New Drug Approvals

Home » Posts tagged 'helsinn'

Tag Archives: helsinn

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,569,946 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,381 other followers

Follow New Drug Approvals on WordPress.com

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,381 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

HM04 or H0900


str2

3-[(1R)-1-(2,3-Dichloro-4-pyrazin-2-ylphenyl)-2,2,2-trifluoroethyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea.png

HM04 or H0900

Cas 1808913-24-7

MF C20 H22 Cl2 F3 N5 O
MW 476.32
Urea, N‘-[(1R)-1-[2,3-dichloro-4-(2-pyrazinyl)phenyl]-2,2,2-trifluoroethyl]-N-methyl-N-(1-methyl-4-piperidinyl)-

(R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl) urea

The compound was disclosed in WO2015134839 . Helsinn under license from Novo Nordisk , is investigating ghrelin antagonists for treating obesity, Prader-Willi syndrome and other metabolic disorders; in May 2015, the program was listed as being in preclinical development

Helps reducing ghrelin signaling activity and treating disorder associated with an increase in ghrelin level (eg food abuse, alcohol addiction, and Prader-Willi syndrome).

Ghrelin, a growth hormone-releasing peptide produced by ghrelinergic cells in the gastrointestinal tract, is understood to function as a neuropeptide that regulates energy metabolism by stimulating appetite. The modulation, for example inhibition, of ghrelin signaling, through the ghrelin/growth hormone secretagogue receptor (GHS-Rla), is an attractive target for pharmacological treatment of disorders associated with high ghrelin level. Potential disorders for treatment using ghrelin modulators include food abuse (such as binge eating, obesity, hyperphagia (or uncontrollable appetite), post-dieting body weight rebound (including post-dieting hyperphagia), alcohol addiction, and genetic diseases associated with increased ghrelin level (e.g., Prader-Willi syndrome (PWS)).

PATENT

US 20150252021

PATENT

WO2015134839

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015134839

Example 1

nthesis of Intermediate lk

Intermediate k

Step 1:

To a solution of la (100 g, 0.62 mol) in DMF (1.2 L) was added N-bromosuccinimide (110 g, 0.62 mol) at 0 °C. The mixture was stirred at room temperature for 4 h, then water (800 mL) was added and the resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was triturated with petroleum ether to provide lb (133.7 g, 89% yield) as a brown solid. !H-NMR (CDC13, 300 MHz): δ= 7.30 (d, 1 H), 6.59 (d, 1 H), 4.22 (br, 2 H). LC-MS: 241 [M+l]+.

Step 2:

To a solution of lb (133.7 g, 0.55 mol) in dry CH2C12 (1.5 L) was added acetic anhydride (110 g, 0.62 mol) dropwise over a period of 20 minutes at room temperature. The mixture was stirred at room temperature overnight, then diluted with CH2C12 (300 mL) and washed with water (150 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was triturated with petroleum ether (300 mL) to provide compound lc (143.0 g, 91% yield) as a white solid. ¾-NMR (CDC13, 400 MHz): δ= 8.26 (d, 1 H), 7.63 (br, 1 H), 7.54 (d, 1 H), 2.26 (s, 3 H). LC-MS: 280 [M-l].

Step 3:

A mixture of compound lc (50.0 g, 0.18 mol), butyl vinyl ether (Id, 89.0 g, 0.89 mol), bis(l,3-diphenylphosphino)propane (DPPP, 22.0 g, 0.053 mol), TEA (100 mL, 0.71 mol) and Pd(OAc)2 (6.4 g, 0.027 mol) in DMSO (1.2 L) was heated at 130 °C under N2 overnight. After the reaction was completed, the mixture was cooled to 0 °C and 2N HC1 (480 mL) was added dropwise over a period of 30 minutes. Then, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous a2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: PE=1 : 10) to provide le (19.5 g, 45% yield) as a yellow solid. 1H-NMR (CDC13, 400 MHz): 3= 8.46 (d, 1 H), 7.82 (br, 1 H), 7.51 (d, 1 H), 2.63 (s, 3 H), 2.29 (s, 3 H). LC-MS: 244 [M-l].

Step 4:

To a solution of le (21.9 g, 89.4 mmol) in MeOH (350 mL) was added 2N NaOH solution (350 mL) at room temperature. The mixture was heated at 50 °C overnight, then cooled and concentrated under reduced pressure. The resulting solid was triturated with water (100 mL) for 30 min and filtered to provide If (18.0 g, 98% yield) as a brown solid. ¾-NMR (CDC13, 400 MHz): 3= 7.48 (d, 1 H), 6.68 (d, 1 H), 4.56 (br, 2 H), 2.62 (s, 3 H). LC-MS: 202[M-1]\

Step 5:

To a mixture of compound If (18.0 g, 89.2 mmol) and ice (360 g) in cone. HC1 (180 mL) was added a solution of NaN02 (9.2 g, 133.7 mmol) in water (20 mL) dropwise over a period of 30 minutes, and the resulting mixture stirred in an ice bath for 30 min. A solution of KI (74.0 g, 446 mmol) in water (360 mL) was added dropwise over 45 min at 0 °C. The mixture was stirred for 30 min and then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: PE=1 :40) to provide lg (23.9 g, 86% yield) as a yellow solid. 1H-NMR (CDC13, 400 MHz): 3= 7.6 (d, 1 H), 7.06 (d, 1 H), 2.62 (s, 3 H).

Step 6:

To a solution of lg (23.9 g, 76.1 mmol) in MeOH (100 mL)/THF (100 mL) was slowly added NaB¾ (2.9 g, 76.1 mmol) at 0 °C. The mixture was stirred at room temperature for 5 min, and then quenched with water (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: PE=1 : 10) to provide lh (22.4 g, 93% yield) as a white solid. 1H-NMR (CDC13, 400 MHz): 3= 7.81 (d, 1 H), 7.26 (d, 1 H), 5.23 (q, 1 H), 2.17 (br, 1 H), 1.47 (d, 3 H).

Step 7:

To a mixture of lh (22.4 g, 70.9 mmol), phthalimide (12.5 g, 85.0 mmol) and PPh3 (22.3 g, 85.0 mmol) in dry THF (450 mL) was added DIAD (21.5 g, 106.3 mmol) at room temperature under N2 protection. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: PE=1 : 15) to provide li (18.5 g, 58% yield) as a white solid. 1H-NMR (CDC13, 400 MHz): 3= 7.78-7.84 (m, 3 H), 7.70-7.73 (m, 2 H), 7.41-7.43 (d, 1 H), 5.76-5.81 (q, 1 H), 1.84 (d, 3 H).

Step 8:

A solution of li (7.2 g, 16.2 mmol) and hydrazine hydrate (98%, 4.0 g, 80.9 mmol) in MeOH (150 mL) was heated under reflux for 2 h, then cooled and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with CH2C12 (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give lj (3.8 g, 75% yield) as a white solid. 1H-NMR (CDC13, 400 MHz): 3= 7.81 (d, 1 H), 7.25 (d, 1 H), 4.55 (q, 1 H), 1.36-1.38 (d, 3 H). LC-MS: 316 [M+l]+.

Step 9:

To a solution of lj (41. Og, 0.13 mol) in methyl tert-butyl ether (750 mL) was added slowly a solution of D-mandelic acid (7.8 g, 0.052 mol) in methyl tert-butyl ether (1 10 mL) at 45°C. The mixture was stirred at this temperature for 30 min then cooled and filtered. White solid obtained was partitioned between 5% NaOH solution (300 mL) and methyl tert-butyl ether (300 mL). The bi -phases were separated and the aqueous phase was extracted with methyl tert-butyl ether (300 mL). The combined organic layer was concentrated to provide Intermediate lk (12 g, 58.5% yield) as a white solid (ee%=98.0%, Chiralpak AD-H, 5 μπι, 4.6*250mm, mobile phase: Hex: EtOH : DEA=80 : 20 : 0.2), retention time = 6.408 min).

Example 2

Synthesis of Compoun

A suspension of N-methyl-4-piperidone 2a (13.3 g, 58.6 mmol), NH2Me (30% in MeOH, 100 mL) and Pd/C (0.66 g) in MeOH (200 mL) was heated at 60 °C under H2 atmosphere (50 psi) overnight, then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in HC1 in dioxane (3N, 100 mL) and stirred for 30 min. The precipitate was filtered and washed with EtOAc (50 mL) to provide 2b (7.7g, 54% yield) as white powder. 1H-NMR (DMSO, 400 MHz): δ= 9.50 (br, 2 H), 3.48 (d, 2 H), 3.15-3.16 (m, 1 H), 2.96-3.01 (m, 2 H), 2.70 (s, 3 H), 2.51 (s, 3 H), 2.22-2.28 (m, 2 H), 1.94-2.02 (m, 2 H), LC-MS: 129 [M+l]+ .

Example 20

Synthesis of H0900

Step 1:

To a mixture of 16d (32 g, 120 mmol) in dry CH2CI2 (800 mL) was added Dess-Martin peroxide reagent (76 g, 180 mmol) portion- wise at 0 °C. The mixture was stirred at room temperature for 1 h, then diluted with DCM (800 mL), washed with aqueous NaHC03 solution (300 mL) and brine (300 mL). The organic phase was separated, dried over anhydrous Na2S04 and

concentrated under reduced pressure to afford crude 18a (31.4 g) which was used directly in the next step without further purification.

Step 2:

To a solution of 18a (12 g, 40 mmol) and 3b (22.2 g, 60 mmol) in DME (560 mL) were added Pd(PPh3)4 (9.25 g, 8 mmol) and Cul (1.52 g, 8 mmol) at room temperature. The mixture was stirred at 90 °C overnight, then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, EA : PE = 1 :5) to provide 18b (8.0 g, 79.3%) as a white solid. LC-MS: 253 [M+l]+.

Step 3:

To a solution of 18b (7 g, 27.7 mmol) and (¾)-tert-butylsulfinamide (7.27 g, 30.56 mmol) in dry THF (200 mL) was added Ti(i-OPr)4 (15.7 g, 55.4 mmol) dropwise at room temperature. The mixture was stirred at 80 °C overnight, and then cooled. Ethyl acetate (40 mL) was added, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, EA:PE =1 :5) to provide 18c (6.8 g, 69%) as a yellow solid. 1H-NMR (CDC13, 400 MHz): 3= 9.10 (s, 1H), 8.97 (s, 1H), 8.72 (s, 1H), 8.64 (d, 1H),8.12 (d, 1H), 7.59 (d, 1H), 1.30 (s, 9H).LC-MS: 356 [M+l]+.

Step 4:

To a stirred solution of 18c (6.8 g, 19 mmol) and Tetrabutylammonium difluorotnphenylsilicate (15.8 g, 29 mmol) in dry THF (250 mL) was added a solution of TMSCF3 (11 g, 77 mmol) in anhydrous THF (50 mL) at -65 °C. The mixture was then stirred at -65 °C for 2 h, and at that point aqueous NH4CI solution (250 mL) was added. The mixture was diluted with ethyl acetate (250 mL), washed with brine (250 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, EA : PE=1 :2) to provide 18d (4.3 g, 52%) as a yellow solid. LC-MS: 426 [M+l]+.

Step 5:

To a stirred solution of 18d (4.3 g, 10.1 mmol) in MeOH (40 mL) was added a solution of HCl/MeOH (4N, 40 mL) at room temperature. The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was triturated with ethyl acetate (40 mL) to afford crude 18e (4.3g) which was directly in the next step without further purification. LC-MS: 322 [M+l]+.

Step 6:

To a solution of 18e (2.7 g, 7.1 mmol), 2b (3.4 g, 21.3 mmol) and TEA (80 mL) in DCM (220 mL) was added thiphosgene (3.15 g, 10.6 mmol) in DCM (40 mL) dropwise at 0 °C. The solution was warmed to ambient temperature and stirred for 1 h, then diluted with DCM ( 100 mL) and washed with aqueous Na2C03 solution (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2SC>4 and concentrated. The residue was purified with silica gel column chromatography (silica, DCM : CH3OH=10 : 1) to provide crude H0900 (2.13 g, ee%=92.5%) which was further purified through chiral separation to afford H0900 (1.6 g, 49% yield) as a white solid. (ee%=98.5%, Chiralpak IC 5um, 4.6*250mm, Phase: Hex: EtOH:

DEA=90: 10:0.2), retention tine =12.829 min. 1H-NMR (CDC13, 400 MHz): δ= 8.86 (d, 1H), 8.63 (dd, 1H), 8.55 (d, 1H), 7.47 (d, 1H), 7.40 (d, 1H), 6.28 (m, 1H), 5.18 (d, 1H), 4.12 (m, 1H), 2.88 (t, 2H), 2.77 (s, 3H), 2.22 (s, 3H), 2.05 (m, 2H), 2.48 (m, 2H), 1.52 (m, 2H), 1.73-1.49 (m, 4H). LC-MS: 476 [M+l]+.

PATENT

WO-2019118298

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019118298&tab=PCTDESCRIPTION&maxRec=1000

Novel crystalline fumarate salt forms of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl) urea (also referred to as HM04 or H0900; designated as Forms 1-4), process for their preparation and compositions comprising them are claimed.

PWS occurs in approximately 1 in 10,000 births and is associated with deletion or lack of expression of region 15ql 1.2 of the paternal chromosome 15.

Characteristics of PWS include short stature, low muscle tone, and hyperphagia. Growth hormone replacement is frequently used to treat growth deficiencies and hypotonia. However, treatment for the insatiable appetite is lacking and PWS children can mature into adults suffering from obesity and type 2 diabetes. Levels of ghrelin are generally elevated in PWS; however, the relationship with ghrelin signaling and food intake in PWS remains unclear. See Purtell L., et ah, In adults with Prader-Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-l levels. Neuropeptides. 201 l;45(4):30l-7; Cummings D.E., et ah, Elevated plasma ghrelin levels in Prader Willi syndrome. Nature Medicine . 2002;8(7):643-4; DelParigi A., et ah, High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader-Willi syndrome. The Journal of Clinical Endocrinology and Metabolism. 2002;87(l2):546l-4.

[005] Accordingly, it is desirable to find treatments that effectively inhibit GHSRla, that are tolerable to the patient, and that do not interfere with other functions of the growth hormones. GHSRla modulators, including inhibitors such as (R)-3-(l-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2, 2, 2-trifluoroethyl)-l -methyl- l-(l-m ethylpiperidin-4-yl) urea (HM04, H0900) depicted below, are reported in LT.S. Patent No. 9,546,157.

Step 1 : Synthesis of compound 2A

[00106] 2,2,6,6-tetramethylpiperidine (7.20 kg, 51.1 mol, 3.0 eq.,

KF=0.30%) was added into a 100 L reactor equipped with a temperature probe and overhead stirrer and mixed at RT under nitrogen protection. THF (50 L) was added into the reactor and stirred. The vessel was purged with nitrogen three times and cooled to 0 °C. n-BuLi (20.4 L, 3.0 eq.; 2.5 M hexane solution) was added to the mixture dropwise while keeping the temperature at about 0 °C to about 5 °C for over one hour. The color of the solution turned yellow. The mixture was stirred at about 0 °C to about 5 °C for 30 minutes. The mixture was cooled to about -78 °C to about -70 °C to form Solution A.

[00107] Compound 1 (3.25 kg, 17.0 mol. 1.0 eq., KF=0.03%) was dissolved in 15 L of THF to form Solution B.

[00108] Solution B was added to solution A dropwise at a temperature of about -70 °C to about -78 °C over one hour and then stirred for 30 minutes to form solution C. Tri-isopropyl borate ((i-PrO)3B) (3.52 kg, 18.7 mol., 1.1 eq.) was added dropwise into solution C over 10 minutes. The reaction mixture was stirred at a

temperature of about -70 °C to about -78 °C for one hour. HC1 (40 L, 3M, 7.0 eq.) was added over 30 minutes to quench the reaction. A 10 degree rise in temperature was noted.

[00109] The resulting aqueous layer was separated and extracted with EtOAc (40 L). The aqueous layer was separated and extracted twice again with EtOAc (35 L, 30 L). The organic layers were combined resulting in about 160 L of liquid. The combined organic layer was washed twice with 50 L of a 1M aqueous HC1 solution saturated with NaCl. The organic layer was concentrated to about 5 L in a 50 L rotavapor at a temperature of about 50 °C to about 55 °C under 30-40 mmHg for about 8 hours.

[00110] The residual EtOAc was swapped with DME for 3 times (10 L x 3). The organic layer was concentrated in the 50 L rotavapor at a temperature of about 50 °C to about 55 °C under 30-40 mmHg for about 6 hours. Each time about 5 L of residual remained. DME (20 L) was added to the residual to obtain a deep brown solution of 14.2% compound 2A (3.55 kg in 25 kg of solution; 88.8% yield; 97.4% purity (AETC by HPLC, retention time = 1.6 minutes); 0.24% residual ethyl acetate). 1H-NMR (400 MHz, DMSO): 5=8.55 (s, 2H), 7.36 (d, 1H), 7.69 (d, 1H). A second batch of compound 2A was prepared by the same method to produce 3.29 kg (95.4% purity, 82.3% yield, 0.11% residual ethyl acetate).

[00111] Step 2: Synthesis of Compound 3A

C! , N


M

K2CO3 (I .O equiv)

2A OH

DME/H20 3:1 (20 vol), 50 e C 3A N

[00112] Compound 2 A (2.91 kg in 20.5 kg solution) was added into a 100

L reactor at room temperature under nitrogen. DME (45 mL), 2-chloropyrazin (1.42 kg,

12.4 mol., 1.0 eq.), and Pd(dppf)Cl2 (10% w/w, 291 g) were added sequentially, and each

mixed at room temperature under nitrogen. Nitrogen was bubbled into the mixture for 20

minutes and the resulting mixture was purged and filled with nitrogen (3 times). The

mixture was heated to 48-52°C over 60 minutes. K2CO3 (2.57 kg, 18.6 mol, 1.5 eq.) was

added to 22 L of water in another reactor at room temperature and then added dropwise to

the compound 2 A mixture over 10 minutes. The mixture was stirred at 48-52°C for 16

hours and then cooled to room temperature. This procedure was repeated twice and all

three batches were combined.

[00113] An aqueous solution of K2CO3 (1.0 kg) was dissolved in 22 L of

water and added to the combined mixture to adjust the pH to 9. TBME (50 L) was added

into the mixture and filtered (PET filter, 3-5 pm, 205g/m2) to remove about 50 g of

sticky, brown solid material (catalyst analog). The aqueous layer was twice separated and

extracted with TBME (40 L, 40L).

[00114] The aqueous layer was combined with the aqueous layer of a

fourth batch prepared according to the above method. The pH of the combined aqueous layers was adjusted to pH<3 with HC1 (2N, 48 L). The solid precipitated out slowly as

the mixture was stirred at room temperature for 1 hour. The mixture was filtered (PET

filter, 3-5 pm, 205g/m2) over 30 minutes to obtain 20 kg of wet product. ACN (40 L) was

added into a 100 L reactor equipped with an overhead stirrer at room temperature. The 20

kg of wet product was added into the reactor and the reaction mixture heated to reflux

and stirred at reflux for 4 hours. The reaction mixture was cooled to room temperature

over 3 hours (around 15 °C/hour) and filtered to obtain 8.5 kg of wet solid. The wet solid

was dried under vacuum (20-30 mmHg) at 50-55 °C for 15 hours to obtain compound 3 A

as a pale white solid (6.1 kg; 97.4% purity (AUC by HPLC, retention time = 3.7

minutes); 83.8% yield). 1H-NMR (400 MHz, DMSO): 5=7.67 (d, 1H), 7.82 (d, 1H), 8.75

(d, 1H), 8.82 (t, 1H), 8.98 (d, 1H), 13.89 (bs, 1H).

[00115] Step 3: Synthesis of compound 6A

3A 6A N

N

[00116] Compound 3 A (6.1 kg, 22.7 mol, 1.0 eq.) was added into a 100 L

reactor equipped with a temperature probe, overhead stirrer, and condenser. Methanol

(92 L) was added into the reactor at room temperature. The mixture was cooled to

0-10 °C and added with SOCk (5.4 kg, 45.3 mol, 2.0 eq.) dropwise at 0-10 °C over 30

minutes. The reaction mixture was heated to reflux (65 °C) and stirred at reflux for 15

hours. A suspension was formed. Most of the solvent and SOCk was removed under

vacuum distillation until about 30 L remained. The mixture was concentrated under

vacuum (30-40 mmHg) at 50-55 °C for about 6 hours. Water (10 L) was added to the residual at -5 to 15 °C. The pH was adjusted to 8-9 with an aqueous solution of K2CO3 (200 g, dissolved in 2L of water) at -5 to 15 °C. The resulting aqueous layer was extracted twice with isopropyl acetate (25 L, 25 L). The combination of organic layers (about 50 kg) was washed with 20 L of NaHCCb aqueous layer. The organic layer was separated and washed with 10 L of of an aqueous solution of NaHCCb. All the aqueous layers were combined (55.8 kg). The organic layer was filtered through a silica pad (30 cm) and the pad washed with extra isopropyl acetate until the compound 6 A was filtered from the silica gel (about 3 hours). The organic layer was concentrated to about 5 L. THF (10 L) was added to the residual and concentrated to about 5 L (3 times) under vacuum (30-40 mmHg) at 50-55 °C for about 3 hours. Another 10 L of THF was added to the residual concentrate, giving a concentrated solution of compound 6A (15.8 kg; 32.83%,

5.19 kg compound 6A in solution; 97.9% purity (AUC by HPLC, retention time = 8.5 min); 80.8% yield). 1H-NMR (400 MHz, DMSO): 5=3.98 (s, 3H), 7.54 (d, 1H), 7.78 (d, 1H), 8.63 (d, 1H), 8.72 (t, 1H), 8.94 (d, 1H).

[00117] Step 4: Synthesis of compound 6B

[00118] THF (26 L) was added into a 100 L reactor equipped with a temperature probe and overhead stirrer under nitrogen. DIBAL-H (26 kg, 46 mol, 5.0 eq.) was added and the system purged and filled with nitrogen three times. The mixture was cooled to -78 to -70 °C to form solution A. A room temperature solution of compound 6A (2.6 kg, 9.2 mol, 1.0 eq.) in 52 L of THF was added dropwise at -78 to -70 °C over 30 minutes under nitrogen. The mixture was warmed to -30 °C over about 5-6 hours. The reaction mixture was stirred at -40 to -30 °C for 30 minutes. The mixture was slowly added to 42 L of 2N HCL over 1 hour reaching a maximum temperature of 35 °C. The mixture was extracted with 26 L of isopropyl acetate. The organic layer was separated and washed with 30 L of brine. This procedure was repeated and both batches of organic layer were combined and concentrated from about 100 L to about 5-10 L under vacuum.

A solid slowly formed during concentration. The mixture was cooled to 5-15 °C and stirred for 1 hour. The mixture was filtered (30-50 pm) over 30 minutes. The solid was dried under vacuum at 50 °C for 6 hours to obtain compound 6B as a brown solid (2.1 kg; 97.5% purity (AUC by HPLC, retention time = 8.6 min); 45.7% yield). 1H-NMR (400 MHz, DMSO): d = 4.65 (d, 2H), 5.68 (t, 1H), 7.62 (d, 1H), 7.68 (d, 1H), 8.72 (d, 1H),

8.80 (t, 1H), 8.94 (d, 1H).

[00119] Step 5: Synthesis of compound 7

[00120] DMSO (10 L) was added to a 50 L flask equipped with a temperature probe and overhead stirrer under nitrogen at room temperature. Compound 6B (2.05 kg, 8.04 mol, 1.0 eq.) was added under nitrogen at room temperature. Et3N (8 L) was added under nitrogen at RT and the mixture was then cooled to 15-20 °C.

SCb. pyridine (5.1 kg, 32.08 mol, 4.0 eq.) was dissolved into 10 L of DMSO at 5-15 °C in a separate flask and added to the mixture dropwise over 3.5 hours at about 20 °C. The reaction mixture was transferred to 70 L of ice-water. The suspension mixture was stirred at 0-10 °C for 1 hour and filtered (PET, 3-5 pm, 205 g/m2) by centrifuge over 1.5 hours to obtain compound 7 as a brown solid. The solid was dissolved in 35 L of DCM at room temperature. The resulting DCM layer was washed with 5 L of brine. The organic layer was separated and concentrated under vacuum at 40-45 °C to dryness to obtain compound 7 as a brown solid (2.33 kg; 96.3% purity (AEiC by HPLC, retention time = 9.2 minutes); 93.5% yield). 1H-NMR (400 MHz, DMSO): d = 7.67 (d, 1H), 7.99 (d, 1H), 8.67 (d, 1H), 8.75 (s, 1H), 8.99 (d, 1H), 10.56 (s, 1H).

[00121] Step 6: Synthesis of compound 8

[00122] THF (23 L) was added to a 50 L flask equipped with a temperature probe and overhead stirrer under nitrogen at room temperature. Compound 7 (2.3 kg, 9.1 mol, 1.0 eq.) and (S)-2-methylpropane-2-sulfmamide (1.21 kg, 10 mol, 1.1 eq.) were added sequentially to the flask under nitrogen. Ti(OEt)4 (6.22 kg, 27.3 mol, 3.0 eq.) was added dropwise to the flask over 1 hour at 30-35 °C under nitrogen. The system was purged with nitrogen three times and then the mixture was stirred at room temperature for 2 hours. Isopropyl acetate (40 L) was added to the reaction mixture. The entire reaction mixture was then charged to 20 L of brine while stirring slowly at RT. A lot of solid was formed and no heat release was observed. The solid (about 18 kg) was filtered using centrifuge, and then the solid was slurried with 20 L of isopropyl acetate again for 20 minutes, and filtered again, resulting is slightly less solid (17.3 kg). The filtrates were then combined and washed with 20 L of brine. The organic layer was separated and concentrated in a rotavapor under vacuum (30-40 mmHg) at 40-50 °C for about 4 hours to remove the solvents and obtain a brown oil (compound 8). The oil was dissolved in DMF to obtain a black solution (7.36 kg; 40.1%; 3.0 kg compound 8 in solution; 92.1% purity (AUC by HPLC, retention time = 9.7 minutes); >100% yield). 1H-NMR (400 MHz, CDCb): d = 1.30 (s, 9H), 7.59 (d, 1H), 8.11 (d, 1H), 8.64 (s, 1H), 8.73 (m, 1H), 8.97 (s, 1H), 9.10 (s, 1H).

[00123] Step 7: Synthesis of compound 11

O

S

10 s C

8

11 N

[00124] DMF (26 L, 10 v/w) was added to a 50 L flask equipped with a temperature probe and overhead stirrer under nitrogen at 15 °C. Compound 8 (7.3 kg of

DMF solution, containing 2.9 kg, 8.1 mol, 1.0 eq.) and TBAA (2.44 kg, 8.1 mol, 1.0 eq.) were added sequentially to the flask under nitrogen. The mixture was cooled to 0-10 °C.

TMSCF3 (2.88 kg, 20.3 mol, 2.5 eq.) was then added to the flask over 60 min at 0-10 °C.

The reaction mixture was stirred at 0-5 °C under nitrogen protection for 3 hours.

Isopropyl acetate (60 L) was added to the mixture, followed by the addition of 45 L of

NaHCCb under stirring at 5-25 °C. The organic layer was separated, washed three times with NaHC03 (30 L x 3), and concentrated from 60 kg to 2.5 kg of brown oil. The oil product was dissolved in 20 L of TBME and filtered through a pad of silica gel (about 40 cm high, 30 cm diameter) over 2 hours to obtain 2.14 kg of compound 1 1 in TBME solution. The solution was concentrated at 45-50 °C to dryness to obtain compound 1 1 as a black oil (1.85 kg; 85.2% purity (AETC by HPLC, retention time = 9.1 minutes, 9.6 minutes for diastereoisomer); 53.6% yield). 1H-NMR (400 MHz, CDCh): d = 1.33 (s, 9H), 3.82-3.85 (d, 1H), 5.61-5.66 (m, 1H), 7.53-7.60 (m, 2H), 8.63-8.64 (d, 1H), 8.71-8.72 (m, 1H), 8.95 (s, 1H).

[00125] Step 8: Synthesis of compound 12 (free base)

[00126] Compound 1 1 (1.8 kg, 4.23 mol, 1.0 eq., crude) was added to a 50 L reactor equipped with a temperature probe and overhead stirrer under nitrogen at 25 °C. Anhydrous MeOH (18 L) was added to dissolve compound 1 1. Then MeOH/HCl (18 L, 1 N) was added dropwise at 25-30 °C over 10 minutes and the mixture was stirred at 25-30 °C for 1 hour. Water (15 L) was added to the reaction and the mixture concentrated in a rotavapor under vacuum (30-40 mmHg) at 45-50 °C for about 4 hours to remove the solvent. The pH of the mixture was adjusted to 10 with 5 L of K2CO3 solution. 20 L of EtOAc was then added to the mixture and the organic layer was separated and the aqueous layer extracted twice with EtOAc (15 L x 2). The organic layers were combined and washed with 10 L of brine. The combined organic layers contained 996 g of

compound 12 in 40 kg of EtOAc solution (84% purity (AUC by HPLC, retention time =

2.8 minutes). The organic layers were concentrated in a rotavapor under vacuum (30-40 mmHg) at 45-50 °C for about 3 hours to a 7.5 kg volume of compound 12 in EtOAc solution (83% purity (AETC by HPLC, retention time = 2.7 minutes).

[00127] In a separate 50 L reactor equipped with a temperature probe and overhead stirrer, D-CSA was added (930 g, 4.0 mol, 1.0 eq. to 1.26 kg compound 12) and stirred at room temperature under nitrogen. EtOAc (10 L) and then the EtOAc solution of compound 12 (1.26 kg, 3.9 mol, 1.0 eq.) were each sequentially added to the reactor. The mixture was stirred at room temperature for 1 hour and slowly became a suspension. The mixture was filtered by centrifuge and washed with EtOAc to produce 2.3 kg of compound 12 as an off-white solid (96.0% purity).

[00128] The solid product, 20 L of EtOAc, and 10 L of 10% aqueous K2CO3 were added sequentially to a 50 L flask and stirred at room temperature until no solid remained (pH = 9-10). The organic layer was separated and the aqueous layer extracted twice with EtOAc (10 L x 2). The organic layers were combined (about 32 kg) and washed with 10 L of brine. The organic layer contained 716 g of compound 12 in

31.8 kg of solution.

[00129] The organic layer was concentrated under vacuum at 45-50 °C to about 8 L. Activated carbon (200 g) was added to the organic layer and the mixture stirred at 60-70 °C for 1 hour, cooled to room temperature, and filtered using a Buchner funnel and filter paper (pore size: 30-50 pm) over 30 minutes to remove the activated carbon. The mixture was concentrated in a rotavapor under vacuum (30-40 mmHg) at 45-50 °C for about 3 hours to yield 710 g of compound 12 as a yellow solid (99.4% purity). [00130] D-CSA (410 g, 1.77 mol, 1.0 eq. to 680 g compound 12), 3.4 L iPrOH, and 68 mL of water were added sequentially to a 10 L reactor equipped with a temperature probe and overhead stirrer and stirred at room temperature under nitrogen. The mixture was heated to reflux (84 °C) to form solution A after 1 hour. Compound 12 (680 g) was dissolved in 3.4 L of iPrOH and added into solution A for one partition. A clear solution was formed and the temperature decreased to 65 °C. The mixture was stirred at 65 °C for about 15 minutes after which a solid appeared. The mixture was cooled to 10 °C over 2 hours, stirred at 10 °C for an additional 30 minutes, and filtered through a Buchner funnel and filter paper (pore size: 30-50 pm) over 30 minutes to collect the 1.1 kg of white solid.

[00131] EtOAc (10 L), 1.1 kg of white solid product, and 5 L of 10% K2CO3 were added sequentially to a 20 L flask and mixed for 5 minutes. The solid dissolved (pH = 9-10). The EtOAc layer was separated and the aqueous layer extracted twice with EtOAc (5 L each). The organic layers were combined (about 20 L), washed with 5 L of brine, and concentrated in a rotavapor under vacuum (30-40 mmHg) at 45-55 °C for about 3 hours to remove most of the solution and until the residue weight reached 1 kg. Heptanes (1 L) was added to the mixture and stirred at room temperature for 30 minutes. The mixture was filtered using a Buchner funnel and filter paper (pore size: 30-50 pm) over 30 minutes to obtain 419 g of compound 12 base as a white solid (99.7% purity). The filtrate was concentrated to 135 g of compound 12 as a yellow solid (98.7% purity). 1H-NMR (400 MHz, CDCh): d = 1.85 (bs, 2H), 5.17 (m, 1H), 7.56 (d, 1H), 7.68 (d, 1H), 8.62 (d, 1H), 8.70-8.71 (m, 1H), 8.93 (s, 1H). Combined, the products resulted in a 40.7% yield of compound 12.

[00132] Step 9: Synthesis of compound 10

10A 10

[00133] Pd/C (40 g, 5% w/w) was added into a 10 L autoclave reactor at room temperature under nitrogen. THF (2 L), 2 L of methylamine (27%-30% alcoholic solution, 2.1 eq.), and 800 g of compound 10A (7 mol, 1.0 eq.) were sequentially added into the reactor. The system was purged with hydrogen three times. The mixture was stirred at hydrogen pressure (50 psi) at 70-75 °C overnight and was then filtered using a Biichner funnel and filter paper (pore size: 30-50 pm) over 10 minutes to remove the Pd/C. The filtrate was concentrated in a rotavapor under vacuum (30-40 mmHg) at 45-50 °C for about 3 hours to obtain 933 g of yellow oil. The mixture was distilled without a column at atmospheric pressure and the 140-170 °C portion was collected to obtain 763 g of compound 10 as a colorless oil (98.6% purity (AUC by HPLC, retention time = 4.8 minutes); 84.2% yield; 8000 ppm residual ethanol). A portion of the oil (563 g) was distilled using a 3 cm column at atmospheric pressure and the 140-170 °C portion was collected to obtain 510 g of compound 10 (75.8% yield; 134 ppm residual ethanol). 1H-NMR (400 MHz, CDCb): d = 0.82 (bs, 1H), 1.10-1.12 (q, 2H), 1.66 (d, 2H), 1.73-1.81 (t, 2H), 2.05 (s, 3H), 2.08-2.19 (m, 1H), 2.22 (s, 3H), 2.60 (d, 2H).

[00134] Step 10: Synthesis of HM04 fumarate salt

[00135] DCM (1L), 200 g CDI (1.23 mol, 2.0 eq.), and 35 g DABCO (0.31 mol, 0.5 eq.) were sequentially added into a 3 L reactor equipped with a temperature probe and overhead stirrer, and stirred at room temperature under nitrogen. The mixture was cooled to -10 to -5 °C. Compound 12 (200 g) was dissolved in 1 L of DCM and added into the mixture dropwise over 1 hour, followed by stirring for 16 hours at -10 to -5 °C. Compound 10 (159 g, 1.24 mol, 2.0 eq.) was added at -10 to 0 °C over 10 minutes. The mixture was then warmed to 0 to 5 °C and held for 2 hours. The mixture was concentrated under vacuum at 40-45 °C to about 1 L. HC1 (1 L of 1 N) was added to the residual and concentrated in a rotavapor under vacuum (30-40 mmHg) at 45-50 °C for about 2 hours to remove the DCM. Another 3 L of 1N HC1 was added to the residual and extracted three times with TBME (4 L, 2 L, 2 L). The aqueous layer was slowly adjusted to pH = 9-10 with 20% aqueous K2CO3 (about 1.5 L) and extracted with DCM (2 L x 3). The organic layers were combined (about 4 L) and washed three times with 0.25 N KH2PO4 (1.2 L x 3). The organic layer was washed with 2 L of brine to bring the pH to neutral and concentrated in a rotavapor under vacuum (30-40 mmHg) at 45-50 °C for about 2 hours to 450 g (335 mL). MTBE (1.5 L) was added to the residual and distilled until 500 mL of liquid was collected. This step was repeated four times with the addition of 500 mL of TBME and collection of 500 mL of distillate, with the exception that 330 mL of liquid was collected at the final distillation. About 1 to 1.2 L of residual remained in the flask. The residual was slowly cooled to room temperature and stirred at room temperature overnight. The mixture was filtered, washed twice with TBME (400 mL x 2), and dried to obtain 192 g of HM04 free base a light yellow solid (99.3% purity (AUC by HPLC, retention time = 11.0 minutes). The product on the wall was dissolved in DCM and concentrated under vacuum to obtain 22 g of HM04 free base as a brown sticky oil (97.6% purity). The filtrate was concentrated under vacuum to obtain 22.5 g of yellow solid (94.0% purity).

[00136] HM04 free base (187 g, 0.39 mol, 1.0 eq., 99.3% purity) and 1.9 L of ACN were sequentially added to a 3 L flask equipped with a temperature probe and overhead stirrer and stirred at 15 °C under nitrogen to obtain a light-yellow suspension. Fumaric acid (45.6 g, 0.39 mol, 1.0 eq.) was added to the flask and generated a white suspension after 1 minute. The reaction suspension was stirred overnight at room temperature, filtered (15-20 pm, ash<0.l5), washed twice with ACN (50 mL x 2), and dried under vacuum at 50 °C for 6 hours to obtain 207 g of HM04 fumarate salt as a light yellow solid (99.4% purity (AUC by HPLC, retention time = 11.1 minutes); 57.8% yield; 3100 ppm residual ACN). The filtrate was concentrated under vacuum to obtain 20.1 g of HM04 fumarate salt as a light yellow solid (97.3% purity).

[00137] A portion of the product (117 g) was further dried in a vacuum oven (20-40 mmHg) to lower the residual acetonitrile content. After drying at 60 °C for 6 hours, 15 hours, and 72 hours; and at 65 °C for 18 hours, the residual acetonitrile content was measured as 3100 ppm, 2570 ppm, 1300 ppm, and 256 ppm, respectively. After the drying process, 98 g of HM04 fumarate salt was isolated (99.4% purity (AUC by HPLC, retention time = 11.0 minutes); 1H-NMR (400 MHz, DMSO): d = 1.49-1.58 (m, 2H),

1.81-1.92 (m, 2H), 2.44-2.53 (m, 5H), 2.78 (s, 3H), 3.12 (m, 2H), 4.06-4.13 (m, 1H), 6.36-6.41 (m, 1H), 6.55 (s, 2H), 7.47 (d, 1H), 7.73 (d, 1H), 8.11 (d, 1H), 8.75 (d, 1H),

8.81-8.82 (m, 1H), 8.99 (d, 1H). The yield of 98g of HM04 fumarate salt isolated after drying the partial batch was extrapolated over the whole batch to calculate an

approximate yield of 48% for step 10.

[00138] XRPD analysis of HM04 fumarate salt products obtained after drying at 60 °C for 6 hours, 15 hours, and 72 hours; and at 65 °C for 18 hours was performed (see Figures 6-9, respectively). The XRPD profile showed that the HM04 fumarate salt product was consistent with Form 1.

Example 6. Streamlined Synthesis of HM04 Fumarate Salt Form 1

[00139] The overall yield of HM04 fumarate salt produced using Step 10 of Example 5 was calculated as approximately 48%. In order to increase the overall yield, a streamlined synthesis was investigated that eliminated the step of isolating HM04 free base. In particular, step 10 of the method of Example 5 shown in Figure 5 was changed. An overview of the streamlined synthesis beginning after step 9 of Example 5 is shown in Figure 10.

[00140] Streamlined HM04 Fumarate Salt Trial 1 : PCM (121.4 g). CPI (20.0 g, 123 mmol, 2 eq.) and DABCO (3.5 g, 31 mmol) were sequentially added into an inertized 1 L reactor. The mixture was cooled to -10 °C. Separately, a solution of DCM (132.5 g) and compound 12 (20.0 g, 62.1 mmol) were charged into a vessel and stirred until a solution was obtained. This solution was dropped into the 1 L reactor over 33 minutes by keeping the internal temperature at -10 to -5 °C. At the end of the addition, the vessel was rinsed with DCM (7.0 g), which was then added to the reaction mixture.

After stirring overnight (19 hours) and positive IPC, compound 10 (15.9 g, 124 mmol, 2 eq.) was added over 15 minutes and the vessel rinsed with DCM (9.0 g). After heating at 0 °C, 1 hour of stirring, positive IPC, and a further 1.5 hours of stirring, the mixture was heated at room temperature and charged with water (200.1 g). The aqueous layer was separated and the organic layer extracted twice with 1 N HC1 (201, 200 g). The combined aqueous layers containing the product were washed with TBME (148 g). After removal of the organic layer, the aqueous layer was charged with DCM (265.0 g) and 50% K2CO3 solution (about 240 ml) until reaching pH 9.61.

[00141] Meanwhile, a solution of KH2PO4 (8.2 g) in water (240 g) was prepared. The organic layer containing the product was charged with the KH2PO4 solution until reaching pH 7.12 (142.2 g). After separation of the aqueous layer, the organic layer was washed with water (200 g). After separation of the aqueous layer, the organic layer was evaporated at 50 °C. ACN (314.4 g) was added and the solvent distilled again at 70-75 °C under vacuum. ACN (235.8 g) was added and the solvent distilled again under vacuum. ACN (141.5 g) was added, the resulting solution polish filtered and the filter washed with ACN (16 g). After heating at 60 °C, fumaric acid (7.2 g, 62 mmol) was added to the solution, causing a white precipitate. After cooling to 20 °C over 1 hour, the suspension was filtered and washed twice with TBME (2 x 30 g). After drying on the filter with nitrogen flow, 70.7 g of wet raw product was obtained. This was slurried with TBME (177.0 g) for 1 hour, filtered, and washed with TBME (70 g). After drying on the filter under nitrogen flow, 33.0 g of wet product was obtained. Heating at 50 °C under vacuum afforded the dry product as a white powder of HM04 fumarate salt (21.1 g;

Patent ID Title Submitted Date Granted Date
US9926337 SUBSTITUTED ASYMMETRIC UREAS AND MEDICAL USES THEREOF 2016-12-02
US9546157 p-Substituted Asymmetric Ureas and Medical Uses Thereof 2015-03-06 2015-09-10

////////////HM04, H0900, Helsinn,  Novo Nordisk, PRECLINICAL, obesity, Prader-Willi syndrome, ghrelin

CN(C1CCN(C)CC1)C(=O)N[C@H](c3ccc(c2cnccn2)c(Cl)c3Cl)C(F)(F)F

Advertisements

Pracinostat


Pracinostat.svg

ChemSpider 2D Image | Pracinostat | C20H30N4O2

Pracinostat.png

2D chemical structure of 929016-96-6

Pracinostat

  • Molecular Formula C20H30N4O2
  • Average mass 358.478 Da
2-Propenamide, 3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxy-, (2E)-
929016-96-6 [RN]
SB939
(2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1,3-benzodiazol-5-yl}-N-hydroxyprop-2-enamide
N-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-indole-6-carboxamide
PCI 34051,  UNII: GPO2JN4UON
929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
929016-96-6 (free base)
929016-97-7 (trifluoroacetate)
S*BIO (Originator)
Leukemia, acute myeloid, phase 3, helsinn
Image result for S*BIO
str1
CAS 929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt

Pracinostat (SB939) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties.

WO-2017192451  describes Novel polymorphic crystalline forms of pracinostat (designated as Form 3) and their hydrates, processes for their preparation and compositions and combination comprising them are claimed. Also claimed is their use for inhibiting histone deacetylase and treating cancer, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), breast cancer, colon cancer, prostate cancer, pancreas cancer, leukemia, lymphoma, ovary cancer, melanoma and neuroblastoma.

See WO2014070948 ,  Helsinn , under sub-license from MEI Pharma (under license from S*Bio), is developing pracinostat, an oral HDAC inhibitor, for treating hematological tumors, including AML, MDS and myelofibrosis.

The oncolytic agent pracinostat hydrochloride is an antagonist of histone deacetylase 1 (HDAC1) and 2 (HDAC2) that was discovered by the Singapore-based company S*BIO. Helsinn obtained the exlusive development and commercialization rights in July 2016, and is conducting phase III clinical trials in combination with azacitidine in adults with newly diagnosed acute myeloid leukemia. Phase II trials are also under way for the treatment of previously untreated intermediate-2 or high risk myelodysplastic syndrome patients and for the treatment of primary or post essential thrombocythemia/polycythemia vera) in combination with ruxolitinib.In North America, S*BIO had been conducting phase II clinical trials of pracinostat hydrochloride in patients with solid tumors and for the treatment of myeloproliferative diseases and phase I clinical trials in patients with leukemia; however, recent progress reports are not available at present. The University of Queensland had been evaluating the compound in preclinical studies for malaria.

Image result for University of Queensland

University of Queensland

Image result for MEI Pharma

MEI Pharma

The Canadian Cancer Society Research Institute (the research branch of the Canadian Cancer Society upon its integration with the National Cancer Institute of Canada to form the new Canadian Cancer Society) is conducting phase II clinical trials in Canada for the treatment of recurrent or metastatic prostate cancer.

Image result for Canadian Cancer Society Research Institute

Canadian Cancer Society Research Institute

In 2012, the product was licensed to MEI Pharma by S*BIO on a worldwide basis. In 2016, MEI Pharma and Helsinn entered into a licensing, development and commercialization agreement by which Helsinn obtained exclusive worldwide rights (including manufacturing and commercialization rights).

Image result for HELSINN

HELSINN

In 2014, the FDA assigned an orphan drug designation to MEI Pharma for the treatment of acute myeloid leukemia. In 2016, the product received breakthrough therapy designation in the U.S. in combination with azacitidine for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are older than 75 years of age or unfit for intensive chemotherapy.

Pracinostat is an orally available, small-molecule histone deacetylase (HDAC) inhibitor with potential antineoplastic activity. Pracinostat inhibits HDACs, which may result in the accumulation of highly acetylated histones, followed by the induction of chromatin remodeling; the selective transcription of tumor suppressor genes; the tumor suppressor protein-mediated inhibition of tumor cell division; and, finally, the induction of tumor cell apoptosis. This agent may possess improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors.

Pracinostat is a novel HDAC inhibitor with improved in vivo properties compared to other HDAC inhibitors currently in clinical trials, allowing oral dosing. Data demonstrate that Pracinostat is a potent and effective anti-tumor drug with potential as an oral therapy for a variety of human hematological and solid tumors

SYNTHESIS

Figure

Clinically tested HDAC inhibitors.

Activity

Pracinostat selectively inhibits HDAC class I,II,IV without class III and HDAC6 in class IV,[1] but has no effect on other Zn-binding enzymes, receptors, and ion channels. It accumulates in tumor cells and exerts a continuous inhibition to histone deacetylase,resulting in acetylated histones accumulation, chromatin remodeling, tumor suppressor genes transcription, and ultimately, apoptosis of tumor cells.[2]

Clinical medication

Clinical studies suggests that pracinostat has potential best pharmacokinetic properties when compared to other oral HDAC inhibitors.[3]In March 2014, pracinostat has granted Orphan Drug for acute myelocytic leukemia (AML) and for the treatment of T-cell lymphoma by the Food and Drug Administration.

Clinical Trials

CTID Title Phase Status Date
NCT03151304 A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes 2 Recruiting
2017-10-27
NCT03151408 An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia 3 Recruiting
2017-10-17
NCT02267278 Ruxolitinib and Pracinostat Combination Therapy for Patients With Myelofibrosis (MF) 2 Active, not recruiting
2017-04-27
NCT01873703 Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome 2 Active, not recruiting
2017-04-21
NCT02118909 Evaluate the Effects of Itraconazole and Ciprofloxacin on Single-Dose PK of Pracinostat in Healthy Nonsmoking Subjects 1 Completed
2017-02-22
NCT02058784 Study to Evaluate the Food Effect of Single-dose Bioavailability of Pracinostat in Healthy Adult Subjects 1 Completed
2017-02-22
NCT01993641 Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA 2 Completed
2017-02-22
NCT01112384 A Study of SB939 in Patients With Translocation-Associated Recurrent/Metastatic Sarcomas 2 Completed
2016-11-25
NCT01184274 A Phase I Study of SB939 in Pediatric Patients With Refractory Solid Tumours and Leukemia 1 Completed
2014-01-16
NCT01200498 Study of SB939 in Subjects With Myelofibrosis 2 Completed
2013-12-13

PATENT

WO2005028447

Inventors Dizhong ChenWeiping DengKanda SangthongpitagHong Yan SongEric T. SunNiefang YuYong Zou
Applicant S*Bio Pte Ltd

Scheme I

Figure imgf000041_0001

Scheme II

Figure imgf000042_0001Scheme III

Figure imgf000043_0001Scheme IV

Figure imgf000044_0001 Scheme V

Figure imgf000045_0001

PAPER

Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

Chemistry Discovery, Biology Discovery, and §Pre-Clinical Development, S*BIO Pte Ltd., 1 Science Park Road, No. 05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore
J. Med. Chem.201154 (13), pp 4694–4720
DOI: 10.1021/jm2003552
Phone: +65-68275019. Fax: +65-68275005. E-mail: haishan_wang@sbio.com.

Abstract

Abstract Image

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC50), liver microsomal stability (t1/2), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

(E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt (3)

The freebase of 3 was prepared according to procedure D. The hydroxamic acid moiety was identified by 1H–15N HSQC (DMSO-d6) with δN = 169.0 ppm (CONHOH). Other nitrogens in 3were identified by 1H–15N HMBC (DMSO-d6) with δN of 241.4 ppm for N3 of the benzimidazole ring, 152.3 ppm for N1, and 41.3 ppm for the diethylamino group (reference to nitromethane δN = 380.0 ppm in CDCl3). The dihydrochloride salt of 3 was prepared according to procedure D as white or off-white solid or powder in ∼60% yield from 9 in two steps. LC–MS m/z 359.2 ([M + H]+).
1H NMR (DMSO-d6) δ 11.79 (brs, 1H, NH or OH), 10.92 (very br s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 5.01 (t-like, J = 7.7 Hz, 2H), 3.48 (m, 2H), 3.30–3.19 (m, 6H), 1.87 (quintet, J = 7.8 Hz, 2H), 1.47 (sextet, J = 7.5 Hz, 2H), 1.29 (t, J = 7.2 Hz, 6H), 0.97 (t, J = 7.3 Hz, 3H);
13C NMR (DMSO-d6) δ 162.3, 156.0, 137.3 (CH), 132.8, 132.3, 132.0 (br, identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2 × CH), 48.2, 46.3, 39.0, 28.1, 25.0, 21.7, 13.6, 8.3.
Anal. (C20H30N4O2·2HCl·0.265H2O) C, H, N, Cl. Water content = 1.09% (Karl Fisher method). HRMS (ESI) m/z [M + H]+ calcd for C20H31N4O2, 359.2442; found, 359.2449.

PATENT

WO 2007030080

http://google.com/patents/WO2007030080A1?cl=en

 
Inventors Dizhong ChenWeiping DengKen Chi Lik LeePek Ling LyeEric T. SunHaishan WangNiefang Yu
Applicant S*Bio Pte Ltd

SEE

WO 2008108741

WO 2014070948

Patent

WO-2017192451

References

  1. Jump up^ “In vitro enzyme activity of SB939 and SAHA”. 22 Aug 2014.
  2. Jump up^ “The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML”. Blood Cancer Journaldoi:10.1038/bcj.2012.14.
  3. Jump up^ Veronica Novotny-Diermayr; et al. (March 9, 2010). “SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer”Mol Cancer Therdoi:10.1158/1535-7163.MCT-09-0689.
PATENT 
Cited Patent Filing date Publication date Applicant Title
WO2005028447A1 * Sep 21, 2004 Mar 31, 2005 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
US20050137234 * Dec 14, 2004 Jun 23, 2005 Syrrx, Inc. Histone deacetylase inhibitors
Reference
1 None
2 See also references of EP1937650A1
Citing Patent Filing date Publication date Applicant Title
WO2009084544A1 * Dec 24, 2008 Jul 9, 2009 Idemitsu Kosan Co., Ltd. Nitrogen-containing heterocyclic derivative and organic electroluminescent device using the same
WO2010043953A2 * Oct 14, 2009 Apr 22, 2010 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2010043953A3 * Oct 14, 2009 Mar 24, 2011 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2017030938A1 * Aug 12, 2016 Feb 23, 2017 Incyte Corporation Heterocyclic compounds and uses thereof
DE102007037579A1 Aug 9, 2007 Feb 19, 2009 Emc Microcollections Gmbh Neue Benzimidazol-2-yl-alkylamine und ihre Anwendung als mikrobizide Wirkstoffe
US8865912 Jan 27, 2014 Oct 21, 2014 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9024029 Sep 3, 2013 May 5, 2015 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9062003 Sep 9, 2014 Jun 23, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797 May 15, 2015 Oct 13, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9402829 Feb 20, 2015 Aug 2, 2016 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9717713 Jun 10, 2016 Aug 1, 2017 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
Patent ID

Patent Title

Submitted Date

Granted Date

US2016158186 USE OF DIANHYDROGALACTITOL AND ANALOGS AND DERIVATIVES THEREOF TO TREAT RECURRENT MALIGNANT GLIOMA OR PROGRESSIVE SECONDARY BRAIN TUMOR
2015-04-09
2016-06-09
US2015051288 Methods and Compositions for Treatment of Autism
2014-10-10
2015-02-19
US2017128534 TREATING ROTATOR CUFF CONDITIONS
2015-07-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2014235649 USE OF PHOSPHATASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS TO TREAT DISEASES CHARACTERIZED BY LOSS OF PROTEIN FUNCTION
2012-05-24
2014-08-21
US2013102595 TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
2012-10-15
2013-04-25
US9624515 System and Method of Producing Volatile Organic Compounds from Fungi
2013-02-01
2013-05-30
US2014349938 METHODS OF DIAGNOSING AND TREATING AMYOTROPHIC LATERAL SCLEROSIS
2012-06-01
2014-11-27
US2017100354 COMPOSITIONS AND METHODS FOR TREATING KABUKI SYNDROME AND RELATED DISORDERS
2015-05-29
Patent ID

Patent Title

Submitted Date

Granted Date

US9387263 RbAp48 TRANSGENIC MICE FOR DRUG DISCOVERY IN AGE-RELATED MEMORY DECLINE
2012-08-02
2014-10-02
US2014051716 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
2012-03-09
2014-02-20
US2010098691 COMBINATION OF BENZIMIDAZOLE ANTI-CANCER AGENT AND A SECOND ANTI-CANCER AGENT
2010-04-22
US2016069887 BIOMARKERS FOR PROGNOSIS
2014-04-08
2016-03-10
US8937050 Methods and compositions for treatment of autism
2012-10-31
2015-01-20
Patent ID

Patent Title

Submitted Date

Granted Date

US2017049784 METHOD OF TREATING ACUTE MYELOID LEUKEMIA AND/OR ACUTE LYMPHOBLASTIC LEUKEMIA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017095484 METHOD OF TREATING RESISTANT NON-HODGKIN LYMPHOMA, MEDULLOBLASTOMA, AND/OR ALK+NON-SMALL CELL LUNG CANCER USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017157141 METHOD OF TREATING LEUKEMIA USING PHARMACEUTICAL FORMULATION CONTAINING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2014-11-26
US2015258068 COMBINATION THERAPIES
2013-10-30
2015-09-17
US2015182490 METHODS FOR TREATING TYROSINE-KINASE-INHIBITOR-RESISTANT MALIGNANCIES IN PATIENTS WITH GENETIC POLYMORPHISMS OR AHI1 DYSREGULATIONS OR MUTATIONS EMPLOYING DIANHYDROGALACTITOL, DIACETYLDIANHYDROGALACTITOL, DIBROMODULCITOL, OR ANALOGS OR DERIVATIVES THEREOF
2013-06-24
2015-07-02
Patent ID

Patent Title

Submitted Date

Granted Date

US8143282 Heterocyclic Compounds
2009-02-19
2012-03-27
US2017020874 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
2015-12-01
US2017231931 PRODUCTS FOR THE TREATMENT AND PREVENTION OF NEUROLOGICAL DISORDERS COURSING WITH A COGNITION DEFICIT OR IMPAIRMENT, AND OF NEURODEGENERATIVE DISEASES
2015-08-25
US2017273988 METHODS OF TREATING LYMPHOMA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-08-19
US2017095436 METHODS FOR TREATING MENDELIAN DISORDERS OF THE EPIGENETIC MACHINERY
2015-05-29
Pracinostat
Pracinostat.svg
Names
IUPAC name

(E)-3-(2-Butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
Other names

Pracinostat
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C20H30N4O2
Molar mass 358.49 g·mol−1
Density 1.1±0.1 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////////Pracinostat, PCI 34051, SB939, orphan drug designation, Leukemia, acute myeloid, phase 3, helsinn

CCCCC1=NC2=C(N1CCN(CC)CC)C=CC(=C2)C=CC(=O)NO

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Chugai Pharma to commercialize Helsinn’s Anamorelin for anorexia-cachexia syndrome in Germany, France, Benelux, UK and Ireland


LUGANO, Switzerland, November 12, 2013 /PRNewswire/ —

Swiss Pharma Group Helsinn seals an alliance with Japanese company Chugai by granting exclusive distribution & licensing rights to commercialize its innovative phase III ghrelin receptor agonist in Germany, France, Benelux, UK andIreland

Swiss-based Helsinn group has granted Chugai Pharma Marketing Ltd., a wholly-owned subsidiary of Chugai Pharmaceutical Co., Ltd., exclusive commercialization rights to their innovative ghrelin receptor agonist, anamorelin, for the three major European pharma markets.

Anamorelin is a new first-in-class, oral, once daily drug, currently in phase III for the treatment of anorexia-cachexia in NSCLC, a detrimental multifactorial disorder that affects over 50% of people with cancer and in which systemic inflammation, reduced food intake and altered metabolism contribute to loss of muscle mass and reduction of body weight leading to reduced quality of life, functional impairment and decreased survival.

http://www.prnewswire.com/news-releases/helsinn-and-chugai-pharma-marketing-enter-into-agreement-for-rights-of-anamorelin-currently-in-development-for-treatment-of-anorexia-cachexia-syndrome-related-to-non-small-cell-lung-cancer-in-top-eu-markets-231514911.html

  • Anamorelin is a synthetic orally active ghrelin receptor agonist which is under development for the management of non-small lung cancer associated cachexia/anorexia.
  • Development status: Phase 3
  • Appetite loss; Aging; Bone injury; Cachexia

Anamorelin HCl

Anamorelin HCl

M. Wt 583.16
Formula C31H43ClN6O3
CAS No. 861998-00-7
Synonyms RC 1291; RC1291; RC 1291-HCl; ONO-7643; ONO7643; ONO 7643.
Chemical Name 2-amino-N-((R)-1-((R)-3-benzyl-3-(1,2,2-trimethylhydrazinecarbonyl)piperidin-1-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-2-methylpropanamide hydrochloride
%d bloggers like this: