New Drug Approvals

Home » Posts tagged 'asthma'

Tag Archives: asthma

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

Blog Stats

  • 2,671,860 hits

Flag and hits

Flag Counter

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

Join 2,434 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

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 2,434 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 →

Archives

Categories

Flag Counter

FEVIPIPRANT


Fevipiprant.svg

Fevipiprant.png

FEVIPIPRANT

Molecular Formula: C19H17F3N2O4S
Molecular Weight: 426.41 g/mol

UNII-2PEX5N7DQ4; 2PEX5N7DQ4; NVP-QAW039; QAW039;

CAS 872365-14-5

Product patent WO2005123731A2, NOVARTIS

Inventors Kamlesh BalaCatherine LeblancDavid Andrew SandhamKatharine Louise TurnerSimon James WatsonLyndon Nigel BrownBrian Cox
Applicant Novartis AgNovartis Pharma Gmbh

Jun 17, 2004 priority   expiry 2014

Synthesis 

Image result for novartis

2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridin-3-yl]acetic acid

  • 2-Methyl-1-[[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]methyl]-1H-pyrrolo[2,3-b]pyridine-3-acetic acid
  • [1-(4-((Methane)sulfonyl)-2-trifluoromethylbenzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]acetic acid

Fevipiprant (INN; code name QAW039) is a drug being developed by Novartis which acts as a selective, orally available antagonistof the prostaglandin D2 receptor 2 (DP2 or CRTh2).[1][2][3]

As of 2016, it is in Phase III[4] clinical trials for the treatment of asthma.[5]

Novartis is developing fevipiprant, a prostaglandin D2 receptor (PD2/CRTh2) antagonist, as an oral capsule formulation for treating asthma and moderate to severe atopic dermatitis.

Image result for FEVIPIPRANT

Inventors Kamlesh BalaCatherine LeblancDavid Andrew SandhamKatharine Louise TurnerSimon James WatsonLyndon Nigel BrownBrian Cox
Applicant Novartis AgNovartis Pharma Gmbh

PATENT

WO2005123731

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005123731

PATENT

CN 106188040

The invention discloses a Fevipiprant and Fevipiprant intermediate preparation method. The method is characterized in that 2-amino-3-bromopyridine and 4-mesyl-2-trifluoromethylbenzaldehyde to condensation reaction to obtain a Schiff base intermediate, then performing reduction reaction to obtain 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine, subjecting the 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine to ullmann ring closing reaction with methyl levulinate or ethyl levulinate, and performing saponification reaction or decarboxylic reaction to obtain Fevipiprant namely N[1-(4-((methane)sulfonyl)-2-trifluoromethylphenyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl] acetic acid. The Fevipiprant and Fevipiprant intermediate preparation method which is a brand new method is short in step, technically convenient in operation, easy in product purification and large-scale production, high yield can be achieved, and Fevipiprant industrial production can be realized easily.

Example 5: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0056] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13.0g, 0. lmo 1) was added 300 mL N, N- dimethylformamide, was added copper iodide (1 · 9g, 0 · 0lmo 1) and N, N- dimethylglycine (1.0g , 0.01 mol), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give the crude product after recrystallization from ethanol in pure 34.5g, yield 81%.

[0057] · ΜΚ (300ΜΗζ, (16-0Μ50) δ: 12 · 3 (ΐ3Γ, 1Η, α) 2Η), 8.24 (s, lH, PhH), 8.11 ~ 8.12 (d, lH, PhH), 8.00 ~ 8.02 (d, lH, PyH), 7.91 ~ 7.93 (d, lH, PyH), 7.09 ~ 7.10 (d, lH, PhH), 6.46 ~ 6.48 (d, lH, PhH), 5.73 (s, 2H, NCH2) , 3.70 (s, 2H, q ^ C〇2H), 3.30 (s, 3H, CH 3).

[0058] HPLC: 99.9%.

[0059] Example 6: N [l- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0060] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – (. 40.9g, 0 lmo 1) pyridin-2-amine and acetyl malonate methyl ester (18.8g, 0. lmol) was added 300 mL N, N- dimethylformamide, was added copper iodide (1.9g, O.Olmol) and N, N- dimethylglycine (1. (^ , 0.01111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL of water, was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol, a crude product was obtained from ethanol crystallized to give pure 34. lg, 80% yield.

[0061] HPLC: 99.8%.

[0062] Example 7: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0063] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13. (^, 0.1111〇1) was added ^ 3,001,111, 1-dimethyl formamide, was added copper iodide (3.88,0.02111〇1) and N, N- dimethylglycine (2. (^, 0.02111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure 34. lg, 80% yield billion

[0064] HPLC: 99.9%.

[0065] Example 8: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0066] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0.01mol) and 2,2,6,6-tetramethyl-heptane-3,5-dione (3.6g, 0.02mo 1), purged with nitrogen , the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g , 0.2 mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 30.2 g, yield 71%.

[0067] HPLC: 99.6%.

[0068] Example 9: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0069] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 1’1 ^ 3,001,111, 1 ‘| – dimethylformamide, was added copper iodide (1.98,0.011] 1〇1) and proline (1.28,0.011] 1〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, after cooling, 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g, 0.2mol) was heated to 60 degrees reaction 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0070] HPLC: 99.8%.

[0071] Example 10: N [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] pyridin – preparation of 3- yl] acetic acid (1).

[0072] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0. Olmol) and N, N- dimethylglycine (1.0g, 0.01 mo 1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, cooled was added 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL of acetic acid and 100mL of concentrated hydrochloric acid was heated to reflux for 6h, cooled to 0 ° C, was added 100mL water analysis crystal was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0073] HPLC: 99.1%.

PATENT

WO 2017056001

Example 3b: Preparation of Compound A

Production of C8: Compound C6, (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol) (20 g, 52 mmol) was dissolved in a mixture of methyl isobutyl ketone (MIBK, 125 g), 25.3 g (156 mmol) of 1 , 1 , 1 -triethoxy ethane, and acetic acid (0.625 g, 10 mmol). The mixture was heated within 40 minutes to 140 °C under a N2 over-pressure of 1 – 4 bar. During the reaction ethanol was formed and removed from the vessel by a pressure-regulated valve. After 3.5 h a second portion of acetic acid (0.625g) was added and the mixture was heated for 3.5 h at 140 °C under a N2 over-pressure of 1 – 4 bar. The resultant product was a solution of Ethyl 2-(l- {[4-methanesulfonyl-2-(trifluoromethyl)phenyl]methyl}-2-methyl-lH-pyrrolo[2,3-¾]pyridin-3-yl)acetate and the conversion rate was measured at 98% and the yield 90%. The solution was filtered and 40 g MIBK was added. The solution was heated to IT=80 °C and cooled down within 3 h to

IT=20 °C. At an IT of 65 °C seed crystals were added. At IT 20 °C intermediate C8 was isolated and washed with 40 g MIBK and dried in the oven at IT=60°C/20mbar.

Conversion to Compound A: The intermediate C8 was concentrated under vacuum at

100 °C/200 mbar and water (6000ml). A sodium hydroxide solution (1734 g, 30%, 13 mol) was added to the mixture and heated for 4 h at 50 °C. The solution was distilled again at 100 °C/100 mbar. The phases were separated at 50 °C and the water phase was extracted with methyl isobutyl ketone (2000 ml). Again the phases were separated and the water phase was filtered at 50 °C. To the filtrate methyl isobutyl ketone (5000 ml) was added and the aqueous solution neutralized in 2 portions with hydrochloric acid (963 g, 37%, 9.8 mol) to pH 4 – 4.5. The phases were heated to 80 °C and the organic phases separated. Water (1000 ml) was added to wash the organic phase and after phase separation the organic phase was cooled down to 70 °C. Seed crystals of Compound A were added along with heptane (1000 ml). The resulting suspension was stirred for 30 minutes before cooling further down to 0 °C within 3 h. The suspension was stirred for 3 h at 0 °C and then filtered through a nutsche. The filter cake was washed first with pre-cooled HPTF/methyl isobutyl ketone (1000 g, 5: 1), then with acetone/water (1000 g, 1 :2) and finally with water (1000 g). Wet Compound A was dried in the oven at 60 °C for 8 h under vacuum to isolate 804 g of compound A. The conversion was calculated to be 99%; the yield was 79%.

Example 3 c: Alternative Preparation of Compound A

Molecular Weight: 426 41

Exact Mass: 384.08 Molecular Weight: 453.48

5 g of (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol), methyl isobutyl ketone (MIBK, 50 ml), and 1 , 1 -dimethoxy-N,N-dimethylethanamine were put together in a 200 ml reactor and stirred for 15 h at 100 °C. The mixture was acidified by addition of hydrochloric acid (15 ml) and kept stirring for 15 h at 100 °C. Then water (25 ml) was added, and the temperature was decreased to 50 °C. Caustic soda (about 15 ml) was added to set the pH around 12. Then, after phase split and a second extraction with water (10 ml), the combined aqueous phases were diluted with methyl isobutyl ketone (25 ml) and acidified at 80 °C to pH 4 with hydrochloric acid. The mixture was cooled to 70 °C, seeded and cooled to 0 °C within 2 h. After 2 h aging at 0 °C, the crystalline solid was collected by filtration, washed with methyl isobutyl ketone (10 ml) and water (10 ml), and dried under vacuum at 60 °C until constant weight. Yield 2.93 g.

PATENT

WO-2017210261

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017210261&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel deuterated analogs of pyrrolo[2,3-b]pyridine compounds, particularly fevipiprant and their salts and compositions and combination comprising them are claimed. Also claims is their use for treating asthma, allergic rhinitis and atopic dermatitis. Compounds are claimed to be a prostaglandin D2 receptor 2 antagonist. Represents first PCT filing from CoNCERT Pharmaceuticals and the inventor on this API.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(5), 582-586

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2Receptor Antagonist for Treatment of Asthma

Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom
ACS Med. Chem. Lett.20178 (5), pp 582–586
DOI: 10.1021/acsmedchemlett.7b00157
*E-mail: david.sandham@novartis.com. Tel: + 1 (617)-871-8000.

Abstract

Abstract Image

Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

RM  sodium methanesulfinate and 4-fluoro-2-(trifluoromethyl)benzaldehyde

Step 1:

4-(methylsulfonyl)-2-(trifluoromethyl)benzaldehyde

A suspension of sodium methanesulfinate (29.6 g, 290 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (50 g, 260 mmol) in DMSO (200 ml) was heated at 90˚C overnight. The thick yellow suspension was poured onto crushed ice (ca 800 g), diluted with water and the solid reside collected by filtration, washed with water and dried in vacuo to afford 4- (methylsulfonyl)-2-(trifluoromethyl)benzaldehyde as an off-white solid (50.7 g, 77%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.14 (3H s), 8.30 (1H d J=7.5), 8.36 (1H d J=7.5), 8.40 (1H s), 10.49 (1H s).

Step 2:

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol as an off-white solid (50.7 g, 99%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 5.02 (2H s), 8.09 (1H d J=7.5), 8.19 (1H d J=7.5), 8.25 (1H s).

STEP 3

1-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene

1-(bromomethyl)-4-(methylsulfonyl)-2- (trifluoromethyl)benzene (47.1 g, 74%) as a white solid. LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 4.67 (2H s), 7.86 (1H d J=7.5), 8.14 (1H d J=7.5), 8.25 (1H s).

STEP 4

methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate

(83:17) of methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-1 product) and methyl 2-(2-methyl-7-(4- (methylsulfonyl)-2-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-7 product) as a white solid (22.5 g 42%). LRMS C20H19F3N2O4S requires M+ 440.4 found [MH]+ m/z 441. 1H NMR (CDCl3) 2.27 (3H s), 3.06 (3H s N-1 product), 3.11 (3H s N-7 product), 3.72 (3H s), 3.77 (2H s), 5.03 (2H s N-7 product), 5.82 (2H s N-1 product), 6.66 (1H d J=8.2), 7.16 (1H dd J=7.8, 4.8), 7.91 (1H d, J=8.3), 7.95 (1H d J=7.7), 8.12 (1H d J=7.8 N-7), 8.19 (1H d J=8.1 N-7), 8.17 (1H s N-7), 8.27 (1H d J=3.6), 8.30 (1H s).

FINAL

2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 11 as needles, m.p. 208˚C (16.3 g, 44%). HRMS C19H18F3N2O4S requires [MH]+ 427.0939 found [MH]+ 427.093. 1H NMR (500 MHz, DMSO-d6) 2.28 (3H s), 3.28 (3H s), 3.73 (2H s), 5.76 (2H s), 6.49 (1H d J=8.3), 7.12 (1H dd J=7.7, 4.8), 7.95 (1H d J=7.8), 8.04 (1H d, J=8.3), 8.14 (1H d J=4.7), 8.26 (1H s), 12.28 (1H br s ). Elemental analysis calcd. for C19H17F3N2O4S: C, 53.52; H, 4.02; N, 6.57; S, 7.52%. Found C, 53.90 ± 0.04; H, 4.28 ± 0.06; N, 6.43 ± 0.02; S, 7.76 ± 0.09%.

PAPER

Drug Metabolism & Disposition (2017), 45(7), 817-825

Patent ID

Patent Title

Submitted Date

Granted Date

US9169251 PYRROLOPYRIDINE DERIVATIVES AND THEIR USE AS CRTH2 ANTAGONISTS
2014-06-26
2014-10-16
Patent ID

Patent Title

Submitted Date

Granted Date

US2016108123 ANTIBODY MOLECULES TO PD-L1 AND USES THEREOF
2015-10-13
2016-04-21
US8455645 Organic compounds
2010-08-19
US8470848 Organic compounds
2010-08-12
US7666878 Pyrrolopyridine Derivatives And Their Use As Crth2 Antagonists
2008-05-15
2010-02-23
US8791256 Pyrrolopyridine derivatives and their use as CRTH2 antagonists
2013-06-05
2014-07-29

References

  1. Jump up to:a b Erpenbeck VJ, Vets E, Gheyle L, Osuntokun W, Larbig M, Neelakantham S, et al. (2016). “Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo-Controlled Studies in Healthy Volunteers”Clin Pharmacol Drug Dev5 (4): 306–13. doi:10.1002/cpdd.244PMC 5071756Freely accessiblePMID 27310331.
  2. Jump up^ Sykes DA, Bradley ME, Riddy DM, Willard E, Reilly J, Miah A, Bauer C, Watson SJ, Sandham DA, Dubois G, Charlton SJ. Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy. Mol Pharmacol. 2016 May;89(5):593-605. doi: 10.1124/mol.115.101832 PMID 26916831
  3. Jump up^ Erpenbeck VJ, Popov TA, Miller D, Weinstein SF, Spector S, Magnusson B, et al. (2016). “The oral CRTh2 antagonist QAW039 (fevipiprant): A phase II study in uncontrolled allergic asthma”. Pulm Pharmacol Ther39: 54–63. doi:10.1016/j.pupt.2016.06.005PMID 27354118.
  4. Jump up^ https://clinicaltrials.gov/ct2/show/NCT02555683
  5. Jump up^ Gonem S, Berair R, Singapuri A, Hartley R, Laurencin M, Bacher G, et al. (2016). “Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial”. Lancet Respir Med4: 699–707. doi:10.1016/S2213-2600(16)30179-5
Fevipiprant
Fevipiprant.svg
Clinical data
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability Unaffected by food[1]
Metabolism Hepatic glucuronidation
Biological half-life ~20 hours
Excretion Renal (≤30%)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C19H17F3N2O4S
Molar mass 426.41 g/mol
3D model (JSmol)

////////////////FEVIPIPRANT, QAW039, PHASE 3, asthma, UNII-2PEX5N7DQ4,2PEX5N7DQ4, NVP-QAW039, QAW039, 872365-14-5,

CC1=C(C2=C(N1CC3=C(C=C(C=C3)S(=O)(=O)C)C(F)(F)F)N=CC=C2)CC(=O)O

GSK 2269557 In Phase 1….Asthma , COPD, is it COMPD A OR B?


COMPD A

 

COMPD B

Compd A OR B IS GSK 2269557

Phosphatidylinositol 3-Kinase (PI3K)
PHASE 1….asthma & COPD
ASHTHMA COPD

DATA FOR COMPD A

6-​(1H-​indol-​4-​yl)​-​4-​[5-​[[4-​(1-​methylethyl)​-​1-​piperazinyl]​methyl]​-​2-​oxazolyl]​-1H-​Indazole,

6-(1 H-lndol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1 H- indazole

CAS 1254036-77-5 hcl salt
base 1254036-71-9, 440.54, C26 H28 N6 O
Formula C26H28N6O.HCl

EMAIL ME amcrasto@gmail.com

DATA FOR COMPD B
Methanesulfonamide, N-​[5-​[4-​[5-​[[(2R,​6S)​-​2,​6-​dimethyl-​4-​morpholinyl]​methyl]​-​2-​oxazolyl]​-​1H-​indazol-​6-​yl]​-​2-​methoxy-​3-​pyridinyl]​-​,
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
1254036-66-2 CAS
C24 H28 N6 O5 S, 512.58
Compound B may be prepared according to known procedures, such as those disclosed in international patent application PCT/EP2010/055666 (publication number WO02010/125082)
EMAIL ME amcrasto@gmail.com

Phosphoinositide 3ΌΗ kinases (hereinafter PI3Ks) are a family of signal transducer enzymes which are involved in various cellular functions including cell growth, proliferation and differentiation. A wide variety of retroviruses and DNA-based viruses activate the PI3K pathway as a way of preventing host cell death during viral infection and ultimately exploiting the host cell synthesis machinery for its replication (Virology 344(1) p. 131-8 (2006) by Vogt et al.; and Nat. Rev. Microbiol. 6(4) p. 265-75 (2008) by Buchkovich et al). It has therefore been postulated that PI3K inhibitors may have potential therapeutic benefit in the treatment of viral infections such as influenza virus infection, in addition to the more established treatment of cancer and inflammatory diseases.

The Influenza NS1 protein activates Class la PI3Ks by binding to their regulatory subunit p85beta but not to other Class la regulatory subunits such as p85alpha. The recent crystal structure of the NS1-p85beta complex (Hale et al. Proc. Natl. Acad. Sci. U S A. 107(5) p.1954-1959 (2010)) is also suggestive of an interaction with the p110 kinase subunit providing a mechanism for catalytic activation of the kinase domain. This observation provides a rationale for isoform specificity not only with the p85 regulatory subunit but also potentially with the p110 catalytic subunit too. The function of PI3K during influenza virus infection has also been investigated by, for example, Ehrhardt et al. (Cell. Microbiol. 8(8) p. 1336-1348 (2006)), and the role of PI3K5 signalling in morbidity and lung pathology induced by influenza virus infection has been reported in WO 2010/083163.

There remains a need to provide compounds which are inhibitors of the activity or function of PI3K5 which may be useful in the treatment or prevention of influenza virus infection.

GSK 2269557 is an inhaled phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor in early clinical trials at GlaxoSmithKline for the treatment of patients with asthma and also for the treatment of chronic obstructive pulmonary disease (COPD) in patients who smoke cigarettes.

  • 18 Nov 2014GlaxoSmithKline plans a phase II trial in Chronic obstructive pulmonary disease in Belgium, Denmark, the Netherlands and Russia (NCT02294734)
  • 01 Jun 2014Phase-II clinical trials in Chronic obstructive pulmonary disease in Germany (Inhalation)
  • 01 May 2014GlaxoSmithKline plans a phase II trial for Chronic obstructive pulmonary disease in Germany (NCT02130635)
Study ID Status Title Patient Level Data
115117 Completed A single-centre. double-blind, placebo controlled three part study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and repeat doses of nebulised GSK2269557 in healthy male subjects
115119 Active not recruiting A Double-Blind, Placebo Controlled, Randomised, Parallel Group Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Multiple Doses of GSK2269557 Administered as a Dry Powder to COPD Patients
116617 Completed A Single-Centre, Double-Blind, Placebo Controlled Two Part Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2269557 as a Dry Powder in Healthy Subjects who Smoke Cigarettes
116678 Not yet recruiting A Randomised, Double-blind (Sponsor Unblinded), Placebo-controlled, Parallel-group, Multicentre Study to Evaluate the Efficacy and Safety of GSK2269557 Administered in Addition to Standard of Care in Adult Subjects Diagnosed With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease

EMAIL ME amcrasto@gmail.com

CLICK ON IMAGES TO VIEW SIMILAR ROUTES FOR COMPD A AND B

EO2

EO1A

CLICK ON IMAGE TO VIEW

EO1B

…………………………………………………………………….

COMPD A

WO 2012032065

http://www.google.com/patents/WO2012032065A1?cl=en

Example 68

6-(1 H-lndol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1 H- indazole

Method A

6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1-(phenylsulfonyl)- 1/-/-indazole (97 mg, 0.194 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole (61.3 mg, 0.252 mmol, available from Frontier Scientific Europe), chloro[2′- (dimethylamino)-2-biphenylyl]palladium-(1 ,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4 )- bicyclo[2.2.1]hept-2-yl]phosphane (10.87 mg, 0.019 mmol) and potassium phosphate tribasic (124 mg, 0.582 mmol) were dissolved in 1 ,4-dioxane (1 ml) and water (0.1 ml) and heated in a Biotage Initiator microwave at 100°C for 30 min. Additional 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxabotolan-2-yl)-1 H-indole (61.3 mg, 0.252 mmol) and chloro[2′- (dimethylamino)-2-biphenylyl]palladium-(1 ,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4 )- bicyclo[2.2.1]hept-2-yl]phosphane (5 mg) were added and the reaction heated at 1 10°C for 30 min, then 140°C for 30 min. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated to give a brown solid which was dissolved in MeOH:DMSO (1 ml, 1 : 1 , v/v) and purified by MDAP (method H). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (30 mg).

LCMS (Method A): Rt 0.57 mins, MH+ 441.

Method B

6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1-(phenylsulfonyl)- 1 H-indazole (75.17 g, 150 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole (73.1 g, 301 mmol), sodium bicarbonate (37.9 g, 451 mmol), and chloro[2′- (dimethylamino)-2-biphenylyl]palladium-(1 ,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4 )- bicyclo[2.2.1]hept-2-yl]phosphane (8.43 g, 15.03 mmol) were suspended in nitrogen purged 1 ,4-dioxane (1200 ml_) and water (300 ml_). The reaction vessel was placed under alternating vacuum and nitrogen five times with overhead stirring, then finally placed under a nitrogen atmosphere and heated to 120°C for 2.5 h.

The reaction mixture was cooled to 45°C and then treated with 2M aqueous sodium hydroxide (376 ml_, 752 mmol). After stirring at 45°C overnight (~ 13h), the mixture was cooled to RT and DCM (600 ml) and water (400 ml) were added. The layers were separated and the aqueous re-extracted with DCM: 1 ,4-dioxane (1 : 1). Brine was added and the mixture filtered through Celite, washing with DCM: 1 ,4-dioxane (1 : 1). The layers were separated and 2M HCI (1000 ml) added to the organic. The mixture was again filtered through Celite washing with 500 ml 2M HCI keeping the washings separate. The filtrate layers were then separated and the organic layer was washed with the acid washings from the Celite. Layers were separated and the acidic aqueous combined. This was then back-washed with 2×500 ml of DCM; each wash requiring a Celite filtration. The acidic aqueous was then given a final filtration through Celite washing the Celite pad with 150 ml of 2M HCI.

The acidic aqueous was transfered to a beaker (5000 ml) and with vigorous stirring 2M NaOH was added to basify the mixture to pH 10-11. The mixture was then extracted using 1 ,4-dioxane: DCM (1 : 1) (5 x 500 ml). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to yield a brown foam that was dried in vacuo at 50°C overnight. This material was split into three batches and each was purified by reverse phase column chromatography (3x 1.9 kg C18 column), loading in DMF/TFA (1 : 1 , 30 ml) then eluting with 3-40% MeCN in Water + 0.25% TFA (Note: Columns 2 & 3 used a different gradient starting with 10% MeCN).

Appropriate fractions were combined, the acetotnitrile removed in vacuo and the acidic aqueous basified to pH10 by addition of saturated aqueous sodium carbonate solution to the stirred solution. The resultant solid was collected by filtration, washed with water then dried in vacuo at 65°C overnight to give the title compound (28.82 g) as a pale brown foam.

LCMS (Method A): Rt 0.68 mins, MH+ 441.

1 H NMR (400MHz ,DMSO-d6) d = 13.41 (br. s., 1 H), 11.35 (br. s., 1 H), 8.59 (br. s., 1 H), 8.07 (d, J = 1.5 Hz, 1 H), 7.90 (br. s., 1 H), 7.51 – 7.44 (m, 2 H), 7.32 (s, 1 H), 7.27 – 7.21 (m, 2 H), 6.61 – 6.58 (m, 1 H), 3.73 (br. s., 2 H), 2.64 – 2.36 (m, 9 H), 0.97 – 0.90 (m, 6 H)

Method C

Potassium hydroxide (145.6 g) was added to a suspension of 6-(1 H-indol-4-yl)-4-(5-{[4-(1- methylethyl)-1-piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1-(phenylsulfonyl)-1 H-indazole (300.7 g) and cetyltrimethylammonium bromide (9.3 g) in tetrahydrofuran (6.0 L) and water (30 ml) stirring under nitrogen at ambient temperature. The mixture was heated at reflux for 17 hours and was then cooled to 20-25°C. Ethyl acetate (3.0 L) and water (3.0 L) were added, stirred for 10 minutes and then separated. The organic layer was extracted with hydrochloric acid (1 M, 1 x 3.0 L, 2 x 1.5L) and the acidic extracts combined and basified to ~pH 8 by the addition of saturated sodium carbonate solution (2.1 L). After ageing for 30 minutes the resultant suspension was filtered, washed with water (300 ml) and the solid dried under vacuum at 65°C to give the title compound as a pale yellow solid (127.9 g).

LCMS (Method B): Rt 2.44 min, MH+ 441.

…………………………………………………………………………

WO 2010125082

http://www.google.co.in/patents/WO2010125082A1?cl=en

Example 6

6-(1 H-lndol-4-yl)-4-(5-{[4-(1 -methylethyl)-1 -piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1 H- indazole

Method A

6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1-(phenylsulfonyl)- 1H-indazole (97 mg, 0.194 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole (61.3 mg, 0.252 mmol, available from Frontier Scientific Europe), chloro[2′- (dimethylamino)-2-biphenylyl]palladium-(1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (10.87 mg, 0.019 mmol) and potassium phosphate tribasic (124 mg, 0.582 mmol) were dissolved in 1 ,4-dioxane (1 ml) and water (0.1 ml) and heated in a Biotage Initiator microwave at 1000C for 30 min. Additional 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxabotolan-2-yl)-1 H-indole (61.3 mg, 0.252 mmol) and chloro[2′- (dimethylamino)-2-biphenylyl]palladium-(1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (5 mg) were added and the reaction heated at 1 1O0C for 30 min, then 14O0C for 30 min. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated to give a brown solid which was dissolved in MeOH:DMSO (1 ml, 1 :1 , v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (30 mg).

LCMS (Method A): Rt 0.57 mins, MH+ 441.

Method B

6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1-(phenylsulfonyl)- 1 H-indazole (75.17 g, 150 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole (73.1 g, 301 mmol), sodium bicarbonate (37.9 g, 451 mmol), and chloro[2′- (dimethylamino)-2-biphenylyl]palladium-(1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (8.43 g, 15.03 mmol) were suspended in nitrogen purged 1 ,4-dioxane (1200 ml.) and water (300 ml_). The reaction vessel was placed under alternating vacuum and nitrogen five times with overhead stirring, then finally placed under a nitrogen atmosphere and heated to 1200C for 2.5 h.

The reaction mixture was cooled to 45°C and then treated with 2M aqueous sodium hydroxide (376 ml_, 752 mmol). After stirring at 450C overnight (~ 13h), the mixture was cooled to RT and DCM (600 ml) and water (400 ml) were added. The layers were separated and the aqueous re-extracted with DCM: 1 ,4-dioxane (1 :1 ). Brine was added and the mixture filtered through Celite, washing with DCM: 1 ,4-dioxane (1 :1 ). The layers were separated and 2M HCI (1000 ml) added to the organic. The mixture was again filtered through Celite washing with 500 ml 2M HCI keeping the washings separate. The filtrate layers were then separated and the organic layer was washed with the acid washings from the Celite. Layers were separated and the acidic aqueous combined. This was then back-washed with 2×500 ml of DCM; each wash requiring a Celite filtration. The acidic aqueous was then given a final filtration through Celite washing the Celite pad with 150 ml of 2M HCI.

The acidic aqueous was transfered to a beaker (5000 ml) and with vigorous stirring 2M NaOH was added to basify the mixture to pH 10-11. The mixture was then extracted using 1 ,4-dioxane:DCM (1 :1 ) (5 x 500 ml). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to yield a brown foam that was dried in vacuo at 500C overnight.

This material was split into three batches and each was purified by reverse phase column chromatography (3x 1.9 kg C18 column), loading in DMF/TFA (1 :1 , 30 ml) then eluting with 3-40% MeCN in Water + 0.25% TFA (Note: Columns 2 & 3 used a different gradient starting with 10% MeCN).

Appropriate fractions were combined, the acetotnitrile removed in vacuo and the acidic aqueous basified to pH10 by addition of saturated aqueous sodium carbonate solution to the stirred solution. The resultant solid was collected by filtration, washed with water then dried in vacuo at 65°C overnight to give the title compound (28.82 g) as a pale brown foam.

LCMS (Method A): Rt 0.68 mins, MH+ 441. 1H NMR (400MHz ,DMSOd6) d = 13.41 (br. s., 1 H), 11.35 (br. s., 1 H), 8.59 (br. s., 1 H), 8.07 (d, J = 1.5 Hz, 1 H), 7.90 (br. s., 1 H), 7.51 – 7.44 (m, 2 H), 7.32 (s, 1 H), 7.27 – 7.21 (m, 2 H), 6.61 – 6.58 (m, 1 H), 3.73 (br. s., 2 H), 2.64 – 2.36 (m, 9 H), 0.97 – 0.90 (m, 6 H)

EMAIL ME amcrasto@gmail.com

COMPD B

WO2010125082

http://www.google.co.in/patents/WO2010125082A1?cl=en

Example 1

Λ/-[5-[4-(5-{[(2/?,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-

6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide

Method A

To a solution of 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1 ,3-oxazol-2- yl)-1-(phenylsulfonyl)-1 H-indazole (0.20 g, 0.411 mmol) and N-[2-(methoxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide (0.175 g, 0.534 mmol) in 1 ,4-dioxane (2 ml) was added chloro[2′-(dimethylamino)-2-biphenylyl]palladium- 1 (1 /?,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4/?)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol), potassium phosphate tribasic (0.262 g, 1.23 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 12O0C under microwave irradiation for 1 h. Additional chloroP’^dimethylamino^-biphenylyOpalladium-^I R^S^bicycloP^.ilhept^- yl[(1 S,4/?)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol) and potassium phosphate tribasic (80 mg) were added and the reaction heated to 12O0C under microwave irradiation for 1 h. Additional potassium phospate tribasic (80 mg) was added and the reaction heated under the same conditions for a further 1 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2x 2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (3ml, 1 :1 , v/v) and purified by MDAP (method A) in 3 injections. The appropriate fractions were combined and concentrated to give a white solid which was dissolved in MeOH:DMSO (1 ml, 1 :1 , v/v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 6 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2x 25 ml). The combined organics were dried and evaporated in vacuo to give a white solid which was further dried under nitrogen at 4O0C for 3 h to give the title compound as a white solid (26 mg). LCMS (Method A): Rt 0.53 mins, MH+ 513.

Method B N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]methanesulfonamide (101 g, 308 mmol), 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4- morpholinyl]methyl}-1 ,3-oxazol-2-yl)-1-(phenylsulfonyl)-1 H-indazole (83.3 g, 154 mmol) and sodium bicarbonate (38.8 g, 462 mmol) were suspended in 1 ,4-dioxane (1840 ml) and water (460 ml) under nitrogen and heated to 800C. Chloro[2′-(dimethylamino)-2- biphenylyl]palladium-1 (1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)-bicyclo[2.2.1]hept-2- yl]phosphane (8.63 g, 15.40 mmol) was added and the mixture stirred overnight at 800C.

The reaction mixture was cooled to 450C, sodium hydroxide 2M aq. (770 ml, 1540 mmol) added and the reaction heated to 45 0C for 4 hours. The mixture was cooled to RT and diluted with water (610 ml_). Dichloromethane (920 ml.) was added, and the mixture was filtered twice through Celite (washed with 200 ml. 1 ,4-dioxane/DCM 2:1 each time). The phases were separated, and aqueous washed with 1 ,4-dioxane/DCM 2:1 (500 ml_). The aqueous phase was neutralised with hydrochloric acid to pH -7 and extracted with 1 ,4- dioxane/DCM 2:1 (1 L), then 1 ,4 dioxane/DCM 1 :1 (2×500 ml_). The organics were washed with brine (500 ml_), and filtered through Celite (washed with 200 ml. 1 ,4 dioxane/DCM 2:1 ), and evaporated to yield a dark black solid, which was purified in 4 batches:

Batch 1 : 28g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 ml.) and purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (14.78 g).

Batch 2: 3Og was dissolved in methanol and mixed with Fluorisil. The solvent was then removed by evaporation and the solid purified by column chromatography (1.5 kg silica column, solid sample injection module), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (9.44 g).

Batch 3: 31 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 ml.) and purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (17 g).

Batch 4: 29g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 ml.) and purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (21 g).

The mixed fractions from the 4 columns were combined and evaporated to yield 19 g which was dissolved in 200 ml. of Toluene/Ethanol/Ammonia 80:20:2 (+ additional 4ml of 0.88 NH3 to help solubility) then purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (6.1 g).

All pure batches were combined (68 g) and recrystallised from ethanol (1200 ml_). The suspension was heated to reflux and a solution formed. The resulting solution was then cooled to room temperature overnight. The resulting solid was then collected by filtration, washed sparingly with ethanol and dried under vacuum to give the title compound as an off-white solid (56 g). This material was recrystallised again from ethanol (1 100 ml_). The suspension was heated to reflux and a solution formed. The resulting solution was then cooled to room temperature overnight with stirring. The resulting solid was collected by filtration and washed sparingly with ethanol. The solid was dried in vacuo at 600C for 5hrs to give the title compound as an off-white solid (45.51 g). LCMS (Method A): Rt 0.61 mins, MH+ 513.

The filtrate from the two recrystallisations was evaporated to yield -23 g of a solid residue that was dissolved in 200 ml. of Toluene/Ethanol/Ammonia 80:20:2 (+ additional 4ml of 0.88 NH3 to help solubility) then purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give a further crop of the title compound as an off-white solid (18.5 g). This solid was then recrystallised from ethanol (370 ml_). The suspension was heated to reflux then the resulting solution stirred for 20 mins before being allowed to cool to room temperature naturally overnight. The solid was then dried in vacuo at 65°C overnight to give the title compound as an off-white solid (11.9O g). LCMS (Method A): Rt 0.62 mins, MH+ 513.

………………………………………..

 http://www.google.co.in/patents/US8735390

Example 1N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide

Method A

To a solution of 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (0.20 g, 0.411 mmol) and N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide (0.175 g, 0.534 mmol) in 1,4-dioxane (2 ml) was added chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol), potassium phosphate tribasic (0.262 g, 1.23 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 120° C. under microwave irradiation for 1 h. Additional chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol) and potassium phosphate tribasic (80 mg) were added and the reaction heated to 120° C. under microwave irradiation for 1 h. Additional potassium phospate tribasic (80 mg) was added and the reaction heated under the same conditions for a further 1 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2×2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (3 ml, 1:1, v/v) and purified by MDAP (method A) in 3 injections. The appropriate fractions were combined and concentrated to give a white solid which was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 6 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×25 ml). The combined organics were dried and evaporated in vacuo to give a white solid which was further dried under nitrogen at 40° C. for 3 h to give the title compound as a white solid (26 mg).

LCMS (Method A): Rt 0.53 mins, MH+ 513.

Method B

N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (101 g, 308 mmol), 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (83.3 g, 154 mmol) and sodium bicarbonate (38.8 g, 462 mmol) were suspended in 1,4-dioxane (1840 ml) and water (460 ml) under nitrogen and heated to 80° C. Chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (8.63 g, 15.40 mmol) was added and the mixture stirred overnight at 80° C.

The reaction mixture was cooled to 45° C., sodium hydroxide 2M aq. (770 ml, 1540 mmol) added and the reaction heated to 45° C. for 4 hours. The mixture was cooled to RT and diluted with water (610 mL). Dichloromethane (920 mL) was added, and the mixture was filtered twice through Celite (washed with 200 mL 1,4-dioxane/DCM 2:1 each time). The phases were separated, and aqueous washed with 1,4-dioxane/DCM 2:1 (500 mL). The aqueous phase was neutralised with hydrochloric acid to pH ˜7 and extracted with 1,4-dioxane/DCM 2:1 (1 L), then 1,4 dioxane/DCM 1:1 (2×500 mL). The organics were washed with brine (500 mL), and filtered through Celite (washed with 200 mL 1,4 dioxane/DCM 2:1), and evaporated to yield a dark black solid, which was purified in 4 batches:

  • Batch 1: 28 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL) and purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (14.78 g).
  • Batch 2: 30 g was dissolved in methanol and mixed with Fluorisil. The solvent was then removed by evaporation and the solid purified by column chromatography (1.5 kg silica column, solid sample injection module), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (9.44 g).
  • Batch 3: 31 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL) and purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (17 g).
  • Batch 4: 29 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL) and purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (21 g).

The mixed fractions from the 4 columns were combined and evaporated to yield 19 g which was dissolved in 200 mL of Toluene/Ethanol/Ammonia 80:20:2 (+additional 4 ml of 0.88 NH3 to help solubility) then purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an off-white solid (6.1 g).

All pure batches were combined (68 g) and recrystallised from ethanol (1200 mL). The suspension was heated to reflux and a solution formed. The resulting solution was then cooled to room temperature overnight. The resulting solid was then collected by filtration, washed sparingly with ethanol and dried under vacuum to give the title compound as an off-white solid (56 g). This material was recrystallised again from ethanol (1100 mL). The suspension was heated to reflux and a solution formed. The resulting solution was then cooled to room temperature overnight with stirring. The resulting solid was collected by filtration and washed sparingly with ethanol. The solid was dried in vacuo at 60° C. for 5 hrs to give the title compound as an off-white solid (45.51 g).

LCMS (Method A): Rt 0.61 mins, MH+ 513.

The filtrate from the two recrystallisations was evaporated to yield ˜23 g of a solid residue that was dissolved in 200 mL of Toluene/Ethanol/Ammonia 80:20:2 (+additional 4 ml of 0.88 NH3 to help solubility) then purified by column chromatography (1.5 kg silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give a further crop of the title compound as an off-white solid (18.5 g). This solid was then recrystallised from ethanol (370 mL). The suspension was heated to reflux then the resulting solution stirred for 20 mins before being allowed to cool to room temperature naturally overnight. The solid was then dried in vacuo at 65° C. overnight to give the title compound as an off-white solid (11.90 g).

LCMS (Method A): Rt 0.62 mins, MH+ 513.

Method C

10M Sodium hydroxide solution (0.70 ml) was added to a stirred suspension of N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (1.17 g) in water (5.8 ml). The resulting mixture was stirred at room temperature for 3.75 hours and was then washed with ethyl acetate (2×6 ml). The layers were separated and the aqueous phase was acidified to pH 6 with 2M hydrochloric acid (0.8 ml). The acidified aqueous layer was extracted twice with ethyl acetate (11 ml then 5 ml). The combined ethyl acetate extracts were dried by azeotropic distillation and diluted with further ethyl acetate (11 ml). The misture was stirred at room temperature for 112 hours. The slurry was seeded and then stirred at room temperature for 48 hours. The resultant suspension was filtered, washed with ethyl acetate (2×2 ml) and the solid dried under vacuum at 40° C. to give the title compound as a pale yellow solid (0.58 g).

LCMS (Method B): Rt 1.86 min, MH+ 513.

Method D

To a suspension of N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (596.5 g, 0.91 mol) in water (3.8 L) is added 5M sodium hydroxide (715 ml, 3.56 mol) over 20 mins at <25° C. The mixture is stirred at 20±3° C. for 2 h 45 min then washed with EtCN (3 L). The pH of the basic aqueous phase is adjusted to pH 6.6 using 2M hydrochloric acid (1.4 L), maintaining the temperature below 30° C. The mixture is then extracted with MeTHF (2×4.8 L), and the combined MeTHF extracts are washed with water (1.2 L). The mixture is concentrated to approx 2.4 L and EtOAc (3 L) is added. This put and take distillation is repeated a further 3 times. The mixture is adjusted to 60±3° C. and seeded twice (2×3 g) 35 mins apart. The resultant is aged for 1 h 10 mins then cooled over 2 h to 20-25° C., and aged for a further 15 h 50 min. The slurry is filtered, washed with EtOAc (2×1.2 L) and dried in vacuo at 45±5° C. for approx 3 day to give the title compound.

Preparation of Polymorphs of Compound A

Form (II)

Ethyl acetate (15 ml) was added to N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (2.1 g) and was stirred at ambient conditions overnight. The resultant slurry was filtered and dried under vacuum at 50° C. to give a new solid state form (91 ckw/w).

