AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

BELINOSTAT, FAST TRACK, ORPHAN DRUG, A hydroxamate-type inhibitor of histone deacetylase.

 phase 2, Uncategorized  Comments Off on BELINOSTAT, FAST TRACK, ORPHAN DRUG, A hydroxamate-type inhibitor of histone deacetylase.
Jan 232014
 

File:Belinostat.svg

 

Belinostat (PXD101)

PHASE 2, FAST TRACK FDA , ORPHAN STATUS

  • PDX101
  • PX 105684
  • PXD-101
  • PXD101
  • UNII-F4H96P17NZ

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

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.

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

…………………………

BELINOSTAT

Belinostat (PXD101) is experimental drug candidate under development byTopoTarget for the treatment of hematological malignancies and solid tumors. It is a histone deacetylase inhibitor.[1]

A hydroxamate-type inhibitor of histone deacetylase.

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

In 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin and paclitaxel for relapsedovarian cancer.[2] Final results in late 2009 of a phase II trial for T cell lymphomawere encouraging.[3] Belinostat has been granted orphan drug and fast trackdesignation by the FDA.[4]

 

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.

 ………………………………………………………………………..

 

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

…………………………………..

GENERAL SYNTHESIS

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

……………………………………………………………………..

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 C15Hι4N204S, %: C 56.59, H 4.43, N 8.80. Found, %: C 56.28, H 4.44, N 8.56.

……………………………………………………………………….

SYNTHESIS

US20100286279

Figure US20100286279A1-20101111-C00034

 

 

…………………………………………………….

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

………………………………………………..

SYNTHESIS

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%.

……………….

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.

………………………..

  1.  Plumb, Jane A.; Finn, Paul W.; Williams, Robert J.; Bandara, Morwenna J.; Romero, M. Rosario; Watkins, Claire J.; La Thangue, Nicholas B.; Brown, Robert (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.
  2.  “CuraGen Corporation (CRGN) and TopoTarget A/S Announce Presentation of Belinostat Clinical Trial Results at AACR-NCI-EORTC International Conference”. October 2007.
  3. Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma, December 2009
  4.  “Spectrum adds to cancer pipeline with $350M deal.”. February 2010.
  5. Helvetica Chimica Acta, 2005 ,  vol. 88,  7  PG. 1630 – 1657, MP 172
  6. WO2009/40517 A2, ….
  7. WO2006/120456 A1, …..
  8. Synthetic Communications, 2010 ,  vol. 40,  17  PG. 2520 – 2524, MP 172
  9. Journal of Medicinal Chemistry, 2011 ,  vol. 54,   13  PG. 4694 – 4720, NMR IN SUP INFO

 

11-7-2008
Histone Deacetylase (Hdac) Inhibitors (Pxd101) for the Treatment of Cancer Alone or in Combination With Chemotherapeutic Agent
9-19-2008
CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION
9-5-2008
Combination Therapies Using Hdac Inhibitors
8-15-2008
Pharmaceutical Formulations Of Hdac Inhibitors
8-6-2008
Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
7-23-2008
Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination
2-28-2007
Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
5-20-2005
Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
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
7-6-2011
HYDROXAMIC ACID DERIVATIVES AS INHIBITORS OF HDAC ENZYMATIC ACTIVITY
4-20-2011
Combined Use of Prame Inhibitors and Hdac Inhibitors
3-32-2011
5-LIPOXYGENASE INHIBITORS
1-7-2011
Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat
11-12-2010
Methods of Synthesis of Certain Hydroxamic Acid Compounds
7-30-2010
Methods for identifying patients who will respond well to cancer treatment
1-15-2010
HDAC INHIBITORS
12-18-2009
COMBINATION OF ORGANIC COMPOUNDS
7-31-2009
CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION
7-8-2009
CARBAMIC ACID COMPOUNDS COMPRISING A SULFONAMIDE LINKAGE AS HDAC INHIBITORS
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GB2312674A * Title not available

 

WO2002030879A2 Sep 27, 2001 Apr 18, 2002 Prolifix Ltd Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors
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WO2008090585A2 * Jan 25, 2008 Jul 31, 2008 Univ Roma Soluble forms of inclusion complexes of histone deacetylase inhibitors and cyclodextrins, their preparation processes and uses in the pharmaceutical field
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US20110003777 * Mar 6, 2009 Jan 6, 2011 Topotarget A/S Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat

………………………..

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/

……………………………..

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
…………………….
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Cicaprost ZK-96480

 phase 2, Uncategorized  Comments Off on Cicaprost ZK-96480
Jan 132014
 

http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0094079808

Cicaprost

94079-80-8 , as in entry 4 ,  J. Org. Chem. 1988,53,1227-1231

ZK-96480

phase 2

Bayer Schering Pharma (Originator)

2-​[2-​[(2E,​3aS,​4S,​5R,​6aS)-​hexahydro-​5-​hydroxy-​4-​[(3S,​4S)-​3-​hydroxy-​4-​methyl-​1,​6-​nonadiyn-​1-​yl]-​2(1H)-​pentalenylidene]ethoxy]-​acetic acid

13,14-Didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6-carbaprostaglandin I2;

5-(7-Hydroxy-6-(3-hydroxy-4-methylnona-1,6-diynyl)-bicyclo(3.3.0)octan-3-yliden)-3-oxapentanoic acid;

2-[(2E,3aβ,6aβ)-4β-[(3S,4S)-3-Hydroxy-4-methyl-1,6-nonadiynyl]-5α-hydroxyoctahydropentalene-2-ylidene]ethoxyacetic acid;

[2-[(2E,3aβ,4S,6aβ)-4β-[(3S,4S)-3-Hydroxy-4-methyl-1,6-nonadiynyl]-5α-hydroxyoctahydropentalene-2-ylidene]ethoxy]acetic acid;

[2-[[(2E,3aS,3aβ,6aβ)-5α-Hydroxy-4β-[(3S,4S)-3-hydroxy-4-methyl-1,6-nonanediynyl]octahydropentalen]-2-ylidene]ethoxy]acetic acid;

Acetic acid, ((2E)-2-((3as,4S,5R,6as)-hexahydro-5-hydroxy-4-((3S,4S)-3-hydroxy-4-methyl-1,6-nonadiynyl)-2(1H)-pentalenylidene)ethoxy)-;

2-[2-[(2E,3aS,4S,5R,6aS)-Hexahydro-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-Methyl-1,6-nonadiyn-1-yl]-2(1H)-pentalenylidene]ethoxy]acetic Acid;

Acetic acid, (2-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1,6-nonadiynyl)-2(1H)-pentalenylidene)ethoxy)-, (3as-(2E,3aalpha,4alpha(3R*,4R*),5beta,6aalpha))-

Molecular Formula C22H30O5
Formula Weight 374.5

Prostaglandin I2 (PGI2, prostacyclin) is the most potent endogenous vasodilator that affects both the systemic and pulmonary circulation.Cicaprost is a PGI2 analog that is orally active with prolonged availabilityin vivo, having a terminal half life in plasma of one hour. In addition to their effects on smooth muscle, PGI2 analogs, including cicaprost, have been shown to inhibit the pro-inflammatory actions of certain leukocytes, suppress cardiac fibrosis, and block mitogenesis of certain cell types.Importantly, cicaprost has been shown to strongly reduce lung and lymph node metastasis in rats, suggesting that it might be useful in cancer therapy.

cicaprost

references

1. Drugs Fut 1986, 11(11): 913

2. Synthesis of a new chemically and metabolically stable prostacyclin analogue with high and long-lasting oral activity
J Med Chem 1986, 29(3): 313

 

3. Journal of Organic Chemistry, 1988 ,  vol. 53,  6  p. 1227 – 1231 entry4

http://pubs.acs.org/doi/pdf/10.1021/jo00241a020

 

4. Journal of the American Chemical Society, 2003 ,  vol. 125,  32  p. 9653 – 9667, nmr

5. WO 2009068190

6. US 5013758

7. WO 2005009446

8. WO 1992014438

9. US2007/196510 A1

10. US2007/293552 A1

11. US2009/221549 A1

12. US2009/54473 A1

 

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cicaprost

 

…………………………

Journal of Organic Chemistry, 1988 ,  vol. 53,  6  p. 1227 – 1231 entry4

http://pubs.acs.org/doi/pdf/10.1021/jo00241a020

ZK 96 480 (4). A solution of 19 (68 mg, 0.13 mmol) in eth-
er-toluene (3 mL, 2:l) was added to tetrabutylammonium hydrogen sulfate containing HzO (2 drops). After adding 50% aqueous NaOH (0.8 mL), the whole reaction mixture was stirred at 55 “C for 48 h. The reaction was quenched with HzO, acidified with 5% aqueous HC1, extracted with ethyl acetate, washed withH20 and brine, and concentrated to give ZK 96 480 (4) (42 mg, 86%) as a colorless viscous oil:

[alZzD +138.25O (c 1.025, CHCI,). see pdf file for correct cut paste

Other spectral data were identical with those of an authentic
sample.’

(1) Skuballa, W.; Schillinger, E.; Stiinebecher, C.-St.; Vorbriiggen, H.
J. Med. Chem. 1986,29, 313.

……………………………….

Skuballa, W.; Schillinger, E.; Stiinebecher, C.-St.; Vorbriiggen, H.
J. Med. Chem. 1986,29, 313.

http://pubs.acs.org/doi/pdf/10.1021/jm00153a001

see original pdf file for structures

we replaced the methylene group in the
3-position of 1, iloprost by an oxygen atom to prevent the 6-oxi-
dation of the upper side chain. The resulting decrease in
intrinsic activity was compensated for by modification of
the lower side chain. We converted the 13,14-double bond
into a triple bond, introduced a further methyl group at
(2-20, and synthesized selectively the pure 16(S)-methyl
diastereomer. These modifications resulted in the struc-
ture of 2 cicaprost (ZK 96 480), a carbacyclin analogue with a bio-
logical activity at least as high as that of prostacyclin and
iloprost.
The synthesis of 2 started with the preparation of the
lower side chain by resolving racemic 2-methyl-4-heptynoic
acid (3).7 By application of the method of Helmchen et
al.,” 3 was converted with phosphorus trichloride into the
acid chloride 4, which gave with D-(-)-a-phenylglycinol a
pair of diastereomeric amides. After chromatographic
separation on SOz, the more polar amide 5 (mp 124 ‘C)
was hydrolyzed with 3 N H2S04 in dioxane to furnish the
optically pure 2s-configurated acid 6 ([a]D -1.2’ (c 1,
EtOH), bp 128 ‘C (12 mm)). The 2s configuration of 6
was determined by hydrogenation of 6 to 2(S)-methyl-
heptanoic acid ([“ID +17.7′ (c 1, EtOH)), which was com-
pared with 2-methyl-alkanoic acids of known absolute
config~ration.~ Esterification of 6 with diazomethane
followed by reaction of the methyl ester 7 ([a]D +12.2’ (c
1, EtOH), bp 70 ‘C (12 mm)) with the lithium salt of ethyl
methylphosphonate afforded the optically pure phospho-
nate 8 ([‘Y]D +35.3’ (c 1, EtOH), bp 123 “C (0.3 mm)).

Condensation of the phosphonate 8 with the readily
available optically pure bicyclic aldehyde 93,4 (NaH, DME,

-20 “C) in the presence of N-bromosuccinimide furnished
the a,P-unsaturated bromo ketone 10 in 60% yield: oil;
(3 H, d, J = 7 Hz, CHCH,), 3.91 (4 H, m, OCH2CH20), 5.21
(1 H, m, H-llp), 7.09 (1 H, d, J = 10 Hz, H-13), 7.42-7.92
(5 H, m, COPh); IR (neat) 1720 (COPh), 1690 (COC=C)
cm-‘. Reduction of 10 (NaBH,, CH,OH, -40 “C) gave a
ca. 1:l mixture of the allylic alcohols lla and llb, which
was separated chromatographically.’O Dehydrobromina-
tion (50% aqueous NaOH, toluene, catalytic NBu4/HS04,
25 “C) of the less polar alcohol lla with concomitant sa-
ponification of the benzoate group followed by acidic
(HOAc, H20) cleavage of the ketal moiety afforded the
ketone 12 (73% from lla): oil; ‘H NMR (CD2C12) 6 1.06
(3 H, d, J = 6.8 Hz, CHCH,), 1.10 (3 H, t, J = 7.5 Hz,
CH,CH,), 4.22 (1 H, m, H-llb), 4.38 (1 H, m, H-158); IR
(neat) 1730 (C=O) cm-‘. After silylation of the hydroxyl
groups in 12 (C1SiMe2-t-Bu, DMF, imidazole), the ketone
13 was subjected to a Horner-Wittig reaction with triethyl
phosphonoacetate (KO-t-Bu, THF, 0 “C). Reduction of
the 1:l mixture of the isomeric a,p-unsaturated esters 14
with diisobutylaluminum hydride (toluene, 0 “C) gave after
chromatographic separation the E isomer 15a (32% from
12) and the less polar 2 isomer 15b.11

Etherification of 15a under phase-transfer conditions
with tert-butyl bromoacetate (50% aqueous NaOH, tolu-
ene, catalytic Bu4NHS04, 25 “C) was accompanied by
simultaneous cleavage of the tert-butyl ester to give 16
(87%). Finally, removal of the silyl ether groups (tetra-
n-butylammonium fluoride, THF, 25 “C) afforded 2 cicaprost,  in
86% yield: oil;

‘H NMR (CD,Cl,) 6= delta    1.07 (3 H, d, J = 6.8
Hz), 16@-CH3), 1.11 (3 H, t, J = 7.5 Hz, CH2CH3), 3.97 (1
H, m, H-llP), 4.06 (2 H, m, OCH,CO), 4.12 (2 H, m, =
H, m, H-5); IR (neat) 1730 (COOH) cm-‘.

 

………………

J. Am. Chem. Soc., 2003, 125 (32), pp 9653–9667
DOI: 10.1021/ja030200l

Abstract Image

 

An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling of a chiral bicyclic C6−C14 ethynyl building block with a chiral C15−C21 ω-side chain amide building block with formation of the C14−C15 bond of the target molecules.

A highly stereoselective reduction of the thereby obtained C6−C21 intermediate carrying a carbonyl group at C15 of the side chain was accomplished by the chiral oxazaborolidine method. The chiral phosphono acetate method was used for the highly stereoselective attachment of the α-side chain to the bicyclic C6−C21 intermediate carrying a carbonyl group at C6.

Asymmetric syntheses of the bicyclic C6−C14 ethynyl building blocks were carried out starting from achiral bicyclic C6−C12 ketones by using the chiral lithium amide method. In the course of these syntheses, a new method for the introduction of an ethynyl group at the α-position of the carbonyl group of a ketone with formation of the corresponding homopropargylic alcohol was devised.

Its key steps are an aldol reaction of the corresponding silyl enol ether with chloral and the elimination of a trichlorocarbinol derivative with formation of the ethynyl group. In addition, a new aldehyde to terminal alkyne transformation has been realized. Its key steps are the conversion of an aldehyde to the corresponding 1-alkenyl dimethylaminosulfoxonium salt and the elimination of the latter with a strong base.

Two basically different routes have been followed for the synthesis of the enantiomerically pure C15−C21 ω-side chain amide building block. The first is based on the chiral oxazolidinone method and features a highly stereoselective alkylation of (4R)-N-acetyl-4-benzyloxazolidin-2-one, and the second encompasses a malonate synthesis of the racemic amide and its efficient preparative scale resolution by HPLC on a chiral stationary phase containing column

 

…….

https://www.google.co.in/patents/EP0119949A1

(5E) -13,14,18,13,19,19-Hecadehydro-3-oxa-6a-carba-prostaglandin I 2derivatives of the general formula I

Figure imgb0016

(5E) – (16S) -13,14-didehydro-16 ,20-dimezhyl-3-oxa-18 ,18,19,19-tetradehydro-6a-carbaprostaglandin 1 2

      Example 1(5E) – (16S) -13,14-didehydro-16 ,20-dimezhyl-3-oxa-18 ,18,19,19-tetradehydro-6a-carbaprostaglandin 1

2

    • [0028]
      To a solution of 0.4 g in 12 ml of tetrahydrofuran was added to 80 mg of 55% sodium hydride (in mineral oil) and cook for 1 hour reflux. Is added to a solution of 127 mg of bromoacetic in 4 ml of tetrahydrofuran, boiled under reflux for 18 hours, diluted with ether and extracted four times with 30 ml of 5% sodium hydroxide. This extract is adjusted with 10% sulfuric acid at 0 ° C to pH 3 and extracted with methylene chloride. The organic extract is shaken with brine, dried over magnesium sulfate and evaporated under vacuum. Obtained 220 mg hydropyranyläther), which are for the elimination of the protective groups is stirred for 18 hours with 15 ml of acetic acid / water / tetrahydrofuran (65/35/10) at 25 ° C. It is evaporated to the addition of toluene, and the residue is chromatographed on silica gel with ethyl acetate / 0.1 – 1% acetic acid. This gives 145 mg of the title compound as a colorless Ö1.
    • [0029]
      IR (CHC1 3): 3600, 3400 (broad), 2 93 0 222 3, 1730, 1600, 1425, 1380/cm.
    • [0030]
      The starting material for the above title compound is prepared as follows:

1 a)

    • [0031]
      To a suspension of 3.57 g of sodium hydride (55% in mineral oil) in 360 ml of dimethoxyethane was added dropwise at O ​​° C, a solution of 21.9 g of 3-methyl-2-oxo-oct-5-in-phosphonsäuredimethyl esters in 140 ml of dimethoxyethane was stirred for 1 hour at 0 ° C and then add 14.56 g of finely powdered N-bromosuccinimide. It is stirred for 1 hour at O ° C, treated with a solution of 22.5 g of (lR, 5S, 6R, 7R) -3,3 – ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo [3.3.0] octane in 180 ml of dimethoxyethane and 4 hours the mixture is stirred at 0 ° C. The reaction mixture is diluted with 3 1 ether, washed neutral with brine, dried with sodium sulfate and evaporated in vacuo. The residue is chromatographed with hexane / ether as eluent on silica gel. Following three chromatography of the respective diastereomeric mixed fractions obtained as polar compound 8.1 g and a polar compound 7.4 g of the title compound as colorless oils.
    • [0032]
      IR: 2935, 2878, 17 15, 1690, 1601, 1595, 1450, 1270, 948/cm.

1 b)

    • [0033]
      To a solution of 7.4. G of produced according to Example 1 a) ketone in 140 ml of methanol is added at -20 ° C. 3 g of sodium borohydride in portions and stirred for 30 minutes at -20 ° C. Then diluted with ether, washed neutral with water, dried over magnesium sulfate and evaporated under vacuum.
    • [0034]
      The crude product (15-epimer) is dissolved in 300 ml of methanol, added to 2.95 g of potassium carbonate and stirred for 21 hours at 23 ° C under argon. Then concentrated in vacuo, diluted with ether and washed neutral with brine. It is dried over magnesium sulfate and evaporated under vacuum. By column chromatography on silica gel with ether / methylene chloride (7 +3) first obtained 2.6 g of the 15SS-configured alcohol as well as 2.1 g of the more polar component 15a-configured alcohol (PG nomenclature) as colorless oils.
    • [0035]
      A solution of 2.1 g of the above prepared alcohol 15a, 20 mg of p-toluenesulfonic acid and 1.4 g of dihydropyran in 50 ml of methylene chloride is stirred for 30 minutes at 0 ° C. Then it is poured into dilute sodium bicarbonate solution, extracted with ether, washed neutral with water, dried over magnesium sulfate and evaporated under vacuum. Chromatography of the residue on silica gel, using hexane / ether (6 +4), 2.6 g of the title compound as a colorless oil.
    • [0036]
      IR: 2939, 2877, 1450, 969, 948 / cm.

1 c) bicyclo [3.3.0] octane-3-one

    • [0037]
      A solution of 290 mg of the of Example 1 b) the compound prepared in 2.5 ml of dimethyl sulfoxide and 1 ml of tetrahydrofuran is mixed with 112 mg of potassium tert-butoxide and stirred for 2 hours at 23 ° C. It is diluted with 10 ml of water and extracted three times with 10 ml of ether / hexane (7 +3), wash the extract with water until neutral, dried over brine and evaporated under vacuum.
    • [0038]
      It is stirred for 22 hours with the residue 15 ml of acetic acid / water / tetrahydrofuran (65/35/10) evaporated in a vacuum with the addition of toluene, and the residue is purified by chromatography on silica gel. With ether eluted 150 mg oily substance, which is reacted in 5 ml of dichloromethane with 140 mg of dihydropyran and 1 mg of p-toluenesulfonic acid at 0 ° C.. After 30 minutes, diluted with ether, extracted with 5% sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under vacuum. Chromatography of the residue on silica gel with hexane / ether (1 +1), 185 mg of the title compound as a colorless oil.
    • [0039]
      IR: 2940, 2876, 2216, 1738, 1020, 970 / cm.

1 d)

  • [0040]
    To a solution of 529 mg Phosphonoessigsäuretri acid ethyl ester in 10 ml of tetrahydrofuran is added at 0 C 225 mg of potassium tert-butoxide, stirred for 10 minutes, treated with a solution of 0.6 g of the product of Example 1 c) ketone in 6 ml of toluene and stirred for 22 hours at 23 ° C. It is diluted with 150 mL of ether, shake once with water, once with 20% sodium hydroxide, washed neutral with water, dried over magnesium sulfate and evaporated under vacuum. The residue is filtered using hexane / ether (6 +4) over silica gel. Thereby obtain 0.58 g of the unsaturated ester as a colorless oil.
  • [0041]
    IR: 2940, 2870, 2212, 1704, 1655, 970 / cm.
  • [0042]
    It adds 150 mg of lithium aluminum hydride in portions at 0 ° C to a stirred solution of 570 mg of the ester prepared in 25 ml of ether and stirred for 30 minutes at 0 ° C. Destroying the excess reagent by dropwise addition of ethyl acetate, added to 1 ml of water, stirred for 3 hours at 20 ° C, filtered and evaporated under vacuum. The residue is chromatographed with ether / hexane (3 +2) on silica gel. Thereby obtained as a non-polar compound 140 mg of 2 – {(Z) – (1S, 5S, 6S, 7R) -7 – (tetrahydropyran-2-yloxy) -6 – / R3S, 4S)-4-methyl-3-( tetrahydropyran-2-yloxy)-nona-1 ,6-diinyl]-bicyclo [3.3.0] octane-3-ylidene} – ethane-1-ol and 180 mg of the title compound as a colorless oil.
  • [0043]
    IR: 3620, 3450 (broad), 2940, 2860, 2212, 970/cm.

 

 

 

 

…………….

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

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CILUPREVIR

 phase 2, Uncategorized  1 Response »
Jan 122014
 

CILUPREVIR

(1S,4R,6S,7Z,14S,18R)-14- {[(cyclopentyloxy)carbonyl]amino}-18-[(7-methoxy-2- {2-[(propan-2-yl)amino]-1,3-thiazol-4-yl}quinolin-4- yl)oxy]-2,15-dioxo-3,16- diazatricyclo[14.3.0.0{4,6}]nonadec-7-ene-4- carboxylic acid

Ciluprevir, BILN-2061, BILN 2061, CHEBI:161337, BILN2061, BILN 2061ZW, BILN-2061-ZW,

CAS , 300832-84-2

Molecular Formula: C40H50N6O8S   Molecular Weight: 774.9254
Abstract Image

Ciluprevir is used in the treatment of hepatitis C. It is manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG under the research code of BILN-2061. It is targeted against NS2-3 protease.[1]

Ciluprevir is an HCV NS3 protease inhibitor which had been in phase II clinical trials at Boehringer Ingelheim for the treatment of hepatitis C, however, no recent developments from the company have been reported.

  1.  Abbenante, G; Fairlie, DP (2005). “Protease inhibitors in the clinic”. Medicinal chemistry 1 (1): 71–104. PMID 16789888.

 

1. Challenge and Opportunity in Scaling-Up Metathesis Reaction: Synthesis of Ciluprevir (BILN 2061)Peter J. Dunn, et al

http://onlinelibrary.wiley.com/doi/10.1002/9781118354520.ch10/summary
DOI: 10.1002/9781118354520.ch10

 

2. Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans
Org Lett 2004, 6(17): 2901

http://pubs.acs.org/doi/full/10.1021/ol0489907

 

3. Efficient synthesis of (S)-2-(cyclopentyloxycarbonyl)-amino-8-nonenoic acid: Key buiding block for BILN 2061, an HCV NS3 protease inhibitor
Org Process Res Dev 2007, 11(1): 60

 

4. Chinese Journal of Chemistry, 2011 ,  vol. 29,  7  pg. 1489 – 1502

DOI: 10.1002/cjoc.201180270

 http://onlinelibrary.wiley.com/doi/10.1002/cjoc.201180270/abstract;jsessionid=F5F4331F5A95D00728394A254C2B1AE7.f01t04

…………………………..

US 8222369

WO 2006071619

WO 2000059929

WO 2004092203

WO 2004039833

WO 2004037855

WO 2006036614

WO 2006033878

WO 2005042570

WO 2004093915

………………………………………………………………………..

https://www.google.co.in/patents/US8222369

 

 

Figure US08222369-20120717-C00019

 

Figure US08222369-20120717-C00021

 

 

…………………………………………………………………..

http://www.google.com/patents/WO2000059929A1

COMPD 822 IS CILUPREVIR IN TABLE 8

EXAMPLE 8 Synthesis of 4-hydroxy-7-methoxy-2[4(2-isopropylaminothiazolyl)] quinoline (8f ) Note: [ A variety of 2-alkylaminothiazolyl substituents were made using the same synthetic scheme where compound 8b was replaced by other alkyl thioureas.]

 

Figure imgf000045_0001

 

Figure imgf000045_0002

8b 8c 8d

Figure imgf000046_0001

A. The protocol used for the conversion of -anisidine to 8a was identical to that described in the literature: F.J. Brown et al. J. Med. Chem. 1989, 32 , 807-826. However, the purification procedure was modified to avoid purification by chromatography. The EtOAc phase containing the desired product was treated with a mixture of MgSO4, charcoal and 5% w/w (based on expected mass) silica gel. After filtration on celite, the product was triturated with ether. Compound 8a was obtained as a pale brown solid in >99% purity (as confirmed by HPLC).

B. A suspension of isopropyl thiourea (8b, 3.55 g, 30 mmol) and 3- bromopyruvic acid (8c, 5 g, 1 eq.) in dioxane (300 mL , 0.1 M) was heated to 80 °C.

Upon reaching 80 C the solution became clear and soon after the product precipitated as a white solid. After 2 hours of heating, the solution was cooled to RT and the white precipitate was filtered to obtain compound 8d in high purity (>98% purity as confirmed by NMR) and 94% yield (7.51 g). C. A mixture of the carboxylic acid 8d (4.85 g, 18.2 mmol) and the aniline derivative 8a (3 g, leq.) in pyridine (150 mL, 0.12 M) was cooled to -30 °C (upon cooling, the clear solution became partially a suspension). Phosphorus oxychloride (3.56 ml, 2.1 eq.) was then added slowly over a 5 min period. The reaction was stirred at -30 C for 1 h, the bath was removed and the reaction mixture was allowed to warm-up to RT. After 1.5 h the reaction mixture was poured into ice, the pH was adjusted to 11 with aqueous 3N NaOH, extracted with CH2C12, dried over anhydrous MgSO4, filtered and concentrated under vacuum. The beige solid was then purified by flash chromatography (45% EtOAc in hexane) to give compound 8e as a pale yellow solid in 73% yield (6.07 g). D. A solution of tBuOK (2.42 g, 21.6 mmol) in anhydrous tBuOH (40ml, 0.14 M, distilled from Mg metal) was heated to reflux. Compound 8e (1.8g, 5.4 mmol) was added portion-wise over 5 min and the dark red solution formed was stirred at reflux for an additional 20 min (completion of the reaction was monitored by HPLC). The mixture was cooled to RT and HCl was added (4 N in dioxane, 1.5 eq.). The mixture was then concentrated under vacuum, in order to assure that all of the

HCl and dioxane were removed, the product was re-dissolved twice in CH2C12 and dried under vacuum to finally obtain the HCl salt of compound 8f as a beige solid (1.62 g, 93% pure by HPLC). The product was then poured into a phosphate buffer

(IN NaH2PO4, pH=~4.5) and sonicated. The beige solid was filtered and dried under vacuum to give compound 8f (1.38 g, 81% yield) as a beige solid (91% pure by HPLC).

*H NMR (400 MHz, DMSO) δ 8.27 (s, IH), 8.12 (d, IH, J = 9.2 Hz), 7.97 (br.s, IH), 7.94 (s, IH), 7.43 (s, IH), 7.24 (dd, IH, J = 9.2, 2.2 Hz), 3.97 (m, IH), 3.94 (s, 3H), 1.24 (d, 2H, J = 6.4 Hz)

…………

METHYL ESTER

EXAMPLE 34c

Using the same procedure as described in example 34 but reacting bromoketone 34f with commercially available N-iso-propylthiourea gave # 822

 

Figure imgf000095_0002

Η NMR (400 MHz, DMSO-d6) δ 8.63 (s, IH), 8.33-8.23 (bs, IH), 8.21 (d, J = 9.2 Hz, IH), 8.04 (d, J = 8.3 Hz, IH), 7.86 (bs, IH), 7.77 (s, IH), 7.35-7.23 (m, 2H), 5.81 (bs, IH), 5.52 (dd, J = 8.5 Hz, IH), 5.27 (dd, J = 9.2 Hz, IH), 4.65 (d, J = 11.8 Hz, IH), 4.51 (dd, J = 7.6 Hz, IH), 4.37 (bs, IH), 4.15 (bs, IH), 4.07-3.98 (m, 2H), 3.97 (s, 3H), 3.88 (d, J = 8.9 Hz, IH), 2.60-2.53 (m, 2H), 2.47-2.37 (m, 2H), 2.19-2.10 (dd, J = 9.2 Hz, IH), 1.80-1.64 (m, 2H), 1.63-1.29 (m, 13H), 1.27 and 1.25 (2 x d, J – 6.5 Hz, 6H), 1.23-1.09 (m, 2H). MS; es+: 775.0 (M + H)+, es : 772.9 (M – H)\

CILUPREVIR IS FREE ACID OF ABOVE AND HAS ENTRY 822 TABLE 8

………

FREE AMINO COMPD

(Table 8)

 

Figure imgf000090_0001

 

Figure imgf000090_0002

 

Figure imgf000091_0001

 

Figure imgf000091_0002

A. To a solution of the macrocyclic intermediate 23b (13.05 g, 27.2 mmol, 1.0 eq.), Ph3P (14.28 g, 54.4 mmol, 2.0 eq) and 2-carboxymethoxy-4-hydroxy-7- methoxyquinoline (WO 00/09543 & WO 00/09558) (6.67 g, 28.6 mmol, 1.05 eq) in

THF (450 mL) at 0°C, DIAD (10.75 mL, 54.6 mmol, 2.0 eq) was added dropwise over a period of 15 min. The ice bath was then removed and the reaction mixture was stirred at RT for 3 h. After the complete conversion of starting material to products, the solvent was evaporated under vacuum, the remaining mixture diluted with

EtOAc, washed with saturated NaHCO3 (2x) and brine (lx), the organic layer was dried over anhydrous MgSO4, filtered and evaporated to dryness. Pure compound 34a was obtained after flash column chromatography; the column was eluted first with hexane/EtOAc (50:50), followed by CHCl3/EtOAc (95:5) to remove Ph3PO and

DIAD byproducts and elution of the impurities was monitored by TLC. Finally, the desired product 34a was eluted from the column with CHC13/ EtOAc (70:30).

Usually, the chromatography step had to be repeated 2-3 times before compound 34a could be isolated in high purity as a white solid with an overall yield of 68% (12.8 g, 99.5% pure by HPLC).

B. To a solution of the Boc-protected intermediate 34a (1.567g) in CH2C12 (15 mL), 4N HCl in dioxane (12 mL) was added and the reaction mixture was stirred at RT for 1 h. [In the event that a thick gel would form half way through the reaction period, an additional 10 mL CH2C12 was added.] Upon completion of the deprotection the solvents were evaporate to dryness to obtain a yellow solid and a paste like material. The mixture was redissolved in approximately 5% MeOH in

CH2C12 and re-evaporated to dryness under vacuum to obtain compound 34b as a yellow solid, which was used in the next step without any purification. C. To a solution of cyclopentanol (614 μL, 6.76 mmoL) in THF (15 mL), a solution of phosgene in toluene (1.93 M, 5.96 mL, 11.502 mmol) was added dropwise and the mixture was stirred at R.T. for 2 h to form the cyclopentyl chloroformate reagent (z). After that period, approximately half of the solvent was removed by evaporation under vacuum, the remaining light yellow solution was diluted by the addition of CH2C12 (5 mL) and concentrated to half of its original volume, in order to assure the removal of all excess phosgene. The above solution of the cyclopentyl chloroformate reagent was further diluted with THF (15 mL) and added to the amine-2HCl salt 34b. The mixture was cooled to 0 C in an ice bath, the pH was adjusted to -8.5-9 with the addition of Et3N (added dropwise) and the reaction mixture was stirred at 0 C for 1 h. After that period, the mixture was diluted with

EtOAc, washed with water (lx), saturated NaHCO3 (2x), H2O (2x) and brine (lx).

The organic layer was dried over anhydrous MgSO4, filtered and evaporated under vacuum to obtain a yellow-amber foam. Compound 34c was obtained as a white foam after purification by flash column chromatography (using a solvent gradient from 30% hexane to 20% hexane in EtOAc as the eluent) in 80% yield (1.27 g) and >93% purity. D. The dimethyl ester 34c (1.17g) was dissolved in a mixture of

THF/MeOH/H2O (20 mL, 2:1:1 ratio), and an aqueous solution of NaOH (1.8 mL,

IN, 1 eq.) was added. The reaction mixture was stirred at RT for 1 h before it was evaporated to dryness to obtain the sodium salt 34d as a white solid (-1.66 mmol). Compound 34d was used in the next step without purification.

E. The crude sodium salt 34d (1.66 mmoL) was dissolved in THF (17 mL), Et3N was added and the mixture was cooled to 0 C in an ice bath. Isobutylchloroformate

(322 μl, 2.5 mmol) was added dropwise and the mixture was stirred at 0 C for 75 min. After that period, diazomethane (15 mL) was added and stirring was continued at 0 C for 30 min and then at RT for an additional 1 h. Most of the solvent was evaporated to dryness under vacuum, the remaining mixture was diluted with EtOAc, washed with saturated NaHCO3 (2x), H2O (2x) and brine (lx), dried over anhydrous MgSO4, filtered and evaporated to dryness to obtain compound 34e as a light yellow foam (1.2g, -1.66 mmol). The diazoketone intermediate 34e was used in the next step without purification.

F. The diazoketone 34e (1.2g, 1.66 mmoL) dissolved in THF (17 mL) was cooled to 0 C in an ice bath. A solution of aqueous HBr (48%, 1.24 mL) was added dropwise and the reaction mixture was stirred at 0 C for 1 h. The mixture was then diluted with EtOAc, wash with saturated NaHCO3 (2x), H2O (2x) and brine (lx), the organic layer was dried over anhydrous MgSO4, filtered and evaporated to dryness to obtain the β-bromoketone intermediate 34f as a light yellow foam (-1.657 mmol).

G. To a solution of the bromoketone 34f (600 mg,0.779 mmol) in isopropanol (5 mL), thiourea (118 mg, 1.55 mmol) was added and the reaction mixture was placed in a pre-heated oil bath at 75 C where it was allowed to stir for 1 hr. The isopropanol was then removed under vacuum and the product dissolved in EtOAc

(100 mL). The solution was washed with saturated NaHCO3 and brine, the organic layer was dried over anhydrous Na2SO4, filtered and evaporated to afford the crude product 34g (522 mg) as a red-brown solid. This material was used in the final step without any further purification.

H. The crude methyl ester 34g (122 mg, 0.163 mmol) was dissolved in a solution of THF/MeOH/H2O (2:1:1 ratio, 4 mL) and saponified using LiOH»H2O (89 mg, 2.14 mmol). The hydrolysis reaction was carried out over a 12-15 h period at RT. The solvents were then removed under vacuum and the crude product purified by C18 reversed phase HPLC, using a solvent gradient from 10% CH3CN in H2O to 100%

CH3CN, to afford the HCV protease inhibitor #812 as a yellow solid (24 mg, 20% overall yield for the conversion of intermediate 34f to inhibitor #812).

*H NMR (400 MHz, DMSO-d6) δ 8.63 (s, IH), 8.26-8.15 (m, 2H), 7.79 (bs, IH), 7.72

(bs, IH), 7.50 (bs, 2H), 7.33-7.25 (m, 2H), 5.77 (bs, IH), 5.52 (dd, J = 8.3 Hz, IH), 5.27 (dd, J = 9.2 Hz, IH), 4.64 (d, J = 10.8 Hz, IH), 4.50 (dd, J = 8.3 Hz, IH), 4.39-4.31 (m, IH), 4.08-3.99 (m, 2H), 3.94 (s, 3H), 3.87 (d, J = 9.5 Hz, 2H), 2.65-2.53 (m, 2H), 2.46- 2.36 (m, 2H), 2.20-2.12 (dd, J = 8.6 Hz, IH), 1.80-1.64 (m, 2H), 1.63-1.06 (m, 14H). MS; es+: 733.2 (M + H)+, es“: 731.2 (M – H)\

………………..

http://www.google.com/patents/WO2006036614A2

(Z)-( 1S,4R, 14S, 18R)- 14-Cyclopentyloxycarbonylamino- 18-[2-(2- isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.0 ‘ ]nonadec-7-ene-4-carboxylic acid , whose chemical structure is as follows:

Figure imgf000015_0001

, provided for in Tsantrizos et al., U.S. Patent No. 6,608,027 Bl,

…………………………

https://www.google.co.in/patents/WO2005090383A2

ENTRY 218

Figure imgf000034_0001

…………………..

http://www.google.com/patents/WO2004039833A1

Figure imgf000015_0003

 

……………..

Org. Process Res. Dev., 2007, 11 (1), pp 60–63
DOI: 10.1021/op0601924

A new procedure for the practical synthesis of (S)-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid, a key building block for BILN 2061, an HCV NS3 protease inhibitor, has been developed. The key step features a kinetic resolution of racemic 2-acetylamino-8-nonenoic acid with acylase I. In addition, the undesired (R)-2-acetylamino-8-nonenoic acid was recycled after racemization. The procedure was implemented for the production of (S)-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid on pilot-plant scale.

Figure

 

Figure

……………

nmr

Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans
Org Lett 2004, 6(17): 2901

http://pubs.acs.org/doi/full/10.1021/ol0489907

http://pubs.acs.org/doi/suppl/10.1021/ol0489907/suppl_file/ol0489907si20040715_032207.pdf  procedure

http://pubs.acs.org/doi/suppl/10.1021/ol0489907/suppl_file/ol0489907si20040715_032254.pdf nmr spectra

BILN 2061:

Methyl ester 18 (2.69 g, 3.41 mmol) was dissolved in a mixture of THF
(40 mL), MeOH (20 mL) and water (20 mL) and added LiOH.H2O (1.14 g, 27.3 mmol).The resulting mixture was left to stir at RT for 15 h. The solvents were then removedunder reduced pressure and the crude product was redissolved with EtOAc and dilutedwith brine. The pH of the aqueous layer was adjusted to 6 with aqueous HCl (1N) and theaqueous phase was extracted with EtOAc (3x). The combined organic phase werewashed with water, brine, dried over MgSO4 and concentrated under reduced pressure toafford BILN 2061 as a yellow solid (2.63 g, 99% yield). HPLC(A) 99%, MS m/z (ES+)773 (M+H)+, (ES-) 775 (M-H)-;

1H NMR (DMSO-d6) δ 8.63 (s, 1H), 8.26-8.15 (m, 2H),
7.79 (bs, 1H), 7.72 (bs, 1H), 7.50 (bs, 2H), 7.33-7.25 (m, 2H), 5.77 (bs, 1H), 5.52 (dd, J=8.3 Hz, 1H), 5.27 (dd, J= 9.2 Hz, 1H), 4.64 (d, J= 10.8 Hz, 1H), 4.50 (dd, J= 8.3 Hz, 1H),4.39-4.31 (m, 1H), 4.08-3.99 (m, 2H), 3.94 (s, 3H), 3.87 (d, J= 9.5 Hz, 2H), 2.65-2.53(m, 2H), 2.46-2.36 (m, 2H), 2.20-2.12 (dd, J= 8.6 Hz, 1H), 1.80-1.64 (m, 2H), 1.63-1.06(m, 14H); HRMS calcd for C40H51N6O8S: 775.3489; found: 775.3476

 

…………………………

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ANTHONY MELVIN CRASTO

THANKS AND REGARD’S

DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463

web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

Share

SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1

 phase 2, Uncategorized  Comments Off on SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1
Jan 062014
 

SOVAPREVIR

(2S, 4R) -1 – [(2S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl) butanoyl]-N-{(1R, 2S) -1 – [(cyclopropanesulfonyl) carbamoyl]-2-ethenylcyclopropyl} -4 – [(7-methoxy-2-phenylquinolin-4-yl) oxy] pyrrolidine-2-carboxamide

http://www.ama-assn.org/resources/doc/usan/sovaprevir.pdf

PATENT

US 2009048297 ENTRY 60

WO 2008008502

CN 103420991

 

THERAPEUTIC CLAIM ….Treatment of hepatitis C

CHEMICAL NAMES

1. 2-Pyrrolidinecarboxamide, N-[(1R,2S)-1-[[(cyclopropylsulfonyl)amino]carbonyl]-2-
ethenylcyclopropyl]-1-[(2S)-3,3-dimethyl-1-oxo-2-[2-oxo-2-(1-piperidinyl)ethyl]butyl]-4-
[(7-methoxy-2-phenyl-4-quinolinyl)oxy]-, (2S,4R)-

2. (2S,4R)-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-1-{(2S)-
3,3-dimethyl-2-[2-oxo-2-(piperidin-1-yl)ethyl]butanoyl}-4-[(7-methoxy-2-phenylquinolin-
4-yl)oxy]pyrrolidine-2-carboxamide

MOLECULAR FORMULA C43H53N5O8S

MOLECULAR WEIGHT 800.0

SPONSOR Achillion Pharmaceuticals, Inc.

CODE DESIGNATION ACH-0141625

CAS REGISTRY NUMBER 1001667-23-7

  • ACH-0141625
  • Sovaprevir
  • UNII-2ND9V3MN6O

Sovaprevir (formerly ACH-0141625), an HCV NS3 protease inhibitor, is in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1.

In 2012, fast track designation was assigned by the FDA for the treatment of hepatitis C (HCV). In 2013, a clinical hold was placed for the treatment of hepatitis C (HCV) in combination with atazanavir after elevations in liver enzymes associated with the combination of both compounds.

Sovaprevir, previously referred to as ACH-1625, is an investigational, next-generation NS3/4A protease inhibitor discovered by Achillion that is currently on clinical hold. In 2012, Fast Track status was granted by the U.S. Food and Drug Administration (FDA) to sovaprevir for the treatment of chronic hepatitis C viral infection (HCV).

Achillion has initiated a Phase 2 clinical trial (007 Study) to evaluate the all-oral, interferon-free combination of sovaprevir and its second-generation NS5A inhibitor, ACH-3102, with ribavirin (RBV), for a 12 week treatment duration, in treatment naïve, genotype 1 (GT1) HCV patients. In July 2013, sovaprevir was placed on clinical hold after elevated liver enzymes were observed in a Phase 1 healthy subject drug-drug interaction study evaluating the effects of concomitant administration of sovaprevir with ritonavir-boosted atazanavir.

In accordance with the clinical hold, the FDA provided that no new clinical trials that included dosing with sovaprevir could be initiated, however, the FDA allowed continued enrollment and treatment of patients in the Phase 2 -007 clinical trial evaluating 12-weeks of sovaprevir in combination with ACH-3102 and RBV for patients with treatment-naive genotype 1 HCV. In September 2013, after reviewing Achillion’s response, the FDA stated that although all issues identified in the June 2013 letter had been addressed, it had concluded that the removal of the clinical hold was not warranted at this time.

The FDA requested, among other things, additional analysis to more fully characterize sovaprevir pharmacokinetics and the intrinsic and extrinsic factors that may lead to higher than anticipated exposures of sovaprevir or other potential toxicities in addition to the observed liver enzyme elevations.

The FDA also requested Achillion’s proposed plan for future clinical trials in combination with other directly-acting antivirals. At the request of the FDA, Achillion plans to submit a proposed plan for analyzing the additional clinical, non-clinical and pharmacokinetic data requested before the end of 2013, and if that analysis plan is approved by the FDA, submit a complete response during the first half of 2014. Achillion retains worldwide commercial rights to sovaprevir.

 

Sovaprevir has demonstrated activity against all HCV genotypes (GT), including equipotent activity against both GT 1a and 1b (IC50 ~ 1nM) in vitro.

 

With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios, sovaprevir has been clinically demonstrated to allow for once-daily, non-boosted dosing.

The current safety database for sovaprevir includes more than 560 subjects dosed to date and demonstrates that sovaprevir is well tolerated in these subjects.

Sovaprevir has demonstrated high rates of clinical cures in combination with pegylated-interferon and RBV in a challenging, real world, patient population of genotype 1 treatment-naive patients.

100% of GT1b subjects achieved a rapid virologic response (RVR) in the 007 Study evaluating the interferon-free combination of sovaprevir + ACH-3102 + RBV for 12 weeks. The Phase 2 study is ongoing.

 

Sovaprevir in vitro retains activity against mutations that confer resistance to 1st-generation protease inhibitors.

In clinical studies to date, sovaprevir has demonstrated a high pharmacologic barrier to resistance with no on-treatment viral breakthrough reported to date in GT1b patients.

 

Sovaprevir is believed to be synergistic when combined with other classes of DAAs, including the second-generation NS5A inhibitor, ACH-3102.

For more information about the next-generation NS3/4A protease inhibitor, sovaprevir, please see the Related Links on this page or visit Resources.

Sovaprevir is an investigational compound. Its safety and efficacy have not been established. (Updated December 2013)

SOVAPREVIR

 

An estimated 3% of the world’s population is infected with the hepatitis C virus. Of those exposed to HCV, 80% become chronically infected, at least 30% develop cirrhosis of the liver and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will clear HCV.

HCV is an enveloped, single-stranded RNA virus that contains a positive-stranded genome of about 9.6 kb. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae. At least 4 strains of HCV, GT-1-GT-4, have been characterized.

The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication, and virion assembly and release. Translation of the HCV RNA genome yields a more than 3000 amino acid long polyprotein that is processed by at least two cellular and two viral proteases. The HCV polyprotein is:

NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.

The cellular signal peptidase and signal peptide peptidase have been reported to be responsible for cleavage of the N-terminal third of the polyprotein (C-E1-E2-p7) from the nonstructural proteins (NS2-NS3-NS4A-NS4B-NS5A-NS5B). The NS2-NS3 protease mediates a first cis cleavage at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis-cleavage at the NS3-NS4A junction. The NS3-NS4A complex then cleaves at three downstream sites to separate the remaining nonstructural proteins. Accurate processing of the polyprotein is asserted to be essential for forming an active HCV replicase complex.

Once the polyprotein has been cleaved, the replicase complex comprising at least the NS3-NS5B nonstructural proteins assembles. The replicase complex is cytoplasmic and membrane-associated. Major enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus. Assembly of a functional replicase complex has been described as a component of the HCV replication mechanism. Provisional application 60/669,872 “Pharmaceutical Compositions and Methods of Inhibiting HCV Replication” filed Apr. 11, 2005, is hereby incorporated by reference in its entirety for its disclosure related to assembly of the replicase complex.

Current treatment of hepatitis C infection typically includes administration of an interferon, such as pegylated interferon (IFN), in combination with ribavirin. The success of current therapies as measured by sustained virologic response (SVR) depends on the strain of HCV with which the patient is infected and the patient’s adherence to the treatment regimen. Only 50% of patients infected with HCV strain GT-1 exhibit a sustained virological response. Direct acting antiviral agents such as ACH-806, VX-950 and NM 283 (prodrug of NM 107) are in clinical development for treatment of chronic HCV. Due to lack of effective therapies for treatment for certain HCV strains and the high mutation rate of HCV, new therapies are needed.

 

…………………………………………

https://www.google.co.in/patents/US20090048297

(2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

 

Figure US20090048297A1-20090219-C00105

 

SOVAPREVIR IS DESCRIBED AS 60 IN CLAIM

 

SYNTHESIS OF INTERMEDIATE 13 BELOW AND ALSO  COMPD 8 IE SOVAPREVIR IN STEP 4

 

Example 1

SYNTHESIS OF 1-((2S,4R)-1-((S)-2-TERT-BUTYL-4-OXO-4-(PIPERIDIN-1-YL)BUTANOYL)-4-(7-METHOXY-2-PHENYLQUINOLIN-4-YLOXY)PYRROLIDINE-2-CARBOXAMIDO)-2-VINYLCYCLOPROPANECARBOXYLIC ACID

Step 1. Preparation of N-(cyclopropylsulfonyl)-1-(BOC-amino)-2-vinylcyclopropanecarboxamide

 

Figure US20090048297A1-20090219-C00047

 

CDI (2.98 g, 18.4 mm, 1.1 eq) is dissolved in ethyl acetate. N-Boc-cyclopropylvinyl acid (3.8 g, 16.7 mm, 1.0 eq), prepared via the procedure given by Beaulieu, P. L. et al. (J. Org. Chem. 70: 5869-79 (2005)) is added to the CDI/ethyl acetate mixture and stirred at RT until the starting material is consumed. Cyclopropyl sulfonamine (2.2 g, 18.4 mm, 1.1 eq) is added to this mixture followed by DBU (2.1 ml, 20.5 mm, 1.23 eq) and the mixture is stirred at RT for 2 h. Workup and purification by silica gel chromatography provides 2g of compound 2.

Step 2. Preparation of (2S,4R)-tert-butyl 2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carboxylate and (2S,4R)—N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

Figure US20090048297A1-20090219-C00048

 

Compound 1 (4.3 g, 9.3 mmol, 1.1 eq), prepared according to the method given ins WO 02/060926, in DMF is stirred with O-(Benzotriazol-lyl)-N,N,N′,N′-Tetramethyluronium hexafluorophosphate (4.1 g, 10.5 mmol, 1.3 eq) for 30 minutes, followed by addition of cyclopropylamine 2 (1.92 g, 8.3 mmol, 1.0 eq) and N-methylmorpholine (2.52 g, 25.0 mmol, 3.0 eq). The mixture is stirred over night and the solvent removed under reduced pressure. The resulting residue is diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic solvent is dried over MgSO4 and concentrated under reduced pressure to afford crude 3, which is used for next step without further purification.

Compound 3 in 10 ml dry CH2Cl2 is treated with 5 mL TFA and stirred over night. The solvent is removed and the residue recrystallized from ethyl acetate to afford 4.12 g Compound 4 (61% yield two steps).

Step 3. Preparation of (3S)-3-((2S,4R)-2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

 

Figure US20090048297A1-20090219-C00049

 

The Acid 5 (58 mg, 0.25 mmol, 1.2 eq), prepared via the procedure given by Evans, D. A., et al. (J. Org. Chem. 64: 6411-6417 (1999)) in 1.2 mL DMF is stirred with 4 (138 mg, 0.21 mmol), HATU (160 mg, 0.42 mmol, 2.0 eq), and DIEA (0.63 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 121 mg 6 (77% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent was removed to provide Compound 7 in 100% yield.

Step 4. Preparation of (2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

Figure US20090048297A1-20090219-C00050

PLEASE  NOTE 8 IS SOVAPREVIR

The Acid 7 (0.15 mmol) in 1.0 mL DMF is stirred with pepridine (excess, 0.6 mmol, 4 eq), HATU (115 mg, 0.3 mmol, 2.0 eq), and DIEA (0.45 mmol, 3.0 eq) for 4 hrs. The mixture is subjected to HPLC purification to afford 77.1 mg 8.

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

 

Figure US20090048297A1-20090219-C00051

 

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

The Acid 5 (105 mg, 0.46 mmol, 1.2 eq) in 1.2 mL DMF is stirred with 9 (202 mg, 0.38 mmol), HATU (290 mg, 0.76 mmol, 2.0 eq), and DIEA (1.2 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 204.3 mg 10 (75% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent is removed to provide 11 in 100% yield.

 

Figure US20090048297A1-20090219-C00052

 

Step 6. Preparation of Final Product

The Acid 11 (30 mg, 0.045 mmol) in 1.0 mL DMF is stirred with pepridine (0.27 mmol, 6 eq), HATU (34 mg, 0.09 mmol, 2.0 eq), and DIEA (0.14 mmol, 3.0 eq) for 2 hrs. The mixture is subjected to HPLC purification to afford 21.2 mg 12 (65% yield), which is hydrolyzed in methanol with 2N NaOH for 6 hrs. The mixture is acidified with 6N HCl and subjected to HPLC purification to afford 7.6 mg 13.

………………………………

 

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ANTHONY MELVIN CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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Gilead Sciences reported that in a recent Phase 2 study, its oral drug idelalisib successfully drove the life-threatening chronic lymphocytic leukemia (CLL) into remission.

 phase 2  1 Response »
May 292013
 

 

3 Biopharma Runners With Fuel in the Tank
Investorplace.com
Gilead Sciences (GILD) stock recently set a new all-time high after reporting that in a recent Phase 2 study, its oral drug idelalisib successfully drove the life-threatening chronic lymphocytic leukemia (CLL) into remission. The regimen produced a 97% …

 

Gilead Sciences (GILD) stock recently set a new all-time high after reporting that in a recent Phase 2 study, its oral drug idelalisib successfully drove the life-threatening chronic lymphocytic leukemia (CLL) into remission. The regimen produced a 97% response rate, with 93% of trial patients surviving progression-free at the end of two years. CLL, which produces too many mature white cells, is the second most common form of leukemia in the U.S.

http://investorplace.com/2013/05/3-biopharma-runners-with-fuel-in-the-tank/

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