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AMG-319

November 17, 2015 4:32 am / Leave a comment

AMG-319

N-((1S)-1-(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine, WO2008118468

(S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine

CAS 1608125-21-8

Chemical Formula: C21H16FN7
Exact Mass: 385.14512

Phosphoinositide-3 kinase delta inhibitor

AMGEN, PHASE 2

PI3K delta isoform selective inhibitor that is being investigated in human clinical trials for the treatment of PI3K-mediated conditions or disorders, such as cancers and/or proliferative diseases

Useful for treating PI3K-mediated disorders such as acute myeloid leukemia, myelo-dysplastic syndrome, myelo-proliferative diseases, chronic myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkins lymphoma, B-cell lymphoma, or breast cancer.

Amgen is developing AMG-319, a small molecule PI3K-δ inhibitor, for treating lymphoid malignancies and solid tumors including, head and neck squamous cell carcinoma.

AMG-319 is a highly selective, potent, and orally bioavailable small molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K) with potential immunomodulating and antineoplastic activities. PI3K-delta inhibitor AMG 319 prevents the activation of the PI3K signaling pathway through inhibition of the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), thus decreasing proliferation and inducing cell death. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic lineages. The targeted inhibition of PI3K-delta is designed to preserve PI3K signaling in normal, non-neoplastic cells.

PATENT

http://www.google.com/patents/WO2008118468A1?cl=en

PATENT

WO2013152150

http://www.google.com/patents/WO2013152150A1?cl=en

PATENT

WO-2015171725

Example 4: Method of making N-((lSM-(7-fluoro-2-(2-pyridinyl)- 3-quinolinyl)ethyl)-9H-purin-6-amine

N-((l S)- 1 -(7-Fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine (4) is synthesized in four steps beginning with (S)-l-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine hydrochloride (1). A nucleophilic aromatic substitution between coupling partners 1 and purine 5 affords the penultimate intermediate 2. Cleavage of the p-methoxybenzyl (PMB) group leads to the isolation of the desired butyl acetate solvate 3. A crystalline form change is induced through an aqueous-acetone recrystallization to afford the target hydrate 4.

Synthetic Scheme

Step 1. Preparation of PMB protected pyridylpurinamine tosylate (2)

(S)- 1 -(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine is prepared similar to that described in US20130267524. The (S)-l-(7-fluoro-2-(pyridin-2-

yl)quinolin-3-yl)ethanamine hydrochloride (1) is coupled to PMB-chloropurine (5, prepared similar to that described in J. Med. Chem. 1988,31, 606-612) in the presence of K₂CO₃ in IPA. Upon reaction completion the K₂CO₃ is removed via filtration and the product is crystallized by the addition of /?-toluenesulfonic acid (pTSA). Isolation of the PMB-protected pyridylpurinamine tosylate (2) is conducted via filtration.

Dry 100 L reactor under nitrogen. Set the temperature to 20 ± 5 °C. Charge (l S)-N-chloro-l-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine HCl salt (1) to the reactor. Then 9-(4-methoxybenzyl)-6-chloro-9H-purine (5) is added. Potassium carbonate is added to the reactor. Isopropyl alcohol is added to the reactor and the mixture is heated to 80 °C and stirred for 24 hours. Additional isopropyl alcohol is added to the reactor and the mixture is cooled to 20 °C. The mixture is filtered through Celite and the solid is washed with isopropyl alcohol and the isopropyl alcohol solutions containing 9-(4-methoxybenzyl)-N-((S)- 1 -(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine are collected.

The 9-(4-methoxybenzyl)-N-((S)- 1 -(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine isopropyl alcohol solution is heated to 50 °C. /^-Toluene sulfonic acid monohydrate is dissolved in isopropyl alcohol and added to the 9-(4-methoxybenzyl)-N-((S)-l-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine in portions. The mixture is slowly cooled to 20 ± 5 °C over 6 ± 2 hrs. The crystalline 9-(4-methoxybenzyl)-N-((S)- 1 -(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)- 9H-purin-6-amine toluene sulfonic acid salt is collected, rinsed with isopropyl alcohol and dried with vacuum.

Example 5: Method of Making the Crystalline Hydrate Form of N-((1S)-1- (7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine Step 1: Isolation of a Butyl Acetate (BuOAc) Solvate of N-((lS)-l-(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine (3)

To a 2 L jacketed reactor equipped with a condenser, a mechanical stirrer, and a bubbler, under an atmosphere of N₂, was added N-((l S)-l-(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine (2, 100.0 g, 0.148 mol), followed by acetic acid (AcOH; 240 mL) and 1 -dodecanethiol (71.1 mL, 0.295 mol). The vessel was evacuated and back-filled with nitrogen three times. Methanesulfonic acid (MSA; 28.7 mL, 0.443 mol) was added to the vessel over 10 minutes. Then, the reaction was heated to 80 °C and stirred for 20 hrs. The reaction was then cooled to ambient temperature, after which toluene (1000 mL) and water (700 mL) were sequentially added. The solution was then stirred for 30 minutes. The phases were separated by removing the organic phase, adding another charge of toluene (1000 mL) to the aqueous phase, and the mixture was stirred for another 30 minutes. After removing the organic phase again, the aqueous phase was charged to a jacketed 5 L reactor equipped with a mechanical stirrer followed by n-butyl acetate (1500 mL,) and heated to 50 °C. The aqueous phase was neutralized to pH 6.3 with 10 N NaOH (350 mL). The organic (BuOAc) phase was azeotropically dried to 600 ppm water, while keeping a constant volume. The dried organic phase was polish filtered at 50 °C to remove salts, which were subsequently washed with hot BuOAc (285 mL). The BuOAc was charged back into the 2 L jacketed reactor equipped with a mechanical stirred and distillation apparatus, and then concentrated to 54 mg/g of N-((l S)-l-(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine in solution. The solution was then seeded with 1 wt% seed of the BuOAc solvate of N-((l S)- 1 -(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine. The slurry was further concentrated to 300 mL total volume and cooled to ambient temperature over 1 hour. Heptane (460 mL) was added dropwise to the solution, and the solution was aged overnight. The supernatant concentration was checked, and determined to be 5.3 mg/g of N-((l S)-l-(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine. The supernatant was filtered and the resulting solid cake was washed with 1 : 1 BuOAc:heptane (280 mL), followed by heptane (280 mL). The washed cake was then

allowed to dry on the filter. The BuOAc solvate of N-((l S)- l -(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine was obtained as a white solid (59.5 g, 99.6 LCAP, 86.3 wt%, 90 % corrected yield). ^!H NMR (400 MHz, CDC1₃) δ 13.72 (s, 1H), 8.80 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 18.8 Hz, 2H), 7.76 (t, J = 1 1.6 Hz, 2H), 7.39 (s, 1H), 7.31 (td, J = 8.7, 2.5 Hz, 1H), 6.15 (s, 1H), 4.06 (t, J = 6.7 Hz, 1H), 2.04 (s, 1H), 1.65 – 1.44 (m, 3H), 1.39 (dt, J = 14.9, 7.4 Hz, 1H), 1.33 – 1.20 (m, 2H), 0.93 (t, J = 7.4 Hz, 1H), 0.88 (t, J = 6.8 Hz, 1H); ¹³C NMR (101 MHz, CDC1₃) δ 152.28 (s), 148.46 (s), 138.10 (s), 137.22 (s), 135.58 (s), 129.47 (s), 124.80 (s), 123.53 (s), 1 13.24 – 1 13.09 (m), 1 12.89 (d, J = 20.3 Hz), 64.40 (s), 48.60 (s), 31.91 (s), 30.67 (s), 29.05 (s), 22.72 (s), 19.15 (s), 14.15 (s); IR: 3193, 3087, 2967, 2848, 1738, 1609, 1493, 1267, 1242, 1 143, 933, 874, 763, 677, 646, 627, 606, 581 , 559, 474 cm^“1; exact mass m/z calcd for C₂iH₁₆FN₇, (M + H)⁺386.1451 , found 386.1529; MP = 144 °C.

Step 2: Isolation of the Crystalline Hydrate of N-((lS)-l-(7-fluoro-2-(2-pyridinvn-3-quinolinyl)ethyl)-9H-purin-6-amine 4

To a 100 L reactor with its jacket set to 20 °C, 1.206 kg butyl acetate solvate of N-((l S)- l -(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine 3 was charged, followed by 6.8 L of acetone and 6.8 L of water. The resulting mixture was stirred at 90 rpm under nitrogen for 13 minutes to ensure complete dissolution of all solids. During these charges, the reactor contents increased in temperature that maximized at 26 °C. The solution was then transferred to another clean 100 L reactor through a 5 μιη filter, and stirred at 85 rpm under nitrogen. The solution was heated to 45 °C, and water (14.8 L) was added to reach a water content (by Karl Fischer, KF) of 75 wt%. The reactor solution was assayed by HPLC and shown to contain 42 mg/g N-((l S)- l -(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine. The solution was seeded with a slurry of 1 13 g of the crystalline hydrate of N-((l S)- l -(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine in 1 L water, and the seed slurry was rinsed into the reactor with an additional 1 L water. The reactor contents were cooled to 0 °C over 16 h and held at that temperature for 1 h. The supernatant was then assayed, and found to contain 7.6 mg/g of N-((l S)- l -(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine. Next, 10 L of water was added to the reactor over 38 min and aged for 1 h. The supernatant was assayed at 4.9 mg/g, and the solids were isolated by filtration. The solids were washed with an acetone/water solution (140 mL acetone in 2.7 L water), then 4 L water, and dried under nitrogen on the filter for 68 h. The crystalline hydrate of N-((l S)-l -(7-fluoro-2-(2-pyridinyl)-3-quinolinyl)ethyl)-9H-purin-6-amine was isolated as an off-

white solid (1.12 kg, 616 ppm acetone, 3.73 wt% water, 99.56 LCAP, 95.88 wt%). This material was co-milled at 3900 rpm using a 0.024″ screen to yield an off-white powder (1.09 kg, 99.7 LCAP, 95.4 wt%, 75% yield). Calculated losses were 212 g (18%) to liquors, 5.5g (0.5%) to washes, and 23 g (2%) to fouling. ¾ NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 8.69 (s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 8.06 – 7.91 (m, 4H), 7.76 (dd, J = 10.4, 2.4 Hz, 1H), 7.50 (ddd, J = 19.2, 9.5, 3.6 Hz, 2H), 6.03 (s, 1H), 3.38 (s, 2H), 1.63 (d, J = 6.6 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 163.58, 161.12, 158.36, 157.94, 151.99, 147.98, 146.49, 146.36, 136.82, 134.07, 130.24, 130.14, 124.69, 124.65, 123.30, 1 17.36, 1 17.1 1, 112.10, 1 1 1.90, 46.02, 22.01. HRMS m/z Calcd. for C₂iH₁₇FN₇ (M + H): 386.15295. Found: 386.15161.

PAPER

1: Cushing TD, Hao X, Shin Y, Andrews K, Brown M, Cardozo M, Chen Y, Duquette J, Fisher B, Gonzalez-Lopez de Turiso F, He X, Henne KR, Hu YL, Hungate R, Johnson MG, Kelly RC, Lucas B, McCarter JD, McGee LR, Medina JC, San Miguel T, Mohn D, Pattaropong V, Pettus LH, Reichelt A, Rzasa RM, Seganish J, Tasker AS, Wahl RC, Wannberg S, Whittington DA, Whoriskey J, Yu G, Zalameda L, Zhang D, Metz DP. Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease. J Med Chem. 2015 Jan 8;58(1):480-511. doi: 10.1021/jm501624r. Epub 2014 Dec 3. PubMed PMID: 25469863.

http://pubs.acs.org/doi/abs/10.1021/jm501624r

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC₅₀ of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

(S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (1)

¹H NMR (400 MHz, [D₆]DMSO) δ ppm 12.76 (1 H, br s), 8.69 (1 H, br s), 8.63 (1 H, s), 8.21 (1 H, br s), 7.96–8.12 (4 H, m), 7.93 (1 H, s), 7.76 (1 H, dd, J = 10.4, 2.5 Hz), 7.45–7.57 (2 H, m), 6.00 (1 H, d, J = 1.2 Hz), 1.61 (3 H, d, J = 6.7 Hz). Mass spectrum (ESI) m/e = 386.0 (M + 1).

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C[C@H](NC1=C2N=CNC2=NC=N1)C3=CC4=CC=C(F)C=C4N=C3C5=NC=CC=C5

LIK 066, Licogliflozin diprolinate

November 16, 2015 7:56 am / 1 Comment on LIK 066, Licogliflozin diprolinate

Licogliflozin

LIK 066

Licogliflozin diprolinate

LIK-066, a new flozin on the horizon

C23 H28 O7 . 2 C6 H11 N O, 642.7795, 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C…WO2011048112

CAS 1291095-45-8, (1S)-1,5-anhydro-1-C-[3-[(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-ethylphenyl]-D-glucitol (1:1) WITH L-Proline, compd., 1:1 Proline Co-crvstal , 1:1 Proline Co-crvstal …..…WO2011048112

CAS BASE 1291094-73-9, 416.46, C₂₃ H₂₈ O₇

(1S)-1,5-Anhydro-1-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethylphenyl]-D-glucitol bis[1-[(2S)-pyrrolidin-2-yl]ethanone]

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Sodium glucose transporter-2 inhibitor

SGLT 1/2 inhibitor

Novartis Ag innovator

Clinical trial……..https://clinicaltrials.gov/ct2/show/NCT01915849

https://clinicaltrials.gov/ct2/show/NCT02470403

10 Jun 2015 Novartis initiates enrolment in a phase II trial for Type 2 diabetes mellitus in USA (NCT02470403)
02 Apr 2014 Novartis terminates a phase II trial in Type-2 diabetes mellitus in USA, Poland, Argentina, Hungary, Puerto Rico and South Africa (NCT01824264)
01 Jan 2014 Novartis completes a phase II trial in Type 2 diabetes mellitus in USA (NCT01915849)

Licogliflozin, a SGLT-1/2 inhibitor, is in phase II clinical development at Novartis for the treatment of metabolic disorders, for the treatment of heart failure in patients with type 2 diabetes, for the treatment of obesity and for the treatment of polycystic ovary syndrome (PCOS) in overweight and obese women. Phase II trials for the treatment of type 2 diabetes had been discontinued.

EMA/415156/2014 European Medicines Agency decision P/0183/2014 of 24 July 2014 on the agreement of a paediatric investigation plan and on the granting of a deferral and on the granting of a waiver for (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran3,4,5-triol (2:1) (LIK066) (EMEA-001527-PIP01-13) in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council

1. Opinion of the Paediatric Committee on the agreement of a Paediatric Investigation Plan and a deferral and a waiver. 2014, EMEA-001527-PIP01-13 (here) [ Novartis revealed the IUPAC name here].

Where name is given

http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2017_Vol31-4/en/

http://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf?ua=1

SYNTHESIS

PATENT

WO 2011048112

https://www.google.com/patents/WO2011048112A1?cl=en

Gregory Raymond Bebernitz, Mark G. Bock, Dumbala Srinivas Reddy, Atul Kashinath Hajare, Vinod Vyavahare, Sandeep Bhausaheb Bhosale, Suresh Eknath Kurhade, Videsh Salunkhe, Nadim S. Shaikh, Debnath Bhuniya, P. Venkata Palle, Lili Feng, Jessica Liang,

Patentscope, Espacenet

Example 61-62:

Ex. 61

Example 61 : Acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester

Step I: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.0 g, 15.74 mmol) in toluene (200 mL) was added tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 mL), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).

Example 62: (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 mL) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 mL) and washed with brine (75 mL), brine containing 5 mL of 5% aqueous KHS0₄ (75 mL), and brine (20 mL) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.59)

H NMR (400 MHz, CD₃OD): δ 1.07 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m, 4H), 3.68 (dd, J = 12.0, 5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J = 9.6 Hz, 1 H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d, J – 8.4 Hz, 1 H), 7.15-7.25 (m, 3H).

MS (ES) m z 434.2 (M+18).

PICK UP IDEAS FROM HERE

Examples 57-58:

Ex. 57 Ex. 58

Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g, 76.48 mmol) in dichloromethane (200 mL) was added oxalyl chloride (10.3 mL, 114.74 mmol) at 0 °C followed by D F (0.9 mL). After complete addition, the reaction mixture was stirred at room temperature for 3h. Volatiles were evaporated under reduced pressure to furnish 2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used for the next step immediately.

Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1 ,4)-dioxane (10.41 g, 76.26 mmol) at 0 °C. To this reaction mixture, AICI₃ (40.78 g, 305.47 mmol) was added in portions. After stirring overnight at room temperature, the reaction mixture was poured into crushed ice. The resulting mixture was extracted with dichloromethane (500 mL X 2). The dichloromethane layers were combined and washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL X 2), and brine (200 mL), then dried over sodium sulfate and concentrated. The solid product was triturated with hexanes, and the triturated product was dried under vacuum to furnish (2-bromo-5-iodo-phenyl)-(2,3- dihydro-benzo[1 ,4]dioxin-6-yl)-methanone (30 g).

¹H N R (400 MHz, DMSO-D₆): δ 4.29-4.37 (m, 4H), 7.02 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.18-7.19 (m, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.77-7.81 (m, 1 H), 7.82 (d, J = 2.0 Hz, 1 H).

Step III: To a stirred solution of (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1 ,4]dioxin- 6-yl)-methanone (30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was added triethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0 mL, 67.42 mmol ) at room temperature. After stirring for 25 min at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (200 mL X 2), water (200 mL), and brine (200 mL), then dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-(2-bromo-5-iodo-benzyl)-2,3- dihydro-benzo[1 ,4]dioxine (26.5 g). H NMR (400 MHz, DMSO-D₆): δ 3.90 (s, 4H), 4.2 (s, 2H), 6.65 (dd, J = 8.4 Hz, J = 2.0 Hz, H), 6.68 (d, J = 2.0 Hz, 1 H), 6.77 (d, J = 8.4 Hz, H), 7.39 (d, J = 8.4 Hz, 1 H), 7.50 (dd, J = 8.4 Hz, J = 2.4 Hz 1 H), 7.67 (d, J = 2.8 Hz, 1 H).

Step IV: To a stirred solution of 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro- benzo[1 ,4]dioxine (26.5 g, 61.47 mmol) in THF:toluene 2:1 (300 mL) was added 1.6 M solution of n-BuLi in hexanes (42.3 mL, 67.62 mmol) at -78 °C. The reaction mixture was stirred for 1 h, and then transferred to a stirred solution of 2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone (28.69 g, 61.47 mmol) in toluene (100 mL) at -78 °C. After stirring for 1 h, 0.6 N methanesulfonic acid in methanol (265 mL) was added dropwise and stirred the reaction mixture for 16 h at room temperature. Reaction was quenched by the addition of aq. NaHC0₃ solution (~75 mL) and extracted with ethyl acetate (250 mL X 3), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish (3R,4S,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran- 3,4,5-triol (28.4 g)

Example 57: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1 ,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate

Step V: To a stirred solution of (3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5- triol (28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1 :1 (250 mL) was added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride diethyletharate complex (14.1 mL, 114.2 mmol) at 10 °C. After stirring for 4 h at 10°C, the reaction was quenched with saturated aqueous sodium bicarbonate (~ 100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 X 150 mL). The organic layers were combined and dried over sodium sulfate, concentrated to furnish (3R,4R,5S,6R)-2- [4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol (28.4 g). Crude product was used for next reaction without purification. Example 58: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2_!3-dihydro-1,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate Step V: To a stirred solution of (3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[ 1 ,4]dioxin-6-yl methyl)-phenyl]-6-hydroxymethyl-tetrahyd ro-pyran-3,4 , 5-triol (28.4 g, 60.81 mmol) in dichloromethane (300 mL) was added pyridine (40 mL, 486.5 mmol), acetic anhydride (50 mL, 486.5 mmol) and DMAP (740 mg, 6.08 mmol) at room temperature. After stirring for 2 h, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (500ml) and washed with 1 N HCI (200 mL X 2) followed by brine (200ml), then dried over sodium sulfate and

concentrated. The resulting crude compound was dissolved in ethanol (320 mL) at 65 °C and allowed to cool to room temperature while stirring. Light yellow solid formed was filtered and washed with cold ethanol (150 mL) followed by hexane (200 mL) to get acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin- 6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester powder (22.5 g, purity 98%).

COCRYSTAL

Example 75: 1:1 Proline Co-crvstal with f2S.3R.4R.5S.6R¾-2-r3-f2.3-Dihvdro- benzori.41dioxin-6-ylmethyl)-4-ethyl-phenvn-6-hvdroxymethyl-tetrahydro-pyran- 3.4.5-triol

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62) was completely amorphous initially but formed a crystalline complex with proline. This was confirmed by powder X-ray diffraction (PXRD) analysis. The stiochiometry of Example 62 and L- proline in the co-crystal prepared by method 1 was found to be 1 :1 by NMR

spectroscopy & HPLC. Characterization data for co-crystals of Example 62 and proline prepared by method 1 is shown in Table 3. Relative intensities of the most prominent powder x-ray diffraction peaks for co-crystals of Example 62 and proline are shown in Table 3A.

Table 3

Table 3A

3.70 15.78 18.36 25.18

9.68 10.68 18.88 36.33

11.07 21.21 20.42 69.29

14.26 14.81 21.18 27.94

14.80 22.97 22.50 12.25

15.40 4 98 23.78 33.08

16.12 8.45 24.56 6.92

16.59 18.78 25.79 21.69

17.31 100.0 27.46 8.90

17.60 20.35 31.97 7.65

17.98 47.20 32.46 5.98

1:1 Proline Co-crvstal

Example 77: 1:1 Proline Co-crvstal with (2S.3R.4R.5S.6Ri-2-f3-(2.3-Dihvdro- benzoh .41dioxin-6-ylmethvh-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol

Method 2:

1 :1 Co-Crvstals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]- 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1500mg,3.6mmol), L- proline (415mg, 3.6mmol) and ethanol (23 ml_) were added to a 50 mL 3-neck round bottom flask equipped with nitrogen purging, magnetic stirring bar,

thermometer pocket & calcium chloride guard tube and the mixture was stirred at 25-30°C for 30 min., then heat to reflux. A clear solution was observed which was refluxed for 30 min., then slowly cool to 25-30°C causing percipitation. Di- isopropyl ether (DIPE, 23 mL) was added while maintaining the mixture at 25-30°C and stirring continuously for additional one to two hours at the same temperature. The precipitate was collected by filtration using vacuum (Nitrogen atmosphere), and the filter cake was washed with ethanol-DIPE mixture (1 :1 v/v, 10ml) followed by DIPE (23 mL). The product was vacuum dried at 65-70°C for 5-6 hrs.

1:1 Proline Co-crvstal (ΔΗ 53 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig. 1. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 2.

2:1 Proline Co-crvstal

Example 78: 2:1 Proline Co-crvstal with f2S.3R.4R.5S.6R>-2-r3-f2.3-Pihvdro-benzof1.41dioxin-6-ylmethvH-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol

Method 3: 1 :2 Co-Crvstals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1 kg) was added to 15 L of ethanol with agitation while maintaining the mixture at 20-25 °C. The mixture was stirred for 10 min at 20-25 °C, then L-proline (537 gm) was added while maintaining the mixture at 20-25 °C. The mixture was stirred at this temperature for 30 min., then heated to reflux and refluxed for 30 min. The mixture was slowly cooled to 25-30°C then stired for 1 hr. DIPE (15 L) was added while maintaining the temperature at 25-30 °C and the mixture was stirred at this temperature for 1 hr. The precipitated product was collected by filtration and the product was washed with DIPE (5 L). The product was air dried at 65-70 °C to yield 1.22 kg

(79%) of a 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C (ΔΗ 85 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig.

3. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 4. Relative

intensities of the most prominent powder x-ray diffraction peaks for the 1 :2 co- crystals of Example 62 and proline are shown in Table 5.

Table 5

PATENT

WO 2012140597

http://www.google.co.in/patents/WO2012140597A1?cl=en

. TABLE 2:

Intermediate 2: (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-

Intermediate 2

Intermediate 1

tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 ml_), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid

(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).

Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 ml.) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 ml.) and washed with brine (75 ml_), brine containing 5 ml. of 5% aqueous KHS0₄ (75 ml_), and brine (20 ml.) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.5 g)

¹H NMR (400 MHz, CD₃OD): δ 1.07 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m, 4H), 3.68 (dd, J = 12.0, 5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J = 9.6 Hz, 1 H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d, J = 8.4 Hz, 1 H), 7.15-7.25 (m, 3H).

MS (ES) m/z 434.2 (M+18).

Example 3: Synthesis of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester diethyl ester

To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)- 4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 500 mg, 1.2 mmol) in pyridine (5 ml) was added diethylchlorophosphate (0.27 ml, 1 .9 mmol) at -40°C. After stirring for 1 h at same temperature, reaction was quenched with the addition of 1 N HCI and extracted with ethyl acetate (2 X 10 ml). Combined organic layers were washed with brine (10 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to give 220 mg of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl ester as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.07 (t, J = 7.6 Hz, 3H), 1.15 (td J = 7.2, 1.2 Hz, 3H), 1.22 (td, J = 6.8, 0.8 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.36-3.46 (m, 3H), 3.53-3.55 (m, 1 H),3.89 (s, 2H), 3.96-4.11 (m, 5H), 4.17 (s, 4H), 4.18-4.22 (m 1 H), 4.30-4.34 (m, 1 H), 6.52 (d, J = 2.0 Hz, 1 H),6.57 (dd, J = 8.4, 2.4 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 7.15- 7.22(m, 3H). MS (ES) m/z 553.3 (M+1 ).

Example 4: Synthesis of disodium salt of phosphoric acid mono- {(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]- 3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester

To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6- ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of Diethyl-phosphoramidic acid di- tert-butyl ester (780 mg, 3.12 mmol) in THF (5 ml) at 0°C followed by a solution of tetrazole (435 mg, 6.2 mmol) in DCM (12.5 ml). After stirring for 5 min at same temperature, it was stirred at room temperature for 20 min. Reaction mixture was cooled to -40 °C and added a solution of m-CPBA (830 mg, 4.8 mmol) in DCM (5 ml). The reaction mixture was stirred at same temperature for 5 min and then at room temperature for 2 h. Reaction mixture was cooled to 0°C and quenched by the addition of 10% sodium bisulfite solution (5 ml). This was extracted with ether (3 X 10 ml). Combined organic layer was washed with brine (5 ml), dried over sodium sulfate and concentrated to give 700 mg of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6- [3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro- pyran-2-ylmethyl ester.

To the stirred solution of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester (500 mg) in methanol (20 ml) was added amberlyst 15 ion exchange resin (250 mg) and refluxed for overnight. Reaction mixture was cooled to room temperature, filtered through celite bed and filtrate was concentrated to give 300 mg of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester. The crude material was taken up for next reaction.

To a solution of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester (300 mg, 0.6 mmol) in methanol (5 ml) was added 1 N sodium bicarbonate solution (80 mg, 0.7 mmol) in water. After stirring at room temperature for 2 h, the volatiles were evaporated under reduced pressure. The resulting solid was triturated with diethyl ether. The resulting residue was purified by preparative HPLC to give 95 mg of disodium salt of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester.

¹H NMR (400 MHz, CD₃OD): δ 1.06 (t, J = 7.4 Hz, 3H), 2.56 ( q, J = 7.3 Hz, 2H), 3.34- 3.41 (m, 2H), 3.49 (t, J = 8.8 Hz, 1 H), 3.81-3.88 (m, ,3H), 3.92-3.99 (m, 1 H), 4.05 (d, J = 9.3 Hz, 1 H), 4.16 (s, 4H), 4.20-4.25 (m, 1 H), 6.54 (m, 2H), 6.67 (d, J = 7.8 Hz, 1 H), 7.12-7.21 (m, 3H). MS (ES) m/z 497.1 (M+1 ) for phosphoric acid.

PATENT

SEE INDIAN PATENT

IN 2009DE02173

Glycoside derivatives and uses thereof

REFERENCES

Pediatric investigation plan (PIP) decision: (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2:1) ( LIK066) (EMEA-001527-PIP01-13)
European Medicines Agency (EMA) Web Site 2014, July 24

Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) assessment of LIK066 in healthy subjects and in patients with type 2 diabetes mellitus (T2DM) (NCT01407003)
ClinicalTrials.gov Web Site 2011, August 07

WO2012140597

WO2011048112

IN 2009DE02173

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INVENTORS OF LIK 066

BEBERNITZ, Gregory, Raymond; (US).
BOCK, Mark, G.; (US).
REDDY, Dumbala Srinivas; (IN).
HAJARE, Atul Kashinath; (IN).
VYAVAHARE, Vinod; (IN).
BHOSALE, Sandeep Bhausaheb; (IN).
KURHADE, Suresh Eknath; (IN).
SALUNKHE, Videsh; (IN).
SHAIKH, Nadim, S.; (IN).
BHUNIYA, Debnath; (IN).
PALLE, P., Venkata; (IN).
FENG, Lili; (US).
LIANG, Jessica; (US)

Mark G Bock

BEBERNITZ, Gregory, Raymond….PIC NOT AVAILABLE

Image result for SRINIVASAREDDY NCL

Dr. Srinivasa Reddy

NADEEM SHAIKH

Venkata Palle

ONLY FEW…………………….

//////Licogliflozin diprolinate

see……..http://medcheminternational.blogspot.in/2015/11/lik-066-novartis-for-treatment-of-type.html

EV 077

November 16, 2015 4:47 am / Leave a comment

EV-077

SER 150 (formerly EV-077)

Also known as: formerly EV-077-3201

EV-077-3201-2TBS

CAS 1384128-29-3

Evolva INNOVATOR

Evolva Sa

Oral thromboxane receptor antagonist and thromboxane synthase inhibitor

EV-077 is a small compound being developed for the treatment of complications of diabetes. In Phase 2. Outlicensed to Serodus in 2013.

In 2013, Serodus licensed the product candidate for the treatment of diabetic nephropathy and it is conducting phase II clinical trials on this research.

EV-077 is an oral, small molecule compound, belonging to a new structural class. Preclinical and early clinical studies indicate EV-077 has potential in reducing vascular inflammation by inhibiting the activity of prostanoids and isoprostanes – in particular in diabetes. Towards the end of 2011, the Russian Patent Office granted patent protection for EV-077 in the treatment of complications of diabetes for a term extending to 2026. Evolva has outlicenced EV-077 to Serodus in 2013. Serodus aims to bring EV-077 further through clinical development and at a future time point decide whether Serodus or a partner will conduct the final clinical trials.

EV-077 is in development as a potential pharmaceutical for the treatment of diabetic nephropathy and other diabetic complications. It is in Phase II clinical studies.

In 2013, Evolva out-licensed EV-077 to Serodus (Oslo, Norway). Serodus aims to bring EV-077 through Phase II and then decide whether or not to partner for the final clinical trials and commercialisation. Evolva is entitled to clinical and regulatory milestones as well as a single-digit royalty on sales. If Serodus sublicenses EV-077 then Evolva will receive up to 30% of Serodus’ total licensing income.

As of Q2 2015 Serodus continues active development of EV-077.

– See more at: http://www.evolva.com/ev-077/#sthash.4mgJ3E0f.dpuf

Patients with diabetes mellitus (DM) have increased propensity to generate thromboxane A2 (TXA2) and other eicosanoids which can contribute to their heightened platelet reactivity. EV-077 is a potent thromboxane receptor antagonist and thromboxane synthase inhibitor and thus represents an attractive therapy in patients with DM. However, the effects of EV-077 on pharmacodynamic (PD) profiles in patients with DM and coronary artery disease (CAD) while on antiplatelet therapy is poorly explored and represented the aim of this in vitro pilot investigation. Patients with DM and stable CAD (n = 10) on low-dose aspirin (81 mg/day) were enrolled and then switched to clopidogrel (75 mg/day) monotherapy for 7-10 days. PD assessments were conducted while on aspirin and on clopidogrel using light transmittance aggregometry following stimuli with U-46619 [TXA2 stable analogue (7 μM)], arachidonic acid [AA (1 mM)], collagen (3 μg/mL) and adenosine diphosphate [ADP (5 μM and 20 μM)] with and without in vitro EV-077. EV-077 completely inhibited U-46619-stimulated platelet aggregation (p = 0.005 for both aspirin and clopidogrel) and also showed a significant reduction of collagen-induced aggregation (aspirin p = 0.008; clopidogrel p = 0.005). EV-077 significantly reduced AA-induced platelet aggregation in clopidogrel (p = 0.009), but not aspirin (p = 0.667) treated patients. Ultimately, EV-077 significantly reduced ADP-mediated platelet aggregation in both aspirin (ADP 5 μM p = 0.012; ADP 20 μM p = 0.032) and clopidogrel (ADP 5 μM p = 0.007; ADP 20 μM p = 0.008) treated patients. In conclusion, in DM patients with CAD on aspirin or clopidogrel monotherapy, in vitro EV-077 exerts potent platelet inhibitory effects on multiple platelet signaling pathways. These data support that EV-077 has only additive platelet inhibiting effects on top of standard antiplatelet therapies. These findings warrant further investigation in ex vivo settings.

Description

EV-077 is a small compound being developed for the treatment of complications of diabetes. In Phase 2. Outlicensed to Serodus in 2013.

Situation Overview

Diabetes and its complications are major global health care problems. Based on estimates by the International Diabetes Federation (IDF), there were 366 million diabetics worldwide in 2011, a number which is expected to increase to 552 million by 2030. IDF estimates the number of deaths in 2011 at 4.6 million and total spending on diabetic health care at USD 465 billion.

EV-077 is an oral, small molecule compound, belonging to a new structural class. EV-077 is being developed for the reduction of vascular inflammation by inhibiting the activity of prostanoids and isoprostanes �� in particular in diabetes. Towards the end of 2011, the Russian Patent Office granted patent protection for EV-077 in the treatment of complications of diabetes for a term extending to 2026. Additional patent applications are pending in all major territories. Evolva has outlicenced EV-077 to Serodus in 2013.

Mechanism of Action

Preclinical and early clinical studies indicate EV-077 has potential in reducing vascular inflammation by inhibiting the activity of prostanoids and isoprostanes in particular in diabetes. The mechanism of action of EV-077 means that it can potentially ameliorate or prevent a range of diabetic complications (including loss of kidney function, reduced peripheral blood flow and increased risk of thrombosis) that derive from the following chain of events:

Diabetic patients have a reduced sensitivity to insulin which increases overall glucose levels in the body;
This increase in glucose increases oxidative stress;
The oxidative stress generates a high level of isoprostanes and prostanoids;
The isoprostanes and prostanoids chronically activate thromboxane prostanoid receptors, that are located on the walls of blood vessels (endothelial cells and smooth muscle cells) and the surface of platelets;
Activation of the thromboxane prostanoid receptors causes vascular inflammation and increased platelet reactivity;
An increased number of vascular events and a progressive deterioration of circulatory and renal function.

Clinical Trials

In November 2011, Evolva received regulatory clearance to progress EV-077 into Phase IIa clinical studies for the treatment of complications of diabetes. It is a single-centre study, conducted in Germany. The study was a randomized, double-blind, and placebo-controlled, and investigated the efficacy and safety of EV-077 in type 2 diabetics with a heightened risk of diabetic vascular complications. Measurements included blood flow and platelet reactivity, biomarkers for oxidative stress and vascular inflammation as well as markers of the function of organs that are often impaired in diabetes (e.g. kidney).

In May 2012, the study was terminated. Interim results for the first 32 patients enrolled in the Phase IIa study show promising efficacy data, indicating that 300mg EV-077 given orally twice daily to patients with type 2 diabetes provided anti-platelet activity, reduced exercise-induced proteinuria and increased forearm blood flow. This was achieved with only a slight increase in bleeding time. The analysis also indicated that EV-077 was generally well tolerated, with adverse events mostly limited to increases in liver enzymes, which were transient or resolved after discontinuation.

In parallel with the Phase IIa study, Evolva is conducting epidemiological studies to identify high risk diabetic patient subgroups that can potentially derive particular benefit from the administration of EV-077. Given success, this is expected to expedite both further clinical development (by reducing the size and duration of late stage clinical trials) and the eventual approval process.

Partners by Region

Evolva has outlicensed EV-077 to Serodus in 2013. Serodus aims to bring EV-077 further through clinical development and at a future time point decide whether Serodus or a partner will conduct the final clinical trials.

WO 2014011273

http://www.google.com/patents/WO2014011273A2?cl=en

Journal of Thrombosis and Haemostasis (2011), 9(10), 2109-2111

Thrombosis Research (2012), 130(5), 746-752

European Journal of Clinical Pharmacology (2013), 69(3), 459-465

Biochemical and Biophysical Research Communications (2013), 441(2), 393-398

Journal of Thrombosis and Thrombolysis (2014), 37(2), 131-138

http://www.google.co.in/patents/WO2008089461A1?cl=en

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid has the 3 groups all up, which has a dramatic effect on its biological activities:

see

WO 2011057262

/////////////// SEE……..http://drugsynthesisint.blogspot.in/2015/11/ev-077.html

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

November 10, 2015 3:37 pm / Leave a comment

Figure imgf000004_0001

GENERAL STRUCTURE

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……….. Glitter Glitter Glitter Glitter

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

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:

Scheme 3:

Scheme 4A:

Figure imgf000021_0001

Scheme 4B.

] Scheme 5 A:

Scheme 5B:

Scheme 6:

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 (CDCl_3, 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 N_2(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 N_2(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.

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.

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.

https://endo.confex.com/endo/2014endo/webprogram/Paper17991.html

LB-PP02-4

ZYDPLA1, a Novel Long-Acting DPP-4 Inhibitor

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

Late-Breaking Abstracts
LBSU 1074-1087-Diabetes & Obesity
Translational

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.

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

GKM 001 in pipeline for Diabetes by Advinus

November 10, 2015 12:55 pm / 1 Comment on GKM 001 in pipeline for Diabetes by Advinus

SEE WO2012020357

HIGH PROBABLITY COMPD.…..4-{2-[2-Cyclopentyloxy-2-(4-cyclopropanesulfonyl-phenyl)-acetylamino]- thiazol-5-yloxy}-benzoic acid, cas 1359151-08-8, 542.62, C₂₆ H₂₆ N₂ O₇ S₂

GKM 001……Several probables

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

Advinus Therapeutics Private L,

A glucokinase activator for treatment of type II diabetes

In October 2012, Takeda and Advinus have entered into an agreement to initiate a three-year discovery collaboration program focused on novel targets for inflammation, CNS, and metabolic diseases.

Company	Advinus Therapeutics Ltd.
Description	Activator of glucokinase (GCK; GK)
Molecular Target	Glucokinase (GCK) (GK)
Mechanism of Action	Glucokinase activator
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase I/II
Standard Indication	Diabetes
Indication Details	Treat Type II diabetes

Advinus chief executive officer/MD Dr. Rashmi Barbhaiya.

PATENT

https://www.google.co.in/patents/WO2009047798A2?cl=en

Example Cl : (-)-{5-ChIoro-2-[2-(4-cyclopropanesulfonylphenyI)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}-acetic acid, ethyl ester

Step I: Preparation of (-)-(4-Cyclopropanesulfonylphenyl)-(2,4- difluorophenoxy)acetic acid (Cl-I):

To a solution of (4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (obtained in example Al -step III) in ethyl acetate was added (S)-(-)-l-phenylethylamine drop wise at -15 °C. After completion of addition the reaction was stirred for 4-6 hours. Solid was filtered and washed with ethyl acetate. The solid was then taken in IN HCl and extracted with ethyl acetate, ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain (-)-(4- cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid. Enantiomeric enrichment was done by repeating the diasteriomeric crystallization. [α]²³ ₅₈₉ = – 107.1 ° (c = 2%Chloroform) Enantiomeric purity > 99. % (chiral HPLC)

Step II: (-)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetyIamino]thiazol-4-yl}-acetic acid ethyl ester : To a solution of (-)-4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (Cl-I) in DCM, was added DMF and cooled to 0 °C, followed by the addition of oxalyl chloride under stirring. Stirring was continued for 1 hour at the same temperature. The resulting mixture was further cooled to -35 °C, and to that, a solution of excess (2- amino-5-chlorothiazol-4-yl)acetic acid ethyl ester in DCM was added drop wise. After completion of reaction, the reaction mixture was poured into IN aqueous HCl under stirring, organic layer was washed with IN HCl, followed by 5% brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by preparative TLC to get the title compound. [α]²³ ₅89 = – ve (c = 2%Chloroform)

¹H NMR(400 MHz, CDCl₃): δ 1.06-1.08 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.33-1.38 (m, 2H), 2.42-2.50 (m, IH), 3.73 (d, J=2 Hz, 2H), 4.22 (q, J=7.2 Hz ,2H), 5.75 (s, IH), 6.76- 6.77 (m, IH), 6.83-6.86 (m, IH), 6.90-6.98 (m, IH), 7.73 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 9.96 (bs, IH). MS (EI) m/z: 571.1 and 573.1 (M+ 1; for ³⁵Cl and ³⁷Cl respectively).

Examples C2 and C3 were prepared in analogues manner of example (Cl) from the appropriate chiral intermediate:

Example Dl : (+)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}acetic acid, ethyl ester

Preparation of (+)-(4-Cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (Dl-I):

To a solution of (4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (obtained in example Al -step III) in ethyl acetate, was added (R) (+)-l- phenylethylamine drop wise at -15 °C. After completion of addition the reaction was stirred for 4-6 hours. Solid was filtered and washed with ethyl acetate. The solid was then taken in IN HCl and extracted with ethyl acetate, ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain (+)-(4-Cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid. Enantiomeric enrichment was done by repeating the diasteriomeric crystallization. [α]²³ ₅₈₉ = +93.07° (c = 2%Chloroform) Enantiomeric purity > 99. % (by chiral HPLC)

(+)-(4-CyclopropanesuIfonylphenyI)-(2,4-difluorophenoxy)acetic acid ethyl ester (Dl)

The example Dl was prepared using (+)-4-cyclopropanesulfonylphenyl)-(2,4- difluorophenoxy)acetic acid (Dl-I), and following the same reaction condition for amide coupling as described in example Cl, [ot]²³ ₅89 = + ve (c = 2%Chloroform)

PATENT

https://www.google.co.in/patents/WO2008104994A2?cl=en

Synthesis Type-P

Example Pl : {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)- propionylamino]-thiazol-4-yI}-acetic acid

To a solution of {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl- phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (0.03 g, 0.05 mmol) in THF: Ethanol: water ( ImI + 0.3ml + 0.3 ml) was added lithium hydroxide (0.0046 g, 0.11 mmol). The resulting mixture was stirred for 5 hours at room temperature followed by removal of solvent under reduced pressure. The residue was suspended in water (15 ml), extracted with ethyl acetate to remove impurities. The aqueous layer was acidified with IN HCl (0.5 ml) and extracted with ethyl acetate (2×10 ml), This ethyl acetate layer was washed with water (15 ml), brine (20 ml), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to give solid product {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4- methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl} -acetic acid (9 mg). ¹H NMR (400 MHz, CDCl₃): δ 1.85 (s, 3H) , 3.07 (s, 3H) , 3.72 ( s, 2H), 6.64-6.69 ( m, 2H ) , 6.89-6.91 (m, IH ), 7.84 ( d, J – 8.4 Hz, 2H), 8.00 ( d, J = 8.8 Hz, 2H). MS (EI) mlz: 530.70 (M + 1), mp: 109-111 ⁰C.

Preparation of {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)- propionylamino)-thiazol-4-yl}-acetic acid methyl ester used in Example Pl:

To a mixture of 2-(2, 4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid (0.110 g, 0.22 mmol), (2-Amino-5-chloro-thiazol-4-yl)-acetic acid methyl ester (0.071 g, 0.32 mmol), HOBt (0.052g, 0.38 mmol), and EDCI (0.074 g, 0.38 mmol) in methylene dichloride (10 ml) was added N-methylmorpholine (0.039 g, 0.38 mmol). The resulting mixture was stirred at room temperature for overnight followed by dilution with 10 ml methylene dichloride. The reaction mixture was poured onto water (20 ml), and organic layer separated, washed with water (2x 20 ml), brine (20 ml), dried over sodium sulfate and solvent evaporated to get residue which was purified by preparative TLC using 50% ethyl acetate in hexane as mobile. To give desired compound (0.30 g). ¹H NMR (400 MHz, CDCl₃): δ 1.45 (t, J = 7.2 Hz, 3H), 1.93 (s, 3H), 3.14 (s, 3H), 3.77 (d, J = 2.8 Hz, IH), 4.26 (q, J = 7.2 Hz, IH), 6.69-6.77(m, 2H), 6.96-7.02 (m, IH), 7.89 (d, J = 8.4 Hz, 2H), 8.07 (d, J= 8.4Hz, IH).; MS (EI) m/z: 559 .00 (M + 1).

PATENT

http://www.google.com/patents/WO2012020357A1?cl=en

4-{2-[2-Cyclopentyloxy-2-(4-cyclopropanesulfonyl-phenyl)-acetylamino]- thiazol-5-yloxy}-benzoic acid, cas 1359151-08-8

Ethyl ester 1359153-10-8

acid cas 1359153-12-0

Step I: (4-Cyclopropylsulfanyl-phenyl)-oxo-acetic acid ethyl ester:

A1C1₃ (7.98 g, 48.42 mmole) was suspended in DCM (50 mL) and cooled to 0 C under argon atmosphere. To this suspension was added chlorooxo ethylacetate (4.5 mL, 39.98 mmol) at 0 °C and stirred for 45 min. followed by addition of a solution of cyclopropylsulfanyl-benzene (5 g, 33.28 mmol) in DCM (10 mL) and stirred at 25 °C for 2 hr. Reaction mixture was slowly poured over crushed ice, organic layer was separated and aqueous layer was extracted with DCM (3 X 50 mL), combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (4- cyclopropylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (3.1 g) as an oily product.

*H NMR (400 MHz, CDC1₃): δ 0.72-0.73 (m, 2H), 1.15-1.17 (m, 2H), 1.40 (t, J = 6.6 Hz, 3H), 2.18-2.21 (m, 1H), 4.41 (q, J = 6.8 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H); MS (EI) m/z: 250.9 (M+l).

Step II: (4-Cyclopropanesulfonyl-phenyl) oxo acetic acid ethyl ester:

(4-Cyclopropylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (3.1 g, 12.53 mmole) in DCM (50 mL) was cooled to 0-5 °C followed by addition of mCPBA (9.8 g , 31.33 mmol) in portion wise at 0 °C. After stirring at 25 °C for 4 hr, the reaction mixture was filtered; filtrate was washed with saturated aq. Na₂S203 and satd. aq. sodium bicarbonate solution followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (4-cyclopropanesulfonyl-phenyl) oxo acetic acid ethyl ester (3 g).

*H NMR (400 MHz, CDC1₃): δ 1.05-1.10 (m, 2H), 1.36-1.39 (m, 2H), 1.40 (t, J = 6.8 Hz, 3H), 2.45-2.50 (m, 1H), 4.42 (q, J = 7.2 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H); MS (EI) m/z: 297.1 (M+NH₄).

Step III: p-Toluene sulfonyl hydrazone (4-cyclopropyl sulfonyl) phenyl acetic acid ethyl ester:

A mixture of (4-cyclopropanesulfonyl-phenyl) oxo acetic acid ethyl ester (0.5 g, 1.77 mmole) and p-toluene sulfonyl hydrazide (0.48 g , 2.3 mmol) in toluene (15 mL) was refluxed for 16 hr using a Dean-Stark apparatus. Reaction mixture was concentrated to give the crude product which was purified by column chromatography over silica gel using 20-25% ethyl acetate in hexane as eluent to provide p-toluene sulfonyl hydrazone (4-cyclopropyl sulfonyl) phenyl acetic acid ethyl ester (0.5 g).

MS (EI) m/z 451.0 (M+l).

Step IV: (4-Cyclopropanesulfonyl-phenyl) diazo acetic acid ethyl ester:

To a solution of p-toluene sulfonyl hydrazone (4-cyclopropyl sulfonyl) phenyl acetic acid ethyl ester (0.5 g, 1.23 mmol) in dry DCM (6 mL), was added triethylamine (0.17 mL, 1.35 mmol) and stirred at 25 °C for 1 hr. Reaction mixture was concentrated to provide (4- cyclopropanesulfonyl-phenyl) diazo acetic acid ethyl ester (0.5 g) which was used in next reaction without any purification.

MS (EI) m/z: 295.1 (M+l).

Step V: Cyclopentyloxy-(4-cyclopropanesulfonyl-phenyl)-acetic acid ethyl ester:

(4-Cyclopropanesulfonyl-phenyl) diazo acetic acid ethyl ester (1 g, 3.37 mmol) was dissolved in DCM (16 mL) under argon atmosphere. To this solution, cyclopentanol (0.77 mL, 8.44 mmol) was added followed by rhodium(II)acetate dimer (0.062 g, 0.14 mmol). Mixture was stirred at 25 C for 12 hr. Reaction mixture was diluted with DCM (25 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by column chromatography using 25-35% ethyl acetate in hexane as eluent to provide cyclopentyloxy-(4- cyclopropanesulfonyl-phenyl)-acetic acid ethyl ester (0.35 g).

*H NMR (400 MHz, CDC1₃): δ 1.02-1.05 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H), 1.35-1.37 (m, 2H), 1.53-1.82 (m, 8H), 2.42-2.50 (m, 1H), 4.02-4.04 (m, 1H), 4.15-4.22 (m, 2H), 5.00 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H); MS (EI) m/z: 370.0 (M+18).

Step VI: Cyclopentyloxy-(4-cyclopropanesulfonyl-phenyl)-acetic acid:

To cyclopentyloxy-(4-cyclopropanesulfonyl-phenyl)-acetic acid ethyl ester (0.35 g, 0.99 mmol) was added a solution of lithium hydroxide (0.208 g, 4.97 mmol) in water (4 mL) followed by THF (2 mL) and methanol (1 drop) and stirred for 12 hours at 25 ⁰ C. Organic solvents were evaporated from the reaction mixture and aqueous layer was acidified IN HCl, extracted with ethyl acetate (3 X 10 mL), organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide cyclopentyloxy-(4- cyclopropanesulfonyl-phenyl)-acetic acid (0.210 g).

*H NMR (400 MHz, CDC1₃): δ 1.02-1.07 (m, 2H), 1.34-1.38 (m, 2H), 1.55-1.62 (m, 2H), 1.69- 1.82 (m, 6H), 2.43-2.47 (m, 1H), 4.08-4.10 (m, 1H), 5.02 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H); MS (EI) m/z: 342.0 (M+18)

Example Al: 4-{2-[2-Cyclopentyloxy-2-(4-cyclopropanesulfonyl-phenyl)-acetylamino]-

To a mixture of cyclopentyloxy-(4-cyclopropanesulfonyl-phenyl)-acetic acid (Preparation 1) (0.1 g, 0.30 mmol), 4-(2-Amino-thiazol-5-yloxy)-benzoic acid methyl ester (0.085 g, 0.33 mmol), HOBt (0.045 g, 0.33 mmol), and EDCI (0.063 g, 0.33 mmol) in DCM (5 mL), was added N-methyl morpholine (0.033 g, 0.30 mmol). The resulting mixture was stirred at room temperature overnight followed by dilution with methylene chloride (20 mL). The reaction mixture was poured into water; organic layer was washed with water, brine, dried over sodium sulfate, and the organic solvent evaporated to get a residue which was purified by preparative TLC to provide the title compound (0.145 g).

*H NMR (400 MHz, CDC13): δ 1.03-1.05 (m, 2H), 1.34-1.38 (m, 2H), 1.58- 1.65 (m, 2H), 1.76- 1.81 (m, 6H), 2.42-2.45 (m, 1H), 3.89 (s, 3H), 4.05-4.15 (m, 1H), 5.08 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 7.15 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 9.72 (s, 1H); MS (EI) m/z: 556.9 (M + 1).

Example Bl: 4-{2-[2-Cyclopentyloxy-2-(4-cyclopropanesulfonyl-phenyl)-acetylamino]- thiazol-5-yloxy}-benzoic acid:

4-{2-[2-Cyclopentyloxy-2-(4-cyclopropanesulfonyl-phenyl)-acetylamino]-thiazol-5-yloxy}- benzoic acid methyl ester (0.145 g, 0.26 mmol, obtained in example Al) was taken in H₂0: THF (1 :2, 6 mL) to it was added MeOH (1 drop) followed by LiOH (0.054 g, 1.30 mmol) and stirred for 12 hr. After completion of the reaction, organic solvent was removed under reduced pressure. The aqueous layer was washed with diisopropyl ether then acidified with 1 N HC1 to pH 4. The solid formed was filtered, washed with water, diisopropyl ether & dried under vacuum to get the title_compound (0.12 g).

IH NMR- (400 MHz DMSO-ifc):- δ 1.01-1.05 (m, 2H), 1.09-1.13 (m, 2H), 1.22-1.49 (m, 2H), 1.59-1.73 (m, 6H), 2.82-2.86 (m, IH), 3.99-4.01 (m, IH), 5.31 (s, IH), 7.16 (d, J = 8.4 Hz, 2H), 7.37 (s, IH), 7.74 (d, J = 8.4 Hz, 2H), 7.91 (m, 4H), 12.55 (br. s, IH), 12.90 (br.s, IH); MS (EI) m/z: 542.9 (M+l)

CLIPPINGS

Advinus’ GK-activator Achieves Early POC for Diabetes

November 29 2011

Partnership Dialog Actively Underway

Advinus Therapeutics, a research-based pharmaceutical company founded by globally experienced industry executives and promoted by the TATA Group, announced that it has successfully completed a 14-day POC study in 60 Type II diabetic patients on its lead molecule, GKM-001, a glucokinase activator. The results of the trial show effective glucose lowering across all doses tested without any incidence of hypoglycemia or any other clinically relevant adverse events.

The clinical trials on GKM-001 validate the company’s pre-clinical hypothesis that a liver selective Glucokinase activator would not cause hypoglycemia (very low blood sugar), while showing robust efficacy.

“GKM-001 is differentiated from most other GK molecules that are in development, or have been discontinued, due to its novel liver selective mechanism of action. GKM-001 has a prolonged pharmacological effect and a half-life that should support a once a day dosing as both mono and combination therapy.” said Dr. Rashmi Barbhaiya, MD & CEO, Advinus Therapeutics. He added that Advinus is actively exploring partnership options to expedite further development and global marketing of GKM-001.

GKM-001 belongs to a novel class of molecules for treatment of type II diabetes. It is an activator of Glucokinase (GK), a glucose-sensing enzyme found mainly in the liver and pancreas. Being liver selective, GKM-001 mostly activates GK in the liver and not in pancreas, which is its key differentiation from most competitor molecules that activate GK in pancreas as well. The resulting increase in insulin secretion creates a potential for hypoglycemia-a risk GKM-001 is designed to avoid. Advinus has the composition of matter patent on GKM-001 for all major markets globally. Both the Single Ascending Dose data, in healthy and type II diabetics, and the Multiple Ascending Dose Study in Type II diabetics has shown that the molecule shows effective glucose lowering in a dose dependent manner and has excellent safety and tolerability profile over a 40-fold dose range. The pharmacokinetic properties of the molecule support once a day dosing. GKM-001 has the potential to be “First-in-Class” drug to address this large, growing and yet poorly addressed market.

Advinus also has identified a clinical candidate as a back-up to GKM-001, which is structurally different. In its portfolio, the company has a growing pipeline for COPD, sickle cell disease, inflammatory bowel disease, type 2 diabetes, acute and chronic pain and rheumatoid arthritis in various stages of late discovery and pre-clinical development.

About the Diabetes Market:

The present 300 million diabetics population is estimated to jump to 450 million by 2030 worldwide. A large proportion of these patients are poorly controlled despite multiple therapies. Total sales of diabetic prescription products were $32 billion in 2010.

Advinus Therapeutics team discovers novel molecule for treatment of diabetes

The first glucokinase modulator discovered and developed in India
A new concept for the management of diabetes for patients, globally
100 per cent ‘made in India’ molecule for the treatment of diabetes
IND approved by DGCI, Phase I clinical trial shows excellent safety and tolerance profiles with efficacy

Bangalore: Advinus Therapeutics (Advinus), the research-based pharmaceutical company founded by leading global pharmaceutical executives and promoted by the Tata group, today, announced the discovery of a novel molecule for the treatment of type II diabetes — GKM-001.The molecule is an activator of glucokinase; an enzyme that regulates glucose balance and insulin secretion in the body.

GKM-001 is a completely indigenously developed molecule and the initial clinical trials have shown excellent results for both safety and efficacy.

“Considering past failures of other companies on this target, our discovery programme primarily focused on identifying a molecule that would be efficacious without causing hypoglycaemia; a side effect associated with most compounds developed for this target.

“Recently completed Phase I data indicate that Advinus’ GKM–001 is a liver selective molecule that has overcome the biggest clinical challenge of hypoglycaemia. GKM-001 is differentiated from most other GK molecules in development due to this novel mechanism of action,” said Dr Rashmi Barbhaiya, MD and CEO, Advinus Therapeutics.

He further added, “We are very proud that GKM-001 is 100 per cent Indian. Advinus’s discovery team in Pune discovered the molecule and entire preclinical development was carried out at our centre in Bangalore. The Investigational New Drug (IND) application was filed with the DGCI for approval to initiate clinical trials in India within 34 months of initiation of the discovery programme. Subsequent to the approval of the IND, we have completed the Phase I Single Ascending Dose study in India within two months.”

GKM-001 is a novel molecule for the treatment of type II diabetes. It is the first glucokinase modulator discovered and developed in India and has potential to be both first or best in class. The success in discovering GKM-001 is attributed to the science-driven efforts in Advinus laboratories and ‘breaking the conventional mold’ for selection of a drug candidate. Advinus has ‘composition of matter’ patent on the molecule for all major markets globally. Glucokinase as a class of target is considered to be novel as currently there is no product in the market or in late clinical trials. The strategy for early clinical development revolved around assessing safety (particularly hypoglycaemia) and early assessment of therapeutic activity (glucose lowering and other biomarkers) in type II diabetics. The Phase I data, in both healthy and type II diabetics, shows excellent safety and tolerability over a 40-fold dose range and desirable pharmacokinetic properties consistent with ‘once a day’ dosing. The next wave of clinical studies planned continues on this strategy of early testing in type II diabetics.

Right behind the lead candidate GKM-001, Advinus has a rich pipeline of back up compounds on the same target. These include several structurally different compounds with diverse potency, unique pharmacology and tissue selectivity. Having discovered the molecule with early indication of wide safety margins, desired efficacy and pharmacokinetic profiles, the company now seeks to out-licence GKM-001 and its discovery portfolio.

Liver Selective Glucokinase Activation for Treating Type 2 Diabetes: Translation fromMouse to Man

Kasim A. Mookhtiar, , Debnath Bhuniya, Siddhartha De, Anita Chugh, Jayasagar

Gundu, Venkata Palle, Dhananjay Umrani, Nimish Vachharajani, Vikram

Ramanathan and Rashmi H. Barbhaiya

Advinus Therapeutics Ltd, Hinjewadi, Pune – 411057, and Peenya Industrial Area,

Bangalore – 560058, India

REFERENCES

http://www.asiabiotech.com/publication/apbn/14/english/preserved-docs/1410/0043_0043.pdf

http://www.thepharmatimes.in/index.php/news/general/national/268-advinus-gk-activator-achieves-early-poc-for-diabetes

http://ctri.nic.in/clinicaltrials/pmaindet2.php?trialid=2869

Patent

wo 2008104994

wo 2008 149382

wo 2009047798

US20100144772

WO2008104994A2 *	25 Feb 2008	4 Sep 2008	Advinus Therapeutics Private L	2,2,2-tri-substituted acetamide derivatives as glucokinase activators, their process and pharmaceutical application

WO2008104994A2 *	Feb 25, 2008	Sep 4, 2008	Advinus Therapeutics Private L	2,2,2-tri-substituted acetamide derivatives as glucokinase activators, their process and pharmaceutical application
WO2009047798A2 *	Oct 7, 2008	Apr 16, 2009	Advinus Therapeutics Private L	Acetamide derivatives as glucokinase activators, their process and medicinal applications

///////GKM 001, pipeline, Diabetes, Advinus, type II diabetes, glucokinase modulator, Rashmi Barbhaiya

Some pics

Annual day party at Advinus !!!with Rashmi Barbhaiya

Dr. Rashmi Barbhaiya, MD & CEO, Advinus Therapeutics Pvt.

with Kaushal Joshi, Vishal Pathade, Ramanareddy Jinugu, Mohammed Kakajiwala, Vishal Baxi and Dilip Reddy.

///////

CEP 18770, Delanzomib

November 8, 2015 1:44 pm / Leave a comment

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CEP-18770, Delanzomib

cas 847499-27-8

Chemical Formula: C21H28BN3O5

Exact Mass: 413.21220, UNII-6IF28942WO;

CT-47098
NPH 007098
NPH007098

[(1R)-1-[[(2S,3R)-3-Hydroxy-2-[[(6-phenylpyridin-2-yl)carbonyl]amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid

[(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid,

Boronic acid, ((1R)-1-(((2S,3R)-3-hydroxy-1-oxo-2-(((6-phenyl-2-pyridinyl)carbonyl)amino)butyl)amino)-3-methylbutyl)-

Cephalon, Inc.

In phase 2, multiple mylenoma, Ethical Oncology Science (EOS), licensee

CEP-18770 was discovered through collaboration between Cephalon and Novuspharma/CTI.

Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, and Cell Therapeutics Europe S.r.l., Via L. Ariosto, 23, I-20091 Bresso, Italy

Cephalon was acquired by Teva in October 2011. In 2013, EOS was acquired by Clovis Oncology.

Chemical Process Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States

CEP-18770 is a reversible P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Displays anti-multimyeloma (MM) effect.

HPLC………http://www.apexbt.com/downloader/document/A4009/HPLC.pdf

NMR………http://www.apexbt.com/downloader/document/A4009/NMR.pdf

CLICK ON IMAGE FOR CLEAR VIEW

Delanzomib, also known as CEP-18770, is An orally bioavailable synthetic P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome, with potential antineoplastic activity. Proteasome inhibitor CEP 18770 represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. The intracellular protein IkappaBalpha functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB

New series of dipeptidyl boronate inhibitors of 20S proteasome were identified to be highly potent drug-like candidates with IC₅₀ values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market

ref

Zhu Y, Zhao X, Zhu X, Wu G, Li Y, Ma Y, et al. Design, synthesis, biological evaluation, and structure−activity relationship (SAR) discussion of dipeptidyl boronate proteasome inhibitors, Part I: Comprehensive understanding of the SAR of á-amino acid boronates. J Med Chem. 2009;52:4192–4199. [PubMed]

Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: A link to clinical adverse events. Clin Cancer Res. 2011;17:2734–2743. [PubMed]

The potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[ [ (2S,3R)- 3-hydroxy-2-[ (6-phenylpyridine- 2-carbonyl) amino]-1 -oxobutyl] amino]- 3-methylbutyl] boronic acid (CEP-18770, has been reported

ref .

Dorsey BD, Iqbal M, Chatterjee S, Menta E, Bernardini R, Bernareggi A, et al. Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem. 2008;51:1068–1072. [PubMed]

Further, the anti-multiple myeloma protea-some inhibitor CEP-18770 enhanced the anti-myeloma activity of bortezomib and melphalan. The combination of anti-multiple myeloma proteasome inhibitor CEP-18770 intravenously and bortezomib exhibited complete regression of bortezomib-sensitive tumours. Moreover, this combination markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone

Paper

Development and scale-up of an optimized route to the peptide boronic acid, CEP-18770
Org Process Res Dev 2013, 17(3): 422

http://pubs.acs.org/doi/abs/10.1021/op400010u

USED AS PRODRUG

CEP-18770 is an unstable peptide boronic acid and an amorphous solid, making it a challenging synthetic target. Process R&D led to a new process that avoided chromatography through crystalline intermediates, increased atom and volume efficiency, provided a chromophore, and gave higher yields and purity. A stable, crystalline diethanolamine adduct was discovered that has the potential to be used as a prodrug.

Compound 8 proved to be a direct substitute for delanzomib in the formulation process. In the first step of the IV formulation process, delanzomib is dissolved in water along with several excipients. Predictably, the delanzomib degrades during this process. It was found that upon dissolution in the lyophilization medium, 8 hydrolyzes to delanzomib,

N-[(1S,2R)-1-[[[(1R)-1–1[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-6-phenyl-2-pyridinecarboxamide (5)

¹H NMR (400 MHz, DMSO-d₆) 8.98 (d,J = 2.99 Hz, 1H), 8.76 (d, J = 8.55 Hz, 1H), 8.2 (m, 3H), 8.11 (t, J = 7.71 Hz, 1H), 8.02 (d, J = 7.54 Hz, 1H), 7.54 (m, 3H), 5.26 (d, J = 4.95 Hz, 1H), 4.49 (dd, J = 4.22, 8.52 Hz, 1H), 4.13 (m, 2H), 2.6 (m, b, 1H), 2.19 (m, b, 1H), 2.02 (br m, 1H), 1.83 (t, J = 5.38 Hz, 1H), 1.75 (br s, 1H), 1.68 (br m, 1H), 1.62 (d, J = 13.9 Hz, 1H), 1.36 (d, J = 10.05 Hz, 1H), 1.3(br m, 3H), 1.22 (d, J = 11.65 Hz, 6H), 1.12 (d, J = 6.26 Hz, 3H), 0.84 (d, J = 6.57 Hz, 6H), 0.79 (s, 3H).

6-(2S,3R)-N-[(1R)-1-(1,3,6,2-dioxoazaborocan-2-yl)-3-methylbutyl]-3-hydroxy-2-[(6-phenylpyridin-2-yl)formamido]butanamide (8)

¹H NMR (400 MHz, DMSO-d₆) 8.8 (d, J = 8.52 Hz, 1H), 8.2 (m, 3H), 8.1 (t, J = 7.68 Hz, 1H), 8.0 (dd, J = 6.7, 0.9 Hz, 1H), 7.5 (m, 3H), 7.2 (br d, 1H), 6.5 (br t, 1H), 5.1 (d, J = 4.92 Hz, 1H), 4.5 (dd, 1H), 4.2 (m, 1H), 3.6 (m, 2H), 3.5 (m, 2H), 3.1 (m, 1H), 3.0 (m, 2H), 2.7 (m, 2H), 1.6 (m, 1H), 1.3 (m, 1H), 1.2 (m, 1H), 1.1 (d, J = 6.32 Hz, 3H), 0.8 (dd, J = 6.68, 6.53 Hz, 6H).

PAPER

Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer

Bruce D. Dorsey*^†, ^{ET AL}

Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, and Cell Therapeutics Europe S.r.l., Via L. Ariosto, 23, I-20091 Bresso, Italy

J. Med. Chem., 2008, 51 (4), pp 1068–1072

DOI: 10.1021/jm7010589

http://pubs.acs.org/doi/abs/10.1021/jm7010589

The ubiquitin−proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.

[(1R)-1-[[(2S,3R)-3-Hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic Acid (20)

¹H NMR (CD₃OD, 400 MHz) δ 8.17 (m, 2H), 8.13 (m, 1H), 8.05 (m, 2H), 7.5 (m, 3H), 4.75 (d, J = 3.04 Hz, 1H), 4.42 (dq, J = 6.4, 2.92 Hz, 1H), 2.77 (t, b, 1H), 1.61 (m, 1H), 1.35 (t, J = 7.48 Hz, 2H), 1.29 (d, J = 6.36 Hz, 3H), 0.89 (d, J = 6.52 Hz, 6H);

¹³C NMR (CD₃OD) δ 20.76, 22.64, 23.78, 27.17, 41.14, 57.19, 68.13, 121.93, 124.95, 128.16, 130.04, 131.18, 139.48, 140.24, 150.05, 157.79, 167.23, 177.43;

MS m/z 452 (M + K), 436 (M + Na), 396 (M − OH), 378, 352, 264.

HRMS (M + Na) Calcd: 435.2056. Found: 435.2057.

Anal. Calcd for C₂₁H₂₈BN₃O₅: C, 61.03; H, 6.83; N, 10.17%. Found: C, 63.22; H, 6.52; N, 10.17%.

Patent

http://www.google.com/patents/WO2010056733A1?cl=en

Preferred among these compounds is [(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid, also known as CEP- 18770, which has the following structure:

PATENT

http://www.google.co.in/patents/WO2005021558A2

NOT SAME BUT SIMILAR

Example E.4 Boronic acid, [(lR)-l-[[(2S,3R)-3-hydroxy-2-[[4-(3-pyridyl)benzoyl]amino]-l- oxobutyI]amino]-3-methyIbutyl].

[00275] A mixture of 4-(pyridin-3-yl)benzamide, N-[(1S,2R)-1-[[[(1R)-1-

[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-l,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]- of Example D.8.3 (155 mg, 0.283 mmol), 2-methylpropylboronic acid (81 mg, 0.793 mmol) and 2N aqueous hydrochloric acid (0.3 ml) in a heterogeneous mixture of methanol (3 ml) and hexane (3 ml) was stirred at room temperature for 24 hours. The hexane layer was removed and the methanolic layer was washed with fresh hexane (about 5 ml). Ethyl acetate (10 ml) was added to the methanol layer which was then concentrated. The residue was taken up with ethyl acetate and the mixture was concentrated. This step was repeated (2-3 times) until an amorphous white solid was obtained. The solid was then triturated with diethyl ether (5 ml) and the surnatant was removed by decantation. This step was repeated. The residue (126 mg) was combined with the product of a similar preparation (140 mg) and dissolved in ethyl acetate (about 40 ml) and a small amount of methanol (2-3 ml). The solution was washed with a mixture of NaCl saturated solution (7 ml) and 10% NaHCO₃ (2 ml). The layers were separated and the aqueous phase was further washed with ethyl acetate (2 x 20 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was taken up with ethyl acetate (about 20 ml) and the minimum amount of methanol, and then concentrated to small volume (about 5 ml). The resulting white was collected by filtration and dried under vacuum at 50°C (160 mg, 65% overall yield).

1H NMR (MeOH-d4): 8.90 (IH, s); 8.49 (IH, d, J=4.0); 8.20 (IH, d, J=8.1); 8.06 (2H, d, J=8.1); 7.85 (2H, d, J=8.1); 7.58 (IH, t br., J=6.0); 4.80 (IH, d, J=3.9); 4.40-4.29 (IH, m); 2.78 (IH, t, J=7.5); 1.73-1.61 (IH, m); 1.38 (2H, t, J=6.9); 1.31 (3H, d, J=6.3); 0.94 (6H, d, J=6.31). [00276] Further compounds prepared according to the above procedure for

Example E.4 are reported in Table E-4. Table E-4

E.4.3 IS THE COMPD

D.8.12 Chemical Name: 6-Phenyl-2-pyridinecarboxamide,N-[(lS,2R)-l-[[[(lR)- l-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-

THIS IS PRECURSOR OF FINAL PDT

methano-l,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: Η -NMR (DMSO-d6): 9.20-8.95 (IH, m); 8.76 (IH, d, J=8.55 Hz); 8.26-8.16 (4H, m); 8.12 (IH, t, J= 7.77 Hz); 8.02 (IH, d, J= 7.56 Hz); 7.60-7.47 (4H, m); 5.27 (IH, d, J= 4.97 Hz); 4.50 (IH, dd, J= 4.22 Hz, J= 8.50 Hz); 4.16-4.07 (2H, m); 2.65-2.56 (IH, m); 2.25-2.15 (IH, m); 2.09-1.98 (IH, m); 1.84 (IH, t, J= 5.62 Hz); 1.79- 1.73 (IH, m); 1.73-1.66 (IH, m); 1.66-1.59 (IH, m); 1.40-1.26 (4H, m); 1.23 (7H, d, J= 10.89 Hz); 1.15-1.10 (4H, m); 0.85 (7H, d, J= 6.56 Hz); 0.79 (IH, bs).

References

1. Fuchs, Ota. Proteasome inhibition as a therapeutic strategy in patients with multiple myeloma. Multiple Myeloma (2009), 101-125. CODEN: 69MVM2 AN 2010:737549

2. Genin, E.; Reboud-Ravaux, M.; Vidal, J. Proteasome inhibitors: recent advances and new perspectives in medicinal chemistry. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10(3), 232-256. CODEN: CTMCCL ISSN:1568-0266. CAN 152:516315 AN 2010:423458

3. Sanchez, Eric; Li, Mingjie; Steinberg, Jeffrey A.; Wang, Cathy; Shen, Jing; Bonavida, Benjamin; Li, Zhi-Wei; Chen, Haiming; Berenson, James R. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. British Journal of Haematology (2010), 148(4), 569-581. CODEN: BJHEAL ISSN:0007-1048. AN 2010:353952

4. Dick, Lawrence R.; Fleming, Paul E. \Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discovery Today (2010), 15(5/6), 243-249. CODEN: DDTOFS ISSN:1359-6446. AN 2010:318415

5. Ruggeri, Bruce; Miknyoczki, Sheila; Dorsey, Bruce; Hui, Ai-Min. The development and pharmacology of proteasome inhibitors for the management and treatment of cancer. Advances in Pharmacology (San Diego, CA, United States) (2009), 57(Contemporary Aspects of Biomedical Research: Drug Discovery), 91-135. CODEN: ADPHEL ISSN:1054-3589. AN 2010:62762

6. Chen-Kiang, Selina; Di Liberto, Maurizio; Huang, Xiangao. Targeting CDK4 and CDK6 kinases or genes thereof in cancer therapy for sensitizing drug-resistant tumors. PCT Int. Appl. (2009), 149pp. CODEN: PIXXD2 WO 2009061345 A2 20090514 CAN 150:531264 AN 2009:586623

7. Rickles, Richard; Lee, Margaret S. Use of adenosine A2A receptor agonists and phosphodiesterase (PDE) inhibitors for the treatment of B-cell proliferative disorders, and combinations with other agents. PCT Int. Appl. (2009), 70 pp. CODEN: PIXXD2 WO 2009011893 A2 20090122 CAN 150:160095 AN 2009:86451

8. Rickles, Richard; Pierce, Laura; Lee, Margaret S. Combinations for the treatment of B-cell proliferative disorders. PCT Int. Appl. (2009), 79pp. CODEN: PIXXD2 WO 2009011897 A1 20090122 CAN 150:160094 AN 2009:83374

9. Hoveyda, Hamid; Fraser, Graeme L.; Benakli, Kamel; Beauchemin, Sophie; Brassard, Martin; Drutz, David; Marsault, Eric; Ouellet, Luc; Peterson, Mark L.; Wang, Zhigang. Preparation and methods of using macrocyclic modulators of the ghrelin receptor. U.S. Pat. Appl. Publ. (2008), 178pp. CODEN: USXXCO US 2008194672 A1 20080814 CAN 149:288945 AN 2008:975261

10. Piva, Roberto; Ruggeri, Bruce; Williams, Michael; Costa, Giulia; Tamagno, Ilaria; Ferrero, Dario; Giai, Valentina; Coscia, Marta; Peola, Silvia; Massaia, Massimo; Pezzoni, Gabriella; Allievi, Cecilia; Pescalli, Nicoletta; Cassin, Mara; di Giovine, Stefano; Nicoli, Paola; de Feudis, Paola; Strepponi, Ivan; Roato, Ilaria; Ferracini, Riccardo; Bussolati, Benedetta; Camussi, Giovanni; Jones-Bolin, Susan; Hunter, Kathryn; Zhao, Hugh; Neri, Antonino; Palumbo, Antonio; Berkers, Celia; Ovaa, Huib; Bernareggi, Alberto; Inghirami, Giorgio. CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood (2008), 111(5), 2765-2775. CODEN: BLOOAW ISSN:0006-4971. CAN 149:486154 AN 2008:292777

11. Dorsey, Bruce D.; Iqbal, Mohamed; Chatterjee, Sankar; Menta, Ernesto; Bernardini, Raffaella; Bernareggi, Alberto; Cassara, Paolo G.; D’Arasmo, Germano; Ferretti, Edmondo; De Munari, Sergio; Oliva, Ambrogio; Pezzoni, Gabriella; Allievi, Cecilia; Strepponi, Ivan; Ruggeri, Bruce; Ator, Mark A.; Williams, Michael; Mallamo, John P. Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer. Journal of Medicinal Chemistry (2008), 51(4), 1068-1072. CODEN: JMCMAR ISSN:0022-2623. CAN 148:345774 AN 2008:146611

12. Dorsey, Bruce D.; Menta, Ernesto; Bernardini, Raffaella; Bernareggi, Alberto; Casara, Paolo G.; D’Arasmo, Germano; Ferretti, Edmondo; De Munari, Sergi; Oliva, Ambrogio; Iqbal, Mohamed; Chatterjee, Sankar; Ruggeri, Bruce; Ator, Mark A.; Williams, Michael; Mallamo, John P. CEP-18770: Discovery of a Potent, Selective and Orally Active Proteasome Inhibitor for the Treatment of Cancer. Frontiers in CNS and Oncology Medicinal Chemistry, ACS-EFMC, Siena, Italy, October 7-9 (2007), COMC-027. CODEN: 69KAR2 AN 2007:1171000

13. Marblestone Jeffrey G Ubiquitin Drug Discovery & Diagnostics 2009 – First Annual Conference. IDrugs : the investigational drugs journal (2009), 12(12), 750-3.

Patent	Submitted	Granted
Proteasome inhibitors and methods of using the same [US7576206]	2005-05-19	2009-08-18
PROTEASOME INHIBITORS AND METHODS OF USING THE SAME [US7915236]	2009-11-26	2011-03-29
BORONATE ESTER COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF [US2009325903]	2009-12-31

Citing Patent	Filing date	Publication date	Applicant	Title
US7442830 *	6 Aug 2007	28 Oct 2008	Millenium Pharmaceuticals, Inc.	Proteasome inhibitors
US7687662 *	2 Jul 2008	30 Mar 2010	Millennium Pharmaceuticals, Inc.	Proteasome inhibitors
US8003819 *	12 Feb 2010	23 Aug 2011	Millennium Pharmaceuticals, Inc.	Proteasome inhibitors
US8962572	4 Oct 2011	24 Feb 2015	Fresenius Kabi Usa, Llc	Bortezomib formulations
WO2012177835A1	21 Jun 2012	27 Dec 2012	Cephalon, Inc.	Proteasome inhibitors and processes for their preparation, purification and use

/////CEP-18770, delanzomib

B(C(CC(C)C)NC(=O)C(C(C)O)NC(=O)C1=CC=CC(=N1)C2=CC=CC=C2)(O)O

AN-2718, a New Borole in the pipeline

November 2, 2015 4:24 am / Leave a comment

AN-2718,

2,1-Benzoxaborole, 5-chloro-1,3-dihydro-1-hydroxy-

5-chloro-1,3-dihydro-l-hydroxy-2,1- benzoxaborole

5-Chloro-2,1-benzoxaborol-1(3H)-ol

CAS 174672-06-1
UNII: 810U6C2DGG

MW 168.3864, MF C7 H6 B Cl O2

MP…150-154 °C [WO 9533754]

MP 142-144 °C [ jmc 2006, 49(15) 447]

M.p. 147- 149 °C. WO2013050591

Anacor Pharmaceuticals Inc, INNOVATOR

Onychomycosis is a disease of the nail caused by yeast, dermatophytes, or other molds, and represents approximately 50% of all nail disorders. Toenail infection accounts for approximately 80% of onychomycosis incidence, while fingernails are affected in about 20% of the cases. Dermatophytes are the most frequent cause of nail plate invasion, particularly in toenail onychomycosis. Onychomycosis caused by a dermatophyte is termed Tinea unguium. Trichophyton rubrum is by far the most frequently isolated dermatophyte, followed by T. mentagrophytes. Distal subungual onychomycosis is the most common presentation of tinea unguium, with the main site of entry through the hyponychium (the thickened epidermis underneath the free distal end of a nail) progressing in time to involve the nail bed and the nail plate. Discoloration, onycholysis, and accumulation of subungual debris and nail plate dystrophy characterize the disease. The disease adversely affects the quality of life of its victims, with subject complaints ranging from unsightly nails and discomfort with footwear, to more serious complications including secondary bacterial infections.

Many methods are known for the treatment of fungal infections, including the oral and topical use of antibiotics (e.g., nystatin and amphotericin B), imidazole anti-fungal agents such as miconazole, clotrimazole, fluconazole, econazole and sulconazole, and non-imidazole fungal agents such as the allylamine derivatives terbinafme and naftifϊne, and the benzylamine butenafine. However, onychomycosis has proven to be resistant to most treatments. Nail fungal infections reside in an area difficult to access by conventional topical treatment and anti-fungal drugs cannot readily penetrate the nail plate to reach the infection sites under the nail. Therefore, onychomycosis has traditionally been treated by oral administration of anti-fungal drugs; however, clearly this is undesirable due to the potential for side effects of such drugs, in particular those caused by the more potent anti-fungal drugs such as itraconazole and ketoconazole. An alternative method of treatment of onychomycosis is by removal of the nail before treating with a topically active anti-fungal agent; such a method of treatment is equally undesirable. Systemic antimycotic agents require prolonged use and have the potential for significant side effects. Topical agents have usually been of little benefit, primarily because of poor penetration of the anti-fungal agents into and through the nail mass.

AN-2718 is a topical benzoxaborole compound that has a high level of nail penetrance [51]. Initial data have suggested that it may be more effective than tavaborole for T. rubrum and T. mentagrophytes [55]. It has recently completed Phase I clinical trials (NCT00781664) [56].

picked from

http://www.tandfonline.com/doi/full/10.1517/14656566.2012.681779

51. Hui X, Baker SJ, Wester RC, In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci 2007;96(10):2622-31 [CrossRef], [PubMed], [Web of Science ®]
55. Mao W, Seiradake E, Crepin T, AN2718 has Broad Spectrum Antifungal Activity Necessary for the Topical Treatment of Skin and Nail Fungal Infections. J Am Acad Dermatol 2007:56(2 Suppl):AB124
56. ClinicalTrials.gov. Cumulative Irritation Test. Available from: http://clinicaltrials.gov/ct2/show/NCT00781664 [Cited 11 December 2011]

SYNTHESIS

Reduction of 2-bromo-5-chlorobenzoic acid with BH3/THF in THF gives 2-bromo-5-chlorobenzyl alcohol , which is protected as the methoxymethyl derivative by treatment with MOM-Cl in the presence of DIEA in CH2Cl2. Metalation and boronylation of aryl bromide either with t-BuLi or BuLi (1,2,3,4) and (i-PrO)3B (4) or B(OMe)3 in THF affords the title compound .

Alternatively, reaction of 3-chlorobenzaldehyde with p-toluenesulfonylhydrazide in MeOH provides tosyl hydrazone which undergoes thermal decomposition in the presence of BBr3 and catalytic FeCl3 in refluxing CH2Cl2, followed by heating with aqueous NaOH to produce the title oxaborole compound .

You can construct from this…………….

OH A

(2-bromo-5-chloro-phenyl)methanol (A)

l-bromo-4-chloro-2-(methoxymethoxymethyl)benzene (B)

5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1)

PATENT

WO 9533754

https://www.google.com/patents/WO1995033754A1?cl=en

Example 1 Preparation of 5-chloro-1,3-dihydro-l-hydroxy-2,1- benzoxaborole (Method B).

Preparation of 3-chlorobenzaldehyde tosyl hydrazide

A solution of 3-chlorobenzaldehyde (15.56 parts; 0.109M;

Aldrich) in methylated spirits (40 ml) was added slowly at below 10°C to a stirred suspension of p-toluene-sulphonylhydrazide (20.7 parts;

0.108M) in methylated spirits (150 ml). The reaction mass was then stirred at 20 to 25°C for 1 hour and then heated at 60-70°C for 1M hours when the reactants and products dissolved. The solvent was then removed by rotary evaporation and the product was obtained as a solid which was slurried with ether and washed with n-hexane. Yield = 27.2 parts (81.5% theory) mpt 122-3°C. Elemental analysis

Theory 54.5%C; 4.2%H; 9.1%N

Found 54.5%C; 4.3%H; 9.1%N

Proton NMR (CDCl₃:ppm)

8.5, s, 1H(-NH-); 7.9, d, 2H(Tosyl aromatic); 7.7,s, 1H(CH=N); 7.5, s, 1H (aromatic); 7.2-7.4, m, 5H(Tosyl aromatic); 2.3, s, 3H(-CH₃) b) Preparation of title compound

A suspension of anhydrous ferric chloride catalyst (0.75 parts, Fisons) in dry dichloromethane (20 ml) was added at 20 to 25°C simultaneously with boron tribromide (25 parts, 0.1M, Aldrich) in dry dichloromethane (100 mis) to a stirred suspension of the hydrazide from a) above (10.18 part, 0.033M) in dry dichloromethane (160 mis) under a nitrogen blanket. The reactants were then stirred under reflux and the evolved hydrogen bromide trapped under aqueous sodium hydroxide. After 3 hours stirring at reflux, the reactants were allowed to stand at 20- 25°C for 48 hours and then stirred under reflux for a further 4 hours. The reaction mass was then cooled and the solvent removed by rotary evaporation. The solid obtained was then stirred under reflux with 2N sodium hydroxide solution (160 ml) for 3 hours. The brown aqueous suspension was extracted with dichloromethane (50 ml), screened and then acidified to about pH 2 by addition of 2N hydrochloric acid. The solid was filtered, slurried with dichloromethane (400 ml) and then washed with a saturated solution of sodium bicarbonate followed by water.

Yield = 24 parts (43% theory). The solid was slurried in hot

dichloromethane and filtered to give 0.36 parts oxaborole mp 140-45°C. The dichloromethane solution was cooled and the solid filtered giving a further 0.35 parts oxaborole mp 146-8°C. The solids were combined and recrystallised from methylated spirits.

Yield = 0.51 parts (9.2% theory) mp 150-4°C.

Elemental Analysis

Theory 49.8%C, 3.5%H, 21.06%C1

Found 49.5%C, 3.5%H, 21.0%C1

Proton NMR (CDCl₃) ppm

9.3, s, 1H(-OH); 7.5, d, s, d, 3H(aromatic);

5.0, s, 2H(-CH₂-O).

PATENT

WO 2006089067

http://www.google.co.in/patents/WO2006089067A2?cl=en

Analytical data for exemplary compounds of structure I are provided below.

4.2. a 5-Chloro-1.3-dihydro-l -hvdroxy-2J-benzoxaborole (Cl) M.ρ. 142-15O⁰C. MS (ESI): m/z = 169 (M+l, positive) and 167 (M-I, negative). HPLC (220 nm): 99% purity. ¹H NMR (300 MHz, DMSO-d₆): δ 9.30 (s, IH), 7.71 (d, J = 7.8 Hz, IH), 7.49 (s, IH), 7.38 (d, J = 7.8 Hz, IH) and 4.96 (s, 2H) ppm.

PAPER

J. Med. Chem., 2006, 49 (15), pp 4447–4450

DOI: 10.1021/jm0603724

http://pubs.acs.org/doi/abs/10.1021/jm0603724?source=chemport

COMPD IS 19d

5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (19d) This compound was made from 18d in the same manner as compound 19b (triturated with hexane, 75% yield):: mp 142-144°C. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 4.96 (s, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 9.30 (s, 1H); ESI-MS m/z 167 (M-H)- ; HPLC purity 99.0%; Anal (C7H6BClO2 ⋅ 0.1H2O) C, H

precursor 18d

2-Bromo-5-chloro-1-(methoxymethoxymethyl)benzene (18d) To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0o C and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10% NaOH (10 mL) was added. The mixture was concentrated and the residue was S6 mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88%): 1 H NMR (300 MHz, DMSO-d6): δ (ppm) 7.57 (d, J = 8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H). 2-Bromo-5-chlorobenzyl alcohol obtained above was dissolved in CH2Cl2 (150 mL) and cooled to 0o C on an ice bath. To this solution under nitrogen were added in sequence i-Pr2NEt (5.4 mL, 31 mmol) and chloromethyl methyl ether (2.0 mL, 26 mmol). The reaction mixture was stirred overnight at room temperature and washed with NaHCO3-saturated water and then brine. The residue after rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 18d (4.67 g, 85%) as a colorless oil: 1 H NMR (300 MHz, DMSO-d6): δ (ppm) 3.30 (s, 3H), 4.53 (s, 2H), 4.71 (s, 2H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (dd, J = 2.4, 0.6 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H).

PATENT

http://www.google.com/patents/WO2013050591A2?cl=en

EXAMPLES Example 1 : Preparation of 5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1)

Step 1 : Preparation of (2-bromo-5-chloro-phenyl)methanol (A)

A solution of borane-tetrahydrofuran complex in THF (0.15 L, 1.5 eq) was added dropwise to a solution of 2-bromo-5-chlorobenzoic acid (24 g) in anhydrous tetrahydrofuran (0.24 L) at 0°C and under argon atmosphere. The reaction mixture was stirred at room temperature for 16 h, before being slowly poured onto 0.10 L of a 2N aqueous solution of hydrogen chloride at 0°C. The mixture was stirred for 15 minutes and the volatiles were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a IN aqueous solution of sodium hydroxide and then water. After drying over sodium sulfate, filtration and concentration under reduced pressure, the crude product was purified by column chromatography; 23.2 g; M.p. 79-80 °C.

Step 2: Preparation of l-bromo-4-chloro-2-(methoxymethoxymethyl)benzene (B)

(2-bromo-5-chloro-phenyl)methanol (A, 12 g) was dissolved in dichloromethane (0.35 mL) and cooled to 0 °C. Under argon atmosphere, diisopropylethylamine (14 mL, 1.5 eq) and chloromethyl methyl ether (5.0 mL, 1.2 eq) were added. After 1 night of stirring at room temperature, the crude reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried over sodium sulfate and evaporated under reduced pressure. Purification by column chromatography afforded 10.5 g of l-bromo-4-chloro-2- (methoxymethoxymethyl)benzene (B) as an oil.

Step 3: Preparation of 5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1)

To a solution of (B) (6.0 g) in anhydrous tetrahydrofuran (120 mL) at -78°C was added dropwise a solution of butyllithium in hexane (15.6 mL, 1.1 eq). To the resulting yellow- brown solution trimethyl borate (2.5 mL, 1.0 eq) was injected in one portion and the cooling bath was removed. The mixture was warmed gradually for 30 minutes. After stirring at room temperature for 2 hours, 8.0 ml of a 6N aqueous solution of hydrogen chloride were added and the reaction mixture was left stirring overnight at room temperature. Evaporation of the volatiles gave a residue which was taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate and then evaporated. The crude product was crystallized from ethyl acetate to give 1.4 g of 5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1) as a white powder. Purification of the filtrate by column chromatography afforded 1.2 g more of 1. M.p. 147- 149 °C.

PATENT

http://www.google.fr/patents/WO2010110400A1?cl=en&hl=fr

Reference Example 187
5-chloro-2,1-benzoxazine ball roll -1 (3H) – All

5-chloro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde 8.50g synthesized in Reference Example 185 was dissolved in methanol 100ml, borohydride Sodium 2.40g was added, and after stirring for 30 minutes at room temperature and stirred for 2 hours at 60 ℃. The reaction solution was concentrated, and the organic layer after the layers were separated with ethyl acetate and saturated aqueous ammonium chloride and then concentrated under reduced pressure. The residue was added 100ml of tetrahydrofuran, and 6N hydrochloric acid 60ml, and stirred for 8 hours at room temperature.After the reaction mixture was dried and the organic layer was extracted with ethyl acetate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound 9.6g. ¹ H-NMR (400MHz, _{DMSO-d 6)} ^δ: 4.95 (2H, s), 7.36 (1H, dd, J = 8.0,1.6Hz), 7.47 (1H, s) , 7.70 (1H, d, J = 8.0Hz), 9.28 (1H, s).

PATENT

http://www.google.com/patents/WO2008070257A2?cl=en

5-Fluoro-l,3-dihvdro-l-hvdroxy-2, 1-benzoxaborole (Cl)

1-Hydroxy-dihydrobenzoxaboroles, such as Cl, were synthesized as shown in Scheme 1. The protected o-bromobenzyl alcohol derivative (18), prepared from 16 or 17, was converted into the corresponding phenyl boronic acid. Deprotection of the methoxymethyl ether using hydrochloric acid followed by spontaneous cyclization gave the target compounds.

Scheme 7

Conditions (a) NaBH₄, MeOH, rt (when X = H ), or BH₃-THF, THF, rt (when X = OH), (b) MeOCH₂CI, /-Pr₂NEt, CH₂CI₂, rt, (c) MeMgBr, THF, -78 ⁰C to rt , (d) NBS, AIBN, CCI₄, reflux, (e) NaOAc, DM F, 70 ⁰C, (f) NaOH, MeOH, reflux, (g) n-BuLι, (/-PrO)₃B, THF, -78⁰C to rt, (h) 6N HCI, THF, rt

References

Hui, Xiaoying; Journal of Pharmaceutical Sciences 2007, 96(10), Pg2622-2631
Baker, Stephen J.; Journal of Medicinal Chemistry 2006, 49(15), Pg4447-4450
Austin, Peter William; WO 9533754 A1 1995 CAPLUS

US5880188 *	26 May 1995	9 Mar 1999	Zeneca Limited	Oxaboroles and salts thereof, and their use as biocides
US6083903 *	16 May 1995	4 Jul 2000	Leukosite, Inc.	Boronic ester and acid compounds, synthesis and uses
WO2005013892A2	15 Jun 2004	17 Feb 2005	Tsutomu Akama	Hydrolytically-resistant boron-containing therapeutics and methods of use

Reference
1	*	Austin et al., 1996, CAS: 124:234024.
2	*	fungicide: definition from Answre.com, 1998.
3		S. J. Baker, et al., “Progress on New Therapeutics for Fungal Nail Infections,“Annual Reports in Medicinal Chemistry, 40:323-335 (2005).
4		Sudaxshina Murdan, “Drug Delivery to the Nail Following Topical Application,” International Journal of Pharmaceutics, 236:1-26 (2002).

see full series on boroles

http://apisynthesisint.blogspot.in/p/borole-compds.html

do not miss out

//////////AN-2718, Borole, PHASE 2

B1(c2ccc(cc2CO1)Cl)O

Voxtalisib, SAR-245409, XL-765

October 28, 2015 5:22 am / 1 Comment on Voxtalisib, SAR-245409, XL-765

Voxtalisib

SAR-245409, XL-765

2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

2-Amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride

C13 H14 N6 O . Cl H, 306.751

934493-76-2

INNOVATOR Exelixis Inc,, LICENSE SANOFI

PHASE 2, Malignant neoplasms

0.2H₂O

Mol. Formula:C₁₃H₁₄N₆O∙0.2H₂O, MW:273.9
NMR………http://www.chemietek.com/Files/Line2/CHEMIETEK,%20XL765,%20Lot%2001,%20NMR%20in%20CD3OD.pdf
Mechanism of Action:selective oral inhibitor of PI3K and mTOR Indication:Cancer Treatment Stage of Development: phase ll study in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). A phase I/II trial is assessing SAR245409 in combination with letrozole in ER/PR+ HER2- breast cancer.

SAR245409 (XL765)

SAR245409 (XL765) is an orally available inhibitor of PI3K and the mammalian target of rapamycin (mTOR), which are frequently activated in human tumors and play central roles in tumor cell proliferation. Exelixis discovered SAR245409 internally and out-licensed the compound to Sanofi. SAR245409 is being evaluated by Sanofi as a single agent and in multiple combination regimens in a variety of cancer indications. Clinical trials have included a single agent phase 2 trial in Non-Hodgkin’s lymphoma, combination phase 1b/2 trials with temozolomide in patients with glioblastoma, with letrozole in hormone receptor positive breast cancer, with bendamustine and/or rituximab in lymphoma or leukemia, and a phase 1 trial in combination with a MEK inhibitor.

SAR-245409 is an investigational drug originated by Exelixis that dually inhibits mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K).

Sanofi is also evaluating the compound in phase I/II clinical trials for the treatment of malignant neoplasm as monotherpay or in combination regimen. It has also completed phase I clinical trials as an oral treatment for brain cancer.

In 2009, the drug candidate was licensed to Sanofi (formerly known as sanofi-aventis) by Exelixis worldwide for the treatment of solid tumors.

XL765 (Voxtalisib, SAR245409, Sanofi)*, a PYRIDOPYRIMIDINONE-derivative, is a highly selective, potent and reversible ATP-competitive inhibitor of pan-Class I PI3K (α, β, γ, and δ) and mTORC1/mTORC2. It is orally active, highly selective over 130 other protein kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway.

In mouse xenograft models, oral administration of XL-765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects

PATENT

WO 2014058947

http://www.google.co.in/patents/WO2014058947A1?cl=en

Example 1. Synthesis of Compound (1)

Compound (1) can be synthesized as described in WO 07/044813, which is hereby incorporated in its entirety.

Briefly, a base and an intermediate, compound (a), are added to solution of commercially available 2-metfiyl-2-thiopseudourea sulfate in a solvent such as water and stirred overnight at room temperature. After neutralization, compound (b) is collected by filtration and dried under vacuum. Treatment of compound (b) with POCI₃ and heating at reflux for 2 hours yields compound (c) which can be concentrated under vacuum to dryness. Compound (c) can be used directly in the following reaction with ethylamine carried out in a solvent such as water with heating to give compound (d). Compound (d) is then treated with iodine monochloride in a solvent such as methanol to form compound (e). Compound (e) is then dissolved in DMA, to which ethyl acrylate, Pd(OAc)₂ and a base are added. This reaction mixture is heated and reacted overnight until completion of the reaction to give compound (f), which can be purified via column chromatography.

Compound (f) is then be treated with DBU in the presence of a base, such as DIEA, and heated at reflux for 15 hours. Upon completion of the reaction, the solvent is evaporated and the residue triturated with acetone to yield compound (g). Bromination of compound (g) can be achieved through drop-wise addition of Br₂ to compound (g) in CH₂C1₂, followed by stirring overnight at room temperature. Next, filtration is carried out, and triethylamine is added so that, upon washing and drying, the product, compound (h) is obtained. A Suzuki coupling between compound (h) and lH-pyrazol-5-yl boronic acid is carried out using a Pd- catalyst such as [1,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of a base to yield compound (i). Finally, compound (i) can be converted to compound (1) of the instant invention through 1) oxidation of the methylthio group with m-CPBA, carried out at room temperature with stirring and 2) treatment of the resulting product dissolved in dioxane, with liquid ammonia. Stirring at room temperature overnight followed by purification by column chromatography gives the desired product, 2-amino-8-ethyl-4-methyl- 6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, compound (1).

PATENT

WO 2007044813

http://www.google.co.in/patents/WO2007044813A1?cl=en

Example 1 2-amino-8-ethyl-4-methyl-6-(lJΪ-pyrazol-5-yl)pyrido[2,3-</]pyrimidin-7(8J?)-one

To a solution of 2-methyl-2-thiopseudourea sulfate (Aldrich, 58.74 g, 0.422 mol) in water (1000 mL) were added sodium carbonate (81.44 g, 0.768 mol) and ethyl acetoacetate (50 g, 0.384 mol) at room temperature. The reaction mixture was stirred overnight. After neutralizing to pH = 8, the solid was collected through filtration followed by drying under vacuum overnight to afford 6-methyl-2-(methylthio)pyrimidin-4(3H)-one (57.2 g, 95% yield) of product. ¹H NMR (400 MHz, DMSO-d6): δ 12.47 (bs, IH), 5.96 (bs, lH), 2.47(s, 3H), 2.17 (s, 3H).

To the round bottom flask containing 6-methyl-2-(methylthio)pyrimidin-4(3H)- one (19 g, 121.6 mmol) was added POCl₃ (30 mL). The reaction mixture was heated to reflux for 2 h and then concentrated on a rotary evaporator to dryness. The crude 4-chloro- 6-methyl-2-(methylthio)pyrimidine was used directly in the next reaction without further purification.

To the 4-chloro-6-methyl-2-(methylthio)pyrimidine from above was added 30 mL of a solution of 70% ethylamine in water. The reaction mixture was heated to 50 ⁰C for 3 h. After completion, excess ethylamine was evaporated on rotary evaporator under vacuum. The solid was filtered and dried under vacuum to afford 7V-ethyl-6-methyl-2- (methylthio)pyrimidin-4-amine (20 g, 90% yield).

To the solution of N-emyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 121.6 mmol) in methanol was added iodine monochloride (26.58 g, 163.7 mmol) in small portions at 0 °C. Then the reaction mixture was stirred overnight. After evaporation of solvent, the residue was triturated with acetone. The product iV-ethyl-5-iodo-6-methyl-2- (methylthio)pyrimin-4-amine (25.2 g, 75% yield) was collected by filtration. ¹H NMR (400 MHz, CDCl₃): δ 5.37 (bs, IH), 3.52 (q, J = 7.2 Hz, IH), 2.50 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).

To the solution of N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimin-4-amine (25.2 g, 81.48 mmol) in DMA (260 mL) were added ethyl acrylate (12.23 g, 122.2 mmol), Pd(OAc)₂ (3.65 g, 16.25 mmol), (+)BINAP and triethyl amine (24.68 g, 244.4 mmol). Then the reaction mixture was heated to 100 ⁰C and reacted overnight. After evaporation of solvent, the residue was diluted with water and the aqueous layer was extracted with ethyl acetate. The product (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5- yl)acrylate (16.8 g, 73% yield) was isolated by silica gel column chromatography with 6-8% ethyl acetate in hexane as eluent. ¹H NMR (400 MHz, CDCl₃): δ 7.65 (d, J = 16.4Hz, IH), 6.20 (d, J = 16.4Hz, IH), 5.15 (bs, IH), 4.28(q, J = 7.2 Hz, 2H), 3.54 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).

To a solution of (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin- 5-yl)acrylate (16.8 g, 59.8 mmol) in DIPEA was added l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 15 h. After evaporation of solvent, the residue was triturated with acetone. The product 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77 g, 77% yield) was collected by filtration. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 9.6 Hz, IH), 6.63 (d, J = 9.6 Hz₅ IH), 4.5(q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[00187] To a solution of 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (6.31 g, 26.84 mmol) in DCM was added Br₂ (4.79 g, 29.52 mmol) dropwise at room temperature. Then the reaction mixture was stirred at room temperature overnight. After filtration the solid was suspended in DCM (100 mL), and triethylamine (20 mL) was added. The mixture was washed with water and dried with Na₂SO₄, and the product 6-bromo-8- ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.96 g, 83 % yield) was obtained after evaporation of DCM. ¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, IH), 4.56 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 2.62 (s, 3H), 1.34 (t, J = 7.2Hz, 3H).

To a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)ρyrido[2,3- d]pyrimidin-7(8H)-one (0.765 g, 2.43 mmol) in DME-H₂O (10:1 11 mL) was added IH- pyrazol-5-ylboronic acid (Frontier, 0.408 g, 3.65 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH₂Cl₂ (Pd(dρρρf),0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 4 h. After cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the. organic layer was dried with Na₂SO₄, and the product 8- ethyl-4-methyl-2-(methylthio)-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.567 g, 77% yield) was obtained by silica gel column chromatography. ¹H NMR (400 MHz, CDCl₃): δ 13.3 (bs, IH), 8.54 (s, IH), 7.82-7.07 (m, 2H), 4.45 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J = 7.2Hz, 3H).

To the solution of 8-ethyl-4-methyl-2-(methylthio)-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.123 g, 0.41mmol) in DCM (2 mL) was added MCPBA (0.176 g, 77%, 0.785 mmol) in a small portion at room temperature. Then the reaction mixture was stirred for 4 h. After evaporation of DCM, dioxane (1 mL) and liquid ammonia (1 mL) were introduced. The reaction was stirred at room temperature overnight. The product 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-(/lpyrimidin-7(8H)- one (50.4 mg) was obtained by silica gel column chromatography. ¹H NMR (400 MHz, CD₃OD): δ 8.41 (s, IH), 7.62 (d, J – 2.0 Hz, IH), 6.96 (d, J = 2.0Hz₅ IH), 4.51 (q, J = 7.2Hz, 2H), 2.64 (s, 3H), 1.29 (t, J = 7.2Hz, 3H); MS (EI) for C₁₃H₁₄N₆O: 271.3 (MH⁺)

References:

1. P. W. Yu, et al., Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway, Mol Cancer Ther, May 2014 13; 1078-91

2. K. P. Papadopoulos, et al., Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors, Clin Cancer Res, May 1, 2014 20; 2445

3 WO 2014058947

4 WO 2013040337

5 WO 2012065019

6 WO 2009017838

7 WO 2008127678

8 WO 2008124161

9 WO 2007044698

10 WO 2007044813

WO2007044813A1	9 Oct 2006	19 Apr 2007	Exelixis Inc	PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kα
WO2012054748A2 *	20 Oct 2011	26 Apr 2012	Seattle Genetics, Inc.	Synergistic effects between auristatin-based antibody drug conjugates and inhibitors of the pi3k-akt mtor pathway
WO2012065019A2 *	11 Nov 2011	18 May 2012	Exelixis, Inc.	Pyridopyrimidinone inhibitors of p13k alpha
US7811572	14 Aug 2006	12 Oct 2010	Immunogen, Inc.	Process for preparing purified drug conjugates
US20040235840	20 May 2004	25 Nov 2004	Immunogen, Inc.	Cytotoxic agents comprising new maytansinoids

Exelixis, Inc.

210 East Grand Avenue
So. San Francisco, CA 94080
(650) 837-7000 phone
(650) 837-8300 fax

////////////Voxtalisib hydrochloride, Exelixis, SANOFI, PHASE 2, Malignant neoplasms, SAR-245409, XL-765

TAK 272, For Hypertension, Takeda’s Next Sartan

October 20, 2015 8:19 am / 1 Comment on TAK 272, For Hypertension, Takeda’s Next Sartan

TAK 272

C27 H41 N5 O4 . Cl H, 536.106

CAS.1202269-24-6. MonoHCl

1202265-90-4 DIHCL

Base cas…1202265-63-1
Metanesulfonate…1202266-34-9

Takeda Pharmaceutical Company Limited, INNOVATOR

see……….http://www.allfordrugs.com/2015/10/21/tak-272-for-hypertension-takedas-next-sartan/
1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)-piperidin-3-yl]-1H-benzimidazole-2-carboxamide

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide dihydrochloride

N-Isobutyl-1-(4-methoxybutyl)-N-[5(R)-(morpholin-4-ylcarbonyl)piperidin-3(S)-yl]-1H-benzimidazole-2-carboxamide hydrochloride

1- (4-methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidine-3 – yl] -1H- benzimidazole-2-carboxamide hydrochloride,

The compound is used as renin inhibitor for treating diabetic nephropathy and hypertension

Takeda’s TAK-272, was reported to be in phase II in October 2015), an oral renin inhibitor, for treating diabetic nephropathy and hypertension

01 Apr 2015Takeda completes a phase I drug-drug interaction trial in Healthy volunteers in Japan (NCT02370615)
18 Feb 2015Takeda plans a phase I drug-drug interaction trial in Healthy volunteers in Japan (NCT02370615)
13 Feb 2015Takeda plans a phase I pharmacokinetics trial in Renal or Hepatic impairment patients in Japan (NCT02367872)

in Patent Document 1, a method for producing a synthetic intermediate of the above heterocyclic compound, the following methods are disclosed.

In the above method, the acid anhydride (BANC) from chiral dicarboxylic acid monoester ((-) – BMPA) were synthesized and then the carboxylic acid after conversion and hydrolysis reaction of the Z amine by the Curtius rearrangement of the carboxylic acid (BAPC) and it was then performs amidation by the condensation reaction with the amine (morpholine), is synthesized heterocyclic amide compound (BMPC).　Further, Patent Document 2, the preparation of compounds useful as synthetic intermediates of the above heterocyclic compounds are disclosed.

(Wherein each symbol is as described in Patent Document 2.)

　TABLE In the above method, the acid anhydride of the formula (VI), in the presence of a chiral amine with the formula (VIIa) or (VIIb) is to produce a chiral dicarboxylic acid monoester compound, then reacted with an amine (R1-NH-R2) is subjected to amidation to, to produce a heterocyclic amide compound of the formula (VIII).

Patent literature

Patent Document 1: Patent No. 4,800,445 Patent
Patent Document 2: International Publication No. 2007/077005

SYNTHESIS…click on image to get clear view

PATENT

WO2009154300

https://www.google.co.in/patents/WO2009154300A2?cl=en

INTERMEDIATES FOR CONSTRUCTION

USE THIS ONE

Reference Example 31 tert-butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate and 1- (4-methoxybutyl) -N-

(2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4- ylcarbonyl)piperidin-3-yl]-lH-benzimidazole-2-carboxamide

tert-Butyl (3S, 5R) -3-{ [ ( {2- [ (4- methoxybutyl) amino] phenyl}amino) (oxo) acetyl] (2- methylpropyl) amino} -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate (9.11 g) was dissolved in acetic acid (50 ml), and the mixture was stirred at 😯⁰C for 15 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert- butyl (3S, 5R) -3- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl } (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate (5.85 g) , and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure to give 1- (4-methoxybutyl) -N- (2- methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin- 3-yl] -lH-benzimidazole-2-carboxamide (580 mg) . [0424] tert-butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl ) piperidine-1-carboxylate 1H-NMR (CDCl₃) δ 0.63-0.80 (2H, m) , 0.89-1.07 (4H, m) , 1.41- 1.59 (9H, m) , 1.59-1.80 (2H, m) , 1.87-2.23 (4H, m) , 2.30-2.98 (3H, m) , 3.21-3. 46 ( 6H, m) , 3.49-3. 91 (1OH, m) , 3. 95-4 . 47 (5H, m) , 7 . 18-7 . 51 (3H, m) , 7. 56-7 . 84 ( IH, m) .

MS (ESI+, m/e) 600 (M+l )

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl)piperidin-3-yl] -lH-benzimidazole-2-carboxamide BASE

¹H-NMR (CDCl₃) δ 0.64-0.74 (2H, m) , 0.95-1.07 (4H, m) , 1.43-

1.74 (3H, m) , 1.84-2.41 (4H, m) , 2.48-2.67 (IH, m) , 2.67-3.01

(3H, m), 3.03-3.44 (8H, m) , 3.47-3.78 (9H, m) , 4.06-4.46 (3H, m) , 7.28-7.47 (3H, m) , 7.62-7.81 (IH, m) . MS (ESI+, m/e) 500 (M+l)

Example 10

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-

4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide dihydrochloride

tert-Butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5-

(morpholin-4-ylcarbonyl)piperidine-l-carboxylate (5.85 g) was dissolved in methanol (20 ml) , 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give 1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide (4.40 g) . The obtained 1- (4-methoxybutyl) -N- (2-methylpropyl) – N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -IH- benzimidazole-2-carboxamide (2.20 g) was dissolved in ethyl acetate (20 ml) , 4M hydrogen chloride-ethyl acetate (5 ml) and methanol (20 ml) were added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure to give the object product (2.52 g).

dihydrochloride

¹H-NMR (DMSO-d₆) δ 0.63-0.76 (2H, m) , 0.85-1.00 (4H, m) , 1.40-

1.60 (2H, m) , 1.68-1.89 (2H, m) , 1.93-2.17 (2H, m) , 2.20-2.44

(2H, m) , 2.81-3.81 (2OH, m) , 4.19-4.39 (3H, m) , 7.23-7.46 (2H, m) , 7.57-7.81 (2H, m) , 8.38-9.77 (2H, m) .

MS (ESI+, m/e) 500 (M+l)

Example 252

1- ( 4-methoxybutyl ) -N- ( 2-methylpropyl ) -N- [ ( 3S ₁. 5R) -5- (morpholin- 4-ylcarbonyl ) piperidin-3-yl ] -lH-benzimidazole-2-carboxamide methanesulfonate

l-(4-Methoxybutyl) -N- (2-methylpropyl) -N- [ (3S,5R)-5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2- carboxamide (208 mg) was dissolved in ethyl acetate (2 ml) , a solution of methanesulfonic acid (40 μl) in ethyl acetate (1 ml) was added at 75°C, hexane (1 ml) was added, and the mixture was heated under reflux and stood at room temperature overnight. The precipitated crystals were collected by filtration, and dried at 7O⁰C for 3 hr to give the object product (158 mg) . MS (ESI+, m/e) 500 (M+l) melting point : 144.4⁰C

EXTRAS IF REQD .………….

Example 32

methyl (3R, 5S)-5-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] piperidine-3-carboxylate dihydrochloride [0675]

MS (ESI+, m/e) 445 (M+l)

Example 33

(3R, 5S) -5- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yljcarbonyl} (2-methylpropyl) amino] piperidine-3-carboxylic acid dihydrochloride

MS (ESI+, m/e) 431 (M+l)

Reference Example 29

{ [ ( 3S , 5R) -1- (tert-butoxycarbonyl ) -5- (morpholin-4- ylcarbonyl ) piperidin-3~yl ] ( 2-itιethylpropyl ) amino } (oxo ) acetic acid

To a solution of tert-butyl (3S,5R)~3-{ [ethoxy (oxo) acetyl] (2-methylpropyl) amino}-5- (morpholin-4- ylcarbonyl) piperidine-1-carboxylate (10.3 g) in ethanol (40 ml) was added 2M aqueous sodium hydroxide solution (22 ml) , and the mixture was stirred at room temperature for 6 hr. The reaction mixture was adjusted to pH 7 with IM hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (10.3 g) .

¹H-NMR (CDCl₃) δ 0.78-0.99 (6H, m) , 1.37-1.52 (9H, m) , 1.79- 2.16 (3H, m) , 2.38-3.86 (14H, m) , 3.93-4.43 (2H, m) . MS (ESI+, m/e) 442 (M+l)

Reference Example 28

tert-butyl (3S, 5R) -3-{ [ethoxy (oxo) acetyl] (2- methylpropyl ) amino } -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate

To a solution of tert-butyl (3S, 5R) -3- [ (2- methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate (9.24 g) and diisopropylethylamine (10.5 ml) in DMA (100 ml) was added dropwise ethyl chloroglyoxylate (3.4 ml) at 0°C. The reaction mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (10.3 g) . 1H-NMR (CDCl₃) δ 0.84-1.00 (6H, m) , 1.37 (3H, q) , 1.42-1.53 (9H, m) , 1.80-2.19 (3H, m) , 2.26-2.42 (IH, m) , 2.59-2.96 (IH, in) , 2.97-3.30 (3H, m) , 3.37-3.92 (9H, m) , 4.01-4.26 (2H, m) , 4.26- 4.40 (2H, m) . MS (ESI4-, m/e) 470 (M+l) ^“

Reference Example 22 tert-butyl (3S, 5R) -3- [ (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate

[0369] tert-Butyl (3S,5R)-3-{ [ (benzyloxy) carbonyl] aminoJ-5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (58 g) and palladium (II) hydroxide-carbon (5 g) were suspended in methanol (400 ml) and the mixture was stirred under a hydrogen atmosphere (1 atom) at room temperature for 16 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue and acetic acid (8.8 ml) were dissolved in methanol (400 ml), 2- methylpropanal (14.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (40.4 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the concentrate was basified with 3.5M aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:5) – ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object product (33.3 g) .

¹H-NMR (CDCl₃) δ: 0.90 (6H, d) , 1.46 (9H, s) , 1.54 (IH, d) , 1.69 (IH, dt), 1.96-2.12 (2H, m) , 2.23-2.37 (IH, m) , 2.47 (3H, d) , 2.66 (IH, d) , 3.61 (IH, br s) , 3.55 (2H, d) , 3.69 (5H, ddd) , 4.01-4.46 (2H, m) .

Example 6 1-tert-butyl 3-methyl (3R, 5S) -5-aminopiperidine-l, 3- dicarboxylate [0318]

(3S, 5R) -1- (tert-Butoxycarbonyl) -5-(methoxycarbonyl)piperidine-3-carboxylic acid (2.83 g) was suspended in toluene (36 ml), diphenylphosphoryl azide (2.60 ml) and triethylamine (1.70 ml) were added, and the mixture was stirred at 100°C for 1 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) were added and the mixture was stirred at 80°C for 3 hr. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water, 0.5M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:3 – 3:1) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (60 ml), 10% palladium carbon (50% in water) (150 mg) was added and the mixture was stirred under a hydrogen pressurization (5 atom) at ambient temperature and normal pressure for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (1.83 g) as an oil.

¹H-NMR (CDCl₃) δ 1.22-1.43 (4H, m) , 1.46 (9H, s), 2.27-2.79 (4H, m) , 3.70 (3H, s) , 4.13 (2H, br s) [0320] In the same manner as in the method shown in Reference Example 6, the following compound (Reference Example 7) was obtained.

Reference Example 8

1-tert-butyl 3-methyl (3R, 5S) -5- [ (2- methylpropyl) amino] piperidine-1, 3-dicarboxylate [0325]

1-tert-Butyl 3-methyl (3R, 5S) -5-aminopiperidine-l, 3- dicarboxylate (1.83 g) , isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, the concentrate was basified with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) – ethyl acetate 100% – ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give the object product (1.42 g) as an oil.

¹H-NMR (CDCl₃) δ 0.90 (6H, d) , 1.22-1.38 (3H, m) , 1.46 (9H, s) , 1.69 (IH, dt), 2.23-2.39 (2H, m) , 2.44-2.59 (IH, m) , 2.47 (2H, d) , 2.74 (IH, br s) , 3.69 (3H, s) , 4.18-4.34 (2H, m)

Reference Example 27

N- (4-methoxybutyl) benzene-1, 2-diamine

To a solution of phenylenediamine (10.8 g) and 4- methoxybutyl methanesulfonate (9.11 g) in acetonitrile (100 ml) was added potassium carbonate (20.7 g) , and the mixture was stirred heated under reflux for 15 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object product (5.44 g) . 1H-NMR (CDCl₃) δ 1.67-1.82 (4H, m) , 3.13 (2H, t) , 3.24-3.39 (6H, m) , 3 . 38 -3 . 50 ( 2H, m) , 6 . 62 – 6 . 74 ( 3H, m) , 6 . 81 ( IH, in) . MS ( ESI+ , m/e ) 195 (M+l )

Reference Example 146 tert-butyl (3S, 5R) -3- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yl]carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate

A solution of tert-butyl (3S, 5R) -3- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate (200 mg) , 4-itιethoxybutyl methanesulfonate (107 mg) and cesium carbonate (254 mg) in N,N-dimethylacetamide (5 ml) was stirred at 60°C for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml*2) . The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95 – 3:7) was concentrated under reduced pressure to give the object product (190 mg) . 1H-NMR (CDCl₃) δ 0.63-0.80 (2H, m) , 0.89-1.07 (4H, m) , 1.41- 1.59 (9H, m) , 1.59-1.80 (2H, m) , 1.87-2.23 (4H, m) , 2.30-2.98 (3H, m) , 3.21-3.46 (6H, m) , 3.49-3.91 (1OH, m) , 3.95-4.47 (5H, m) , 7.18-7.51 (3H, m) , 7.56-7.84 (IH, m) . MS (ESI+, m/e) 600 (M+l)

ALTERNATE METHOD IN THIS PATENT

Figure imgf000106_0001

Figure imgf000127_0002

Reference Example 61

2- (trichloromethyl) -lH-benzimidazole

O-Phenylenediamine (25 g) was dissolved in acetic acid (750 ml), and methyl 2, 2, 2-trichloroacetimidate (28.5 ml) was added dropwise over 15 min. After stirring at room temperature for 1 hr, the reaction mixture was concentrated to about 150 ml, and poured into water (1500 ml) . The precipitated crystals were collected by filtration, washed with water (1000 ml) and suspended in toluene (500 ml) . The solvent was evaporated under reduced pressure. The residue was again suspended in toluene (500 ml) and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (51.8 g) . 1H-NMR (CDCl₃) δ 7.31-7.45 (2H, m) , 7.49-7.55 (IH, m) , 7.89 (IH, d) , 9 . 74 ( IH, br s )

Reference Example 64

1-tert-butyl 3-methyl (3R, 5S) -5- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] piperidine-1, 3-dicarboxylate

2- (Trichloromethyl) -lH-benzimidazole (19 g) and 1-tert- butyl 3-methyl (3R, 5S) -5- [ (2-methylpropyl) amino] piperidine- 1,3-dicarboxylate (25 g) were dissolved in THF (1200 ml), sodium hydrogen carbonate (67 g) and water (600 ml) were added, and the mixture was stirred at room temperature for 1 hr and at 5O⁰C for 1 hr. After evaporation of the solvent, the residue was extracted 3 times with ethyl acetate (700 ml) . The extract was washed successively with 10%-aqueous citric acid solution (500 ml) and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

The residue was dissolved in ethyl acetate (1000 ml), subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (30.6 g) .

¹H-NMR (CDCl₃) δ 0.78-1.09 (6 H, m) , 1.17-1.55 (9 H, m) , 1.77-2.95 (5 H, m) , 3.11-3.79 (6 H, m) , 3.99-4.73 (4 H, m) , 7.24- 7.41 (2 H, m) , 7.45-7.59 (1 H, m) , 7.72-7.88 (1 H, m) , 10.66-10.98 (1 H, m)MS (ESI+, m/e) 459 (M+l)

Reference Example 69

1-tert-butyl 3-methyl (3R, 5S) -5- [ { [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] piperidine-1 , 3-dicarboxylate

1-tert-Butyl 3-methyl (3R, 5S) -5- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] piperidine-1, 3-dicarboxylate (30 g) and 4-methoxybutyl methanesulfonate (12.5 g) were dissolved in DMA (600 ml), cesium carbonate (32 g) was added, and the mixture was stirred at 70°C for 12 hr. The reaction mixture was poured into ice water (1000 ml), and the mixture was extracted twice with ethyl acetate (1000 ml) . The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4 – 1:1) was concentrated under reduced pressure to give the object product (28.7 g) .

¹H-NMR (CDCl₃) δ 0.76 (4H, d) , 1.01 (2H, d) , 1.30-1.52 (9H, m) , 1.58-2.07 (4H, m) , 2.10-2.93 (4H, m) , 3.27-3.75 (12H, m) , 4.06-4.57 (5H, m) , 7.26-7.48 (3H, m) , 7.79 (IH, d) MS (ESI+, m/e) 545 (M+l)

Example 71

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide

tert-Butyl (3S, 5R) -3- [{ [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (5.85 g) was dissolved in methanol (20 ml) , 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with aqueous sodium bicarbonate,…and, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give the object product (4.40 g) . MS (ESI+, m/e) 500 (M+l)

Example 101

1- (5-methoxypentyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2- carboxamide dihydrochloride

[1144] tert-Butyl (3S, 5R) -3- [ { [1- (5-methoxypentyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (123 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml) , and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (76 mg) . MS (ESI+, m/e) 514 (M+l)

PATENT

WO2013122260

http://www.google.co.in/patents/WO2013122260A1?cl=en

PATENT

WO 2011158880

http://www.google.co.in/patents/WO2011158880A1?cl=en

Reference Example 1
1- (4-methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H- benzimidazole -2 – carboxamide hydrochloride (A-type crystal)
tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl) was suspended dissolved piperidine-1-carboxylate The (300g) in 3N- hydrochloric acid water (1200mL) and Ethyl acetate (60mL), and stirred over 3 h at 25 ~ 35 ℃. After completion of the reaction, it was added ethyl acetate (2400mL) in the same temperature. After the addition, it was added 25% aqueous ammonia (600mL) with cooling. After the addition stirring and extracted the organic layer of 5% aqueous ammonia (600mL) was added and stirred. After stirring, the resulting organic layer it was concentrated until the solvent no longer distilled off. After concentrated, dissolved with ethyl acetate (1500mL), and transferred to solution to the crystallizer vessel, and washed with ethyl acetate (750mL). After washing, it was raised in stirring under 45 ~ 55 ℃. After raising the temperature, at the same temperature 4N- hydrogen chloride – it was dropped ethyl acetate (131.3mL). After dropping, it was to dissolve the precipitate at the same temperature. After dissolution confirmation, it was added heptane (750mL) at 40 ~ 50 ℃, after the addition, then cooled to 25 ~ 35 ℃. After cooling, the addition of A-type crystals of the seed crystals (300mg) which was obtained according to the method described in Example 265 of WO2009 / 154300, and stirred for 30 minutes or more. After stirring, the temperature was raised to 40 ~ 45 ℃, it was dropped heptane (1500mL). After the completion of the dropping, it was stirred at the same temperature. Then gradually cooled to 5 ℃ below, followed by stirring at the same temperature for 1 hour. After stirring, ethyl acetate and filtered crystals – heptane: washed with (1 1,600mL), to obtain a wet crystal. The obtained wet crystals dried under reduced pressure at 50 ℃, 1- (4- methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-yl carbonyl) piperidin-3-yl] -1H- obtained a crystalline powder of benzimidazole-2-carboxamide hydrochloride (A-type crystal, 198.82g, 74.1% yield). FINAL PRODUCT

TERT BUTYL DERIVATIVE, N-1

Reference Example 4
tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl) piperidine-1-carboxylate 1)

o- nitro aniline (50.0g, 0.362mol), tetrabutylammonium bromide (58.3g, 0.181mol), potassium bromide (43.1g, 0.362mol) in toluene (500mL ) and it was added. At a temperature of 20 ~ 30 ℃ 1- chloro-4-methoxy-butane (66.6g, 0.543mol) and, I was added to 50w / v% sodium hydroxide solution (145mL, 1.81mol). The reaction was heated to a temperature 85 ~ 95 ℃, and stirred for 6 hours. After cooling to a temperature 20 ~ 30 ℃, the reaction mixture water (250mL), 1N- aqueous hydrochloric acid (250mL × 2), 5w / v% aqueous solution of sodium bicarbonate (250mL), it was washed successively with water (250mL). After concentration under reduced pressure the organic layer to Contents (250mL), was added toluene (100mL), was obtained

N- (4- methoxy-butyl) -2-nitroaniline in toluene (350mL, 100% yield).
¹ H-NMR (300MHz, CDCl ₃₎ ^δ 1.64-1.89 (m, 4H), 3.25-3.39 (m, 2H), 3.35 (s, 3H), 3.44 (t, J = 6.1 Hz, 2H), 6.63 ( ddd, J = 8.5, 6.9, 1.2 Hz, 1H), 6.86 (dd, J = 8.5, 1.2 Hz, 1H), 7.43 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 8.07 (br s, 1H ), 8.17 (dd, J = 8.5, 1.5 Hz, 1H).

2) N- (4-methoxy-butyl) -2-10 percent in nitroaniline of toluene solution (350mL) Pd / C (K-type, 50% water-containing product) (10.0g) and toluene (100mL) it was added. Hydrogen pressure of 0.1MPa, it was stirred for 3 hours at a temperature of 20 ~ 30 ℃. A stream of nitrogen, the catalyst was filtered, I was washed with toluene (100mL). After the water in the filtrate was separated off and adding magnesium sulfate (25.0g) at a temperature 20 ~ 30 ℃, and stirred at the same temperature for 30 minutes. Filtered over magnesium sulfate, washed with toluene (100mL), was obtained N- (4- methoxybutyl) -o- toluene solution of phenylenediamine (100% yield).
¹ H NMR (500 MHz, CDCl ₃₎ ^δ1.67-1.78 (m, 4H), 3.12-3.14 (m, 2H), 3.32 (br, 3H), 3.35 (s, 3H), 3.41-3.47 (m, 2H), 6.63-6.69 (m, 2H), 6.69-6.74 (m, 1H), 6.82 (td, J = 7.57, 1.58 Hz, 1H).

3) N- (4- methoxy-butyl) -o- After the toluene solution of phenylenediamine cooled to a temperature 0 ~ 10 ℃, acetic acid (65.2g, 1.09mol) and 2,2,2 trichloroacetimide acid methyl ( 70.3g, 0.398mol) and I were added. After stirring for 30 minutes at a temperature 0 ~ 10 ℃, it was stirred for 3 hours at a temperature of 20 ~ 30 ℃. The reaction was 5w / v% saline (250mL), 2N- aqueous hydrochloric acid / 5w / v% sodium chloride solution: a mixture of (1 1) (250mL × 2), 5w / v% aqueous solution of sodium bicarbonate (250mL), 5w / v It was washed successively with% saline solution (250mL). A stream of nitrogen, was added magnesium sulfate (25.0g) to the organic layer at a temperature 20 ~ 30 ℃, and stirred at the same temperature for 30 minutes. Filtered magnesium sulfate, and washed with toluene (100mL). The filtrate was concentrated under reduced pressure and the amount of contents (150mL). Stir the concentrated solution at a temperature 20 ~ 30 ℃, was allowed to precipitate crystals, was added dropwise heptane (750mL). The crystals bleeding is heated to a temperature 40 ~ 50 ℃, after stirring for 30 min, cooled to a temperature 0 ~ 10 ℃, and the mixture was stirred at the same temperature for 2 hours.The precipitated crystals were collected by filtration, toluene – heptane: was washed with (1 5,150 mL). And dried under reduced pressure at 40 ℃, it was obtained 1- (4-methoxy-butyl) -2-fine brown crystals of trichloromethyl -1H- benzimidazole (96.5g, 82.9% yield from o- nitroaniline).
¹ H-NMR (300MHz, CDCl ₃₎ ^δ: 1.68-1.85 (m, 2H), 1.99-2.17 (m, 2H), 3.37 (s, 3H), 3.48 (t, J = 6.1 Hz, 2H), 4.50 -4.65 (m, 2H), 7.27-7.49 (m, 4H), 7.82-7.93 (m, 1H).
. Anal Calcd _for C ₁₃ H ₁₅ Cl ₃ N ₂ O:. C, 48.55; H, 4.70; N, 8.71; Cl, 33.07 Found: C, 48.30; H, 4.61; N, 8.74; Cl, 33.30.

4) pyridine-3,5-dicarboxylic acid (110g, 0.66mol), it was dropped methanol (660 mL) mixture of concentrated sulfuric acid at a temperature of 50 ℃ or less of (226.0g, 2.30mol). Thereafter, the mixture was stirred and heated to a temperature 55 ~ 65 ℃ 7 hours. The reaction was the temperature 40 ~ 50 ℃, was added water (220mL). And further dropping temperature 40-50 5% aqueous ammonia at ℃ (about 1.10L) was adjusted to pH8.0 ~ 8.5. After stirring at a temperature 40 ~ 50 ℃ 30 minutes and stirred for 1 hour and cooled to a temperature 0 ~ 10 ℃. Was collected by filtration precipitated crystals, methanol – water (1: 3,165mL), and washed successively with water (440mL). To obtain a white crystalline powder pyridine-3,5-dicarboxylic acid dimethyl and dried under reduced pressure at 50 ℃ (105.0g, 82.0% yield).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 4.00 (s, 6H), 8.87 (s, 1H), 9.37 (s, 2H).
. Anal Calcd for C ₉ H ₉ NO _4:. C, 55.39; H, 4.65; N, 7.18; O, 32.79 Found: C, 55.42; H, 4.65; N, 7.16.

5) 1 L autoclave pyridine-3,5-dicarboxylic acid dimethyl (100g, 0.51mol) and was charged with dimethylacetamide (400mL), temperature 30 ℃ below with trifluoroacetic acid (59.2mL, after dropping the 0.77mol), 10% Pd-C (PE-type) the (20.0g) it was added. Hydrogen pressure of 0.5 ~ 0.7MPa, it was stirred for 12 hours at a temperature of 55 ~ 65 ℃. The catalyst was filtered off, it was washed with dimethylacetamide (50mL × 2). Triethylamine and the combined filtrates at a temperature 20 ~ 30 ℃ (77.8g, 0.77mol) was added dropwise, and adjusted to pH9.0 ~ 10.0. Temperature 30 ~ 40 ℃ by di -tert- butyl (134g, 0.614mol) was added dropwise and stirred at the same temperature for 2 hours. After the reaction mixture as a 20 ~ 30 ℃, it was added ethyl acetate (600mL), washed with water (900mL). The aqueous layer it was re-extracted with ethyl acetate (400mL). The combined organic layers 5w / v% citric acid -10w / v% sodium chloride solution (600mL), 3% aqueous sodium bicarbonate (600mL), and washed successively with water (600mL). Contents The organic layer (200mL) until it was concentrated under reduced pressure, methanol (250mL) was added to the concentrated solution, and then concentrated under reduced pressure until Contents (200mL). The addition of methanol (250mL) again concentrate, After concentration under reduced pressure until Contents (200mL), was added methanol (2.40L). The solution in water (18.5g, 1.03mol), cesium carbonate (417g, 1.28mol) was added and stirred for about 24 hours at a temperature 55 ~ 65 ℃. The reaction solution was the temperature 20 ~ 30 ℃, concentrated to Contents (700mL), it was added tetrahydrofuran (500mL). The solution temperature at 15 ~ 35 ℃ 2N- hydrochloric acid solution (1.28L, 2.56mol) was added dropwise and adjusted to pH3.0 ~ 3.5, and the mixture was stirred for 30 minutes at a temperature 20 ~ 30 ℃. Extracted with ethyl acetate (750mL × 2), and the organic layer was washed with 10w / v% aqueous sodium chloride solution (500mL × 3). Contents The organic layer (300mL) until it was concentrated under reduced pressure, to obtain a weight content by adding ethyl acetate (650mL).Heating the concentrate to a temperature of 55 ~ 65 ℃, it was added dropwise heptane (500mL). It cooled to a temperature 20 ~ 30 ℃ and stirred for 1 hour. The precipitated crystals were collected by filtration, ethyl acetate – heptane: was washed with (1 1,120mL). Dried under reduced pressure at 50 ℃ 1- (tert- butoxycarbonyl) to give a white crystalline powder of piperidine-3,5-dicarboxylic acid (113.3g, 80.9% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.40 (s, 9H), 1.44-1.61 (m, 1H), 2.21-2.26 (m, 1H), 2.31-2.41 (m, 2H), 4.10- 4.12 (m, 2H).
. Anal Calcd for C ₁₂ H ₁₉ NO _6:. C, 52.74; H, 7.01; N, 5.13; O, 35.13 Found: C, 52.96; H, 6.99; N, 5.39.

6) Under a nitrogen stream, 1- (tert- butoxycarbonyl) piperidine-3,5-dicarboxylic acid (5.00g, 18.3mmol) was suspended in tetrahydrofuran (10.0mL), trifluoroacetic acid anhydride at a temperature 20 ~ 30 ℃ It was dropping things (3.80mL, 27.5mmol). After the completion of the dropping, it was stirred for 1 hour at a temperature of 20 ~ 30 ℃. It was added dropwise heptane (20.0mL) at a temperature 20 ~ 30 ℃ the reaction solution, and stirred for 3 hours then cooled to a temperature 0 ~ 10 ℃. The precipitated crystals were collected by filtration, and washed with heptane (3.00mL). Dried under reduced pressure at 40 ℃ 2,4- dioxo-3-oxa-7-azabicyclo [3,3,1] white crystalline powder of nonane-7-carboxylic acid tert- butyl was obtained (4.03g, yield 86.1%).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 1.43 (s, 9H), 1.93-1.99 (m, 1H), 2.40-2.46 (m, 1H), 3.06-3.11 (m, 4H), 4.50-4.54 ( m, 2H).
. Anal Calcd for C ₁₂ H ₁₇ NO _5:. C, 56.46; H, 6.71; N, 5.49; O, 31.34 Found: C, 56.51; H, 6.63; N, 5.69.

7) Under a nitrogen stream, quinidine (69.9g, 0.215mol) and was charged with tetrahydrofuran (200mL), and cooled to a temperature -5 ~ 5 ℃. At the same temperature 2,4-dioxo-3-oxa-7-azabicyclo [3,3,1] nonane-7-carboxylic acid tert- butyl (50.0g, 0.196mol) was added and washed with tetrahydrofuran (50.0mL) crowded. Temperature -5 ~ 5 methanol at ℃ (9.41g, 0.29 4mol) was added dropwise, and the mixture was stirred for 2 hours at a temperature -5 ~ 5 ℃. Ethyl acetate (350mL) to the reaction mixture, was by adding minute solution 20w / v% citric acid aqueous solution (250mL). The aqueous layer it was re-extracted with ethyl acetate (125mL × 2). The organic layers were combined 20w / v% aqueous solution of citric acid (250mL), I was washed successively with water (250mL × 2). The organic layer it was concentrated under reduced pressure. To the residue ethanol (100mL) was added ethyl acetate (450mL) was heated to a temperature 60 ~ 70 ℃, (R) – was added phenethylamine (23.7g, 0.196mol). Temperature 50-60 for one hour at ℃, 1 hour at a temperature of 20 ~ 30 ℃, it was stirred for 1 hour at a temperature of -5 ~ 5 ℃. The precipitated crystals were collected by filtration, ethanol – ethyl acetate: and washed with (2 9,100mL). And dried under reduced pressure at 50 ℃ (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidin-3 to give a white crystalline powder of the carboxylic acid (1R) -1- phenylethylamine salt It was (55.7g, 69.6% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.42 (s, 9H), 1.43-1.51 (m, 3H), 2.06-2.14 (m, 1H), 2.21-2.26 (m, 1H), 2.39- 2.44 (m, 1H), 2.52-2.53 (m, 1H), 2.57 (br s, 2H), 3.64 (s, 3H), 4.12 (br s, 2H), 4.19-4.26 (m, 1H), 7.30- 7.40 (m, 3H), 7.45-7.48 (m, 2H).
. Anal Calcd for C ₂₁ H ₃₂ N ₂ O _6:. C, 61.75; H, 7.90; N, 6.86; O, 23.50 Found: C, 61.54; H, 7.77; N, 6.86.

8) (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid (1R) -1- phenylethylamine salt (20.0g, 49.0mmol), methanol (20mL) and it was charged with water (80mL). Temperature 20-30 citric acid at ℃ (11.3g, 58.8mmol) was added dropwise a solution prepared by dissolving in water (20.0mL), and the mixture was stirred 1.5 hours at the same temperature. The precipitated crystals were collected by filtration and washed with water (60mL). And dried under reduced pressure at 50 ℃ (3S, 5R) -1- (tert- butoxycarbonyl) -5- give a white crystalline powder (methoxycarbonyl) piperidine-3-carboxylic acid (13.5g, 96.1% yield ).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 1.40 (s, 9H), 1.46-1.59 (m, 1H), 2.22-2.27 (m, 1H), 2.37-2.45 (m, 2H), 2.63-2.73 ( m, 2H), 3.63 (s, 3H), 4.14 (br s, 2H), 12.51 (br s, 1H).
. Anal Calcd for C ₁₃ H ₂₁ NO _6:. C, 54.35; H, 7.37; N, 4.88; O, 33.41 Found: C, 54.14; H, 7.28; N, 4.85.

9) Under a nitrogen stream, (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid (30.0g, 104mmol), triethylamine (31.7g, 313mmol) and toluene ( It was charged with 180mL). Diphenylphosphorylazide at a temperature of 15 ~ 35 ℃ (28.7g, 313mmol) I was dropped a toluene (30.0mL) solution. After stirring at a temperature 30 ± 5 ℃ 30 minutes, and the mixture was stirred and heated to a temperature 65 ~ 75 ℃ 30 minutes. Temperature 60 ~ 70 ℃ in the benzyl alcohol (12.4g, 115mmol) it was dropped. To a temperature 80 ~ 90 ℃ was stirred and heated for 3 hours. The reaction mixture was cooled to a temperature 20 ~ 30 ℃, sodium nitrite (7.20g, 104mmol) and after stirring was added a solution prepared by dissolving in water (150mL) 1 hour, the aqueous layer was separated. The organic layer 5w / v% aqueous sodium bicarbonate solution (150mL), 20w / v% aqueous citric acid solution (150mL), washed successively with 5w / v% aqueous sodium chloride solution (150mL), the organic layer was concentrated under reduced pressure. The residue methanol (60.0mL) was added and concentrated under reduced pressure to. The more we went once in the same manner.To the residue was added methanol and the content amount of the (90.0g). Temperature 15 ~ 35 ℃ 2N- aqueous sodium hydroxide (62.6mL, 125mmol) was added and stirred for 1 hour at a temperature 30 ± 5 ℃. Temperature 20 ~ 30 ℃ in methanol (120mL), was added to 20w / v% aqueous citric acid solution (300mL), it was a pH3.0 ~ 3.5. After stirring for 30 minutes at a temperature 50 ~ 60 ℃, cooled to a temperature 20 ~ 30 ℃ and stirred for 1 hour. It was stirred for 1 hour at the temperature 0 ~ 10 ℃. The precipitated crystals were collected by filtration, and washed with water (90.0mL). And dried under reduced pressure at 50 ℃ (3R, 5S) -5 – {[(benzyloxy) carbonyl] amino} -1- (tert- butoxycarbonyl) to yield a white crystalline powder piperidine-3-carboxylic acid (35.0 g, 88.6% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.41 (s, 9H), 2.11 (d, J = 12.4 Hz, 1H), 2.40-2.48 (m, 4H), 2.62 (br s, 1H), 4.08 (t, J = 14.4 Hz, 2H), 5.04 (s, 2H), 7.31-7.41 (m, 5H), 12.53 (br s, 1H).
. Anal Calcd for C ₁₉ H ₂₆ N ₂ O _6:. C, 60.30; H, 6.93; N, 7.40; O, 25.37 Found: C, 60.03; H, 6.99; N, 7.41.

10) Under a nitrogen stream, (3R, 5S) -5 – {[(benzyloxy) carbonyl] amino} -1- (tert- butoxycarbonyl) piperidine-3-carboxylic acid (30.0g, 79.3mmol), morpholine (7.60 g, 87.2mmol), 1- hydroxybenzotriazole monohydrate (2.43g, it was charged with 15.9mmol) and dimethylacetamide (90.0mL). Hydrochloride 1-ethyl at a temperature 20 ~ 30 ℃ -3- (3- dimethylaminopropyl) carbodiimide (16.7g, 87.1mmol) after addition and stirred for 1 hour at a temperature 45 ~ 55 ℃. Temperature 45 ~ 55 ℃ with tetrahydrofuran (90.0mL), sequentially dropwise addition of water (210mL), and stirred for 1 hour. After stirring for 1 hour and cooled to a temperature 20 ~ 30 ℃, were collected by filtration the precipitated crystals, tetrahydrofuran – water: washing with (1 3,120mL). And dried under reduced pressure at 50 ℃ tert- butyl piperidine -1- (3S, 5R) -3 – a white crystalline powder of {[(benzyloxy) carbonyl] amino} -5 (morpholin-4-yl-carbonyl) carboxylate It was obtained (32.7g, 92.3% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.41 (s, 9H), 1.49-1.57 (m, 1H), 1.87 (d, J = 12.3 Hz, 1H), 2.43 (br s, 1H), 2.63-2.71 (m, 1H), 2.79-2.83 (m, 1H), 3.37-3.54 (m, 9H), 3.89 (d, J = 11.5 Hz, 1H), 4.06 (br s, 1H), 5.03 (s , 2H), 7.30-7.38 (m, 5H).
. Anal Calcd for C ₂₃ H ₃₃ N ₃ O _6:. C, 61.73; H, 7.43; N, 9.39; O, 21.45 Found: C, 61.59; H, 7.50; N, 9.43.

11) tert- Butyl piperidin -1- (3S, 5R) -3 – {[(benzyloxy) carbonyl] amino} -5- (morpholin-4-ylcarbonyl) carboxylate (30.0g, 67.0mmol), isobutyraldehyde (7.25g, 101mmol), it was charged with 10% Pd-C (PE type) (1.50g) and methanol (240mL).Hydrogen pressure of 0.2 ~ 0.3MPa, it was stirred for 4 hours at a temperature of 20 ~ 30 ℃. The catalyst is filtered off and washed with methanol (60.0mL). The filtrate was concentrated under reduced pressure, ethyl acetate was added (60.0mL), and concentrated under reduced pressure again. The residue ethyl acetate was added, followed by the amount of contents (360mL). Temperature 45-55 succinate by heating to ℃ (7.90g, 67.0mmol) was added. After stirring for 1 hour at a temperature 45 ~ 55 ℃, cooled to a temperature 20 ~ 30 ℃, and stirred for 1 hour. The precipitated crystals were collected by filtration, and washed with ethyl acetate (90.0mL). And dried under reduced pressure at 50 ℃ tert- butyl (3S, 5R) -3 – [(2- methyl-propyl) amino] -5- (morpholin-4-yl-carbonyl) piperidine – 1-carboxylate white crystals of alert succinate got sex powder (30.2g, 92.5% yield).
¹ H-NMR (300 MHz, D ₂ O) ^δ 1.02 (s, 3H), 1.04 (s, 3H), 1.47 (s, 9H), 1.97-2.09 (m, 2H), 2.26-2.30 (m, 1H ), 2.55 (s, 4H), 2.99 (d, J = 7.0 Hz, 2H), 3.23 (br s, 1H), 3.39-3.45 (m, 2H), 3.53-3.80 (m, 10H), 3.82-3.93 (br s, 1H).
. Anal Calcd for C ₂₃ H ₄₁ N ₃ O _8:. C, 56.66; H, 8.48; N, 8.62; O, 26.25 Found: C, 56.48; H, 8.46; N, 8.39.

12) tert- Butyl (3S, 5R) -3 – [(2- methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine – 1 – carboxylate succinate (30.3g, 62.2mmol), acetonitrile (60.0mL) and, it was charged with water (40.0mL). Then after stirring was added potassium carbonate (34.4g, 0.249mmol) 10 minutes, 1- (4-methoxybutyl) -2-trichloromethyl -1H- benzimidazole (20.0g, 62.2mmol) was added. After stirring for 2 hours at a temperature of 70 ~ 80 ℃, it was added dimethyl sulfoxide (15.0mL), and the mixture was stirred for 6 hours at a temperature 70 ~ 80 ℃. After cooling the reaction mixture to a temperature 20 ~ 30 ℃, water (120mL), it was separated and by adding toluene (240mL). The organic layer 10w / v% sodium chloride solution (100mL), 10w / v% aqueous solution of citric acid (100mL), it was washed sequentially with 10w / v% sodium chloride solution (100mL). The organic layer of activated carbon Shirasagi A a (1.0g) was added, and the mixture was stirred for 30 minutes at a temperature 20 ~ 30 ℃. Activated carbon was filtered, washed with toluene (40.0mL), and concentrated under reduced pressure of the filtrate to 110 mL. By heating to a temperature 35 ~ 45 ℃ was added dropwise heptane (280mL). At a temperature 35 ~ 45 ℃ tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5 – and the mixture was stirred for 1 hour at (morpholin-4-ylcarbonyl) piperidine-1-carboxylate was added to the same temperature the crystals (10mg) of the acrylate. Heptane (140mL) was stirred and added dropwise to 30 minutes at a temperature 35 ~ 45 ℃. It was cooled to a temperature 20 ~ 30 ℃ and stirred for 2 hours. The precipitated crystals were collected by filtration, toluene – heptane: was washed with (1 5,40.0mL). And dried under reduced pressure at 50 ℃ tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] – 5- (morpholin-4-ylcarbonyl) piperidine-1-carboxylate was obtained a pale yellowish crystalline powder of alert (27.7g, 74.2% yield).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 0.68-0.80 (m, 3H), 0.96-1.08 (m, 3H), 1.31 (br s, 5H), 1.49 (s, 4H), 1.61-1.71 (m , 2H), 1.71 (br s, 0.5H), 1.92-2.05 (m, 3H), 2.05-2.24 (m, 2H), 2.45 (br s, 1H), 2.60 (br s, 1H), 2.72-2.96 (m, 2H), 3.26-3.35 (m, 3H), 3.35-3.47 (m, 2H), 3.47-3.73 (m, 10H), 4.02-4.26 (m, 2H), 4.26-4.34 (m, 1H) , 4.34-4.47 (m, 0.5H), 7.25-7.29 (m, 1H), 7.29-7.41 (m, 1H), 7.41-7.53 (m, 1H), 7.64 (br s, 0.5H), 7.79 (d , J = 8.2 Hz, 0.5H).
. Anal Calcd for C ₃₂ H ₄₉ N ₅ O _6:. C, 64.08; H, 8.23; N, 11.68; O, 16.01 Found: C, 63.82; H, 8.12; N, 11.64.

PATENT

WO 2015156346

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=AEE60471E3EF3D2BBE2D20033D4D0CD7.wapp2nC?docId=WO2015156346&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

TAKEDA PHARMACEUTICAL COMPANY LIMITED [JP/JP]; 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP)

Provided is a method for producing a synthetic intermediate of a heterocyclic compound having a renin inhibitory activity and effective as a prophylactic or therapeutic drug against diabetic renal disease, hypertension, and the like. A method for producing a compound represented by formula (III-1a), (III-1b), (III-1c), and/or (III-1d) [where the symbols in the formulas are as defined in the description], or a salt thereof, said method characterized in that a compound represented by formula (Ia) or (Ib) [where the symbols in the formulas are as defined in the description] or a salt thereof is reacted with a compound represented by formula (II) [where the symbols in the formula are as defined in the description] or a salt thereof in the presence of an aluminum compound and a chiral amine compound.

in Patent Document 1, a method for producing a synthetic intermediate of the above heterocyclic compound, the following methods are disclosed.

Formula 2]

(Wherein each symbol is as described in Patent Document 2.)

Prior art documents

Patent literaturePatent Document 1: Patent No. 4,800,445 Patent

Patent Document 2: International Publication No. 2007/077005

Reference Example 1

3-oxabicyclo [3.3.1] nonane-2,4-dione
reaction vessel (1R, 3S) – was added to cyclohexane-1,3-dicarboxylic acid (10g) and THF (20mL), 5 It was cooled to ℃. It was added dropwise trifluoroacetic anhydride (8.19mL), and the mixture was stirred for about 1 hour. The reaction mixture was allowed to warm to room temperature, heptane (20mL) was added, up to 5 ℃ was cooled and stirred for about 30 minutes. The precipitate was filtered off, washed with heptane to give the title compound. Yield (6.7g)

Reference Example 2

(3S, 5R) – tert – butyl 3- (isobutyl-amino) -5- (morpholine-4-carbonyl) piperidine-1-carboxylic acid ester succinate
reactor in THF (240ml), (3S, 5R) -1- (tert – butoxycarbonyl) -5- (morpholine-4-carbonyl) piperidine-3-carboxylic acid (20.0g), triethylamine (12.2mL) and diphenylphosphoryl azide (15.1mL) They were charged and allowed to react for 1 hour at 60 ℃, cooled to 25 ℃. After cooling the THF (60ml) and sodium trimethyl silanolate (19.7g) to charged 0 ℃ separately reaction vessel, was added dropwise to this was allowed to react before the reaction solution over about 1 hour, 0 at 0 ℃. 5 hours it was allowed to react. 0 slowly added dropwise acetic acid (40mL) at ℃, After stirring for 10 minutes, was added ethanol (60ml) and isobutyraldehyde (5.3mL) at 25 ℃, and stirred for 10 minutes. Then added sodium borohydride (1.88g), and the mixture was stirred for 30 minutes, and further addition of sodium borohydride (1.88g) at 25 ℃, and the mixture was stirred for 30 minutes. After completion of the reaction, water (100mL) was added and stirred for 10 minutes at room temperature. The organic layer was concentrated, then added dropwise slowly toluene (140ml) and 5N aqueous sodium hydroxide solution (120ml), the layers were separated. After washing and addition of aqueous 1N sodium hydroxide (100ml) the organic layer was washed 1N aqueous sodium hydroxide (100ml) was added again organic layer. The aqueous layers were combined and extracted by addition of toluene (100ml). The organic layers were combined, washed with 10w / v% aqueous sodium chloride solution (100ml), and the organic layer was concentrated. It was added ethanol (100ml), after it was concentrated under reduced pressure until about 60ml, warmed to 60 ℃ by the addition of ethyl acetate (40ml). Was added succinic acid (6.9g), After stirring for 30 minutes, it was added dropwise ethyl acetate (200ml) at 60 ℃, and stirred for 30 minutes. After stirring for 1 hour at room temperature, and the mixture was stirred for 1 hour at 0 ℃. The crystals were collected by filtration and washed with a mixture of ethyl acetate / n-heptane (6/1) (60mL). The obtained crystals at an external temperature of 50 ℃ to constant weight and then dried under reduced pressure to give the title compound as almost white crystals. Yield (22.8g)

Example 1

(3S, 5R) -1- (tert – butoxycarbonyl) -5- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid
the reaction vessel in chlorobenzene (7.5mL) and quinine (0.70g ) is added and stirred, it was added dropwise DIBAL1.0M hexane solution (2.16mL). The reaction mixture was cooled to -40 ℃, tert – butyl 2,4-dioxo-3-oxa-7-azabicyclo [3.3.1] was added nonane-7-carboxylic acid ester (0.50g), about 1 hour stirring. Was added chlorobenzene to another reaction vessel (2.5mL) and morpholine (0.17mL), the resulting solution was cooled to -40 ℃ was added dropwise to the previous reaction solution. After completion of the reaction, the mixture was separated with ethyl acetate and 10w / w% aqueous citric acid solution, and the resulting aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, washed with 10w / w% saline, and concentrated to give the title compound. ¹ H NMR (500 MHz, DMSO-D ₆ ) delta ppm 1.41 (s, 9 H), 1.47 – 1.72 (M, 1 H), 1.89 – 2.10 (M, 1 H), 2.36 – 2.49 (M, 1 H ), 2.55 – 2.83 (m, 3 H), 3.40 – 3.50 (m, 2 H), 3.51 -.. 3.57 (m, 4 H), 3.59 (br s, 2 H), 3.83 – 4.04 (m, 1 H), 4.05 – 4.29 (m, 1 H), 12.52 (s, 1 H) optical purity of 94.3% EE <HPLC analytical conditions> column: CHIRALPAK IC (Co., Ltd. Daicel) column temperature: constant around 15 ℃ Temperature Mobile phase: A solution) 0.02 mol / L KH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 70: 30　　　　B solution) 0.02 mol / L KH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 50 : 50 gradient program

Example 30 (1R, 3S) -3- (morpholin-4-ylcarbonyl) cyclopentanecarboxylic acid

(anhydride: 3-oxabicyclo [3.2.1] octane-2,4-dione; Amine: Morpholine ) ¹ H NMR (500 MHz, DMSO-D ₆ ) delta ppm 1.72 – 1.91 (M, 5 H), 2.04 (dt, J = 12.69, 7.84 Hz, 1 H), 2.65 – 2.74 (M, 1 H), 2.99 – 3.07 (m, 1 H), 3.42 – 3.51 (m, 4 H), 3.51 – 3.58 (m, 4 H), 11.96 – 12.17 (m, 1 H) optical purity of 52.3% EE <HPLC analysis conditions > column: CHIRALPAK IF (Co., Ltd. Daicel) column temperature: 15 ℃ constant temperature in the vicinity ofmobile phase: A solution) 0.02 mol / LKH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 70: 30 　　　　B solution) 0.02 mol / LKH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 50: 50 gradient Program

WO2010150840A1	24 Jun 2010	29 Dec 2010	Dainippon Sumitomo Pharma Co., Ltd.	N-substituted-cyclic amino derivative
WO2011158880A1	15 Jun 2011	22 Dec 2011	Takeda Pharmaceutical Company Limited	Crystal of amide compound
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US8742097	2 Nov 2011	3 Jun 2014	Hoffmann-La Roche Inc.	Triazole compounds I
US9018374	15 Jun 2011	28 Apr 2015	Takeda Pharmaceutical Company Limited	Crystal of amide compound
US9090601	28 Jan 2010	28 Jul 2015	Millennium Pharmaceuticals, Inc.	Thiazole derivatives

///////////TAK 272, Hypertension

Daprodustat, ダプロデュスタット

October 13, 2015 7:28 am / Leave a comment

ChemSpider 2D Image | daprodustat | C19H27N3O6

Daprodustat, GSK1278863

ダプロデュスタット

CAS 960539-70-2

GSK1278863; GSK 1278863; GSK-1278863; Daprodustat

C19H27N3O6
Exact Mass: 393.18999

(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycine

N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine

2-(1,3-dicyclohexyl-2,4,6-triohexahydropyrimidine-5-carboxamide acetic acid
Mechanism of Action: HIF-prolyl hydroxylase inhibitor
Indication: anemia, diabetic wounds, and reduction of ischemic complications
Development Stage: Phase II
Developer:GlaxoSmithKline

UNII:JVR38ZM64B

ダプロデュスタット
Daprodustat

C₁₉H₂₇N₃O₆ : 393.43
[960539-70-2]

Daprodustat , also known as GSK1278863, is a novel HIF-prolyl hydroxylase inhibitor. Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease

Originator GlaxoSmithKline
Class Antianaemics; Pyrimidines; Small molecules
Mechanism of ActionErythropoiesis stimulants; Prolyl hydroxylase inhibitors

Phase II Anaemia; Perioperative ischaemia
Phase I Diabetic foot ulcer; Tendon injuries
DiscontinuedPeripheral arterial disorders

Most Recent Events

27 Jul 2015No recent reports of development identified – Phase-II for Anaemia in India and New Zealand (PO)
27 Jul 2015Daprodustat is still in phase II trials for Anaemia in the USA, Australia, Canada, Czech Republic, Denmark, France, Germany, Hungary, Japan, Poland, Russia, Spain, South Korea, and United Kingdom
01 Jun 2015GlaxoSmithKline completes a phase I trial in Tendon injuries (In volunteers) in USA (PO) (NCT02231190)

WHO ATC code:

B03 (Antianemic Preparations)C (Cardiovascular System)

C01 (Cardiac Therapy)

D03 (Preparations for Treatment of Wounds and Ulcers)

M09A-X (Other drugs for disorders of the musculo-skeletal system)

EPhMRA code:

B3 (Anti-Anaemic Preparations)C1 (Cardiac Therapy)

C6A (Other Cardiovascular Products)

D3A (Wound Healing Agents)

M5X (All Other Musculoskeletal Products)

Daprodustat (INN) (GSK1278863) is a drug which acts as a HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and red blood cells. It is in Phase III clinical trials for the treatment of anemia secondary to chronic kidney disease.^[1]^[2] Due to its potential applications in athletic doping, it has also been incorporated into screens for performance-enhancing drugs.^[3]

SYN 1

SYN 2

^PATENT

WO 2007150011

https://www.google.com.ar/patents/WO2007150011A2

Illustrated Methods of preparation

Scheme 1

a) 1. NaH, THF, rt 2. R¹NCO, 60 ⁰C; b) 1. NaH, THF or dioxane, rt 2. R⁴NCX, heat; c) H₂NCH₂CO₂H, DBU, EtOH, 160⁰C, microwave.

Scheme 2

a) R¹NH₂, CH₂Cl₂ or R¹NH₂-HCl, base, CH₂Cl₂; b) CH₂(C(O)Cl)₂, CH₂Cl₂, reflux or CH₂(CO₂Et)₂, NaOEt, MeO(CH₂)₂OH, reflux or 1. EtO₂CCH₂COCl, CHCl₃, 70 ⁰C 2.

DBU, CHCl₃, 70 ⁰C; c) 1. YCNCH₂CO₂Et,, EtPr’₂N, CHCl₃ or CH₂Cl₂ 2. aq NaOH, EtOH, rt. Scheme 3 (for R¹ = R⁴)

a) CDI,

DMF, 70 ⁰C or , EtOAc, rt

Scheme 4

a) OCNCH₂CO₂Et, EtPr’₂N, CHCl₃ or CH₂Cl₂; b) 1. R¹HaI, Na/K₂CO₃, DMF or DMA, 100 ⁰C or R¹HaI, pol-BEMP, DMF, 120 ⁰C, microwave 2. aq NaOH, MeOH or EtOH, rt.

Scheme 5

a) 1. CH₂(CO₂H)₂, THF, O ⁰C – rt 2. EtOH, reflux; b) 1. OCNCH₂CO₂Et, EtPr’₂N, CH₂Cl₂ 2. aq NaOH, EtOH, rt.

Scheme 6

a) 1. Phthalimide, DIAD, PPh₃, THF 2. (NH₂)₂, EtOH, reflux.

Scheme 7

a) Ac₂O, AcOH, 130 ⁰C.

Example 18

N-T(1 ,3-Dicvclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahvdro-5-pyrimidinyl)carbonyl1grycine Method 1

18.1a) h3-Dicvclohexyl-2A6(lH,3H,5H)-pyrimidinetrione. Dicyclohexylurea (3.0 g, 13.39 mmoles) was stirred in chloroform (80 mL) and treated with a solution of malonyl dichloride (1.3 mL, 13.39 mmoles) in chloroform (20 mL), added dropwise under argon. The mixture was heated at 50⁰C for 4 hours, wasahed with 1 molar hydrochloric acid and evaporated onto silica gel. Flash chromatography (10-30% ethyl acetate in hexane) to give the title compound (2.13 g, 55%). 1Η NMR (400 MHz, OMSO-d₆) δ ppm 4.46 (tt, J=12.13, 3.54 Hz, 2 H), 3.69 (s, 2 H), 2.15 (qd, J=12.46, 3.28 Hz, 4 H), 1.77 (d, J=13.14 Hz, 4 H), 1.59 (t, J=12.76 Hz, 6 H), 1.26 (q, J=12.97 Hz, 4 H), 1.04 – 1.16 (m, 2 H)

18.1b) N-r(1.3-Dicvclohexyl-6-hvdroxy-2.4-dioxo-1.2.3.4-tetrahvdro-5- pyrimidinvDcarbonyll glycine. Ethyl isocyanatoacetate (802 uL, 7.15 mmoles) was added to a mixture of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (2.1 g, 7.15 mmoles) and diisopropylethylamine (2.47 mL, 14.3 mmoles) in dichloromethane (100 mL) and stirred overnight. The reaction mixture was washed with 1 molar hydrochloric acid (x2) and evaporated. The residue was dissolved in ethanol (10 mL) and treated with 1.0 molar sodium hydroxide (5 mL). The mixture was stirred for 72 hours, acidified and extracted into ethyl acetate. Some ester remained, therefore the solution was evaporated and ther residue was dissolved in 1 molar soldium hydroxide solution with warming and strred for 2 hours. The mixture was acidified with IM HCl and extracted with ethyl acetate (x2). The combined extracts were washed with 1 molar hydrochloric acid , dried and evaporated to a solid which was slurried in a mixture of diethyl ether and hexane, collected, washed with the same solvent mixture and dried to give the title compound (1.86 g, 66%). IH NMR (400 MHz, DMSO-^₆) δ ppm 13.07 (br. s., 1 H), 10.19 (t, J=5.31 Hz, 1 H), 4.63 (t, J=10.99 Hz, 2 H), 4.12 (d, J=5.56 Hz, 2 H), 2.27 (q, J=I 1.71 Hz, 4 H), 1.79 (d, J=12.88 Hz, 4 H), 1.50 – 1.69 (m, 6 H), 1.28 (q, J=12.97 Hz, 4 H), 1.12 (q, J=12.72 Hz, 2 H)

Method 2

18.2a) 1.3-Dicvclohexyl-2.4.6πH.3H.5H)-pyrimidinetrione. A solution of N₅N- dicyclohexylcarbodiimide (254 g; 1.23 mol.) in anhydrous TΗF (700 mL) was added dropwise to a cold (0 ⁰C) solution of malonic acid (64.1 g; 0.616 mol.) in anhydrous TΗF (300 mL) over a period of- 30 minutes. The mixture was stirred and allowed to warm to room temperature over 2 h. (After 1 h, the mixture became very thick with precipitate so further anhydrous TΗF (500 mL) was added to facilitate agitation.). The mixture was filtered and the filtrate evaporated to afford a yellow solid which was immediately slurried in ethanol (1 L) and heated to reflux temperature. The mixture was then allowed to cool to room temperature then filtered and the solid washed with cold ethanol (250 mL) to afford the title compound (129.4 g; 72%) as a colorless solid. 1Η NMR (400 MHz, DMSO-(Z₆) δ ppm 1.03 – 1.18 (m, 2 H) 1.18 – 1.34 (m, 4 H) 1.59 (t, J=13.14 Hz, 6 H) 1.76 (d, J=12.88 Hz, 4 H) 2.04 – 2.24 (m, 4 H) 3.69 (s, 2 H) 4.35 – 4.54 (m, 2 H).

18.2b) Ethyl N-[(l .3-dicvclohexyl-6-hvdroxy-2.4-dioxo- 1.2.3.4-tetrahydro-5- pyrimidinyPcarbonyll glycinate. A solution of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (120.0 g; 0.41 mol.) and diisopropylethylamine (105.8 g; 0.82 mol.) in dichloromethane (1 L) was stirred and treated dropwise with a solution of ethyl isocyanatoacetate (53.0 g; 0.41 mol.) in dichloromethane (500 mL) and the mixture was then stirred at room temperature overnight. The mixture was then treated dropwise with 6M aq. hydrochloric acid (500 mL) and the separated organic layer was dried and evaporated. The resulting solid was slurried in hexanes (500 mL) and heated to reflux temperature. The mixture was then allowed to cool and filtered to afford ethyl N- [(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.1 g; 92%) as a cream powder. IH NMR (400 MHz, CHLOROFORM-,/) δ ppm 1.24 (s, 2 H) 1.37 (s, 7 H) 1.52 – 1.76 (m, 6 H) 1.78 – 1.94 (m, 4 H) 2.25 – 2.48 (m, 4 H) 4.17 (d, J=5.81 Hz, 2 H) 4.28 (q, J=7.24 Hz, 2 H) 4.74 (s, 2 H) 10.37 (t, J=4.67 Hz, 1 H). 18.2c)

N-rπ^-Dicyclohexyl-ό-hydroxy^^-dioxo-l^J^-tetralivdro-S- pyrimidinyDcarbonyll glycine. A stirred suspension of ethyl Ν-[(l,3-dicyclohexyl-6-hydroxy-2,4- dioxo-l,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.0 g; 0.377 mol.) in ethanol (1.5 L) was treated dropwise with 6M aq. Sodium hydroxide (250 mL) and stirred at room temperature for 3 h. The solution was then acidified by the dropwise addition of 6M aq. hydrochloric acid (300 mL), diluted with water (IL) and then filtered. The crude solid was slurried in water (2 L) then stirred vigorously and heated at 35 ⁰C for 1 h and filtered and dried. The solid material (~ 138 g) was then crystallized from glacial acetic acid (1.5 L) (with hot filtration to remove a small amount of insoluble material). The solid, which crystallized upon cooling, was collected and washed with cold glacial acetic acid (3 x 100 mL) to afford N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine (116.2 g; 78%) as a colorless solid.

IH NMR (400 MHz, DMSO-(Z₆) δ ppm 1.11 (d, J=12.88 Hz, 2 H) 1.27 (q, J=12.80 Hz, 4 H) 1.62 (s, 6 H) 1.70 – 1.90 (m, J=12.88 Hz, 4 H) 2.11 – 2.44 (m, 4 H) 4.11 (d, J=5.81 Hz, 2 H) 4.45 – 4.77 (m, 2 H) 10.19 (t, J=5.81 Hz, 1 H) 13.08 (s, 1 H).

References

Jump up^ Schmid H, Jelkmann W. Investigational therapies for renal disease-induced anemia. Expert Opin Investig Drugs. 2016 Aug;25(8):901-16. . doi:10.1080/13543784.2016.1182981. PMID 27122198. Missing or empty |title= (help)
Jump up^ Ariazi JL, Duffy KJ, Adams DF, Fitch DM, Luo L, Pappalardi M, Biju M, DiFilippo EH, Shaw T, Wiggall K, Erickson-Miller C. Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia. J Pharmacol Exp Ther. 2017 Dec;363(3):336-347. . doi:10.1124/jpet.117.242503. PMID 28928122. Missing or empty |title= (help)
Jump up^ Thevis M, Milosovich S, Licea-Perez H, Knecht D, Cavalier T, Schänzer W. Mass spectrometric characterization of a prolyl hydroxylase inhibitor GSK1278863, its bishydroxylated metabolite, and its implementation into routine doping controls. Drug Test Anal. 2016 Aug;8(8):858-63. . doi:10.1002/dta.1870. PMID 26361079. Missing or empty |title= (help)

Daprodustat
Clinical data

Synonyms	GSK1278863
ATC code	None
Identifiers
IUPAC name [show]
CAS Number	960539-70-2
PubChem CID	91617630
Chemical and physical data
Formula	C₁₉H₂₇N₃O₆
Molar mass	393.44 g/mol
3D model (JSmol)	Interactive image

//////////////Daprodustat, GSK1278863, ダプロデュスタット , HIF-prolyl hydroxylase inhibitor, anemia, diabetic wounds, reduction of ischemic complications, Phase II, GlaxoSmithKline

C1CCC(CC1)N2C(=O)C(C(=O)N(C2=O)C3CCCCC3)C(=O)NCC(=O)O

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