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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

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RO-28-1675 for Type 2 Diabetes


RO-28-1675

  • (2R)-3-Cyclopentyl-2-[4-(methanesulfonyl)phenyl]-N-(thiazol-2-yl)propionamide
  • Ro 028-1675
  • Ro 0281675
  • Ro 28-1675

3-Cyclopentyl-2(R)-[4-(methylsulfonyl)phenyl]-N-(2-thiazolyl)propionamide

MW 378.51 .-70.4 °

Conc 0.027 g/100mL; chloroform, 589 nm;  23 °C

 

Formula C18H22N2O3S2
CAS No 300353-13-3

Glucokinase Activators

Ro 28-1675 (Ro 0281675) is a potent allosteric GK activator with a SC1.5 value of 0.24± 0.0019 uM.

Roche (Innovator)

Hoffmann La Roche

PHASE 1    Type 2  DIABETES,
IC50 value: 0.24± 0.0019 uM (SC1.5) [1]
Target: Glucokinase activator
The R stereoisomer Ro 28-1675 activated GK with a SC1.5 of 0.24 uM, while the S isomer did not activated GK up to 10 uM. Oral administration of Ro 28-1675 (50 mg/Kg) to male C57B1/6J mice caused a statistically significant reduction in fasting glucose levels and improvement in glucose tolerance relative to the vehicle treated animals [1].
Comparison of rat PK parameters indicated that Ro 28-1675 displayed lower clearance and higher oral bioavailability compared to 9a.

Following a single oral dose, Ro 28-1675 reduced fasting and postprandial glucose levels following an OGTT, was well tolerated, and displayed no adverse effects related to drug administration other than hypoglycemia at the maximum dose (400 mg).

 

 

.

RO-28-1675 as glucokinase activator.

Joseph Grimsby et al., of Roche have recently discovered activators of glucokinase that increase kcat and decrease the S0.5 for glucose, and these may offer a treatment for type II diabetes. Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic β cells and hepatocytes.

By screening of a library of 120,000 structurally diverse synthetic compounds, they found one small molecule that increased the enzymatic activity of GK. Chemical optimization of this initial molecule led to the synthesis of RO-28-0450 as a lead GK activator which is a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. RO-28-0450 is a racemic compound.

Activation of GK was exquisitely sensitive to the chirality of the molecule: The R enantiomer, RO-28-1675, was found to be a potent GKA, whereas the S enantiomer, RO-28-1674, was inactive. RO-28-1675 also reversed the inhibitory action of the human glucokinase regulatory protein (GKRP). The activators binding in a glucokinase regulatory site originally was discovered in patients with persistent hyperinsulinemic hypoglycemi.

The result of RO-28-1675 as a potent small molecule GKA may shed light to the chemical biologists to devise strategy for developing activators. Thus for a success to this end we must focus on highly regulated enzymes, or cooperative enzymes such as glucokinase, where nature has provided binding sites that are designed to modulate catalysis.

.SYNTHESIS

 

 

 

Paper

J. Med. Chem., 2010, 53 (9), pp 3618–3625
DOI: 10.1021/jm100039a
Abstract Image

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate) afforded (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (2.10 g, 74%) as a white foam.

[α] 23 589 = –70.4° (c=0.027, chloroform).

EI-HRMS m/e calcd for C18H22N2O3S2 (M+ ) 378.1072, found 378.1081.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.48 (br. s., 1 H), 7.88 (d, J=8.6 Hz, 2 H), 7.53 (d, J=8.6 Hz, 2 H), 7.50 (d, J=3.5 Hz, 1 H), 7.06 (d, J=3.5 Hz, 1 H), 3.76 (t, J=7.7 Hz, 1 H), 3.03 (s, 3 H), 2.28 (dt, J=13.6, 7.7 Hz, 1 H), 1.88 – 1.98 (m, 1 H), 1.42 – 1.84 (m, 7 H), 1.07 – 1.19 (m, 2 H).

Anal. Calcd for C18H22N2O3S2: C, 56.94; H, 5.59; N, 7.28. Found: C, 57.12; H, 5.86; N, 7.40.

PATENT

WO 2000058293

http://www.google.com/patents/WO2000058293A2?cl=en

Example 3 (A) 3-CyclopentyI-2-(4-methanesulfonyl-phenyI)-N-thiazol-2-yI-propionamide

Figure imgf000047_0001

A solution of dπsopropylamine (3.3 mL, 23.5 mmol) in dry tetrahydrofuran (50 mL) and 1.3-dιmethyl-3,4,5,6-tetrahydro-2(lH)-pyπmιdιnone (10 mL) was cooled to -78°C under nitrogen and then treated with a 10M solution of n-butyllithium m hexanes (2.35 mL, 23 5 mmol) The yellow reaction mixture was stiπed at -78°C for 30 mm and then treated dropwise with a solution of 4-methylsulfonylphenylacetιc acid (2.40 g, 11.2 mmol) in a small amount of dry tetrahydrofuran. After approximately one-half of the 4- methylsulfonylphenylacetic acid m dry tetrahydrofuran was added, a precipitate formed Upon further addition of the remaining 4-methylsulfonylphenylacetιc acid in dry tetrahydrofuran, the reaction mixture became thick in nature After complete addition of the 4-methylsulfonylphenylacetιc acid in dry tetrahydrofuran, the reaction mixture was very thick and became difficult to stir An additional amount of dry tetrahydrofuran (20 mL) was added to the thick reaction mixture, and the reaction mixture was stirred at –

78 C for 45 mm, at which time, a solution of lodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of dry tetrahydrofuran was added dropwise The reaction mixture was allowed to warm to 25°C where it was stiπed for 15 h. The reaction mixture was quenched with water (100 mL), and the resulting yellow reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified to pH = 2 using concentrated hydrochloπc acid The aqueous layer was extracted with ethyl acetate The organic phase was dπed over magnesium sulfate, filtered, and concentrated in vacuo Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propιonιc acid (1.80 g, 52%) as a white solid: mp 152-154°C; EI-HRMS m/e calcd for C15H20O4S (Nf) 296.1082, found 296.1080

A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propιonιc acid (4.91 g, 16.56 mmol) and tnphenylphosphine (6.52 g, 24.85 mmol) m methylene chloπde (41 mL) was cooled to 0°C and then treated with N-bromosuccinimide (5.01 g, 28.16 mmol) m small portions The reaction mixture color changed from light yellow to a darker yellow then to brown After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25°C over 30 min. The brown reaction mixture was then treated with 2-aminothiazole (4.98 g, 49.69 mmol). The resulting reaction mixture was stiπed at 25°C for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with a 10% aqueous hydrochloric acid solution (400 mL) and then extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1 x 200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2- yl-propionamide (4.49 g, 72%) as a white solid: mp 216-217°C; EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1071.

Example 13

(2R)-3-Cyclopentyl-2-(4-methanesuIfonylphenyl)-N-thiazol-2-yl-propionamide

Figure imgf000068_0001

A solution of ^-( ethanesulfonyl)phenyl acetic acid (43 63 g, 0.204 mol) in methanol (509 mL) was treated slowly with concentrated sulfunc acid (2 mL) The resulting reaction mixture was heated under reflux for 19 h The reaction mixture was allowed to cool to 25°C and then concentrated in vacuo to remove methanol The residue was diluted with ethyl acetate (800 mL) The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1 x 200 mL), washed with a saturated aqueous sodium chlonde solution (1 x 200 mL), dned over sodium sulfate, filtered, and concentrated in vacuo Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.42 g, 98%) as a yellow oil which solidified to a cream colored solid upon sitting over time at 25°C mp 78-80°C, EI-HRMS m/e calcd for Cι0H12O4S (M+) 228 0456, found 228 0451.

A mechanical stiπer was used for this reaction A solution of dnsopropylamme (29.2 mL, 0.21 mol) in dry tetrahydrofuran (186 mL) and l,3-dιmethyl-3,4,5,6-tetrahydro- 2(lH)-pyπmιdιnone (62 mL) was cooled to -78°C and then treated with a 2.5M solution of n-butylhthium in hexanes (83 4 mL, 0.21 mol) The yellow-orange reaction mixture was stiπed at -78°C for 35 min and then slowly treated with a solution of 4- (methanesulfonyl)phenyl acetic acid methyl ester (45.35 g, 0.20 mol) in dry tetrahydrofuran (186 mL) and l,3-dιmethyl-3,4,5,6-tetrahydro-2(lH)-pyπmιdmone (62 mL) The reaction mixture turned dark in color. The reaction mixture was then stiπed at -78°C for 50 mm, at which time, a solution of lodomethylcyclopentane (50.08 g, 0.24 mol) in a small amount of dry tetrahydrofuran was added slowly. The reaction mixture was then stiπed at -78°C for 50 mm, and then allowed to warm to 25°C, where it was stirred for 36 h. The reaction mixture was quenched with water (100 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran The remaining residue was diluted with ethyl acetate (1.5 L). The organic phase was washed with a saturated aqueous sodium chloπde solution (1 x 500 mL), dned over sodium sulfate, filtered, and concentrated in vacuo Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4- methanesulfonylphenyl)propιonιc acid methyl ester (41.79 g, 68%) as a yellow viscous oil EI-HRMS m/e calcd for Cι6H22O4S (M+) 310.1239. found 310.1230.

A solution of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propιonιc acid methyl ester (50 96 g, 0.16 mol) in methanol (410 mL) was treated with a IN aqueous sodium hydroxide solution (345 mL, 0.35 mol). The reaction mixture was stirred at 25°C for 24 h. The reaction mixture was concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH = 2 with concentrated hydrochlonc acid and then extracted with ethyl acetate (5 x 200 mL) The combined organic layers were dned over sodium sulfate, filtered, and concentrated in vacuo to afford pure 3-cyclopentyl-2-(4- methanesulfonylphenyl)propιonιc acid (43 61 g, 90%) as a white solid which was used without further puπfication. mp 152-154°C, EI-HRMS m e calcd for C15H20O4S (M+) 296.1082, found 296.1080.

Two separate reactions were setup in parallel: (1) A solution of (R)-(+)-4-benzyl-2- oxazohdmone (3.67 g, 20.73 mmol) m dry tetrahydrofuran (35 mL) was cooled to -78°C and then treated with a 2.5M solution of n-butylhthium in hexanes (7.9 mL, 19.86 mmol). The resulting reaction mixture was stiπed at -78°C for 30 mm and then allowed to warm to 25°C, where it was stirred for 1.5 h (2) A solution of racemic 3-cyclopentyl-2-(4- methanesulfonylphenyl)propιonιc acid (5.12 g, 17.27 mmol) in dry tetrahydrofuran (35 mL) was cooled to 0°C and then treated with tnethylamme (2.8 mL, 19.86 mmol). The reaction mixture was stiπed at 0°C for 10 nun and then treated dropwise with tπmethylacetyl chlonde (2.6 mL, 20.73 mmol). The resulting reaction mixture was stiπed at 0°C for 2 h and then cooled to -78°C for the addition of the freshly prepared chiral oxazolidmone. The reaction mixture containing the oxazolidmone was then added to the cooled (-78°C) mixed anhydπde solution The resulting reaction mixture was stiπed as -78°C for 1 h and allowed to gradually warm to 25°C. The reaction mixture was then stiπed at 25°C for 3 d. The resulting reaction mixture was quenched with water (100 mL) and then concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (600 mL). The organic layer was washed with a saturated aqueous sodium chloπde solution (1 x 300 mL), dπed over sodium sulfate, filtered, and concentrated in vacuo Thin layer chromatography using 13/7 hexanes/ethyl acetate as the developing solvent indicated the presence of two products The higher moving product had a Rf =0.32 and the lower moving product had a Rf = 0.19. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 then 13/7 hexanes/ethyl acetate) afforded two products: (1) The higher Rf product (4R, 2’S)-4-benzyl-3-[3- cyclopentyl-2-(4-methanesulfonylphenyl)propιonyl]-oxazohdm-2-one (2.12 g, 54%) as a white foam- mp 62-64°C; [c.]23 589 = +6.3° (c=0.24, chloroform); EI-HRMS m/e calcd for C25H29NO5S (M+) 455.1766, found 455.1757. (2) The lower Rf product (4R, 2R)-4- benzyl-3-[3-cyclopentyl-2-(4-methanesulfonylphenyl)propιonyl]-oxazolιdm-2-one (3.88 g, 99%) as a white foam: mp 59-61°C; [α]23 589 = -98.3° (c=0.35, chloroform); EI-HRMS m/e calcd for C25H29NO5S (M +) 455.1766, found 455.1753. The combined mass recovery from the two products was 6.00 g, providing a 76% conversion yield for the reaction

An aqueous solution of lithium hydroperoxide was freshly prepared from mixing a solution of anhydrous lithium hydroxide powder (707.3 mg, 16.86 mmol) m 5.27 mL of water with a 30% aqueous hydrogen peroxide solution (3.44 mL, 33.71 mmol). This freshly prepared aqueous lithium hydroperoxide solution was cooled to 0°C and then slowly added to a cooled (0°C) solution of (4R, 2’R)-4-benzyl-3-[3-cyclopentyl-2-(4- methanesulfonylphenyl)propιonyl]-oxazolιdm-2-one (3.84 g, 8.43 mmol) in tetrahydrofuran (33 mL) and water (11 mL). The reaction mixture was stiπed 0°C for 1.5 h The reaction mixture was then quenched with a 1.5N aqueous sodium sulfite solution (25 mL) The reaction mixture was further diluted with water (300 mL) The resulting aqueous layer was continuously extracted with diethyl ether until thm layer chromatography indicated the absence of the recovered chiral oxazolidmone in the aqueous layer The aqueous layer was then acidified to pH = 2 with a 10% aqueous hydrochlonc acid solution and extracted with ethyl acetate (300 mL) The organic extract was dned over sodium sulfate, filtered, and concentrated in vacuo to afford (2R)-3- cyclopentyl-2-(4-methanesulfonylphenyl)propιomc acid as a white solid (2.23 g, 89%) which was used without further puπfication Flash chromatography (Merck Silica gel 60, 70-230 mesh, 30/1 methylene chlonde/methanol then 10/1 methylene chlonde/methanol) was used to obtain a punfied sample for analytical data and afforded pure (2R)-3- cyclopentyl-2-(4-methanesulfonylphenyl)propιomc acid as a white foam- mp 62-64°C (foam to gel), [α]23 589 = -50.0° (c=0.02, chloroform), EI-HRMS m/e calcd for C15H20O4S (M+) 296 1082, found 296 1080

A solution of tnphenylphosphme (3.35 g, 12.79 mmol) m methylene chloπde (19 mL) was cooled to 0°C and then slowly treated with N-bromosuccmimide (2.28 g, 12.79 mmol) in small portions. The reaction mixture was stiπed at 0°C for 30 mm, and dunng this time penod, the color of the reaction mixture changed from light yellow to a darker yellow then to a purple color. The cooled purple reaction mixture was then treated with the (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propιonιc acid (2.23 g, 7.52 mmol) The resulting reaction mixture was then allowed to warm to 25°C over 45 mm, at which time, the reaction mixture was then treated with 2-amιnothιazole (1.88 g, 18.81 mmol) The resulting reaction mixture was stiπed at 25°C for 12 h. The reaction mixture was then concentrated in vacuo to remove methylene chloπde The remaining black residue was diluted with ethyl acetate (300 mL) and then washed well with a 10% aqueous hydrochlonc acid solution (2 x 100 mL), a 5% aqueous sodium bicarbonate solution (3 x 100 mL), and a saturated aqueous sodium chloride solution (1 x 200 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate) afforded (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl- propionamide (2.10 g, 74%) as a white foam: mp 78-80°C (foam to gel); [α]23 589 = -70.4° (c=0.027, chloroform); EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1081.

REFERENCES

[1]. Haynes NE, et al. Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675).

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

http://www.nature.com/nrd/journal/v8/n5/fig_tab/nrd2850_T2.html

NMR…..http://www.medchemexpress.com/product_pdf/HY-10595/Ro%2028-1675-NMR-HY-10595-13569-2014.pdf

http://www.medchemexpress.com/product_pdf/HY-10595/Ro%2028-1675-Lcms_Ms-HY-10595-13569-2014.pdf

J Grimsby et al. Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy. Science Signaling 2003, 301(5631), 370-373.
T Kietzmann and GK Ganjam. Glucokinase: old enzyme, new target. Exp. Opin. Ther. Patents. 2005, 15(6), 705-713.

 

 

///////////RO-28-1675, Ro 0281675

O=C(Nc1nccs1)[C@H](CC2CCCC2)c3ccc(cc3)S(C)(=O)=O

Chemical structures of Roche’s glucokinase activators (GKAs) RO-28-1675 and piragliatin, as well as the related GKA 1.

Pfizer’s PF 04937319 glucokinase activators for the treatment of Type 2 diabetes


 

Graphical abstract: Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

 

 

 

 

 

 

PF 04937319

N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide

MW 432.43

MF C22 H20 N6 O4
CAS 1245603-92-2
2-​Pyrimidinecarboxamid​e, N,​N-​dimethyl-​5-​[[2-​methyl-​6-​[[(5-​methyl-​2-​pyrazinyl)​amino]​carbonyl]​-​4-​benzofuranyl]​oxy]​-
N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide
Pfizer Inc. clinical candidate currently in Phase 2 development.

CLINICAL TRIALS

A trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of PF-04937319 in subjects with type 2 diabetes mellitus (NCT01044537)

Multiple dose study of PF-04937319 in patients with type 2 diabetes (NCT01272804)
Phase 2 study to evaluate safety and efficacy of investigational drug – PF04937319 in patients with type 2 diabetes (NCT01475461)

SYNTHESIS

PF 319 SYN

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

 

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type Il diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM. As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity. Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414; 821 -827, (2001 )): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents. Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No’s. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

*Corresponding authors
aPfizer Worldwide Research & Development, Eastern Point Road, Groton
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421
Med. Chem. Commun., 2011,2, 828-839

DOI: 10.1039/C1MD00116G

http://pubs.rsc.org/en/content/articlelanding/2011/md/c1md00116g/unauth#!divAbstract

http://www.rsc.org/suppdata/md/c1/c1md00116g/c1md00116g.pdf

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

Graphical abstract: Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide (28). To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethoxyethane (315 mL) in a 3-neck flask equipped with overhead stirring and a condenser at 0 o C was added Me2AlCl (1 M solution in hexanes) (715 mL). The mixture was warmed to room temperature and stirred for 1.5 h. In a separate flask, 26 (52.6 g, 142.5 mmol) was dissolved in dimethoxyethane (210 mL). This mixture was then added to the amine mixture. A gum precipitated and upon scratching the flask it dissipated into a solid. The reaction was refluxed for 3.5 h. Aq. Rochelle’s salt (5 L) and 2-MeTHF (2 L) was added to the mixture and this was allowed to stir with overhead stirring for 14 h, after which time, a yellow solid precipitated. The solid was collected by filtration, washing with 2-MeTHF. The resulting solid was dried in a vacuum oven overnight to afford the desired material (50.0g) in 81% yield.

1 H NMR (400MHz, CDCl3) δ 9.54 (d, J = 1.56 Hz, 1H), 8.50 (s, 2H), 8.37 (s, 1H), 8.14 (d, J = 0.78 Hz, 1H), 7.88 – 7.92 (m, 1H), 7.52 (d, J = 1.37 Hz, 1H), 6.28 (t, J = 0.98 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 2.55 (s, 3H), 2.49 (d, J = 1.17 Hz, 3H);

MS(ES+ ): m/z 433.4 (M+1), MS(ES- ): m/z 431.3 (M-1).

PAPER

 

http://pubs.rsc.org/en/content/articlelanding/2013/md/c2md20317k#!divAbstract

PAPER

Bioorganic & Medicinal Chemistry Letters (2013), 23(16), 4571-4578

http://www.sciencedirect.com/science/article/pii/S0960894X13007452

Glucokinase activators 1 and 2.

Figure 1.

Glucokinase activators 1 and 2.

 

 

PATENT

Pfizer Inc.

WO 2010103437

https://www.google.co.in/patents/WO2010103437A1?cl=en

Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).

Figure imgf000011_0001
PF 319 SYN

Preparations of Starting Materials and Key Intermediates

Preparation of Intermediate (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but- 3-enoic acid (I- 1a):

Figure imgf000024_0001

(Ma) To a vigorously stirred solution of 5-methyl-2-furaldehyde (264 ml_, 2650 mmol) and diethyl succinate (840 ml_, 5050 mmol) in ethanol (1.820 L) at room temperature was added sodium ethoxide (0.93 L of a 21 weight % solution in ethanol) in one portion. The reaction mixture was then heated at reflux for 13 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was partitioned between ethyl acetate (1 L) and hydrochloric acid (1 L of a 2M aqueous solution). After separation, the aqueous layer was extracted with ethyl acetate (2 x 1 L). The combined organic extracts were then extracted with sodium hydrogen carbonate (2 x 1 L of a saturated aqueous solution). These aqueous extracts were combined and adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give desired (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (J1 Ia: 34.34 g, 5%). The original organic extract was extracted with sodium hydroxide (2 L of a 2M aqueous solution). This aqueous extract was adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give additional desired materials (395.2 gram, 63%) as red liquid. 1H NMR (CDCI3, 300 MHz) δ ppm 7.48 (s, 1 H), 6.57 (d, 1 H), 6.09 (d, 1 H), 4.24 (q, 2H), 3.87 (s, 2H), 2.32 (s, 3H), 1.31 (t, 3H).

Preparation of Intermediate ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (1-1 b):

Figure imgf000025_0001

(M b) To a vigorously stirred solution of (E)-3-(ethoxycarbonyl)-4-(5- methylfuran-2-yl)but-3-enoic acid (1-1 a: 326.6 g, 1 .371 mol) in acetic anhydride (1 .77 L, 18.72 mol) at room temperature was added sodium acetate (193 g, 2350 mmol) in one portion. The reaction mixture was then heated at reflux for 2.5 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was suspended in dichloromethane (1 .5 L) and filtered, washing the solids with dichloromethane (3 x 500 ml_). The combined filtrate and washings were then washed with sodium hydrogencarbonate (2 x 1 L of a saturated aqueous solution) and brine (2 L), then concentrated in vacuo to give desired ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (H b: 549.03 g, quantitative). 1H NMR (CDCI3, 300 MHz) δ ppm 8.00-7.99 (m, 1 H), 7.64 (d, 1 H), 6.32-6.32 (m, 1 H), 4.38 (q, 2H), 2.47 (d, 3H), 2.37 (s, 3H), 1 .39 (t, 3H).

Preparation of Intermediate ethyl 4-hydroxy-2-methylbenzofuran-6- carboxylate (1- 1 c):

Figure imgf000026_0001

(He) To a stirred solution of ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (Hb: 549.03 g, 1 .37 mol) in ethanol (4.00 L) at room temperature was added potassium carbonate (266 g, 1 .92 mol) in one portion. The reaction mixture was then heated at 600C for 3 hours. Potassium carbonate (100 g, 0.720 mol) was then added in one portion and the reaction mixture was heated at 600C for a further 3 hours. After cooling to room temperature the mixture was diluted with dichloromethane (2 L) and the suspension filtered, washing the solids with dichloromethane (2 x 1 L) (all batches were combined at this point). The combined filtrate and washings were then washed with citric acid (2.5 L of a 1 M aqueous solution), then concentrated in vacuo and the resulting residue purified by dry flash chromatography (hexane then 2:1 hexane:ethyl acetate). All fractions containing the desired product were combined and concentrated in vacuo. The resulting residue, which solidified on standing, was slurried with cold toluene and filtered. The solids were then stirred with hot toluene and decolourising charcoal for 1 hour, followed by filtration of the hot mixture through a pad of celite. The filtrate was allowed to cool and the resulting precipitate isolated by filtration to give desired ethyl 4-hydroxy-2- methylbenzofuran-6-carboxylate (1-1 c: 360 g, 90%) as orange powder.

1H NMR (CDCI3, 300 MHz) δ ppm 7.73-7.73 (m, 1 H), 7.45 (d, 1 H), 6.51 -6.50 (m, 1 H), 5.85 (s, 1 H), 4.39 (q, 2H), 2.48 (d, 3H), 1.40 (t, 3H). LCMS (liquid chromatography mass spectrometry): m/z 221.06 (96.39 % purity).

 

 

Preparation of SM-25-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-

£1:

Figure imgf000029_0001

(SM-2) Oxalyl chloride (47.4g, 369mmol) was added to a suspension of 5-

Bromo-pyrimidine-2-carboxylic acid (5Og, 250mmol) in dichloromethane (821 ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture. The acid dissolved after 30 minutess. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 100%). The 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 250mmol) was dissolved in tetrahydrofuran (828ml) and dimethyl-amine (2M solution in tetrahydrofuran) (373ml, 745mmol) was added portionwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500ml) and washed with H2O (500ml). The water layer was further extracted with CH2CI2 (5x500ml), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated in vacuo and then suspended in methyl-/-butylether (650ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-t-butylether (100ml) the solid was dried in a vacuum oven at 550C for 12 hourrs to afford the title compound 5-bromo-N,N-dimethylpyhmidine-2-carboxamide (SM-2: 44g, 77%) as a pink solid.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.94 (s, 3 H) 3.13 (s, 3 H) 8.85 (s, 2 H) m/z (M+1 ) = 232.

Preparation of Intermediate Ethyl 4-(2-(dimethylcarbamoyl)Dyrimidin-5- yloxy)-2-methylbenzofuran-6-carboxylate (l-2a):

Figure imgf000030_0001

A mixture of Cs2CO3 (62.1 g, 191 mmol), 5-bromo-N,N- dimethylpyrimidine-2-carboxamide (SM-2: 24g, 104mmol) and ethyl 4- hydroxy-2-methylbenzofuran-6-carboxylate (1-1 c: 2Og, 91 mmol); 1 ,10- phenanthroline (1.64g, 9.07mmol) and copper iodide (864mg, 4.54mmol) in dimethylformamide (200ml) was purged with N2 gas and then heated to 90°C using a mechanical stirrer. The heterogeneous reaction mixture was stirred at this temperature for 18 hours. HPLC indicated near completion. The reaction mixture was cooled to 350C and diluted with ethyl acetate (300ml). The mixture was filtered to remove any cesium carbonate. The filtrate was then partitioned between water (500ml) and ethyl acetate (500ml); however, no separation was observed. Concentrated HCL (20ml) was added to the mixture. When the aqueous phase was about pH1 , the phases separated. The organics were separated and the aqueous layer reextracted with ethyl acetate (2x500ml). All organics were combined and back extracted with water (200ml) and brine (500ml). The organics were separated and treated with activated charcoal (10g) and magnesium sulfate. The mixture was allowed to stir for 10 minutes and then filtered through a plug of celite to afford a crude yellow solution. The filter cake was washed with ethyl acetate (100 ml_). The organics were concentrated in vacuo to afford a crude solid this was dried under high vacuum for 4 days. The dry crude solid was triturated using methanol (80 ml_). The solids were dispersed into a fine light orange crystalline powder with a red liquor. The solids were isolated by filtration and rinsed with methanol (20 ml_). The solid was dried in the vacuum oven at 550C for 12 hours to afford ethyl 4-(2- (dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (J1 2a) as a yellow solid (18.2g, 54%)

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.12 Hz, 3 H) 2.50 (d, J=0.98 Hz, 3 H) 3.00 (s, 3 H) 3.17 (s, 3 H) 4.41 (d, J=7.22 Hz, 2 H) 6.29 (s, 1 H) 7.62 (d, J=1.17 Hz, 1 H) 8.06 (s, 1 H) 8.50 (s, 2 H). m/z (M+1 ) = 370.5

Preparation of Starting material 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3):

Figure imgf000031_0001

(SM-3) Oxalyl chloride (1 .45g, 1 1 .1 mmol) was added to a suspension of 5-

Bromo-pyrimidine-2-carboxylic acid (1 .5g, 7.4mmol) in dichloromethane (50ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture and all of the acid dissolved after 30 minutes. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (1 -6g). 5-Bromo-pyrinnidine-2-carbonyl chloride (1600mg, 7.225mnnol) was dissolved in dichloromethane (25ml) and triethylamine (4.03ml, 28.9mmol) was added followed by ethyl-methyl-amine (0.68 mL, 7.92 mmol). The reaction was stirred at room temperature under nitrogen for 16 ours, after which time, LCMS indicated completion. The mixture was diluted with dichloromethane (50ml) and washed with water (50ml) followed by 10% citric acid (50ml) and brine (50ml). The organic layer was separated and dried over MgSO4, the residue was filtered and the solvent was removed in vacuo to afford the title compound 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3): (1.4g, 79.4%) as a brown oil.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 – 1.31 (m, 3 H) 2.99 (d, J=79.05 Hz, 3 H) 3.19 (q, J=7.22 Hz, 1 H) 3.59 (q, J=7.22 Hz, 1 H) 8.84 (d, J=3.12 Hz, 2 H)

Example 2

Preparation of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2- yl)carbamoyl)-benzofuran-4-yloxy)Dyrimidine-2-carboxamide (2):

Figure imgf000035_0001

(2)

To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethylether (315 ml_) in a 3-neck flask equipped with overhead stirring and a condensor at O0C was added Me2AICI (1 M solution in hexanes) (715 ml_). The mixture was warmed at room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2- methylbenzofuran-6-carboxylate (l-2a: 52.6g, 142.5mmol) was dissolved in dimethylether (210 ml_). This mixture was then added to the complexed amine. A gum precipitated upon scratching the flask and dissipated into a solid. The resultant reaction was refluxed for 3.5 hours HPLC indicated 93% complete. Five liters of Rochelles salt made up in water and 2 liters of 2- methyltetrahydrofuran was added to the mixture. The reaction mixture was then poured into the biphasic system. The mixture was allowed to stir with overhead stirring for 14 hours, after which time, a yellow solid precipitated. The solid was collected through filteration. The solid retained was washed with 2-methyltetrahydrofuran. The resultant solid was dried in vacuo oven overnight to afford the title compound N,N-dimethyl-5-(2-methyl-6-((5- methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyhmidine-2-carboxamide (2): (49.98g, 81 %)

1H NMR (400 MHz, CHLOROFORM-d) d ppm 2.49 (d, J=1 .17 Hz, 3H) 2.55 (s, 3H) 2.98 (s, 3 H) 3.14 (s, 3 H) 6.28 (t, J=0.98 Hz, 1 H) 7.52 (d, J=1 .37 Hz, 1 H) 7.88 – 7.92 (m, 1 H) 8.14 (d, J=0.78 Hz, 1 H) 8.37 (s, 1 H) 8.50 (s, 2 H) 9.54 (d, J=1 .56 Hz, 1 H).

m/z (M+1 ) = 433.4, m/z (M-1 )= 431 .5

 

REFERENCES

Beebe, D.A.; Ross, T.T.; Rolph, T.P.; Pfefferkorn, J.A.; Esler, W.P.
The glucokinase activator PF-04937319 improves glycemic control in combination with exercise without causing hypoglycemia in diabetic rats
74th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 13-17, San Francisco) 2014, Abst 1113-P

 

Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A.
Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes
Diabetes Obes Metab 2015, 17(8): 751

 

Study to compare single dose of three modified release formulations of PF-04937319 with immediate release material-sparing-tablet (IR MST) formulation previously studied in adults with type 2 diabetes mellitus (NCT02206607)

OTHERS

///////////Pfizer , PF 04937319,  glucokinase activators,  Type 2 diabetes

Zydus Cadila’s new 2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds in pipeline for diabetes type 2


List of compounds as DPP-IV inhibitors

Figure imgf000015_0001
Figure imgf000083_0001

Watch out on this post as I get to correct structure………..GlitterGlitterGlitterGlitter

2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds

Figure imgf000038_0002

 

One Example of 2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds

CAS  1601479-87-1

(2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(5-(methylsulfonyl)-5, 6- dihydropyrrolo [ 3, 4-c]pyrrol-2(lH, 3H, 4H)-yl)tetrahydro-2H-pyran-3-amine

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[5-(methylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]tetrahydro-2H-pyran-3-amine

MW 399.45, C18 H23 F2 N3 O3 S

INTRODUCTION

Dipeptidyl peptidase IV , CD26; DPP-IV; DP-IV inhibitors acting as glucose lowering agents reported to be useful for the treatment of type 2 diabetes.  compound inhibited human DPP-IV enzyme activity (IC50 < 10 nM) in fluorescence based assays.

It lowered glucose levels (with -49.10% glucose change) when administered to C57BL/6J mice at 0.3 mg/kg p.o. in oral glucose tolerance test (OGTT).

Compound displayed the following pharmacokinetic parameters in Wistar rats at 2 mg/kg p.o.: Cmax = 459.04 ng/ml, t1/2 = 59.48 h and AUC = 4751.59 h·ng/ml.

Dipeptidyl peptidase 4 (DPP-IV) inhibitor that inhibited human DPP-IV enzyme activity with an IC50 of < 10 nM in a fluorescence based assay.

Watch out on this post as I get to correct structure………..GlitterGlitterGlitterGlitter

 

 

 

 

 

PATENT

http://www.google.com/patents/WO2014061031A1?cl=en

Compound 8: (2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(5-(methylsulfonyl)-5, 6- dihydropyrrolo [ 3, 4-c]pyrrol-2(lH, 3H, 4H)-yl)tetrahydro-2H-pyran-3-amine

Figure imgf000038_0002

1H NMR: (CD3OD, 400 MHz): 7.32-7.28 (m, IH), 7.26-7.23 (m, 2H), 4.77 (d, IH, J= 10Hz), 4.32(dd, IH, J,= 2.0Hz, J2= 10.8Hz), 4.19 (s, 4H), 3.89-3.83 (m, 4H), 3.70- 3.65 (m, IH), 3.61 (t, IH, J= 11.6Hz), 3.53-3.46 (m, IH), 3.04 (s, 3H), 2.65-2.62 (dd, IH, Ji= 1.2Hz, J2= 12Hz), 1.84 (q, IH, J = 12 Hz); ESI-MS: (+ve mode) 400.0 (M+H)+ (100 %); HPLC: 99.4 %.

Compound 4: (2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(hexahydropyrrolo[3, 4-c Jpyrrol- 2(lH)-yl)tetrahydro-2H-pyran-3-amine

1H NMR: (CD3OD, 400 MHz):

.23-7.20 (m, 2H), 4.64 (d, IH, J= 10.4 Hz), 4.38-4.35 (dd, IH, J,= 2.4Hz, J2= 10.4Hz), 3.69 (t, IH, J= 11Hz), 3.57-3.53 (m, 4H), 3.34-3.30 (m, 8H), 2.68-2.65 (m, IH), 2.04 (q, IH, J = 1 1.6 Hz); ESI-MS: (+ve mode) 323.9 (M+H)+ (100 %), 345.9 (M+Na)+ (20%); HPLC: 98.6 %

 

 

PATENT

IN 2012MU03030

“NOVEL DPP-IV INHIBITORS”

3030/MUM/2012

Abstract:
The present invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoisomers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prevention of diabetes mellitus (DM), obesity and other metabolic disorders. The invention also relates to process for the manufacture of said compounds, and pharmaceutical compositions containing them and their use.

 

Pankaj R. Patel (right), Chairman and Managing Director,

////////////2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds, DPP-IV inhibitors

ZYD 1/ZYDPLA 1 From Zydus Cadila, a New NCE in Gliptin class of Antidiabetic agents.


Figure imgf000004_0001

GENERAL STRUCTURE

zydk 1

 

3-​[4-​(5-​methyl-​1,​3,​4-​oxadiazol-​2-​yl)​phenoxy]​-​5-​[[(3R)​-​1-​methyl-​2-​oxo-​3-​pyrrolidinyl]​oxy]​-​N-​2-​thiazolyl- Benzamide

3-(4-(5-Methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-(l-methyl-2-oxopyrrolidin-3- yloxy)-iV-(thiazol-2-yl)benzainide

(S)-3-(4-(5-Methyl-l,3,4-oxadiazol-2-yI)phenoxy)-5-((l-methyl-2-oxopyrrolidin-3- yl) oxy)-N-(thiazol-2-yl)benzamide……S CONF…..WO2011013141A2

(Λ)-3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-((l-methyl-2-oxopyrrolidin-3- yl) oxy)-Λ’-(thiazol-2-yl)benzamide…..R CONF…..WO2011013141A2

CAS 1263402-84-1  R CONF

CAS 1263402-76-1  S CONF

ZYD 1/ZYDPLA 1……….Probable Representative structure only, I will modify it as per available info

Watch out on this post as I get to correct structure………..GlitterGlitterGlitterGlitter

 

Cadila Healthcare Limited

ZYDPLA1 is an orally active, small molecule NCE, discovered and developed by the Zydus Research Centre, the NCE research wing of Zydus. ZYDPLA1 is a novel compound in the Gliptin class of antidiabetic agents. It works by blocking the enzyme Dipeptidyl Peptidase-4 (DPP-4), which inactivates the Incretin hormone GLP-1.

By increasing the GLP-1 levels, ZYDPLA1 glucose-dependently increases insulin secretion and lowers glucagon secretion. This results in an overall improvement in the glucose homoeostasis, including reduction in HbA1c and blood sugar levels.

In October 2013, Zydus received IND approval from the US FDA to initiate a phase I trial in type II diabetes

Clinical trials..Type 2 Diabetes Mellitus

NCT01972893; ZYD1/1001;

CTRI/2011/04/001684;

ZYD1

ZYD1/1001

ZYD1 is a novel GLP-1 receptor agonist. The ZYD1 exhibits increased stability to proteolytic cleavage, especially against dipeptidyl peptidase-4 (DPP-IV).ZYD1 is a potent antidiabetic agent without gastrointestinal side-effects. A first in human (FIH) Phase I study intends to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ZYD1 in normal healthy adult volunteers……..https://clinicaltrials.gov/show/NCT01972893

A randomized, double blind, placebo controlled Phase I clinical study to evaluate the safety, tolerability and pharmacokinetics of ZYD1, a selective GLP-1 agonist, following the subcutaneous administrations in healthy volunteers …………http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=2263&EncHid=&modid=&compid=%27,%272263det%27

Some clippings I found

zy2

ONE MORE……………

zy3

 

Zydus announces data presentations on ZYDPLA1 “A once-weekly small molecule DPP-IV inhibitor for treating diabetes”, at the ENDO conference in Chicago, Illinois, USA. Ahmedabad, India June 9, 2014 The Zydus group will be presenting data on its molecule ZYDPLA1 a novel compound in the Gliptin class of anti-diabetic agents during the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 to be held from June 21-24, 2014 in Chicago, Illinois.

ZYDPLA1, currently in Phase I clinical evaluation in USA, is an orally active, small molecule NCE, discovered and developed by the Zydus Research Centre. ZYDPLA1 works by blocking the enzyme Dipeptidyl Peptidase-4 (DPP-4), which inactivates the Incretin hormone GLP-1. By increasing the GLP- 1 levels, ZYDPLA1 glucose-dependently increases insulin secretion. This results in an overall improvement in the glucose homoeostasis, including reduction in HbA1c and blood sugar levels.

The Chairman & Managing Director of Zydus, Mr. Pankaj R. Patel said, “Currently, all available DPP-4 inhibitors are dosed once-daily. ZYDPLA1 with a once-a-week dosing regimen would provide diabetic patients with a more convenient treatment alternative. ZYDPLA1 will offer sustained action, which will result in an improved efficacy profile.”

The abstract of Poster Number: LB-PP02-4 can also be viewed on the ENDO web program at https://endo.confex.com/endo/2014endo/webprogram/authora.html. The Poster Preview is scheduled on Sunday, June 22, 2014 at McCormick Place West.

The number of diabetics in the world is estimated to be over 360 million. In 2025 nearly half of the world’s diabetic population will be from India, China, Brazil, Russia and Turkey. The sales of the DPP IV inhibitors is expected to peak at almost $14 billion by 2022. Research in the field of anti-diabetic therapy seeks to address the problems of hypoglycemia, GI side effects, lactic acidosis, weight gain, CV risks, edema, potential immunogenicity etc., which pose a major challenge in the treatment of diabetes.

About Zydus

Headquartered in Ahmedabad, India, Zydus Cadila is an innovative, global pharmaceutical company that discovers, manufactures and markets a broad range of healthcare therapies. The group employs over 16,000 people worldwide including over 1100 scientists engaged in R & D and is dedicated to creating healthier communities globally. As a leading healthcare provider, it aims to become a global researchbased pharmaceutical company by 2020. The group has a strong research pipeline of NCEs, biologics and vaccines which are in various stages of clinical trials including late stage.

About Zydus Research Centre

The Zydus Research Centre has over 20 discovery programmes in the areas of cardio-metabolic disorders, pain, inflammation and oncology. Zydus has in-house capabilities to conduct discovery research from concept to IND-enabling pre-clinical development and human proof-of-concept clinical trials. The Zydus Research group had identified and developed Lipaglyn™ (Saroglitazar) which has now become India’s first NCE to reach the market. Lipaglyn™ is a breakthrough therapy in the treatment of diabetic dyslipidemia and Hypertriglyceridemia. The company recently announced the commencement of Phase III trials of LipaglynTM (Saroglitazar) in patients suffering from Lipodystrophy.

PATENT

http://www.google.com/patents/WO2011013141A2?cl=en

Rajendra Kharul, Mukul R. Jain, Pankaj R. Patel

Substituted benzamide derivatives as glucokinase (gk) activators

Figure imgf000018_0001

Scheme 2:

Figure imgf000019_0001

Scheme 3:

Figure imgf000020_0001

Scheme 4A:

Figure imgf000020_0002

 

 

Figure imgf000021_0001

Scheme 4B.

] Scheme 5 A:

Figure imgf000022_0001

Scheme 5B:

Figure imgf000022_0002

Scheme 6:

Figure imgf000022_0003

Example 1

3-(4-(5-Methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-(l-methyl-2-oxopyrrolidin-3- yloxy)-iV-(thiazol-2-yl)benzainide

4-(Dimethylamino)pyridine (DMAP) (0.149 g), N-(3-Dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride (EDCI.HC1) (0.524 g) were added to a solution of 3-

( 1 -Methoxypropan-2-yloxy)-5-(4-(5 -methyl- 1 ,3,4-oxadiazol-2-yl) phenoxy) benzoic acid (0.5 g) (Intermediate 1) in dry DCM under nitrogen at 0-5 0C. 2-Aminothiazole (0.134 g) was added and the mixture was stirred for 16 h at room temperature. It was diluted with commercially available DCM. Organic phase was washed with dil HCl, saturated solution of NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated in vacuo to get the crude residue. The residue was chromatographed using silica gel as stationary phase and MeOH: CHCl3 gradient as mobile phase up to yield the product (0.3 g) as a white solid.

1H NMR (DMSO-<4, 400 MHz) δ ppm: 1.92-2.01 (m, 1 H), 2.59 (s, 3 H), 2.60-2.65 (m,

I H), 2.79 (s, 3 H), 3.31-3.34 (m, 1 H), 3.36-3.44 (m ,1 H), 5.15 (t, J = 7.6 Hz, 1 H),

7.08 (s, 1 H), 7.24 (d, J= 8.8 Hz, 2 H), 7.27-7.29 (m, 1 H), 7.40 (s, 1 H), 7.54 (s, 1 H),

7.62 (s, 1 H), 7.99 (d, J = 8.8 Hz, 2 H), 12.60 (bs, 1 H); ESI-MS mix (relative intensities): 492.03 (M+H)+ (100 %), 514.02 (M+Na)+(15 %); UPLC Purity: 93.59 %, Rettime: 3.59 min.

Intermediate 1: 3-(4-(5-Methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-(l-methyl-2-oxo pyrrolidin -3-yloxy)benzoic acid

A solution of Methyl 3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-(l-methyl- 2-oxopyrrolidin-3-yloxy)benzoate (7 g) (Intermediate 2) in a mixture of THF and methanol (1 :1 ratio) was treated with a solution of sodium hydroxide (2 g) in water and the reaction mixture was stirred for 1 h at room temperature. The resulting solution was concentrated under vacuum to remove THF and methanol, diluted with water, and washed with EtOAc. The aqueous phase was cooled and acidified with 0.1 N HCl and extracted with DCM, combined organic extracts washed with brine, dried over Na2SO4 and concentrated in vacuo to give the product (3.5 g) as white solid.

1H NMR (CDCl3, 400 MHz) δ ppm: 2.20-2.27 (m, 1 H), 2.59-2.67 (m, 1 H), 2.77 (s, 3 H), 2.95 (s, 3 H), 3.38-3.44 (m, 1 H), 3.49-3.54 (m, 1 H), 4.96 (t, J = 7.2 Hz, 1 H), 6.93-6.95 (m, 1 H), 7.07 (d, J= 8.8 Hz, 2 H), 7.32-7.34 (m, 1 H), 7.52 (d, J= 8.8 Hz, 2 H), 9.96-9.98 (m, 2 H); ESI-MS (relative intensities): 431.9 (M+ Na)+ (70%).

Intermediate 2: Methyl 3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-(l-methyl-2- oxo- pyrrolidin-3-yloxy)benzoate

To a stirred mixture of Methyl 3-hydroxy-5-(l-methyl-2-oxopyrrolidin-3-yloxy) benzoate (15 g) (Intermediate 3), N,N-dimethylglycine hydrochloride (2.3 g), copper (II) iodide (1 g) in dry 1,4-dioxane was added 2-(4-iodophenyl)-5 -methyl- 1,3,4- oxadiazole (15.4 g) (Intermediate 4) under nitrogen. The reaction mixture was refluxed for 24 h. The reaction mixture was cooled, quenched with water and extracted with DCM. Combined organic washings were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to get the crude product. The crude product was purified by column chromatography using silica gel as stationary phase and ethyl acetate: petroleum ether (9:1) as mobile phase to give the product (7 g) as thick liquid. 1H NMR (DMSO-<4, 400 MHz) δ ppm: 1.91-1.98 (m, 1 H), 2.49-2.54 (m, 1 H), 2.56 (s, 3 H), 2.77 (s, 3 H), 3.34-3.41 (m, 2 H), 3.81 (s, 3 H), 5.12 (t, J= 7.6 Hz, 1 H), 7.13- 7.15 (m, 2 H), 7.22 (d, J = 8.8 Hz, 2 H), 7.42 (s, 1 H), 7.97 (d, J = 8.8 Hz, 2 H); ESI- MS (relative intensities): 423.9 (M+H)+ (100%), 446.2 (M+ Na)+ (30%).

Intermediate 3: Methyl 3-hydroxy-5-(l-methyl-2-oxopyrrolidin-3-yloxy)benzoate

To a stirred solution of Methyl 3, 5-dihydroxybenzoate (20 g) [CAS No. 2150- 44-9] in dry DMF was added potassium carbonate (48 g) and the suspension stirred at ambient temperature under nitrogen. To this 3-Bromo-l-methyl-pyrrolidin-2-one (4Og) (Intermediate 5) [J. Med. Chem., 1987, 30, 1995-98] was added in three equal portions in 4 h intervals at room temperature and stirred overnight at ambient temperature. It was then quenched with water. The aqueous suspension was extracted with DCM. The combined extracts were washed with water, brine, dried over Na2SO4, and filtered, concentrated under reduced pressure to get the thick liquid residue. The crude product was purified by column chromatography using silica gel as stationary phase and ethyl acetate: petroleum ether as a mobile phase to yield the product as white solid (15 g).1H NMR (CDCl3, 400 MHz) δ ppm: 2.08-2.10 (m, 1 H), 2.60-2.67 (m, 1 H), 3.04 (s, 3 H), 3.40-

3.43 (m, 1 H), 3.48-3.51 (m, 1 H), 3.87 (s, 3 H), 4.91 (t, J = 7.2 Hz, 1 H), 6.59- 6.61 (m, 1 H), 7.07-7.09 (m, 1 H), 7.09-7.13 (m, 1 H), 8.02 (s, 1 H); ESI-MS (relative intensities): 287.9 (M+ Na)+ (30%).

Example 68…. S CONFIGURATION

(S)-3-(4-(5-Methyl-l,3,4-oxadiazol-2-yI)phenoxy)-5-((l-methyl-2-oxopyrrolidin-3- yl) oxy)-N-(thiazol-2-yl)benzamide

To a stirring solution of S-(-)-3-[4-(5-Methyl-l,3,4-oxadiazol-2-yl)phenoxy]-5- [(l-methyl-2-oxo-pyrrolidin-3-yl)oxy]benzoic acid (3.5 g) (Intermediate 13) in dry DCM in single necked round bottomed flask fitted with stop cock with N2(g) balloon, 4- (dimethylamino)pyridine (2.24 g) followed by N-(3-Dimethy lam inopropy I)-N5– ethylcarbodiimide hydrochloride (EDCI. HCl) (3.3 g) were added at room temperature. After stirring at the same temperature for 15 min, 2-aminothiazole (0.94 g) was added and stirring was continued for 16 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with DCM (200 mL), washed with dil HCl (20 mL, 0.05 Ν), saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude brown solid (3.5 g). The crude brown solid was purified by solvent trituration.

1H ΝMR (CDCl3, 400 MHz) δ ppm: 2.13-2.22 (m, 1 H), 2.62 (s, 3 H), 2.56-2.64 (m, 1 H), 2.93 (s, 3 H), 3.39-3.43 (m, 1 H), 3.48-3.53 (m ,1 H), 4.92 (t, J= 7.2 Hz, 1 H), 7.01 (s, 1 H), 7.04 (t, J= 2 Hz, 1 H), 7.21 (d, J = 8.8 Hz, 2 H), 7.26 (s, 1 H), 7.36 (s, 1 H), 7.44 (s, 1 H), 7.99 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 492.1 (M+H)+ (100 %), 513.8 (M+Νa)+ (10 %); UPLC Purity: 98.13 %, Ret. time: 3.577 min. Chiral Purity by HPLC: 97.31 %, Ret. time: 22.93 min. % ee: 94.62 %

Intermediate 13: S-(-)-3-[4-(5-Methyl-l, 3, 4-oxadiazol-2-yl)phenoxy]-5-[(l-methyl-2- oxo-pyrro- lidin-3-yl)oxy] benzoic acid

Sodium hydroxide (pallets, 1.5 g) was added to a stirring mixture of (.S)-(-)-Methyl 3- [4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]-5-[(l-methyl-2-oxo-pyrrolidin-3-yl)oxy] benzoate (5.3g) (Intermediate 14) in MeOH:H2O (1:1) at room temperature. The reaction was monitored by TLC. After completion, methanol was evaporated from the reaction mixture and water was added. The aqueous layer was washed with EtOAc, acidified with dil. HCl (0.05 N) to obtain solid. The solid obtained was filtered, washed with water, dried under suction or vacuum to get pure white solid (3.5 g).

1H NMR (CDCl3, 400 MHz) δ ppm: 2.17-2.22 (m, 1 H), 2.62 (s, 3 H), 2.58-2.66 (m, 1 H), 2.93 (s, 3 H), 3.39-3.43 (m, 1 H), 3.48-3.53 (m ,1 H), 4.99 (t, J= 7.2 Hz, 1 H), 6.89 (t, J = 2.4 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 2 H), 7.28 (s, 1 H), 7.53 (s, 1 H), 7.95 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 410 (M+H)+ (100 %); UPLC Purity: 97.85 %, Ret. time: 3.136 min. Chiral Purity by HPLC: 99.59 %, Ret. Time: 57.46 min. % ee: 99.18 %

Intermediate 14: (S) -(-) -Methyl 3-[4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]-5-[(l- methyl-2-oxo- pyrrolidin-3-yl) oxyjbenzoate

Sodium hydride suspension (0.71 g, 50 %) was added to a stirring solution of (£)-(-)- methyl 3 -(4-(5 -methyl- 1 ,3,4-oxadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin-3- yl)oxy)benzoate (5.5 g) (Intermediate 15) in dry DMF taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube at room temperature. The reaction mixture was stirred at the same temperature for 15 min. Methyl iodide (0.91 mL) was added and stirred till the reaction completion. The reaction mixture was quenched with ice-water, extracted with DCM. All organic layers were combined, washed with water, brine, dried over sodium sulphate, filtered and concentrated in vaccuo to get the thick liquid product. The liquid was triturated with EtOAc: hexane to get the white solid product (5.3 g).

1H NMR (CDCl3, 400 MHz) δ ppm: 2.14-2.21 (m, 1 H), 2.58-2.63 (m, 1 H), 2.64 (s, 3 H), 2.93 (s, 3 H), 3.39-3.43 (m, 1 H), 3.48-3.53 (m , 1 H), 3.89 (s, 3 H), 4.99 (t, J = 7.2 Hz, 1 H), 6.99 (t, J = 2 Hz, 1 H), 7.07 (d, J= 8.8 Hz, 2 H), 7.35 (s, 1 H), 7.53 (s, 1 H), 7.99 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 424.1 (M+H)+ (100 %); UPLC Purity: 96.1 1 %, Ret. time: 3.68 min. Chiral Purity by HPLC: 92.05 %, Ret. Time: 39.33 min.

Intermediate 15: (S) -(-) -Methyl 3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-((2- oxo pyrrolidin-3-yl)oxy) benzoate

To a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-l,3,4-oxadiazol-2- yl)phenoxy] benzoate (7 g) (Intermediate 7) and (/?)-(+)-3-hydroxy-2-pyrrolidinone (Intermediate 16) (2.4g) in dry THF (200 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (1 1.3 g) was added. Diisopropyl azodicarboxylate (DIAD) (6.2 mL) in dry THF (10 mL) was added drop wise to the above reaction mixture. The reaction was stirred at room temperature. Reaction was monitored by TLC for completion. After completion, reaction mixture was concentrated under vacuum to remove the solvents. Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (6 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 2.26-2.33 (m, 1 H), 2.62 (s, 3 H), 2.64-2.71 (m, 1 H), 3.40-3.47 (m, 1 H), 3.51-3.55 (m, 1 H), 3.89 (s, 3 H), 4.89 (t, J= 7.6 Hz, 1 H), 6.07 (bs, 1 H), 6.99 (t, J= 2.4 Hz, 1 H), 7.11 (d, J= 8.8 Hz, 2 H), 7.36 (s, 1 H), 7.51 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 410.1 (M+H)+ (100 %); UPLC Purity: 98.35 %, Ret. time: 3.47 min. Chiral Purity by HPLC: 95.31 %, Ret. Time: 47.97 min. ee: 90.62 %.

Intermediate 16: (R)-(+)-3-Hydroxy-2-pyrrolidinone

To a stirring mixture of 4-Nitrobenzoic acid (21.5 g) and (5)-(-)-3-hydroxy-2- pyrrolidinone (11.8 g) (Intermediate 17) in dry THF (360 mL) taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (61.2 g) was added. To this reaction mixture, diisopropyl diazodicarboxylate (DIAD) (34 mL) was added drop wise in three portions at room temperature. The reaction was stirred at room temperature. The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4). After completion, reaction mixture was concentrated under vacuum to obtain residue. Methanol (360 mL) was added to the residue followed by potassium carbonate (10 g) at room temperature. The reaction was stirred at room temperature. The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4). After completion, reaction mixture was diluted with CHCl3 and filtered through celite. Celite bed was successively washed with 1 % MeOH:CHCl3. The filtrates were combined and concentrated to dryness to remove solvents. The residues were partitioned between EtOAc: dil. HCl (200 mL, 9:1) and stirred for 15 min. Layers were separated, aq. layer was washed with EtOAc thrice until all organic impurities were washed out. The aq. Layer was concentrated to dryness to remove the water and solid residues were obtained. The residues obtained were washed with 1-2 % MeOH: CHCl3 (3 x 100 mL), dried over sodium sulfate, filtered trough cotton, concentrated to get brown thick liquid product.

1U NMR (CDCl3, 400 MHz) δ ppm: 2.03-2.13 (m, 1 H), 2.46-2.54 (m, 1 H), 3.28-3.35 (m, IH), 3.38-3.48 (m, 1 H), 4.50 (t, J = 8.4 Hz, 1 H), 4.55 (bs, 1 H), 7.02 (bs, 1 H); [α]D25: + 68, c = l, CHCl3

Intermediate 17: (S)-(-)-3-hydroxy-2-pyrrolidinone

Cone. H2SO4 (14.8 g, 8 mL) was added drop wise over 5 min to the stirring solution of (5)-(-)-4-Amino-2-hydroxybutyric acid (15 g) [CAS No. 40371-51-5] in MeOH (95 rnL) under dry conditions using anhydrous CaCl2 guard tube. After refluxing for 4 h, the reaction mixture was allowed to cool to room temperature and diluted with water (15 mL). Potassium carbonate (24 g) was added in portions to the reaction mixture and stirred overnight (20 h). Reaction mixture was diluted with CHCl3, filtered through celite. Celite bed was thoroughly washed with 1 % MeOHiCHCl3. The filtrates were combined and evaporated to dryness to obtain thick liquid residue. The residue was subjected to aging using 1-2 % MeOHiCHCl3 and then filtered. Organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated to obtain the white solid. (1 1.8 g)

1H NMR (CDCl3, 400 MHz) δ ppm: 2.03-2.13 (m, 1 H), 2.48-2.55 (m, 1 H), 3.30-3.35

(m, IH), 3.36-3.50 (m, 1 H), 4.34 (t, J = 8.4 Hz, 1 H), 6.51 (bs, 1 H); [α]D25: + 98, c =

1, CHCl3

Following examples (Example 70-76) were prepared by using similar procedure as that of example lwith suitable modifications as are well within the scope of a skilled person

Example 77    R CONFIGURATION

(Λ)-3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-((l-methyl-2-oxopyrrolidin-3- yl) oxy)-Λ’-(thiazol-2-yl)benzamide

CORRECTED AS (R)-3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-((l-methyl-2-oxopyrrolidin-3- yl) oxy)-N-(thiazol-2-yl)benzamide

To a stirring solution of (/?j-(+)-3-[4-(5-Methyl-l,3,4-oxadiazol-2-yl)phenoxy]-5-

[(l-methyl-2-oxo-pyrrolidin-3-yl)oxy]benzoic acid (0.2 g) (Intermediate 18) in dry DCM in single necked round bottomed flask fitted with stop cock with N2(g) balloon, N.ΛP-dimethylamino pyridine (0.060 g) followed by EDCI. HCl (0.23 g) were added at room temperature. After stirring at the same temperature for 15 min, 2-aminothiazole (0.054 g) was added and stirring was continued for 16 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with DCM (20 mL), washed with dil HCl (5 mL, 0.05 Ν), saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude brown solid (0.080 g). The crude brown solid was purified by solvent trituration.

1H NMR (CDCl3, 400 MHz) δ ppm: 2.15-2.20 (m, 1 H), 2.55-2.60 (m, 1 H), 2.62 (s, 3 H), 2.93 (s, 3 H), 3.38-3.43 (m, 1 H), 3.47-3.53 (m, 1 H), 4.91 (t, J= 6.8 Hz, 1 H), 6.99 (d, J= 8.8 Hz, 2 H), 7.10-7.14 (m, 2 H), 7.23-7.26 (m, 1 H), 7.36 (s, 1 H), 7.43 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H), 10.75 (bs, 1 H); ESI MS m/z (relative intensities): 492.1 (M+H)+ (100 %), 514.0 (M+Na)+ (20 %); UPLC Purity: 95.25 %, Ret.time: 3.578 min. Chiral Purity by HPLC: 95.93 %, Ret.time: 14.17min. % ee: 91.86 %

Intermediate 18: (R)-(+)-3-[4-(5-Methyl-l, 3, 4-oxadiazol-2-yl)phenoxy]-5-[(l-methyl- 2-oxo- pyrrolidin-3-yl)oxy] benzoic acid

Sodium hydroxide (pallets, 0.35 g) was added To a stirring mixture of (/?)-(+)-Methyl 3-[4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]-5-[(l-methyl-2-oxo- pyrrolidin-3-yl) oxyjbenzoate (1.1 g) (Intermediate 19) in MeOH:H2O (1:1) at room temperature. The reaction was monitored by TLC. After completion, methanol was evaporated from the reaction mixture and water was added. The aqueous layer was washed with EtOAc, acidified with dil. HCl (0.05 N) to obtain solid. The solid obtained was filtered, washed with water, dried under suction or vacuum to get pure white solid (0.76 g).

1H NMR (DMSO-J6, 400 MHz) δ ppm: 1.92-1.99 (m, 1 H), 2.62 (s, 3 H), 2.58-2.66 (m, 1 H), 3.31 (s, 3 H), 3.32-3.40 (m, 2 H), 5.12 (t, J = 7.2 Hz, 1 H), 7.08 (s, 1 H), 7.14 (s, 1 H), 7.23 (d, J= 8.8 Hz, 2 H), 7.40 (s, 1 H), 7.99 (d, J= 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 410.1 (M+H)+ (65 %), 410.1 (M+H)+ (100 %); UPLC Purity: 96.95 %, Ret. time: 3.12 min. Chiral Purity by HPLC: 89.04 %, Ret. Time: 48.15 min. Intermediate 19: (R)-(+)-Methyl 3-[4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]-5-[(l- methyl-2-oxo- pyrrolidin-3-yl) oxyjbenzoate:

Sodium hydride suspension (0.16 g, 50 %) was added to a stirring solution of (R)- (+)-Methyl 3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin-3- yl)oxy)benzoate (1.5 g) (Intermediate 20) in dry DMF taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube, at room temperature. The reaction mixture was stirred at the same temperature for 15 min. Methyl iodide (0.20 mL) was added and stirred till the reaction completed. The reaction mixture was quenched with ice-water, extracted with DCM. All organic layers were combined, washed with water, brine, dried over sodium sulphate, filtered and concentrated in vacuum to get the thick liquid product. The liquid was triturated with EtOAc: hexane to get the white solid product

(1.2 g).

1U NMR (DMSO-J6, 400 MHz) δ ppm: 1.95-1.98 (m, 1 H), 2.51-2.55 (m, 1 H), 2.56 (s, 3 H), 2.88 (s, 3 H), 3.29-3.34 (m, 1 H), 3.37-3.40 (m ,1 H), 3.81 (s, 3 H), 5.12 (t, J = 7.2 Hz, 1 H), 7.13-7.17 (m, 2 H), 7.24 (d, J= 8.8 Hz, 2 H), 7.41 (s, 1 H), 7.99 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 423.9 (M+H)+ (100 %); UPLC Purity: 90.38 %, Ret. time: 3.68 min.

Intermediate 20: (R)-(+)-Methyl 3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy)-5-((2- oxopyrrolidin -3-yl)oxy)benzoate

To a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-l,3,4-oxadiazol-2- yl)phenoxy] benzoate (2.5 g) (Intermediate 7) and (5)-(-)-3-hydroxy-2-pyrrolidinone (Intermediate 17) (0.8 g) in dry THF (70 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (3.77 g) was added. Diisopropyl azodicarboxylate (DIAD) (2.1 mL) in dry THF (2 mL) was added drop wise to the above reaction mixture. The reaction was stirred at room temperature. Reaction was monitored by TLC for completion. After completion, reaction mixture was concentrated under vacuum to remove the solvents. Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (2 g).

1H NMR (CDCl3, 400 MHz) δ ppm: 2.23-2.30 (m, 1 H); 2.62 (s, 3 H), 2.64-2.71 (m, 1 H), 3.40-3.46 (m, 1 H), 3.50-3.55 (m, 1 H), 3.89 (s, 3 H), 4.89 (t, J= 7.6 Hz, 1 H), 6.99 (t, J= 2.4 Hz, 1 H), 7.11 (d, J= 8.8 Hz, 2 H), 7.36 (s, 1 H), 7.51 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 410.1 (M+H)+ (45 %); UPLC Purity: 96.40 %, Ret. time: 3.48 min. Chiral Purity by HPLC: 90.92 %, Ret. Time: 48.36 min.

 
ZY4
Zydus announces US FDA approval for initiating Phase I clinical trials of ‘ZYDPLA1’ – a novel next generation orally active, small molecule DPP-4 inhibitor to treat Type 2 Diabetes Ahmedabad, October 23, 2013
• Zydus strengthens its cardiometabolic pipeline with the addition of ZYDPLA1
• Novel next generation New Chemical Entity (NCE) would offer once-a-week oral treatment option, a significant benefit to Type-2 diabetic patients
Close on the heels of launching Lipaglyn, the breakthrough therapy to treat diabetic dyslipidemia and India’s first NCE to reach the market, the Zydus group announced the Phase I clinical trial approval from the USFDA for ZYDPLA1 – a Next Generation, long-acting DPP-4 Inhibitor.
ZYDPLA1 is an orally active, small molecule NCE, discovered and developed by the Zydus Research Centre, the NCE research wing of Zydus. ZYDPLA1 is a novel compound in the Gliptin class of antidiabetic agents.
It works by blocking the enzyme Dipeptidyl Peptidase-4 (DPP-4), which inactivates the Incretin hormone GLP-1. By increasing the GLP-1 levels, ZYDPLA1 glucose-dependently increases insulin secretion and lowers glucagon secretion. This results in an overall improvement in the glucose homoeostasis, including reduction in HbA1c and blood sugar levels.
Currently, all available DPP-4 inhibitors are dosed once-daily. ZYDPLA1 with a once-a-week dosing regimen, would provide diabetic patients with a more convenient treatment alternative. ZYDPLA1 will offer sustained action, which will result in an improved efficacy profile.
Speaking on the new development, Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Group, said, “After a promising start with Lipaglyn, we take another big leap forward in the area of diabetic research and long term management of Type 2 diabetes. The IND approval by USFDA is another major regulatory milestone for us. We believe that ZYDPLA1 holds promise and would take us closer to our mission of reducing the burden of chronic diseases and addressing unmet medical needs in the treatment of diabetes.”
The number of diabetics in the world is estimated to be over 360 million. In 2025 nearly half of the world’s diabetic population will be from India, China, Brazil, Russia and Turkey. The sales of the DPPIV inhibitors is expected to peak at almost $14 billion by 2022. Research in the field of anti-diabetic therapy seeks to address the problems of hypoglycemia, GI side effects, lactic acidosis, weight gain, CV risks, edema, potential immunogenicity etc., which pose a major challenge in the treatment of diabetes.
About Zydus Zydus
Cadila is an innovative, global pharmaceutical company that discovers, develops, manufactures and markets a broad range of healthcare therapies. The group employs over 15,000 people worldwide and is dedicated to creating healthier communities globally. Zydus is the only Indian pharma company to launch its own patented NCE – Lipaglyn™, the world’s first drug to be approved for the treatment of diabetic dyslipidemia. It aims to be a leading global healthcare provider with a robust product pipeline, achieve sales of over $3 billion by 2015 and be a research-based pharmaceutical company by 2020.
About Zydus Research Centre
The Zydus Research Centre has over 20 discovery programmes ongoing with several candidates in the pre-clinical development stage focused on metabolic, cardiovascular, pain, inflammation and oncology therapeutic areas. With over 400 research professionals spearheading its research programme, Zydus has inhouse capabilities to conduct discovery research from concept to IND-enabling pre-clinical development and human proof-of-concept clinical trials. ZYDPLA1 is the latest addition to the group’s strong research pipeline of 6 NCEs which are in various stages of clinical trials. For more information, please visit: http://www.zyduscadila.com
REFERENCES
International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 to be held from June 21-24, 2014 in Chicago, Illinois.
The abstract of Poster Number: LB-PP02-4 can also be viewed on the ENDO web program at https://endo.confex.com/endo/2014endo/webprogram/authora.html. The Poster Preview is scheduled on Sunday, June 22, 2014 at McCormick Place West

Mukul R Jain, PhD1, Amit Arvind Joharapurkar, PhD1, Rajesh Bahekar, PhD2, Harilal Patel, MSc3, Samadhan Kshirsagar, MPharm1, Pradip Jadav, MSc2, Vishal Patel, MPharm1, Kartikkumar Patel, MPharm1, Vikram K Ramanathan, PhD3, Pankaj R Patel, MPharm4 and Ranjit Desai, PhD2, (1)Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, India
(2)Medicinal Chemistry, Zydus Research Centre, Ahmedabad, India
(3)Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Ahmedabad, India
(4)Cadila Healthcare Limited, Ahmedabad, India

Poster Board Number: LBSU-1075

http://zyduscadila.com/wp-content/uploads/2015/09/ZYDPLA1-a-Novel-LongActing-DPP-4-Inhibitor.pdf

http://zyduscadila.com/wp-content/uploads/2015/05/PressNote23-10-13.pdf

http://zyduscadila.com/wp-content/uploads/2015/07/annual_report_14-15.pdf

http://pharmaxchange.info/press/2012/08/glucokinase-activators-gkas-in-diabetes-management/

LB-PP02-4 ZYDPLA1, a novel long-acting DPP-4 inhibitor
Jt Int Congr Endocrinol Annu Meet Endocr Soc (ICE/ENDO) (June 21-24, Chicago) 2014, Abst LBSU-1075

LB-PP02-4 ZYDPLA1, a Novel Long-Acting DPP-4 Inhibitor

Program: Late-Breaking Abstracts
Session: LBSU 1074-1087-Diabetes & Obesity
Translational
Sunday, June 22, 2014: 1:00 PM-3:00 PM
Hall F (McCormick Place West Building)
Poster Board LBSU-1075
Mukul R Jain, PhD1, Amit Arvind Joharapurkar, PhD1, Rajesh Bahekar, PhD1, Harilal Patel, MSc1, Samadhan Kshirsagar, MPharm1, Pradip Jadav, MSc1, Vishal Patel, MPharm1, Kartikkumar Patel, MPharm1, Vikram K Ramanathan, PhD1, Pankaj R Patel, MPharm2 and Ranjit Desai, PhD1
1Zydus Research Centre, Ahmedabad, India, 2Cadila Healthcare Limited, Ahmedabad, India
DPP-4 inhibitors inhibit degradation of glucagon like peptide-1 (GLP-1) and GIP, the endogenous incretin hormones responsible for stimulating glucose-dependent insulin secretion. ZYDPLA1 is a novel and potent DPP-4 inhibitor under clinical development for the treatment of type 2 diabetes and has shown potential for once a week administration in humans. The in vitro effect of ZYDPLA1 was assessed using recombinant DPP-4 enzyme.  ZYDPLA1 competitively inhibited DPP-4 activity in vitro with an IC50 of 2.99 nM, and Ki of 9.3 nM. The calculated  Koff rate for ZYDPLA1 was 5.12 × 10–5S-1. ZYDPLA1 was more than 8000 fold selective for DPP-4 relative to DPP-8, and DPP-9, and was more than 10000 fold selective relative to fibroblast activation protein in vitro. The potency of ZYDPLA1 for DPP-4 inhibition was similar across the species. In C57BL/6J mice ZYDPLA1 administration showed a potent antihyperglycemic effect in oral glucose tolerance test. This effect was mediated through elevated circulating levels of GLP-1 and insulin. Potent antihyperglycemic  effect was also observed in Zucker fatty rats following meal tolerance test. Significant DPP-4 inhibition was observed for more than 48 hours in mice and rats and up to 168 hours in dogs and non-human primates. In conclusion, ZYDPLA1 is a potent, selective inhibitor of DPPP-4 that has the potential to become once a week therapy for treatment of type 2 diabetes.

Disclosure: MRJ: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. AAJ: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. RB: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. HP: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. SK: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. PJ: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. VP: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. KP: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. VKR: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. PRP: Chairman, Cadila Healthcare Limited, Ahmedabad, India. RD: Employee, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.

screenshot-www ctri nic in 2015-11-16 12-06-43

http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=2263&EncHid=&modid=&compid=%27,%272263det%27

////////Dipeptidyl Peptidase IV, CD26,  DPP-IV,  DP-IV,  Inhibitors

MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan


MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved MARIZEV® (omarigliptin) 25 mg and 12.5 mg tablets, an oral, once-weekly DPP-4 inhibitor indicated for the treatment of adults with type 2 diabetes. Japan is the first country to have approved omarigliptin……….http://www.mercknewsroom.com/news-release/prescription-medicine-news/marizev-omarigliptin-mercks-once-weekly-dpp-4-inhibitor-type

syn…….https://newdrugapprovals.org/2014/04/18/omarigliptin-mk-3102-in-phase-3-for-type-2-diabetes/

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/////////////MARIZEV,  (Omarigliptin), Merck’s,  Once-Weekly,  DPP-4 Inhibitor,   Type 2 Diabetes, Approved, Japan

TENELIGLIPTIN


Teneligliptin.svg

TENELIGLIPTIN

Teneligliptin; 760937-92-6; UNII-28ZHI4CF9C; Teneligliptin (INN); 28ZHI4CF9C
MF C22H30N6OS
MW 426.5782 g/mol

Teneligliptin (INN; trade name Tenelia) is a pharmaceutical drug for the treatment of type 2 diabetes mellitus. It is approved for use in Japan.[1] It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors or “gliptins”.[2] {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidin-3-yl)methanone

Teneligliptin was launched in Japan in 2012 by Mitsubishi Pharma and Daiichi Sankyo for the treatment of type 2 diabetes mellitus. In 2013, the indication was partially changed to include it as a combination therapy with existing oral hypoglycemic agents, such as biganides, alpha-glucosidaseinhibitors, rapid-acting insulin secretagogues, and insulin preparations, as well as sulfonylureas and thiazolidines that had been approved for the combination.

In 2014, the product was registered in KR for the treatment of type 2 diabetes mellitus.
In 2013, Mitsubishi Tanabe Pharma filed for approval in Japan for use of the compound as combination therapy for the treatment of diabetes type 2.

CAS  760937-92-6

Teneligliptin.png

3-{(2S,4S)-4-[4-(3-methyl-l -phenyl- 1 H- pyrazol-5-yl)- l-piperazinyl]-2-pyrrolidinylcarbonyl}-l , 3-thiazolidine is represented structurally by a compound of formula (I):

 

Figure imgf000003_0001

Teneligliptin (CAS 760937-92-6) is a novel, potent and long-lasting dipeptidyl peptidase-4 inhibitor in treatment of type 2 diabetes. Dipeptidyl-peptidase-4 (DPP- 4) inhibitor has been demonstrated to improve glycemic control, in particular postparandial hyperglycemic control.

Despite of their common mechanism of action, DPP-4 inhibitors show marked structural heterogeneity. DPP-4 inhibitors may be classified into peptidomimetic (i.e. sitagliptin, vildagliptin, saxagliptin, and anagliptin) and non-peptidomimetic (i.e. alogliptin and linagliptin) subtypes.

Teneligliptin, is chemically known as a 3- {((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl 25 carbonyl}thiazolidine hemipentahydrobromide hydrate and is peptidomimetic with the molecular formula of C22H30N6OS.2½HBr.xH2O and molecular weight of 642.88 g/mol for hemipentahydrobromide. The hydrate can be from mono to dihydrate.

U.S. Patent No. 7,074,794 B2 (the US ‘794) discloses teneligliptin as L-proline derivative and its pharmaceutically acceptable salts which exhibits a Dipeptidyl 5 peptidase IV (DPP-IV) inhibitory activity, which is useful for the treatment or prophylaxis of diabetes, obesity, HIV infection, cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis, autoimmune diseases and the like.

The example-222 of the US ‘794 discloses the process for the preparation of teneligliptin as trihydrochloride salt U.S. Patent No. 8,003,790 B2 (the US ‘790) discloses salts of proline derivative, solvate thereof and production method thereof. In particular, the US ‘790 discloses 2.0 hydrochloride or 2.5 hydrochloride; 2.0 hydrobromide or 2.5 hydrobromide, and hydrates thereof teneligliptin.

The US ‘790 B2 further discloses different salts 15 of teneligliptin which are incorporated herein as reference in their entirety U.S. PG-Pub. No. 2011/0282058 A1 discloses salts of 3-{((2S,4S)-4-(4-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl}thiazolidine with mono-, di- and tri-basic acids or a solvate thereof. 20 International (PCT) publication No. WO 2012/165547 A1 discloses a process for preparation of teneligliptin and pharmaceutically acceptable salts thereof.

International (PCT) publication No. WO 2007/127635 A2 (the WO ‘635 A2) discloses a process for the preparation of diketo-piperazine and piperidine 25 derivatives. In particular, the WO ‘635 A2 discloses the process for preparation of 4-oxo-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (III)] by reacting piperazine with aryl halide.

International (PCT) publication No. WO 2012/099915 A1 (the WO ‘915 A1) 5 discloses the process for the preparation of deuterated thiazolidine derivatives. The WO ‘915 A1 also discloses the process for the preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by condensation of 5- chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by deprotection of Boc-protected 1-(3-methyl-1-phenyl-1Hpyrazol-5-yl)piperazine with triflouroacetic acid.

U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine by condensation of 5-chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine in presence of n-BuLi in tetrahydrofuran. Bioorganic & Medicinal Chemistry, 14(11), 3662-3671 (2006),

Bioorganic & Medicinal Chemistry, 20(16), 5033-5041 (2012) and U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate by reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid with 25 thiazolidine in presence of HOBT and EDC.HCl in dimethylformamide solvent.

Bioorganic & Medicinal Chemistry, 15(2), 641-655 (2007) discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3- carbonyl)pyrrolidine-1-carboxylate by treating (2S,4S)-tert-butyl 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate with tetrabutylammonium fluoride in tetrahydrofuran.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the 5 process for the preparation of herein compound (II) after by reacting 1-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) with (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate in presence of sodium triacetoxyborohydride. There is provided different alternative processes for the preparation of teneligliptin and intermediates thereof.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) also discloses the process for the preparation of 4-[4-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-piperazin- 1-yl]-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (II)] after by reacting 1-(3-methyl-1-phenyl-1H-pyrazol-5- 15 yl)piperazine [herein compound (V)] with (2S,4S)-tert-butyl 4-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate in presence of trifluoromethylsulfonic anhydride and diisopropylethylamine. 3 – [[(2S, 4S) -4- [4- (3- methyl-1-phenyl–1H- pyrazol-5-yl) -1-piperazinyl ] -2-pyrrolidinyl] carbamoyl] thiazolidine, having the formula below, is a very novel DPP-4 inhibitor potential.

Figure CN104177295AD00031

World Patent Application No. W02012099915 for Ge Lieting discloses a process for the preparation route is as follows:

Figure CN104177295AD00032

Journal B10rganic & Medicinal Chemistry, 2012, 20, 5705-5719 also discloses a preparation method for Ge Lieting, the route is as follows:

Figure CN104177295AD00041

[0009] 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine, was prepared for the Ge Lieting key intermediate. Journals B10rganic & Medicinal Chemistry, 2012,20,5705-5719 reported the preparation of the intermediates prepared route is as follows:

Figure CN104177295AD00042

[0011] The preparative route after the N-Boc-N- acetoacetyl piperazine phenylhydrazine and methanesulfonic acid in an ethanol solution of the reaction at room temperature 14h, concentrated under reduced pressure after addition of pyridine.Was added phosphorus oxychloride in pyridine, 20h post treatment reaction at room temperature the reaction system. The compound obtained above was then added trifluoroacetic acid was dissolved in methylene chloride after, after treatment at room temperature for 1.5h to give 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine.

The reaction process requires mesylate mesylate flammable, easy-absorbent deliquescence, and has a strong corrosive and irritating, easy to cause the body burns; phosphorus oxychloride, a highly toxic substance, water violent hair in the air smoke, hydrolyzed into phosphoric acid and hydrogen chloride, is very unstable, to operate a lot of trouble; trifluoroacetic acid is highly corrosive and irritant, can cause the body burns; low yield of the reaction (10%). Seeking a simple operation, high reaction yield, low cost and suitable for industrial production production process 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine has a very important role in the field of medicine.

…………………………………….

ten 1

ten 2 ten 3

ten 4

ten 1

ten 2

 

ten 4

 

since the capture is staggered, compd 165 is not clear in above pic see below

 

ten 3

 

 

…………

 

 

 

 

 

if above section iis not clear see at ……..http://www.allfordrugs.com/2015/07/03/teneligliptin/

…………………….

CN104177295

reaction scheme in   http://www.google.com/patents/CN104177295A?cl=en

Figure CN104177295AD00043

Description: LR as Lawesson reagent (Lawesson Reagent), is a sulfur oxygen exchange reagent. The present invention provides a method for preparing key intermediates Ge Lieting method, comprising the steps of: (I) N-Boc-N- acetoacetyl piperazine Lawesson’s reagent in the presence of an organic solvent, with a phenylhydrazine of the formula occurs ⑴ reaction shown:

Figure CN104177295AD00051

(2) the step (1) The product was dissolved in an organic solvent, the following formula (II) in concentrated hydrochloric acid to deprotected shown:

Figure CN104177295AD00052
格列汀 refers to 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine
……………………………..

Volume 20, Issue 19, 1 October 2012, Pages 5705–5719

Full-size image (24 K)
…………………………………..

 

………………………..

http://www.google.co.in/patents/WO2015019238A1?cl=en

Example 5: Preparation of {(2^,.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -vHpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)

Activated carbon (10 g) was added to a solution of the residue (obtained in Example 4) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was filtered through a Hyflo® bed. The filtrate was heated to a temperature of 70°C to 75°C. Hydrobromic acid (48%; 168 g) was slowly added to the filtrate at 70°C to 75°C over a period of 10 minutes to 15 minutes. The reaction mixture was stirred for 2.5 hours at 70°C to 77°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes. The reaction mixture was filtered to obtain a solid. The solid obtained was washed with isopropyl alcohol (2 x 200 mL), and dried at 50°C under reduced pressure for 15 hours to obtain crude {(25*,45)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl} ( 1 ,3 -thiazolidin-3 -yl)methanone

hemipentahydrobromide hydrate.

Yield: 90%

Example 6: Purification of {(2^’.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)

A reaction mixture containing {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin- 1 -yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone

hemipentahydrobromide hydrate (100 g; prepared according to the process of Example 5) in ethanol (700 mL) was heated at 70°C to 75°C to obtain a solution. The solution was filtered at the same temperature. The filtrate was allowed to cool to a temperature of 65 °C to 68°C, and deionized water (10 mL) was added at the same temperature. The solution was cooled to a temperature of 55°C to 60°C, and stirred at the same temperature for 2 hours. The solution was further cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes to obtain a solid. The solid was filtered, washed with ethanol (100 mL), and dried at 45°C to 50°C under reduced pressure for 18 hours to 20 hours to obtain pure {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l- yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate .

Yield: 90%

HPLC Purity: 99.93%

WO2012099915A1 * 18 Jan 2012 26 Jul 2012 Hongwen Zhu Thiazolidine derivatives and their therapeutic use
WO2012165547A1 * 31 May 2012 6 Dec 2012 Mitsubishi Tanabe Pharma Corporation Method for manufacturing pyrazole derivative
WO2014041560A2 * 28 Aug 2013 20 Mar 2014 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of teneligliptin
US7074794 10 Aug 2001 11 Jul 2006 Mitsubishi Pharma Corporation Proline derivatives and the use thereof as drugs
US8003790 17 Feb 2006 23 Aug 2011 Mitsubishi Tanabe Pharma Corporation Salt of proline derivative, solvate thereof, and production method thereof
US20050256310 * 12 May 2005 17 Nov 2005 Pfizer Inc Therapeutic compounds
EP1854795A1 * 17 Feb 2006 14 Nov 2007 Mitsubishi Pharma Corporation Salt of proline derivative, solvate thereof, and production method thereof
EP1894567A1 * 2 Jun 2006 5 Mar 2008 Mitsubishi Tanabe Pharma Corporation Concomitant pharmaceutical agents and use thereof
US20040106655 * 10 Aug 2001 3 Jun 2004 Hiroshi Kitajima Proline derivatives and the use thereof as drugs
 Patent Filing date Publication date Applicant Title
WO2015019238A1 * 28 Jul 2014 12 Feb 2015 Ranbaxy Laboratories Limited Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one
Patent Submitted Granted
Proline derivatives and use thereof as drugs [US7060722] 2005-11-03 2006-06-13
Proline derivatives and the use thereof as drugs [US7074794] 2004-06-03 2006-07-11
Proline derivatives and use thereof as drugs [US2006173056] 2006-08-03
SALT OF PROLINE DERIVATIVE, SOLVATE THEREOF, AND PRODUCTION METHOD THEREOF [US8003790] 2009-08-27 2011-08-23
METHOD OF TREATING ABNORMAL LIPID METABOLISM [US2010305139] 2010-12-02
COMBINED USE OF DIPEPTIDYL PEPTIDASE 4 INHIBITOR AND SWEETENER [US2010113382] 2010-05-06
CONCOMITANT PHARMACEUTICAL AGENTS AND USE THEREOF [US2009082256] 2009-03-26
PROPHYLACTIC/THERAPEUTIC AGENT FOR ABNORMALITIES OF SUGAR/LIPID METABOLISM [US2009088442] 2009-04-02
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  1.  Joanne Bronson, Amelia Black, T. G. Murali Dhar, Bruce A. Ellsworth, and J. Robert Merritt. “Teneligliptin (Antidiabetic)”. Annual Reports in Medicinal Chemistry 48: 523–524. doi:10.1016/b978-0-12-417150-3.00028-4
  2.  Kishimoto, M (2013). “Teneligliptin: A DPP-4 inhibitor for the treatment of type 2 diabetes”Diabetes, metabolic syndrome and obesity : targets and therapy 6: 187–95. doi:10.2147/DMSO.S35682PMC 3650886PMID 23671395.

see gliptins at…………http://drugsynthesisint.blogspot.in/p/gliptin-series.html

 

 

 

EU approves Lilly diabetes drug Trulicity, dulaglutide


EU approves Lilly diabetes drug Trulicity

Regulators in Europe have given the green light to Eli Lilly’s Trulicity, its once-weekly glucagon-like peptide-1 receptor agonist for type 2 diabetes.

Read more at: http://www.pharmatimes.com/Article/14-11-25/EU_approves_Lilly_diabetes_drug_Trulicity.aspx

Dulaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 agonist) for the treatment of type 2 diabetes that can be used once weekly.[1][2]GLP-1 is a hormone that is involved in the normalization of level of glucose in blood (glycemia). The FDA approved dulaglutide for use in the United States in September 2014.[3] The drug is manufactured by Eli Lilly under the brand name Trulicity.[3]

Mechanism of action

Dulaglutide binding to glucagon-like peptide 1 receptor, slows gastric emptying and increases insulin secretion by beta cells in the pancreas. Simultaneously the compound reduces the elevated glucagon secretion by alpha cells of the pancreas, which is known to be inappropriate in the diabetic patient. GLP-1 is normally secreted by L cells of the gastrointestinal mucosa in response to a meal.[4]

Medical uses[

The compound is indicated for adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control. Dulaglutide is not indicated in the treatment of subjects with type 1 diabetes mellitus or patients with diabetic ketoacidosis. Dulaglutide can be used either stand-alone or in combination with other medicines for type 2 diabetes, in particular metformin, sulfonylureas, thiazolidinediones, and insulin taken concomitantly with meals.[5]

Side effects

The most common side effects include gastrointestinal disorders, such as dyspepsia, decreased appetite, nausea, vomiting, abdominal pain, diarrhea.[6] Some patients may experience serious adverse reactions: acute pancreatitis (symptoms include persistent severe abdominal pain, sometimes radiating to the back and accompanied by vomiting),hypoglycemia, renal impairment (which may sometimes require hemodialysis). The risk of hypoglycemia is increased if the drug is used in combination with sulfonylureas orinsulin.[7][8]

Contraindications

The compound is contraindicated in subjects with hypersensitivity to active principle or any of the product’s components. As a precautionary measure patients with a personal or family history of medullary thyroid carcinoma or affected by multiple endocrine neoplasia syndrome type 2 should not take dulaglutide, because for now it is unclear whether the compound can increase the risk of these cancers.[9]

References

  1. JCourtney Aavang Tibble, Tricia Santos Cavaiola, Robert R Henry (2013). “Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes: A Review of Current Literature”. Expert Rev Endocrinol Metab 8 (3): 247–259.doi:10.1586/eem.13.20.
  2.  “Lilly’s Once-Weekly Dulaglutide Shows Non-Inferiority to Liraglutide in Head-to-Head Phase III Trial for Type 2 Diabetes”. Eli Lilly. Feb 25, 2014.
  3.  “FDA approves Trulicity to treat type 2 diabetes” (Press release). FDA. Sep 18, 2014.
  4.  Nadkarni P, Chepurny OG, Holz GG (2014). “Regulation of glucose homeostasis by GLP-1”. Prog Mol Biol Transl Sci 121: 23–65. doi:10.1016/B978-0-12-800101-1.00002-8.PMC 4159612. PMID 24373234. Retrieved 2014-09-29.
  5.  Terauchi Y, Satoi Y, Takeuchi M, Imaoka T (July 2014). “Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study”. Endocr. J. PMID 25029955. Retrieved 2014-09-29.
  6.  Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z (August 2014). “Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5)”. Diabetes Care 37 (8): 2149–58.doi:10.2337/dc13-2761. PMID 24742660.
  7.  Amblee A (April 2014). “Dulaglutide for the treatment of type 2 diabetes”. Drugs Today50 (4): 277–89. doi:10.1358/dot.2014.50.4.2132740. PMID 24918645.
  8.  Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E (February 2014). “Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials”. Diabetes Res. Clin. Pract. 103 (2): 269–75. doi:10.1016/j.diabres.2014.01.010.PMID 24485345.
  9. Samson SL, Garber A (April 2013). “GLP-1R agonist therapy for diabetes: benefits and potential risks”. Curr Opin Endocrinol Diabetes Obes 20 (2): 87–97.doi:10.1097/MED.0b013e32835edb32. PMID 23403741. Retrieved 2014-09-30.
Identifiers
CAS number 923950-08-7
ATC code None
Chemical data
Formula C2646H4044N704O836S18 
Mol. mass 59669.81 g/mol

NAVEGLITAZAR (LY519818)


NAVEGLITAZAR

2(S)-Methoxy-3-[4-[3-(4-phenoxyphenoxy)propoxy]phenyl]propionic acid

476436-68-7

C25 H26 O6, 422.4703

  • CCRIS 9448
  • LY 519818
  • LY 9818
  • LY519818
  • LY9818
  • Naveglitazar
  • UNII-Y995M7GM0G

http://clinicaltrials.gov/search/intervention=NAVEGLITAZAR

Naveglitazar, a peroxisome proliferator-activated receptor (PPAR) modulator, had been in phase II clinical trials for the once-daily oral treatment of type 2 diabetes, however, no recent development for this indication has been reported. The compound was originally discovered through an ongoing research collaboration between Lilly and Ligand, but, in 2006, Lilly discontinued the development program.

Naveglitazar [LY519818; benzenepropanoic acid, alpha-methoxy-4-[3-(4-phenoxyphenoxy)propoxy], (alpha-S)-] is a nonthiozolidinedione peroxisome proliferator-activated receptor alpha-gamma dual, gamma-dominant agonist that has shown glucose-lowering potential in animal models and in the clinic.

Studies have been conducted to characterize the disposition, metabolism, and excretion of naveglitazar in mice, rats, and monkeys after oral and/or i.v. bolus administration.

………………………………

2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents.

Martín JA, Brooks DA, Prieto L, González R, Torrado A, Rojo I, López de Uralde B, Lamas C, Ferritto R, Dolores Martín-Ortega M, Agejas J, Parra F, Rizzo JR, Rhodes GA, Robey RL, Alt CA, Wendel SR, Zhang TY, Reifel-Miller A, Montrose-Rafizadeh C, Brozinick JT, Hawkins E, Misener EA, Briere DA, Ardecky R, Fraser JD, Warshawsky AM.

Bioorg Med Chem Lett. 2005 Jan 3;15(1):51-5.

………………………………………..

http://www.google.im/patents/US20050020684?cl=un

EXAMPLE 153

′2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid

Figure US20050020684A1-20050127-C00299

The title compound was prepared from 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example 152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a manner analogous as in Example 152, Step E. MS (ES) for C25H26O6[M+NH4]+: 440.2, [M+Na]+: 445.2. 1H-NMR (CDCl3, 200.15 MHz): 7.33-7.17 (m, 3H), 7.07-6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.25 (qui, 2H, J=5.9)ppm.

澳格列汀, SP2086, Retagliptin


Figure imgb0068 Figure imgb0002   澳格列汀, SP2086, Retagliptin 1174122-54-3(Retagliptin), 1174038-86-8 (Retagliptin Hydrochloride), 1256756-88-3(Retagliptin Phosphate) (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester Methyl (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo [1,5-a]pyrazine-1-carboxylate, DPP-4 inhibitor Type II diabetes

Jiangsu Hengrui Medicine Co., Ltd

  Nanjing Changao Pharmaceutical 澳格列汀 is a novel DPP-4 inhibitor (gliptin) for the treatment of type II diabetes. Because Shanghai Sun Sail Pharmaceutical, a wholly owned subsidiary of Nanjing Changao Pharmaceutical, has filed two patents to protect DPP-4 inhibitors (WO2011147207 and CN101786978), it is unknown which one covers this drug. Relevant data’s from WHO showed morbidity rate, disability rate, death rate of diabetes mellitus and overall health level of diabetes mellitus patients have already ranked the third place in non-infectious diseases, diabetes, together with tumors and cardiovascular diseases were the three main diseases which threats human health. Diabetes mellitus is usually classified into type 1 and type 2, there are more than 240 million diabetes patients, and 90% of them are suffering from type 2 diabetes, which also has a 1% growth rate every year, so, type 2 diabetes will be the main new growth point of diabetes drug market. The incidence of diabetes in China is about 5%, the number of patients of which ranks second place in the world just behind India. There are many antidiabetic drugs on the market, insulin injection, metformin, rosiglitazone, pioglitazone are representations of them. However, there is no drug alone can keep the HbA1c level of type 2 diabetes patients within the aimed range in a long term. Even though used in combination, the effect of the drugs will go down year by year after 3-4 years. Adverse reaction is one of the problems of many hypoglycemic drugs, wherein the fatal hypoglycemia is most worried by clinicians; secondly, many oral hypoglycemic drugs, such as sulfonylureas, α-glycosidase inhibitors and thiazolidinediones may all induce weight gain to patients, some of the drugs may also induce cardiovascular diseases. Therefore, developing new type hypoglycemic drugs with brand new mechanism of action, higher safety and effectiveness is an important task that should be completed quickly for the scientists. In the process of constantly finding new methods endocrine hormones were found to play an important role in the pathology and physiology of type 2 diabetes. Dipeptidyl peptidase-IV (DPP-IV) is an important enzyme related to diabetes, inhibiting the action of which to treat type 2 diabetes is a new method with good prospect. DPP-IV inhibitors can indirectly stimulate the secretion of insulin, the action of which is generated by inhibit DPP-IV to stabilize endocrine hormones such as incretin hormones, glucagons-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). GLP-1 is a production expressed by glucagon protogene after eating, and mainly secreted by intestinal mucosa L-cell, and it can stimulate the secretion of insulin by pancreatic β-cells, which plays a significant role in the stability of blood sugar. Experiments prove that GLP-1 has physiological functions as following: acting on pancreatic β-cells in a glucose-dependent manner, facilitating the transcription of insulin genes, increasing the biosynthesis and secretion of insulin, stimulating the proliferation and differentiation of β-cells, inhibiting the apoptosis of β-cells to increasing the number of pancreatic β-cells; inhibiting the secretion of glucagon; inhibiting the appetite and food intake; retarding the emptying of gastric contents, etc., all of these functions are helpful to reduce blood sugar after food intake and to keep blood sugar within constant level. In addition, it won’t cause the danger of severe hypoglycemia. GLP-1 well controlled the blood sugar of type 2 diabetes animal models and patients by multiple mechanisms. However, GLP-1 may lose biological activity through quick degradation by DPP-IV, and the half life of it is shorter than 2 minutes, which utterly limits the clinical use of GLP-1. It was found in researches that DPP-IV inhibitors can totally protect endogenous and even extraneous GLP-1 from inactivation by DPP-IV, improve activated GLP-llevel, and reduce the antagonistic effect of GLP-1 metabolites. Moreover, DPP-IV inhibitors can also delay the incidence of diabetes through stimulating the regeneration of pancreatic β-cells and the improving the glucose tolerance and insulin sensitivity. Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with Type 2 diabetes. For reviews on the application of DPP-IV inhibitors for the treatment of Type 2 diabetes, reference is made to the following publications: (1) H.-U.Demuth.et al. “Type 2 diabetes-Therapy with dipeptidyl peptidase IV inhibitors“, Biochim.Biophvs. Acta. 1751:33-44 (2005) and (2) K.Augustyns. et al. “Inhibitors of proline-specific dipeptidyl peptidases: DPP4 inhibitors as a novel approach for the treatment of Type 2 diabetes“, Expert Opin. Ther. Patents, 15:1387-1407 (2005). At present, some DPP-IV inhibitors have been disclosed ( US5462928 , US5543396 , WO9515309 ,WO2003004498 , WO2003082817 , WO2004032836 , WO2004085661 ), including MK-0431 as an DPP-IV inhibitor made by Merck which showed good inhibition activity and selectivity, and which has been on the market by 2006.

    • Figure imgb0001sitagliptin

      (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester of the following formula is compound A, the code of which is SP2086.

      Figure imgb0002

恒瑞医药旗下1.1类口服降糖药物瑞格列汀的制备方法 Synthesis of Hengrui Medicine’s diabetes drug Retagliptin courtesy yaopha see enlarged image at http://www.yaopha.com/2014/02/10/chemical-structure-and-synthesis-of-hengrui-medicines-diabetes-drug-retagliptin/ …………………………………………………………..

            EP2436684A1
                  Example 1. Preparation of hydrochloride of compound A (SP2086-HCL)
                  (R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester (SM2086-15) (1.35kg, 2.40mol), HCL-ethyl acetate (greater than 2M) (12.3kg) were added into a 100L reaction kettle and stirred to dissolved. The mixture was reacted for more than 2 hours at normal temperature. Detected with TLC to reaction completely before evaporated and pumped to dryness with oil pump to give 1.15∼1.20kg of white to light yellow solid product with [α]

D20

                -28.0∼-33.0° (C=1, methanol), yield 96.0∼100%. The product was hydrochloride of (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester (SP2086-HCL). (TLC detection: silica gel GF254plate; developing reagent: chloroform: methanol: ammonia= 40: 1: 0.1; raw material 15: Rf=0.80, product 1: Rf=0.50; ultraviolet visualization).

Example 2. Preparation of phosphate of compound A (SP2086-HPO4)

    • SP2086-HCL(1.20kg, 2.40mol) was added into 100L reaction kettle, and dissolved in dichloromethane (15.2kg), then washed with saturated sodium bicarbonate solution (5.8kg). The aqueous layer was extracted once with dichloromethane ( 6.0 kg). The organic layers were combined and washed once with water (5kg), dried with anhydrous sodium sulphate. The mixture was filtrated and concentrated to dryness under reduced pressure at 40°C to give 1.12 kg of oil. The oil was stirred and dissolved with 30 times amount of isopropanol (26.0kg). A solution of 85% phosphoric acid (305.2g, 2.65mol) in isopropanol (1.22kg) was added immidiately after the oil completely dissolved. The solid was separated out, filtered after stirring for 2 hours and washed with cold isopropanol. The wet product was dried under reduced pressure at 40°C to give 1.16∼1.24kg of white to light yellow solid with a yield of 86.0∼92.0% (the wet product could be directly suspended in isopropanol without drying).

……………………………………… http://www.google.com/patents/EP2230241A1?cl=en Example 1(R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride

        • Figure imgb0068
          Figure imgb0069

Step 1

        • 2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 2,2-Dimethyl-[1,3]dioxane-4,6-dione (5.69 g, 39.5 mmol) was dissolved in 400 mL of dichloromethane under stirring, followed by addition of (2,4,5-trifluoro-phenyl)-acetic acid 1a (7.15 g, 37.6 mmol) and 4-dimethylaminopyridine (7.35 g, 60.2 mmol) in an ice-water bath. Then a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.28 g, 43.2 mmol) in 250 mL of dichloromethane was added dropwise slowly. After stirring at room temperature for 36 hours, the reaction mixture was washed with the solution of 5% potassium bisulfate (250 mL×7) and saturated brine (250 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2,2-dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (11.4 g, yield 96%) as a white solid. MS m/z (ESI): 315.5 [M-1]

Step 23-Oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester

        • 2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (15.72 g, 49.6 mmol) was dissolved in 280 mL of ethanol under stirring, then the reaction mixture was heated to 70 °C in an oil bath overnight. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (12 g, yield 88%) as a yellow oil. MS m/z (ESI): 259 [M-1]

Step 33-Amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester

        • 3-Oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (24.6 g, 94.5 mmol) was dissolved in 240 mL of methanol, and ammonium acetate (36.4 g, 473 mmol) was added to the solution. The reaction mixture was heated to reflux for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure, then 100 mL of water was added to the residue. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a light yellow solid. The resulting solid was dissolved in 50 mL of ethyl acetate at 80 °C, then 50 mL of n-hexane and seed-crystal were added to the solution. The mixture was cooled to room temperature, half an hour later, 100 mL of n-hexane was added. The mixture was stored in refrigerator overnight and then filtered under reduced pressure to obtain the title compound 3-amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester 1d(19.5 g, yield 80%) as a white solid. MS m/z (ESI): 260.1 [M+1]Step 43-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester
        • 3-Amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester 1d (4.1 g, 15.8 mmol) was added into an autoclave, followed by addition of 70 mL of methanol, di-tert-butyl dicarbonate (3.8 g, 17.4 mmol), chloro(1, 5-cyclooctadiene)rhodium( I ) dimer (32 mg, 0.0632 mmol) and (R)-1-[(S)-2-(diphenyl phosphino)ferrocenyl]-ethyl-tert-butylphosphine (68 mg, 0.126 mmol). The reaction mixture was hydrogenated for 24 hours under 6.67 atmosphere at 30 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure. Then 34 mL of methanol was added to the residue at 50 °C, followed by addition of 12 mL of water until all dissolved. After cooling to room temperature, the mixture was stored in the refrigeratory overnight and then filtered. The solid product was washed with the solvent mixture of methanol/water (v:v = 3:2), dried in vacuo to obtain the title compound 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (4 g, yield 70%) as a light yellow solid. MS m/z (ESI): 362.4 [M+1]Step 5(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid
        • 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in the solvent mixture of 100 mL of methanol and 50 mL of water under stirring. The reaction mixture was reacted at 40-45 °C for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residue was added with some water, then pH was adjusted to 2-3 with 1 N hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mLx3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step. MS m/z (ESI): 332.3 [M-1] Reference: Tetrahedron Asymmetry, 2006, 17(2), 205-209

Step 6C-Pyrazin-2-yl-methylamine

        • Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 °C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1]

Step 72,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide

        • C-Pyrazin-2-yl-methylamine 1h (10.9 g, 100 mmol) was added into a reaction flask, then 20 mL of trifluoroacetic anhydride was added dropwise slowly within an hour at 0 °C in an ice-water bath. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. Then it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2,2,2-trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g) as a brown oil. MS m/z (ESI): 206.1 [M+1]

Step 83-Trifluoromethyl-imidazo[1,5-a]pyrazine

        • 2,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g, 100 mmol) was added into a reaction flask at room temperature, followed by addition of 100 mL of phosphorus oxychloride. After stirring at room temperature for 30 minutes, phosphorous pentoxide (17.8 g, 125 mmol) was added to the solution. The reaction mixture was heated to reflux for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. Phosphorus oxychloride was removed, and the reaction system was quenched with deionized water. The mixture was adjusted to pH 5-6 with 20% sodium hydroxide solution in an ice-water bath. The mixture was extracted with ethyl acetate (250 mL×4), and the combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, yield 65%) as a yellow solid. MS m/z (ESI): 188.0 [M+1] 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H)

Step 93-Trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

        • 3-Trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, 64.2 mmol) was dissolved in 150 mL of anhydrous ethanol under stirring, then 10% Pd/C (500 mg) was added to the solution. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through a pad of coarse silica gel and concentrated under reduced pressure to obtain the title compound 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (12.2 g, yield 99%) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 6.84 (s, 1H), 4.10 (m, 4H), 3.26 (m, 2H), 1.81 (s, 1H)

Step 10(R)-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo [1,5-a]pyrazin-7-yl)-propyl]-carbamic acidtert-butyl ester

        • Under a nitrogen atmosphere, 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1k (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane under stirring. After stirring at room temperature for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1f (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1l (20.0 g, yield 88%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (m, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.34 (s, 9H)

Step 11(R)-[3-(1-Bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acidtert-butyl ester

        • (R)-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 11 (20.0 g, 39.6 mmol) was dissolved in 300 mL of anhydrous ethanol under stirring, and 1-bromo-2,5-pyrolidinedione (14.1 g, 79.2 mmol) was then added to the solution at room temperature. After stirring for an hour, potassium carbonate (10.9 g, 79.2 mmol) and di-tert-butyl dicarbonate (8.6 g, 39.6 mmol) were added to the mixture, and the mixture was stirred for an hour and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was filtered through a pad of coarse silica gel to remove potassium carbonate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-i midazo [1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1m (20.0 g, yield 86%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.063 (m, 1H), 6.88 (m, 1H), 4.72 (s, 1H), 4.56 (s, 1H), 4.13 (m, 3H), 3.88 (m, 2H), 2.94 (m, 2H), 2.62 (m, 2H), 1.36 (s, 9H)

Step 12(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester

      • Octacarbonyldicobalt (4.02 g, 11.76 mmol), ethyl chloroacetate (0.71 g, 5.88 mmol), potassium carbonate (1.62 g, 11.76 mmol) and 50 mL of methanol were added into the reaction flask. After stirring for 5 minutes, (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acidtert-butyl ester 1m (2.3 g, 3.92 mmol) was added. The reaction mixture was reacted at 60 °C in an oil bath, and the colour of the reaction mixture turned from puce to purple. 2 hours later, Electro-Spray Ionization (ESI) mass spectrometry showed the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (1.1 g, yield 50%) as a white solid. MS m/z (ESI): 565.0 [M+1] Reference: Journal of Organometallic Chemistry, 1985, 285(1-3), 293-303

Step 13(R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride

  • [0064]
    (R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (0.12 g, 2.12 mmol) was added to a solution of 2.2 N hydrochloric acid in 5 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 1 (0.12 g, yield 94.3%) as a light yellow solid. MS m/z (ESI): 465.2 [M+1] 1H NMR (400 MHz, CD3OD): δ 7.101-7.08 (m, 1H), 6.906-6.864 (m, 1H), 5.343-4.995 (m, 2H), 4.221-4.093 (m, 5H), 3.954 (s, 3H), 2.978-2.937 (m, 2H), 2.71-2.643 (m, 2H), 2.061 (s, 2H)
EP2230241A1 * Nov 27, 2008 Sep 22, 2010 Jiangsu Hengrui Medicine Co., Ltd. Tetrahydro-imidazoý1,5-a¨pyrazine derivatives, preparation methods and medical uses thereof
WO2003004498A1 * Jul 5, 2002 Jan 16, 2003 Merck & Co Inc Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2005003135A1 * Jun 18, 2004 Jan 13, 2005 Alex Minhua Chen Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor

FDA Approves Trulicity (dulaglutide) for Type 2 Diabetes


FDA Approves Trulicity (dulaglutide) for Type 2 Diabetes

 

DULAGLUTIDE
PRONUNCIATION doo” la gloo’ tide
THERAPEUTIC CLAIM Treatment of type II diabetes
CHEMICAL NAMES
1. 7-37-Glucagon-like peptide I [8-glycine,22-glutamic acid,36-glycine] (synthetic
human) fusion protein with peptide (synthetic 16-amino acid linker) fusion protein with immunoglobulin G4 (synthetic human Fc fragment), dimer
2. [Gly8,Glu22,Gly36]human glucagon-like peptide 1-(7-37)-peptidyltetraglycyl-Lseryltetraglycyl-L-seryltetraglycyl-L-seryl-L-alanyldes-Lys229-[Pro10,Ala16,Ala17]human immunoglobulin heavy constant γ4 chain H-CH2-CH3 fragment, (55-55′:58-58′)-bisdisulfide dimer

 

  • Dulaglutide
  • LY 2189265
  • LY-2189265
  • LY2189265
  • UNII-WTT295HSY5

 

GLP-1 immunoglobulin G (IgG4) Fc fusion protein with extended activity; a hypoglycemic agent.
  • 7-37-Glucagon-like peptide I (8-glycine,22-glutamic acid,36-glycine) (synthetic human) fusion protein
    with peptide (synthetic 16-amino acid linker) fusion protein with immunoglobulin G4 (synthetic human Fc fragment), dimer

 

sept 18 2014

The US Food and Drug Administration (FDA) has approved dulaglutide (Trulicity, Eli Lilly & Co), as a once-weekly injection for the treatment of type 2 diabetes.

A member of the glucagon-like peptide-1 receptor agonist class, dulaglutide joins liraglutide (Victoza, Novo Nordisk), exenatide (Byetta, AstraZeneca/Bristol-Myers Squibb), and albiglutide (Tanzeum, GlaxoSmithKline), on the US market.

Once-weekly dulaglutide was approved based on 6 clinical trials involving a total of 3342 patients who received the drug. It was studied as a stand-alone therapy and in combination withmetformin, sulfonylurea, thiazolidinedione, and prandial insulin.

In one trial the once-weekly dulaglutide was non-inferior to daily liraglutide and in another it topped the oral dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck).

The most common side effects observed in patients treated with dulaglutide were nausea, diarrhea, vomiting, abdominal pain, and decreased appetite.

Dulaglutide should not be used to treat people with type 1 diabetes, diabetic ketoacidosis, or severe abdominal or intestinal problems, or as first-line therapy for patients who cannot be managed with diet and exercise.

As with others in its class, dulaglutide’s label will include a boxed warning that thyroid C-cell tumors have been observed in rodents but the risk in humans is unknown. The drug should not be used in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2.

The FDA is requiring Lilly to conduct the following postmarketing studies for dulaglutide:

•  A clinical trial to evaluate dosing, efficacy, and safety in children

•  A study to assess potential effects on sexual maturation, reproduction, and central nervous system development and function in immature rats

•  An MTC case registry of at least 15 years duration to identify any increase in MTC incidence with the drug

•  A clinical trial comparing dulaglutide with insulin glargine on glycemic control in patients with type 2 diabetes and moderate or severe renal impairment

•  A cardiovascular outcomes trial to evaluate the drug’s cardiovascular risk profile in patients with high baseline risk for cardiovascular disease.

The FDA approval also comes with a Risk Evaluation and Mitigation Strategy, including a communication plan to inform healthcare professionals about the serious risks associated with the drug.

 

 

STRUCTURAL FORMULA
Monomer
HGEGTFTSDV SSYLEEQAAK EFIAWLVKGG GGGGGSGGGG SGGGGSAESK 50
YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP 100
EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC 150
KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG 200
FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN 250
VFSCSVMHEA LHNHYTQKSL SLSLG 275
Disulfide bridges location
55-55′ 58-58′ 90-150 90′-150′ 196-254 196′-254′
MOLECULAR FORMULA C2646H4044N704O836S18
MOLECULAR WEIGHT 59.67 kDa

MANUFACTURER Eli Lilly and Company
CODE DESIGNATION LY2189265
CAS REGISTRY NUMBER 923950-08-7

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

LY2189265 (dulaglutide), a glucagon-like peptide-1 analog, is a biologic entity being studied as a once-weekly treatment for type 2 diabetes.

Dulaglatuide works by stimulating cells to release insulin only when blood sugar levels are high.

Gwen Krivi, Ph.D., vice president, product development, Lilly Diabetes, said of the drug, “We believe dulaglutide, if approved, can bring significant benefits to people with type 2 diabetes.”

In fact, it might help to control both diabetics’ blood sugar and their high blood pressure.

Eli Lilly CEO John Lechleiter believes the drug has the potential to be a blockbuster. Lilly could be ready to seek approval by 2013.

For more information on dulaglutide clinical studies, click here.

 

 

PRESS RELEASES

Data Preseted at 49th EASD Annual Meeting Show Treatment with Lilly’s Investigational Dulaglutide Resulted in Improved Patient-Reported Health Outcomes – September 26, 2013

Lilly’s Investigational GLP-1 Receptor Agonist, Dulaglutide, Showed Superior Glycemic Control Versus Comparators in Patients with Type 2 Diabetes – June 22, 2013

Lilly Announces Positive Results of Phase III Trials of Dulaglutide in Type 2 Diabetes – April 16, 2013

Lilly Diabetes Announces Positive Results of Phase III Trials of Dulaglutide in Type 2 Diabetes
 – October 22, 2012

Lilly Diabetes Presents Phase II Blood Pressure and Heart Rate Data on Investigational GLP-1 Analog Candidate, Dulaglutide, in Patients with Type 2 Diabetes at the 27th American Society of Hypertension Scientific Meeting – May 22, 2012

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