New Drug Approvals

Home » Phase2 drugs » GSK-1292263 Glucose-Dependent Insulinotropic Receptor (GDIR, GPR119) Agonists

GSK-1292263 Glucose-Dependent Insulinotropic Receptor (GDIR, GPR119) Agonists

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

PAYPAL DONATIONS

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,309,803 hits

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

Join 1,782 other followers

add to any

Share

  • str1

    str1


    GSK-1292263

    CAS 1032823-75-8

    3-isopropyl-5-(4-(((6-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole

    5-[1-(3-Isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ylmethoxy]-2-[4-(methylsulfonyl)phenyl]pyridine

    5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine

    MF C23H28N4O4S

    MW: 456.18313

    1292263
    GSK-1292263
    GSK-1292263A
    GSK-263A

    Smithkine Beecham Corp, INNOVATOR

    GSK-1292263 is a novel GPR119 receptor agonist that is currently under development for the treatment of type 2 diabetes. Treatment of male Sprague-Dawley rats with a single dose of GSK-1292263 (3-30 mg/kg) in the absence of nutrients correlated with increased levels of circulating gastrointestinal peptides; glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY) and glucagon.

    GSK-1292263 had been evaluated in phase II clinical studies at GlaxoSmithKline for the oral treatment of type 2 diabetes and as monotherapy or in combination with sitagliptin for the treatment of dyslipidemia; however no recent development has been reported for this research.

    Following administration of glucose in the oral glucose tolerance test (OGTT), greater increases in total GLP-1, GIP and PYY were seen in GSK-1292263-treated rats than in control animals. Despite significant decreases in the glucose AUC, no statistically significant differences in insulin responses and insulin AUC were observed between rats administered GSK-1292263 and those receiving vehicle control.

    In the intravenous glucose tolerance test, significant increases in the peak insulin response and insulin AUC(0-15 min) of 30-60% were reported in the GSK-1292263 treatment group, compared with values in the vehicle control cohort. This insulin upregulation correlated with a significant increase in the glucose disposal rate (Brown, K.K. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 407).

    The safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of GSK-1292263 were evaluated in a recently completed randomized, placebo-controlled clinical trial in healthy volunteers (ClinicalTrials.gov Identifier NCT00783549).

    A total of 69 subjects received single escalating doses of GSK-1292263 (10-400 mg) prior to administration of a 250-mg dose given once daily for 2 and 5 days, which was also evaluated in combination with sitagliptin (100 mg). Treatment with GSK-1292263 at all doses was described as well tolerated, with the most common drug-related effects being mild headache, dizziness, hyperhidrosis, flushing and post-OGTT hypoglycemia.

    NMR

    1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.0 Hz, 1H), 8.28 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.99 (bd, J = 8.5 Hz, 2H), 7.54 (dd, J = 8.8, 3.0 Hz, 1H), 4.03 (d, J = 6.3 Hz, 2H), 4.03–3.97 (m, 2H), 3.25 (s, 3H), 3.20–3.09 (m, 2H), 2.81 (q, J = 6.7 Hz, 1H), 2.13–2.00 (m, 1H), 1.88 (bd, J = 12.8 H, 2H), 1.42–1.29 (m, 2H), 1.18 (d, J = 7.0 Hz, 6H).

    13C NMR (100.6 MHz, DMSO-d6) 175.3, 170.9, 155.5, 147.0, 143.5, 140.5, 138.6, 127.9, 127.0, 122.4, 122.3, 72.5, 45.7, 44.1, 35.0, 28.0, 26.7, 20.8.

    HRMS calcd for C23H29N4O4S (M + H)+ 457.1904, found, 457.1900.

    Anal. Calcd for C23H28N4O4S: C, 60.51; H, 6.18; N, 12.27. Found: C, 60.64; H, 6.16; N, 12.24.

    str1

    str1

    str1

    Hypoglycemia was not reported with the 5-day dosing schedule. Pharmacokinetic profiling revealed dose-proportional AUC and Cmax at single lower doses, but not at single higher ones. Following repeated once-daily dosing (5 days), drug accumulation was observed consistent with a mean half-life of 12-18 hours. A dose-dependent increase in glucose AUC(0-3 h) during OGTT was seen in GSK-1292263-treated subjects. The treatment was also associated with an increase in PYY during the prandial periods.

    Coadministration with sitagliptin led to increases in the plasma concentrations of active GLP-1 but reduced the levels of total GLP-1, GIP and PYY. Sitagliptin affected the exposure to GSK-1292263 (50% increase) but GSK-1292263 did not affect sitagliptin exposure. The data support further evaluation of GSK-1292263 for the treatment of type 2 diabetes (Source: Nunez, D.J. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 80-OR).

    WO 2008070692

    http://www.google.com.au/patents/WO2008070692A2?cl=en

    Example 169: 5-[({1 -[3-(1 -Methylethyl)-1,2,4-oxadiazol-5-yl]-4- piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine hydrochloride

    Figure imgf000171_0001

    Step 1 : A mixture of 6-bromo-3-pyridinol (7 g, 40 mmol), [4-(methylsulfonyl)phenyl]boronic acid (8 g, 40 mmol), 2M Na2CO3 (30 ml_), PdCI2(PPh3)2 (1 g) and DME (60 ml.) under N2 was heated at 80 0C overnight. The reaction was allowed to cool to room temperature and was diluted with EtOAc and water. The resulting precipitate was filtered off and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The aqueous phase was also concentrated. Each of the residues was recrystallized from MeOH. The solid material from the organic phase recrystallization and the mother liquors from both aqueous and organic recrystallizations were combined, concentrated and purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2CI2 to give 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (2.9 g, 29%) as a tan solid. Step 2: Diisopropyl azodicarboxylate (0.175 ml_, 0.89 mmol) was added dropwise to a solution of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (150 mg, 0.59 mmol), {1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 200 mg, 0.89 mmol), PPh3 (233 mg, 0.89 mmol), and THF (10 ml.) at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was concentrated, and the resulting crude was purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (10:90 to 100:0) with 0.05% TFA as a modifier, then taken up in CH2CI2 and free-based with saturated NaHCO3 (aq) to give 5-[({1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine (220 mg) as a white solid. Step 3: A mixture of the resulting white solid (50 mg, 0.1 1 mmol) in THF (3 ml.) was stirred at ambient temperature as 4Λ/ HCI in dioxane (28 μl_) was added dropwise. The resulting white precipitate was filtered, air-dried, then triturated with diethyl ether to give 35 mg (65%) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3): δ 8.46 (d, 1 H, J = 0.7 Hz), 8.18 (bs, 2H), 8.05 (bs, 2H), 7.83 (bs, 1 H), 7.61- 7.45 (m, 1 H), 4.24 (d, 2H, J = 10.4 Hz), 4.00 (d, 2H, J = 0.6 Hz), 3.21-3.03 (m, 5H), 2.89 (m, 1 H), 2.15 (d, 1 H, J = 1.1 Hz), 1.96 (bs, 2H), 1.50 (bs, 2H), 1.28 (d, 6H, J = 6.9 Hz); LRMS (ESI), m/z 457 (M+H).

    PATENT

    http://www.google.co.ug/patents/US20120077812

    Example 100

    5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine[0480]Figure US20120077812A1-20120329-C00124

    Step 1: A mixture of 2-methylpropanenitrile (100 g, 1.45 mol), hydroxylamine hydrochloride (111 g, 1.59 mol) and NaOH (64 g, 1.59 mol) in EtOH (2 L) and water (500 mL) was stirred at reflux overnight. The mixture was evaporated to dryness and extracted with dichloromethane. The organic extract was dried over Na2SO4 and concentrated to afford the desired N-hydroxy-2-methylpropanimidamide (50 g, 34%).

    Step 2: A solution of 4-piperidinemethanol (140 g, 1.22 mol) in CH2Cl2 (1 L) was treated with a slurry of NaHCO3(205 g, 2.44 mol) in water (1.4 L) at 0° C. The mixture was stirred at 0° C. for 15 min, and then charged with a solution of cyanogen bromide in CH2Cl2, (1.34 mol) at 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was combined with other batches made similarly and purified by chromatography on a silica gel column to give 300 g of 4-(hydroxymethyl)-1-piperidinecarbonitrile. Step 3: A solution of 1N ZnCl2 in Et2O (182 mL, 182 mmol) was added to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (21.3 g, 152 mmol) and N-hydroxy-2-methylpropanimidamide (18.6 g, 182 mmol) in EtOAc (50 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 30 min, decanted, and was treated with concentrated HCl (45 mL) and ethanol 20 mL). The mixture was heated at reflux for 2 h. The mixture was evaporated to dryness, and the resulting residue was charged with water and the pH was adjusted to basic with K2CO3. The mixture was extracted with EtOAc and the material obtained was combined with 9 other batches prepared similarly and purified by silica gel chromatography to give 150 g of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol.

    Step 4: A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Step 3, 174 g, 0.77 mol) and triethylamine (140 mL, 1.0 mol) in dichloromethane (1 L) at 5° C. was treated with a solution of methanesulfonyl chloride (69 mL, 0.89 mol) in dichloromethane (150 mL) over a 1 h period. The mixture was stirred at 5° C. for 30 min, and then was quenched by the addition of water (400 mL). The mixture was stirred for 30 min, and then the organic extract was washed with water (2×400 mL), dried (MgSO4) and concentrated. The residue was treated with heptane (1 L), stirred for 3 h, and the resulting solid was collected by filtration (heptane wash) and air-dried to afford {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (219.7 g, 94%) as an off-white solid. 1NMR (400 MHz, CDCl3): δ 4.21-4.15 (m, 2H), 4.08 (d, 2H, J=6.6 Hz), 3.04 (m, 2H), 3.01 (s, 3H), 2.86 (septet, 1H, J=6.9 Hz), 2.05-1.93 (m, 1H), 1.88-1.81 (m, 2H), 1.43-1.31 (m, 2H), 1.26 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 304 (M+H).

    Step 5: A mixture of 6-bromo-3-pyridinol (36 g, 207 mmol), [4-(methylsulfonyl)phenyl]boronic acid (50 g, 250 mmol), 2M Na2CO3 (315 mL) and DME (500 mL) was degassed with N2 for 30 min, and then Pd(PPh3)4 (12 g, 10 mmol) was added and the mixture was heated at 80° C. for 18 h. The reaction was allowed to cool to room temperature and was diluted with dichloromethane (500 mL) and water (500 mL) and stirred for 30 min. The reaction was filtered and the solids were rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic extracts were extracted with 1N NaOH (2×600 mL), and then cooled to 5° C. and the pH was adjusted to ˜8 with 6N HCl. The resulting precipitate was collected by filtration (water wash) and air-dried to afford a yellow solid. This procedure was repeated and the solids were combined to provide (71.2 g, 68%) of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol. 1H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.25 (d, 1H, J=2.7 Hz), 8.21 (d, 2H, J=8.5 Hz), 8.00-7.90 (m, 3H), 7.27 (dd, 1H, Ja=8.7 Hz, Jb=2.8 Hz), 3.21 (s, 3H); LRMS (ESI), m/z 250 (M+H).

    Step 6: A mixture of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (82.3 g, 271 mmol), 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (71.0 g, 285 mmol), powdered potassium carbonate (118 g, 855 mmol) and N,N-dimethylformamide (750 mL) was mechanically stirred and heated at 80° C. under nitrogen for 20 h. The reaction was cooled to ambient temperature, poured onto ice water (3 L) and allowed to stand for 1 h. The resulting solid was filtered, rinsed with water (2×500 mL) and air-dried. The solid was taken up in dichloromethane (300 mL) and methanol (500 mL). The dichloromethane was slowly removed via rotovap at 55° C. The methanol solution was allowed to stand at ambient temperature for 16 h. The resulting crystalline solid was filtered, rinsed with cold methanol and dried under vacuum at 60° C. for 18 h to afford the desired product (105.7 g, 84%) as a light tan solid. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.8 Hz), 8.13 (d, 2H, J=8.6 Hz), 8.01 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, Ja=8.7 Hz, Jb=3.0 Hz), 4.24 (d, 2H, J=13.1 Hz), 3.95 (d, 2H, J=6.2 Hz), 3.17-3.04 (m, 5H), 2.94-2.84 (m, 1H), 2.11 (bs, 1H), 1.97 (d, 2H, J=12.6 Hz), 1.54-1.42 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 457 (M+H).

    Alternative preparation: Step 1: 2-Bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 29%) was prepared as a white solid from {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 348 mg, 2.0 mmol), 6-bromo-3-pyridinol (348 mg, 2.0 mmol) and Ph3P (629 mg, 2.4 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.51 mL, 2.6 mmol) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 7.37 (d, 1H, J=8.8 Hz), 7.08 (d, 1H, J=8.8 Hz), 4.26-4.16 (m, 2H), 3.85 (d, 2H, J=6.2 Hz), 3.14-3.04 (m, 2H), 2.95-2.76 (m, 1H), 2.11-1.96 (m, 1H), 1.98-1.88 (m, 2H), 1.52-1.36 (m, 2H), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 381/383 (M+H).

    Step 2: 5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (51 mg, 21%) was prepared from 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 0.52 mmol), [4-(methylsulfonyl)phenyl]boronic acid (105 mg, 0.52 mmol), 2M Na2CO3 (5 mL), Pd(PPh3)4 (50 mg, 0.04 mmol) and DME (5 mL) in a manner similar to Example 21, Step 3.

    Paper

    Development of Large-Scale Routes to Potent GPR119 Receptor Agonists

    API Chemistry Department, Analytical Science & Development Department, #Medicinal Chemistry Department, and§Particle Sciences and Engineering Department, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States
    Org. Process Res. Dev., Article ASAP
    Publication Date (Web): July 13, 2016
    Copyright © 2016 American Chemical Society

    Abstract

    Abstract Image

    Practical and scalable syntheses were developed that were used to prepare multikilogram batches of GSK1292263A (1) and GSK2041706A (15), two potent G protein-coupled receptor 119 (GPR119) agonists. Both syntheses employed relatively cheap and readily available starting materials, and both took advantage of an SNAr synthetic strategy.

    ///////////1292263, GSK-1292263, GSK-1292263A, GSK-263A, GSK1292263, GSK1292263A,  GSK 1292263, GSK 1292263A, GSK 263A, GSK263A, 1032823-75-8

    O=S(C1=CC=C(C2=CC=C(OCC3CCN(C4=NC(C(C)C)=NO4)CC3)C=N2)C=C1)(C)=O


1 Comment

  1. medchemnintabelle says:

    Reblogged this on MedCheminAustralia.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Paypal Donate

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

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

Join 1,782 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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: