitrogen. A solution of Intermediate 2 (5.23 g, 12.68 mmol) in anhydrous THF (75 mL) was added dropwise to the reaction over 15–30 minutes. The reaction was refluxed under nitrogen for 9 hours. The reaction was cooled in an ice bath and a 1M NaOH solution was carefully added dropwise. After stirring at room temperature for 15 minutes, water (50 mL) and ethyl acetate (75 mL) was added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate (75 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL). After drying with Na2SO4 the solution was filtered and rotoevaporated to yield a colorless to yellow foamy oil. Intermediate 3 was obtained in 99% yield (5.3 g).

PATENT

WO 2016001885

EXAMPLES

Example 1 : Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 14 mL of dichloromethane at 26°C and stirred for 15 min. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 45°C. After distillation the solid was dried under vacuum at 45°C.

PATENT

str1

 

PAPER

Journal of Medicinal Chemistry (2012), 55(9), 4322-4335

 

 

OLD CLIPS

Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease


Eliglustat tartrate (USAN)

CAS:928659-70-5
February 15, 2013
Genzyme , a Sanofi company (EURONEXT: SAN and NYSE: SNY), today announced positive new data from the Phase 3 ENGAGE and ENCORE studies of eliglustat tartrate, its investigational oral therapy for Gaucher disease type 1. The results from the ENGAGE study were presented today at the 9th Annual Lysosomal Disease Network WORLD Symposium in Orlando, Fla. In conjunction with this meeting, Genzyme also released topline data from its second Phase 3 study, ENCORE. Both studies met their primary efficacy endpoints and together will form the basis of Genzyme’s registration package for eliglustat tartrateThe data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease”The company is developing eliglustat tartrate, a capsule taken orally, to provide a convenient treatment alternative for patients with Gaucher disease type 1 and to provide a broader range of treatment options for patients and physicians. Genzyme’s clinical development program for eliglustat tartrate represents the largest clinical program ever focused on Gaucher disease type 1 with approximately 400 patients treated in 30 countries.“The data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease,” said Genzyme’s Head of Rare Diseases, Rogerio Vivaldi MD. “We are excited about this therapy’s potential and are making excellent progress in our robust development plan for bringing eliglustat tartrate to the market.”ENGAGE Study Results:In ENGAGE, a Phase 3 trial to evaluate the safety and efficacy of eliglustat tartrate in 40 treatment-naïve patients with Gaucher disease type 1, improvements were observed across all primary and secondary efficacy endpoints over the 9-month study period. Results were reported today at the WORLD Symposium by Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & Internal Medicine at Yale University School of Medicine, and an investigator in the trial.The randomized, double-blind, placebo-controlled study had a primary efficacy endpoint of improvement in spleen size in patients treated with eliglustat tartrate. Patients were stratified at baseline by spleen volume. In the study, a statistically significant improvement in spleen size was observed at nine months in patients treated with eliglustat tartrate compared with placebo. Spleen volume in patients treated with eliglustat tartrate decreased from baseline by a mean of 28 percent compared with a mean increase of two percent in placebo patients, for an absolute difference of 30 percent (p<0.0001).

Genzyme

Eliglustat tartate (Genz-112638)

What is Eliglustat?

  • Eliglustat is a new investigational phase 3 compound from Genzyme Corporation that is being studied for type 1 Gaucher Disease.
  • Eliglustat works as a substrate reduction therapy by reducing glucocerebroside. formation.
  • This product is an oral agent (i.e. a pill) that is taken once or twice a day in contrast to an IV infusion for enzyme replacement therapy. Enzyme replacement therapy focuses on replenishing the enzyme that is deficient in Gaucher Disease and breaks down glucocerebroside that accumulates.
  • The clinical trials for eliglustat tartate are sponsored by Genzyme Corporation.

Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.

Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.

Formula I

Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.

Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.

U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:

(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,

(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,

(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,

(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=234E6BE008E68831F6875FB703760826.wapp2nA?docId=WO2015059679&recNum=1&office=&queryString=FP%3A%28dr.+reddy%27s%29&prevFilter=%26fq%3DCTR%3AWO&sortOption=Pub+Date+Desc&maxRec=364

WO 2015059679

Process for the preparation of eliglustat free base – comprising the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.
Dr Reddy’s Laboratories Ltd
New crystalline eliglustat free base Form R1 and a process for its preparation are claimed. Also claimed is a process for the preparation of eliglustat free base which comprises the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.Further eliglustat oxalate, its crystalline form, and a process for the preparation of crystalline eliglustat oxalate, are claimed.

Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.

Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.

Formula I

Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.

Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.

U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:

(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,

(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,

(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,

(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

Example 1 : Preparation of 5-phenyl morpholine-2-one hydrochloride

To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath

temperature less than 25° C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50%, Mass: m/z = 177.6; HPLC (% Area Method): 90.5%

Example 2: Preparation of (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4] dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one.

5-phenyl morpholine-2-one hydrochloride (100g) obtained from above stage 1 is dissolved in toluene (2500ml) under nitrogen atmosphere at 25-30°C. 1 ,4-benzodioxane-6-carboxaldehyde (185.3g) and sodium sulphate (400g) was added to the above solution and the reaction mixture was heated at 100-105°C for 72h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25° C to get a residue. The residue was cooled to 10°C, ethyl acetate (2700ml) and 50% sodium bisulphate solution (1351 ml) was added to the residue and stirred for 1 h at 10°C to obtain a white solid. The obtained white solid was filtered and washed with ethyl acetate. The separated ethyl acetate layer was washed with water (1000ml), brine (1000ml) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at a water bath temperature of 45-50°C to get a crude material. The obtained crude material is triturated with diethyl ether (1500ml) to get a solid material which is filtered and dried under vacuum at room temperature for 2-3h to afford (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (148g) as a yellow solid. Yield: 54%, Mass: m/z = 487.7; HPLC (% Area Method): 95.4 %

Example 3: Preparation of (2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 ”^henyl-ethy^

(1 R,3S,5S,8aS)-1 !3-Bis-(2′!3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (70g) obtained from above stage 2 was dissolved in chloroform (1400ml) at room temperature. It was cooled to 0-5°C and pyrrolidone (59.5ml) was added at 0-5°C over a period of 30 minutes. The reaction mixture was allowed to room temperature and stirred for 16-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature of 40-45°C to obtain a crude. The obtained crude was dissolved in methanol (1190ml) and 1 N HCI (1 190ml) at 10-15° C, stirred for 10 minutes and heated at 80-85°C for 7h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C.The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 1 N HCI (50ml). The aqueous layer was basified with saturated sodium bicarbonate solution up to pH 8-9 and extracted with ethyl acetate (3x70ml). The combined organic layers was washed with brine (100ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50-55°C to afford (2S,3R,1″S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (53g) as a yellow foamy solid. Yield: 90%, Mass: m/z = 412.7, HPLC (% Area Method): 85.1 %

Example 4: Preparation of (1 R,2R,1 “S)-1-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2”-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol.

(2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6’-yl)-3-hydroxy-2-(2”-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (2.5g) obtained from above stage 3 dissolved in Tetrahydrofuran (106ml) was added to a solution of Lithium aluminium hydride (12.2g) in tetrahydrofuran (795ml) at 0°C and the reaction mixture was heated at 60-65°C for 10h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 5- 10°C and quenched in saturated sodium sulphate solution (100ml) at 5-10°C. Ethyl acetate was added to the reaction mass and stirred for 30-45 min. The obtained solid is filtered through celite bed and washed with ethyl acetate. Filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50°C to afford (1 R,2R, 1″S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (43.51 g) as a yellow gummy liquid. The crude is used for the next step without further purification. Yield: 85%, Mass: m/z = 398.7, HPLC (% Area Method): 77 %

Example 5: Preparation of (1 R, 2R)-2-Amino-1-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol.

(1 R,2R,1 “S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6’-yl)2-hydroxy-2-(2”-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (40g) obtained from above stage 4 was dissolved in methanol (400ml) at room temperature in a 2L hydrogenation flask. Trifluoroacetic acid (15.5ml) and 20% Pd (OH) 2(40g) was added to the above solution under nitrogen atmosphere. The reaction mixture was hydrogenated under H2, 10Opsi for 16-18h at room temperature. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was filtered through celite bed and washed with methanol (44ml) and water (44ml). Methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C and the aqueous layer was washed with ethyl acetate. The aqueous layer was basified with 10M NaOH till the PH reaches 12-14 and then extracted with dichloromethane (2x125ml). The organic layer was dried over anhydrous sodium sulphate (3gm) and concentrated under reduced pressure at a water bath temperature of 45°C to obtain a gummy liquid. The gummy liquid was triturated with methyl tertiary butyl ether for 1 h to get a white solid, which is filtered and dried under vacuum at room temperature to afford (1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (23g) as a white solid. Yield: 82.3%, Mass (m/zj: 278.8, HPLC (% Area Method): 99.5%, Chiral HPLC (% Area Method): 97.9%

Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2′,3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.

(1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.

Example 7: Preparation of Eliglustat oxalate.

Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] +> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %

References

  1.  Eligustat (PDF), AMA By subscription only
  2. FDA approves new drug to treat a form of Gaucher disease, U.S. Food and Drug Administration, 19 August 2015, retrieved 18 July 2015
  3. Lee, L.; Abe, A.; Shayman, J. A. (21 May 1999). “Improved Inhibitors of Glucosylceramide Synthase”. Journal of Biological Chemistry 274(21): 14662–14669. doi:10.1074/jbc.274.21.14662.
  4.  Shayman, JA (1 August 2010). “Eliglustat Tartrate: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease.”. Drugs of the future 35 (8): 613–620. PMID 22563139.
  5.  Pramod K. Mistry, Elena Lukina, Hadhami Ben Turkia, Dominick Amato, Hagit Baris, Majed Dasouki, Marwan Ghosn, Atul Mehta, Seymour Packman, Gregory Pastores, Milan Petakov, Sarit Assouline, Manisha Balwani, Sumita Danda, Evgueniy Hadjiev, Andres Ortega, Suma Shankar, Maria Helena Solano, Leorah Ross, Jennifer Angell, M. Judith Peterschmitt (17 February 2015), “Effect of Oral Eliglustat on Splenomegaly in Patients With Gaucher Disease Type 1: The ENGAGE Randomized Clinical Trial”, Journal of the American Medical Association 313 (7): 695–706, doi:10.1001/jama.2015.459
  6.  Robert Weisman (2 September 2014), New Genzyme pill will cost patients $310,250 a year, The Boston Globe, retrieved 18 July 2015

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3
Patent 6916802
Expiration Apr 29, 2022
Applicant GENZYME CORP
Drug Application N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE)
FDA Orange Book Patents: 2 of 3
Patent 7196205
Expiration Apr 29, 2022
Applicant GENZYME CORP
Drug Application N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE)
FDA Orange Book Patents: 3 of 3
Patent 7615573
Expiration Apr 29, 2022
Applicant GENZYME CORP
Drug Application N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE)
Patent ID Date Patent Title
US8003617 2011-08-23 Methods of Treating Diabetes Mellitus
US2010298317 2010-11-25 METHOD OF TREATING POLYCYSTIC KIDNEY DISEASES WITH CERAMIDE DERIVATIVES
US7763738 2010-07-27 SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYLTRANSFERASE INHIBITORS
US7615573 2009-11-10 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US2009105125 2009-04-23 Methods of Treating Fatty Liver Disease
US7265228 2007-09-04 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US7196205 2007-03-27 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US6855830 2005-02-15 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
Patent ID Date Patent Title
US2016068519 2016-03-10 INHIBITORS OF THE ENZYME UDP-GLUCOSE: N-ACYL-SPHINGOSINE GLUCOSYLTRANSFERASE
US2015148534 2015-05-28 SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYL TRANSFERASE INHIBITORS
US2015051261 2015-02-19 Methods of Treating Fatty Liver Disease
US8779163 2014-07-15 Synthesis of UDP-Glucose: N-acylsphingosine glucosyl transferase inhibitors
US2013137743 2013-05-30 AMORPHOUS AND A CRYSTALLINE FORM OF GENZ 112638 HEMITARTRATE AS INHIBITOR OF GLUCOSYLCERAMIDE SYNTHASE
US2013095089 2013-04-18 GLUCOSYLCERAMIDE SYNTHASE INHIBITORS AND THERAPEUTIC METHODS USING THE SAME
US2012322786 2012-12-20 2-ACYLAMINOPROPOANOL-TYPE GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
US8138353 2012-03-20 SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYLTRANSFERASE INHIBITORS
US2012022126 2012-01-26 Method Of Treating Diabetes Mellitus
US8003617 2011-08-23 Methods of Treating Diabetes Mellitus
Eliglustat
Eliglustat.svg
Systematic (IUPAC) name
N-[(1R,2R)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide
Clinical data
Trade names Cerdelga
Legal status
Legal status
Identifiers
CAS Number 491833-29-5
ATC code A16AX10 (WHO)
PubChem CID 23652731
ChemSpider 28475348
ChEBI CHEBI:82752 Yes
Chemical data
Formula C23H36N2O4
Molar mass 404.543 g/mol

 

Patent Number Pediatric Extension Approved Expires (estimated)
US6916802 No 2002-04-29 2022-04-29 Us
US7196205 No 2002-04-29 2022-04-29 Us
US7615573 No 2002-04-29 2022-04-29 Us

///////////491833-29-5, 928659-70-5, eliglustat hemitartrate, eliglustat L-tartrate, ELIGLUSTAT,  Cerdelga,  Genz 99067,  Genz-99067,  UNII-DR40J4WA67,  GENZ-112638, エリグルスタット酒石酸塩 , FDA 2014,  GAUCHERS DISEASE, 依利格鲁司特, エリグルスタット,サーデルガ

CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@@H](C2=CC3=C(C=C2)OCCO3)O

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FDA approves first non-invasive DNA screening test for colorectal cancer

 FDA 2014, Uncategorized  Comments Off on FDA approves first non-invasive DNA screening test for colorectal cancer
Aug 132014
 

Cologuard.jpg

August 11, 2014

The U.S. Food and Drug Administration today approved Cologuard, the first stool-based colorectal screening test that detects the presence of red blood cells and DNA mutations that may indicate the presence of certain kinds of abnormal growths that may be cancers such as colon cancer or precursors to cancer.

Colorectal cancer primarily affects people age 50 and older, and among cancers that affect both men and women, it is the third most common cancer and the second leading cause of cancer-related death in the United States, according to the Centers for Disease Control and Prevention (CDC). Colorectal cancer screening is effective at reducing illness and death related to colon cancer. The CDC estimates that if everyone age 50 or older had regular screening tests as recommended, at least 60 percent of colorectal cancer deaths could be avoided.

Colorectal cancer occurs in the colon (large intestine) or rectum (the passageway that connects the colon to the anus). Most colorectal cancers start as abnormal raised or flat tissue growths on the wall of the large intestine or rectum (polyps). Some very large polyps are called advanced adenomas and are more likely than smaller polyps to progress to cancer.

Using a stool sample, Cologuard detects hemoglobin, a protein molecule that is a component of blood. Cologuard also detects certain mutations associated with colorectal cancer in the DNA of cells shed by advanced adenomas as stool moves through the large intestine and rectum. Patients with positive test results are advised to undergo a diagnostic colonoscopy.

“This approval offers patients and physicians another option to screen for colorectal cancer,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health. “Fecal blood testing is a well-established screening tool and the clinical data showed that the test detected more cancers than a commonly used fecal occult test.”

Today’s approval of the Cologuard does not change current practice guidelines for colorectal cancer screening. Stool DNA testing (also called “fecal DNA testing”) is not currently recommended as a method to screen for colorectal cancer by the United States Preventive Services Task Force (USPSTF). Among other guidelines, the USPSTF recommends adults age 50 to 75, at average risk for colon cancer, be screened using fecal occult blood testing, sigmoidoscopy, or colonoscopy.

The safety and effectiveness of Cologuard was established in a clinical trial that screened 10,023 subjects. The trial compared the performance of Cologuard to the fecal immunochemical test (FIT), a commonly used non-invasive screening test that detects blood in the stool. Cologuard accurately detected cancers and advanced adenomas more often than the FIT test. Cologuard detected 92 percent of colorectal cancers and 42 percent of advanced adenomas in the study population, while the FIT screening test detected 74 percent of cancers and 24 percent of advanced adenomas. Cologuard was less accurate than FIT at correctly identifying subjects negative for colorectal cancer or advanced adenomas. Cologuard correctly gave a negative screening result for 87 percent of the study subjects, while FIT provided accurate negative screening results for 95 percent of the study population.

Today the Centers for Medicare & Medicaid Services (CMS) issued a proposed national coverage determination for Cologuard. Cologuard is the first product reviewed through a joint FDA-CMS pilot program known as parallel review where the agencies concurrently review medical devices to help reduce the time between the FDA’s approval of a device and Medicare coverage. This voluntary pilot program is open to certain premarket approval applications for devices with new technologies and to medical devices that fall within the scope of a Part A or Part B Medicare benefit category and have not been subject to a national coverage determination.

“Parallel review allows the last part of the FDA process to run at the same time as the CMS process, cutting as many as six months from the time from study initiation to coverage,” said Nancy Stade, CDRH’s deputy director for policy. “The pilot program is ongoing, but we will apply what we have learned to improve the efficiency of the medical device approval pathway for devices that address an important public health need.”

“This is the first time in history that FDA has approved a technology and CMS has proposed national coverage on the same day,” said Patrick Conway, chief medical officer and deputy administrator for innovation and quality for CMS. “This parallel review represents unprecedented collaboration between the two agencies and industry and most importantly will provide timely access for Medicare beneficiaries to an innovative screening test to help in the early detection of colorectal cancer.”

CMS proposes to cover the Cologuard test once every three years for Medicare beneficiaries who meet all of the following criteria:

  • age 50 to 85 years,
  • asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test or fecal immunochemical test), and
  • average risk of developing colorectal cancer (no personal history of adenomatous polyps, of colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or an adenomatous polyp, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

Cologuard is manufactured by Exact Sciences in Madison, Wisconsin.

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