1H NMR (400 MHz, DMSO d6) d=13.49 (br s, 1H), 9.39 (s, 1H), 8.58 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H), 3.74 (s, 2H), 3.58 (m, 2H), 3.11 (s, 3H), 2.80 (d, J=10.3 Hz, 2H), 1.78 (t, J=10.3 Hz, 2H), 1.05 (d, J=6.4 Hz, 6H)

 SODIUM SALT OF COMPD B

http://www.google.com/patents/US20140256721

Method D

To a suspension of N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (596.5 g, 0.91 mol) in water (3.8 L) is added 5M sodium hydroxide (715 ml, 3.56 mol) over 20 mins at <25° C. The mixture is stirred at 20±3° C. for 2 h 45 min then washed with EtCN (3 L). The pH of the basic aqueous phase is adjusted to pH 6.6 using 2M hydrochloric acid (1.4 L), maintaining the temperature below 30° C. The mixture is then extracted with MeTHF (2×4.8 L), and the combined MeTHF extracts are washed with water (1.2 L). The mixture is concentrated to approx 2.4 L and EtOAc (3 L) is added. This put and take distillation is repeated a further 3 times. The mixture is adjusted to 60±3° C. and seeded twice (2×3 g) 35 mins apart. The resultant is aged for 1 h 10 mins then cooled over 2 h to 20-25° C., and aged for a further 15 h 50 min. The slurry is filtered, washed with EtOAc (2×1.2 L) and dried in vacuo at 45±5° C. for approx 3 day to give the title compound.

http://www.google.com/patents/US20140256721

Preparation of Salts of Compound ASodium Salt

Methanol (2 ml) was added to N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.3 g) followed by aqueous sodium hydroxide (0.129 ml) to give a solution. Tert-butylmethylether (4 ml) was added to the solution followed by seed crystals of the sodium salt and this suspension was stirred overnight at ambient conditions. The suspension was filtered, washed with tert-butylmethylether (2 ml) and air dried to give the sodium salt (0.2312 g) as a hydrate.

NMR: Consistent with salt formation

1H NMR (400 MHz, DMSO d6) d=13.35 (br s, 1H), 8.53 (s, 1H), 7.90 (d, J=1.2 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.33 (s, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.59 (m, 2H). 2.83 (d, J=10.3, 2H), 2.61 (s, 3H), 1.78 (t, J=10.5 Hz, 2H), 1.05 (d, J=6.1 Hz, 6H)

EMAIL ME amcrasto@gmail.com

EMAIL ME amcrasto@gmail.com

US20100280029 * 28 Apr 2010 4 Nov 2010 Julie Nicole Hamblin Novel compounds
WO2010125082A1 28 Apr 2010 4 Nov 2010 Glaxo Group Limited Oxazole substituted indazoles as pi3-kinase inhibitors
US20140256721 * 14 Apr 2014 11 Sep 2014 Glaxosmithkline Intellectual Property Development Limited Novel Polymorphs and Salts
WO2012032065A1 6 Sep 2011 15 Mar 2012 Glaxo Group Limited Indazole derivatives for use in the treatment of influenza virus infection
WO2012032067A1 6 Sep 2011 15 Mar 2012 Glaxo Group Limited Polymorphs and salts of n- [5- [4- (5- { [(2r,6s) -2, 6 – dimethyl – 4 -morpholinyl] methyl} – 1, 3 – oxazol – 2 – yl) – 1h- inda zol-6-yl] -2- (methyloxy) – 3 – pyridinyl] methanesulfonamide
WO2012055846A1 25 Oct 2011 3 May 2012 Glaxo Group Limited Polymorphs and salts of 6-(1h-indol-4-yl)-4-(5- { [4-(1-methylethyl)-1-pi perazinyl] methyl} -1,3-oxazol-2-yl)-1h-indazole as pi3k inhibitors for use in the treatment of e.g. respiratory disorders
WO2012064744A2 * 8 Nov 2011 18 May 2012 Lycera Corporation Tetrahydroquinoline and related bicyclic compounds for inhibition of rorϒ activity and the treatment of disease
WO2013088404A1 14 Dec 2012 20 Jun 2013 Novartis Ag Use of inhibitors of the activity or function of PI3K
WO2014068070A1 31 Oct 2013 8 May 2014 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for preventing antiphospholipid syndrome (aps)
US8524751 5 Mar 2010 3 Sep 2013 GlaxoSmithKline Intellecutual Property Development 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases
US8536169 3 Jun 2009 17 Sep 2013 Glaxo Group Limited Compounds
US8575162 28 Apr 2010 5 Nov 2013 Glaxosmithkline Intellectual Property Development Limited Compounds
US8580797 28 Apr 2010 12 Nov 2013 Glaxo Smith Kline Intellectual Property Development Limited Compounds
US8586583 2 Oct 2012 19 Nov 2013 Glaxosmithkline Intellectual Property Development Limited Compounds
US8586590 2 Oct 2012 19 Nov 2013 Glaxosmithkline Intellectual Property Development Limited Compounds
US8609657 2 Oct 2012 17 Dec 2013 Glaxosmithkline Intellectual Property Development Limited Compounds
US8658635 3 Jun 2009 25 Feb 2014 Glaxosmithkline Intellectual Property Development Limited Benzpyrazol derivatives as inhibitors of PI3 kinases
US8735390 6 Sep 2011 27 May 2014 Glaxosmithkline Intellectual Property Development Limited Polymorphs and salts
US8765743 3 Jun 2009 1 Jul 2014 Glaxosmithkline Intellectual Property Development Limited Compounds

…..

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.
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.
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.




COCK WILL TEACH YOU NMR
COCK SAYS MOM CAN TEACH YOU NMR

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE
Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK
Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

 amcrasto@gmail.com

  JALGAON, MAHARASHTRA, INDIA

.

 

 Image result for jalgaon railway station

 

 

 

 

 

.

http://www.aai.aero/allAirports/jalgaon_airport.jpg

.

MANUDEVI

%d bloggers like this: