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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

New “mTOR” inhibitor from Exelixis, Inc., XL 388

October 28, 2015 4:18 am / 3 Comments on New “mTOR” inhibitor from Exelixis, Inc., XL 388

XL 388

A Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)

Benzoxazepine-Containing Kinase Inhibitor

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone

[7-(6-amino-3-pyridinyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]-Methanone,

(7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone

MW 455.50, CAS 1251156-08-7, MF C₂₃ H₂₂ F N₃ O₄ S

Exelixis, Inc. INNOVATOR, IND Filed

½H2O

C23H22FN3O4S.½H2O , Molecular Weight: 464.51

MONO HYDROCHLORIDE…..CAS 1777807-51-8, [7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)

TLC Rf = 0.33 (Dichloromethane:Methanol [95:5])

Potent and selective mTOR inhibitor (IC₅₀ = 9.9 nM). Inhibits mTOR activity in an ATP-competitive manner. Exhibits >300-fold selectivity for mTOR over PI 3-K and a range of other kinases. Displays antitumor activity in athymic nude mice implanted with tumor xenografts.

SYNTHESIS

CLICK ON IMAGE FOR CLEAR VIEW……………..

Tyrosine kinases are important enzymes for signal transduction in cells. Therefore, they are often targets for the treatment of diseases that are caused by dysregulation of cellular processes, such as cancers. Mammalian target of rapamycin (mTOR) is a kinase in the phosphatidylinositol-3-kinase (PI3K) family of enzymes and is implicated in the regulation of cell growth and proliferation. Various inhibitors of mTOR have been explored as possible agents for treatment of various cancers

The mammalian target of rapamycin (mTOR) is a large protein kinase that integrates both extracellular and intracellular signals of cellular growth, proliferation, and survival. Both extracellular mitogenic growth factor signaling from cell surface receptors and intracellular signals that convey hypoxic stress, energy, and nutrient status converge at mTOR. mTOR exists in two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

mTORC1 is a key mediator of translation and cell growth, via its substrates p70S6 kinase (p70S6K) and eIF4E binding protein 1 (4E-BP1), and promotes cell survival via the serum and glucocorticoid-activated kinase (SGK), whereas mTORC2 promotes activation of prosurvival kinase AKT. mTORC1, but not mTORC2, can be inhibited by an intracellular complex between rapamycin and FK506 binding protein (FKBP). However, rapamycin–FKBP may indirectly inhibit mTORC2 in some cells by sequestering mTOR protein and thereby inhibiting assembly of mTORC2.

Given the role of mTOR signaling in cellular growth, proliferation, and survival as well as its frequent deregulation in cancers, several rapamycin analogues (rapalogues) that are selective allosteric mTORC1 inhibitors have been extensively evaluated in a number of cancer clinical trials.

Demonstrated clinical efficacy for rapalogues is currently limited to patients with advanced, metastatic renal cell carcinoma (RCC) despite extensive development efforts.

This result is likely attributed not only to a lack of inhibition of mTORC2 by rapalogues that leads to upregulation of Akt through a negative feedback loop, but also to only partial inhibition of mTORC1.Therefore, ATP-competitive mTOR inhibitors that should simultaneously inhibit both mTORC1 and mTORC2 may offer a clinical advantage over rapalogues.

As a key component of the phosphoinositide 3-kinase-related kinase (PIKK) family, which is comprised of phosphoinositide 3-kinases (PI3Ks), DNA-PK, ATM, and ATR, mTOR shares the highly conserved ATP binding pockets of the PI3K family with sequence similarity of 25% in the kinase catalytic domain.

In light of this fact, it is not surprising that many of the first reported ATP-competitive mTOR inhibitors such as BEZ235 and GDC-0980 also inhibited PI3Ks. PI3Ks are responsible for the production of 3-phosphoinositide lipid second messengers such as phosphatidylinositol 3,4,5-triphosphate (PIP3), which are involved in a number of critical cellular processes, including cell proliferation, cell survival, angiogenesis, cell adhesion, and insulin signaling.

Therefore, the development of ATP-competitive mTOR inhibitors that are selective over PI3Ks may offer an improved therapeutic potential relative to rapalogues as well as dual PI3K/mTOR inhibitors. Recently, several selective ATP-competitive mTOR inhibitors such as Torin 2 and AZD8055 have been reported with sufficient promise to warrant clinical trials.

PATENT

WO 2010118208

http://www.google.com.ar/patents/WO2010118208A1?cl=en

Example 2:

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl] [3-fluoro- 2-methyl-4-(methylsulfonyl)phenyl]methanone

tørt-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/] [l,4]oxazepine-4(5H)- carboxylate. To a mixture of 4-(te/t-butoxycarbonyl)-2,3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1 ,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol%) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77 %) as an off-white solid. MS (EI) for Ci₉H₂₃N₃O₃: 342 (MH⁺).

5-(2,3,4,5-Tetrahydrobenzo[/] [l,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/][l,4]oxazepine- 4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1 ,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5 % methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96 %). MS (EI) for Ci₄Hi₅N₃O: 242 (MH⁺).

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl][3-fluoro-2- methyl-4-(methylsulfonyl)phenyl]methanone.

To a stirred suspension of 5-(2, 3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4- (methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0 ⁰C for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.24-8.03 (dd, IH), 7.79-7.71 (m, IH), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, IH), 7.05-7.01 (dd, IH), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, IH), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36(d, 3H), 2.12-1.77 (d, 3H).

MS (EI) C₂₃H₂₂FN₃O₄S: 456 (MH⁺).

PAPER

Journal of Medicinal Chemistry (2013), 56(6), 2218-2234.

J. Med. Chem., 2013, 56 (6), pp 2218–2234

DOI: 10.1021/jm3007933

http://pubs.acs.org/doi/abs/10.1021/jm3007933

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

(7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone (28)

¹H NMR (400 MHz, DMSO-d₆): δ (rotamers are observed) 8.24 and 8.03 (d, J = 2.4 Hz, 1H), 7.77 and 7.72 (t, J = 7.6 Hz, 1H), 7.71–7.39 (m, 2H), 7.57 and 6.63 (d, J = 2.4 Hz, 1H), 7.28 and 7.19 (d, J = 7.6 Hz, 1H), 7.04 and 7.02 (d, J = 8.0 Hz, 1H), 6.52 and 6.46 (d, J = 8.8 Hz, 1H), 6.05 (br s, 2H), 4.93–4.31 (m, 2H), 4.28–3.56 (m, 4H), 3.37 and 3.34 (s, 3H), 2.12 and 1.77 (d,J = 1.6 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 167.3, 167.2, 166.6, 166.6, 158.9, 158.9, 158.4, 158.4, 157.4, 157.2, 155.9, 155.8, 145.4, 145.1, 145.1, 144.0, 143.9, 135.0, 134.7, 132.9, 132.8, 129.4, 129.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 125.9, 125.6, 125.4, 123.6, 123.5, 123.3, 123.1, 122.8, 122.0, 122.0, 121.9, 121.9, 121.2, 120.7, 107.8, 107.8, 70.9, 70.8, 51.1, 51.1, 47.4, 46.5, 43.5, 43.5, 43.5, 43.4, 11.0, 10.9, 10.7, 10.6. IR (KBr pellet): 1623, 1487, 1457, 1423, 1385, 1314, 1269, 1226, 1193, 1144, 1133, 1054, 1031, 962, 821, 768 cm^–1. Mp: 204–205 °C. MS (EI): m/z for C₂₃H₂₂FN₃O₄S, 456.0 (MH⁺). High-resolution MS (FAB MS using glycerol as the matrix): m/z calcd for C₂₃H₂₂FN₃O₄S 456.13878, found 456.13943.

PATENT

US20100305093

http://www.google.com/patents/US20100305093

SYNTHETIC EXAMPLES

1-Bromo-3,4-difluoro-2-methylbenzene. To a stirred mixture of 2,3-difluorotoluene (1.9 g, 14.8 mmol) and iron (82.7 mg, 1.48 mmol) in chloroform (10 mL) at rt was added bromine (76 μL, 14.8 mmol) over 2 h. The resulting mixture was stirred at rt overnight. Excess water (10 mL) was added and the reaction mixture was diluted with ether (20 mL). The separated organic layer was washed with aqueous sodium thiosulfate, brine, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was distilled to give the desired product (2.49 g, 81%) as a colorless oil.
3,4-Difluoro-2-methylbenzoic acid. To a stirred solution of 1-bromo-3,4-difluoro-2-methylbenzene (940 mg, 4.54 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium bromide (3.0 mL, 6.0 mmol) over 1 h at 0° C. The resulting mixture was stirred at rt for 24 h. Carbon dioxide (CO₂), generated from dry ice, was introduced to the reaction mixture over 2 h and the resulting mixture was stirred for an additional 30 min. The reaction mixture was quenched with addition of an excess amount of water (5 mL) and the tetrahydrofuran was removed on a rotary evaporator. The resulting aqueous layer was diluted with water (5 mL) and acidified with concentrated hydrochloric acid to pH 1-2. The white precipitate was filtered and washed with water and cold hexanes and dried under high vacuum to give the desired product (630 mg, 81%) as a white powder. MS (EI) for C₈H₆F₂O₂: 171 (MH⁻).
3-Fluoro-2-methyl-4-(thiomethyl)benzoic acid. To a stirred solution of acid 3,4-difluoro-2-methylbenzoic acid (700 mg, 4.1 mmol) in dimethylsulfoxide (5 mL) was added powdered potassium hydroxide (274 mg, 4.9 mmol) and the mixture was stirred at rt for 30 min. Sodium thiomethoxide (342 mg, 4.9 mmol) was added to the mixture and the resulting mixture was stirred at 55-60° C. for 4 h. Additional powdered potassium hydroxide (70 mg, 1.2 mmol), sodium thiomethoxide (60 mg, 0.8 mmol), and dimethylsulfoxide (2 mL) were added to the reaction mixture. After stirring for 4 h, the mixture was cooled to 0° C. and quenched with excess water (10 mL). The resulting suspension was acidified at 0° C. with concentrated hydrochloric acid to pH 1-2. The white precipitate was collected by suction filtration, washed with water and dried under vacuum overnight to give the desired product (870 mg, 100%). The intermediate sulfide was used in the next step without further purification. MS (EI) for C₉H₉FO₂S: 199.1 (MH⁻).
3-Fluoro-2-methyl-4-(methylsulfonyl)benzoic acid. To a stirred suspension of 3-fluoro-2-methyl-4-(thiomethyl)benzoic acid in an acetone/water (1 mL/10 mL) mixture was added sodium hydroxide (330 mg, 8.25 mmol) and sodium bicarbonate (680 mg, 8.1 mmol). Oxone (˜4 g) was added portionwise to the reaction mixture at 0° C. over 2 h. The reaction was monitored by LC/MS. Concentrated hydrochloric acid was added to adjust the pH 2-3 and the white precipitate was collected by suction filtration, washed with water, and dried under vacuum. Dried precipitate was suspended in water (10 mL), stirred vigorously at rt for 1 h, filtered, washed with water, and hexanes and dried under vacuum to give the desired product (886 mg, 94%) as a white powder. MS (EI) for C₉H₉FO₄S: 231 (MH⁻).
3-Fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride. A mixture of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (860 mg, 3.7 mmol) in thionyl chloride (10 mL) was heated to reflux for 3 h. (the reaction mixture became homogenous). The reaction mixture was concentrated on a rotary evaporator to give the crude acid chloride. This acid chloride was triturated with dichloromethane (2 mL) and concentrated under reduced pressure. The trituration process was repeated 3 times until the product (900 mg, 98%) was obtained as a white powder.

Reference Example 2Ethyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate hydrochloride salt

4-(ethoxycarbonyl)phenylboronic acid (22.16 g, 114 mmol), tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-carboxylate (34.08 g, 104 mmol), prepared as described in Reference Example 4, Pd(dppf)Cl₂and TEA (21 g, 208 mmol) were combined in a mixture of dioxane (200 mL) and water (20 mL). The reaction mixture was heated to 90° C. for 2 h, then cooled and the solvent removed. Purification of the residue by silica chromatography gave the desired product ester (31.3 g, 69% yield).
To the solution of tert-butyl 7-(4-(ethoxycarbonyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10.3 g, 25.93 mmol) in MeOH (120 mL) was added a solution of 4 N HCl in dioxane (50 mL). The reaction mixture was heated to 50° C. for 3 h (monitored by LC/MS). The reaction mixture was allowed to cool to rt. Ethyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate as the hydrochloride salt (8.8 g, 99% yield) was collected by suction filtration.

tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate. Commercially-available 5-bromo-2-hydroxybenzaldehyde (4.0 g, 10 mmol) and 2-aminoethanol were combined in THF/MeOH (100 mL, 10:1) and sodium borohydride (0.76 g, 2.0 mmol) was added with stirring. The resulting reaction mixture was stirred at 40° C. for 4 h, concentrated on a rotary evaporator then diluted with EtOAc (50 mL) and saturated NaHCO₃(30 mL). To this suspension was added di-tert-butyl dicarbonate (2.83 g, 13 mmol). The mixture was stirred at rt overnight. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was filtered to obtain the desired product (6.8 g, 98%) as a white solid. MS (EI) for C₁₄H₂₀BrNO₄, found 346 (MH+).
tert-Butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate (3.46 g, 10 mmol) and triphenylphosphine (3.96 g, 15 mmol) were combined in DCM (100 mL) and diisopropyl azodicarboxylate (3.03 g, 15 mmol) was added. The resulting reaction mixture was stirred at rt for 12 h. The reaction mixture was washed with water, dried, filtered, and concentrated on a rotary evaporator. The resulting crude product was purified via silica gel chromatography eluting with 8:2 hexane/ethyl acetate to give the desired product (1.74 g, 53%) as a white solid. MS (EI) for C₁₄H₁₈BrNO₃, found 328 (MH+).

Reference Example 54-(tert-Butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid

To a stirred solution of tert-butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10 g, 30.5 mmol), prepared as described in Reference Example 4, and triisopropylborate (9.1 mL, 40 mmol) in dry tetrahydrofuran (100 mL) was added dropwise n-butyllithium in tetrahydrofuran (1.6 M, 25 mL, 40 mmol) while maintaining the temperature below −60° C. Upon completion of addition, the reaction mixture was stirred for 30 min, then quenched with 1 N aqueous hydrochloric acid (35 mL) and allowed to warm to rt. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was stirred for 1 h and filtered to obtain 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (8.6 g, 95%) as a white solid. MS (EI) for C₁₄H₂₀BNO₅: 194 (M-Boc).

tert-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. To a mixture of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol %) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77%) as an off-white solid. MS (EI) for C₁₉H₂₃N₃O₃: 342 (MH⁺).
5-(2,3,4,5-Tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5% methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96%). MS (EI) for C₁₄H₁₅N₃O: 242 (MH⁺).
[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone. To a stirred suspension of 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0° C. for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.24-8.03 (dd, 1H), 7.79-7.71 (m, 1H), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, 1H), 7.05-7.01 (dd, 1H), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, 1H), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36 (d, 3H), 2.12-1.77 (d, 3H). MS (EI) C₂₃H₂₂FN₃O₄S: 456 (MH⁺).

PAPER

Org. Process Res. Dev., 2015, 19 (7), pp 721–734

DOI: 10.1021/acs.oprd.5b00037

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00037

The benzoxazepine core is present in several kinase inhibitors, including the mTOR inhibitor 1. The process development for a scalable synthesis of 7-bromobenzoxazepine and the telescoped synthesis of 1 are reported. Compound 1 consists of three chemically rich, distinct fragments: the tetrahydrobenzo[f][1,4]oxazepine core, the aminopyridyl fragment, and the substituted (methylsulfonyl)benzoyl fragment. Routes were developed for the preparation of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (17) and tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2). The processes for the two compounds were scaled up, and over 15 kg of each starting material was prepared in overall yields of 42% and 58%, respectively.

A telescoped sequence beginning with compound 2 afforded 7.5 kg of the elaborated intermediate 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-2-amine dihydrochloride (6) in 63% yield. Subsequent coupling with benzoic acid 17 gave 7.6 kg of the target compound 1 in 84% yield. The preferred hydrochloride salt was eventually prepared. The overall yield for the synthesis of inhibitor 1 was 21% over eight isolated synthetic steps, and the final salt was obtained with 99.7% HPLC purity.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone (1)

Compound 1 was observed as a mixture of two rotational isomers in the ¹H and ¹³C NMR spectra.

¹H NMR (400 MHz, DMSO-d₆): δ 8.24–8.03 (dd, 1H), 7.79–7.71 (m, 1H), 7.71–7.69 (dd, 0.5H), 7.57–7.57 (d, 0.5H), 7.44–7.40 (m, 1.5H), 7.29–7.19 (dd, 1H), 7.05–7.01 (dd, 1H), 6.64–6.63 (d, 0.5H), 6.54–6.45 (dd, 1H), 6.06 (s, 2H), 4.93–4.31 (m, 2H), 4.31–3.54 (m, 4H), 3.37–3.36 (d, 3H), 2.12–1.77 (d, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 167.3, 167.2, 166.6, 166.6, 158.9, 158.9, 158.4, 158.4, 157.4, 157.2, 155.9. 155.8, 145.4, 145.1, 145.1, 144.0, 143.9, 135.0, 134.7, 132.9, 132.8, 129.4, 129.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 125.9, 125.6, 125.4, 123.6, 123.5, 123.3, 123.1, 122.8, 122.0, 122.0, 121.9, 121.9, 121.2, 120.7, 107.8, 107.8, 70.9, 70.8, 51.1, 51.1, 47.4, 46.5, 43.5, 43.5, 43.5, 43.4, 11.0, 10.9, 10.7, 10.6. IR (KBr pellet): 1623, 1487, 1457, 1423, 1385, 1314, 1269, 1226, 1193, 1144, 1133, 1054, 1031, 962, 821, 768 cm^–1. MS (EI) C₂₃H₂₂FN₃O₄S: found 456.2 ([M + H]⁺). High-resolution MS (FAB-MS using glycerol as a matrix) for C₂₃H₂₂FN₃O₄S: found 456.13943 ([M + H]⁺), calcd 456.13878.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)

1·HCl as a white solid (7.81 kg, 95%, 99.7% purity by AN-HPLC).

Analyses: OVI: DMF < 100 ppm, DMC < 100 ppm, acetone = 3081 ppm, MTBE < 100 ppm, iPAc < 100 ppm, THF < 100 ppm. Heavy metals: Pd ≤ 0.2 ppm, others < 20 ppm (USP ⟨231⟩). ¹H NMR (400 MHz, DMSO-d₆), equimolar amounts of two rotamers: δ 8.20–8.40 (br s, 2H), 8.33 (s, 0.5H), 8.31 (d, J = 2.8 Hz, 0.5H), 8.15 (d, J = 2.0 Hz, 0.5H), 7.96 (dd, J = 9.7, 2.0 Hz, 0.5H), 7.70–7.78 (m, 1.5H), 7.55–7.57 (m, 0.5H), 7.51–7.55 (m, 0.5H), 7.28 (d, J = 8.6 Hz, 0.5H), 7.17 (d, J = 3.1 Hz, 0.5H), 7.15 (d, J = 5.1 Hz, 0.5H), 7.05–7.11 (m, 1.5H), 6.83 (d, J = 2.7 Hz, 0.5H), 4.86–4.99 (m, 1H), 4.29–4.56 (m, 1H), 4.10–4.27 (m, 2H), 3.93–4.04 (m, 0.5H), 3.45–3.65 (m, 1.5H), 3.37 (s, 1.5 H), 3.35 (s, 1.5H), 2.12 (d, J = 2.0 Hz, 1.5H), 1.76 (d, J = 2.0 Hz, 1.5H). ¹³C NMR (100 MHz, DMSO-d₆), equimolar amounts of two rotamers: δ 168.1, 167.5, 159.4, 159.2, 159.1, 156.6, 153.9, 153.8, 144.6, 142.9, 142.3, 133.0, 132.7, 130.0, 129.9, 129.7, 129.5, 129.1, 129.0, 128.9, 128.8, 128.5, 127.7, 127.6, 127.5, 127.1, 126.9, 124.4, 124.3, 124.1, 122.7, 122.1, 121.6, 114.4, 71.2, 51.7, 51.3, 47.9, 46.9, 44.3, 44.2, 11.7, 11.4.

REFERENCES

Anand, N.; Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of their Use and Manufacture. U.S. Patent 8,648,066, Feb 11, 2014.

Aay, N.; Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of their Use and Manufacture. U.S. Patent 8,637,499, Jan 28,2014.

US20100305093

US8637499 *	May 25, 2010	Jan 28, 2014	Exelixis, Inc.	Benzoxazepines as inhibitors of PI3K/mTOR and methods of their use and manufacture
US20120258953 *	May 25, 2010	Oct 11, 2012	Exelixis, Inc.	Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of Their Use and Manufacture

PROFILE

Sriram Naganathan

Senior Director

Chemical Development at Dermira, Inc.

Lives San jose caifornia

Sriram Naganathan, S.N.: Dermira, Inc., 275 Middlefield Road, Suite 150, Menlo Park, CA 94025.

E-mail: sriram.naganathan@dermira.com.

LINKS

https://www.linkedin.com/pub/sriram-naganathan/3/50a/5b6

https://www.facebook.com/sriram.naganathan.5

snaganat@exelixis.com, sriramrevathi@yahoo.com

sriram.naganathan@dermira.com

Summary

Chemical process-development and CMC professional offering 20 years of experience from preclinical development through commercialization of small molecules and peptides.

Hands-on experience in multi-step synthesis, route-scouting, process development, scale-up, tech transfer to CRO/CMO, including manufacture under cGMP and process validation.

Extensive knowledge of CMC regulatory landscape (FDA, EMEA) including preparation of CMC sections of IND, IMPD, NDA and MAA

Experience

Senior Director, Chemical Development

Dermira, Inc.

January 2015 – Present (10 months)Menlo Park, CA

Consultant

Intarcia Therapeutics

December 2014 – January 2015 (2 months)

Senior Director

Exelixis

March 2013 – November 2014 (1 year 9 months)South San Francisco, CA

Exelixis , Inc.

210 E. Grand Ave

South San Francisco , California 94080
United States

Company Description: Exelixis, Inc. (Exelixis) is developing therapies for cancer and other serious diseases. Through its drug discovery and development activities, the Company is… more

Director

Exelixis, Inc

July 2008 – February 2013 (4 years 8 months)

Senior Scientist II

Exelixis

August 2004 – January 2008 (3 years 6 months)

Associate Director

CellGate, Inc.

2000 – 2004 (4 years)

Research Scientist

Roche Bioscience

1997 – 2000 (3 years)

Research Scientist

Cultor

1995 – 1997 (2 years)

Research Scientist

Pfizer

1994 – 1997 (3 years)

Research Assistant Professor

University of Pittsburgh

April 1992 – October 1994 (2 years 7 months)

Worked on Vitamin K mechanism in the labs of (Late) Prof Paul Dowd

Education

University at Albany, SUNY

Ph.D., Organic Chemistry (Organosulfur)

1988 – 1992

The University of Kansas

MS, Organic Chemistry

1983 – 1988

Vivekananda College (University of Madras), India

Bachelor of Science (B.Sc.), Chemistry

1980 – 1983

Shri Nehru Vidyalaya

(Above) Former Group members join Professor Block at the National ACS Meeting in San Francisco, March 2010: from left, Dr. Shuhai Zhao, Dr. Sherida Johnson, Professor Block, Dr. Sriram Naganathan.

Sriram Naganathan, Ph.D. 1992, snaganat@exelixis.com, sriramrevathi@yahoo.com

snaganathan

As many things change, many things remain constant. One such constant is the frequent reminder that “You can take the boy out of sulfur chemistry but you cannot take sulfur chemistry out of the boy”. At every stage of my professional career organic chemistry of sulfur and sulfur-containing compounds have followed me (or is it the other way around?). Not many can point to the cover of an Angewandte Chemie issue as a synopsis of his/her thesis work – I will be forever grateful for that opportunity received in the Block Group.

As a post-doc in the late Prof. Paul Dowd’s lab at the University of Pittsburgh we used sulfur-containing analogs of vitamin K to probe the mechanism of action. I was then hired at Pfizer Central Research in Groton, CT in the Specialty Chemicals Division to investigate possible decomposition pathways of sulfur-containing high-intensity artificial sweeteners.

At Roche Bioscience (Palo Alto, CA) and Exelixis (South San Francisco, CA – my current job………CHANGED……Dermira) I was involved in process development for the preparation of therapeutic agents, several of them sulfur-containing molecules. Between those two positions I was a Senior Scientist at CellGate (Sunnyvale, CA).

We attempted to exploit the chemistry of sulfur-containing linkers to target the delivery active pharmaceutical agents, using the transport properties of polyarginines. Although I thought I was only training to become a synthetic organic chemist, I did not realize that my passion was really organic reaction mechanisms until I arrived in the Block lab – the two arms of the science are truly inseparable.

I realize after many years that the seed was really sown and nurtured during the many friendly and sometimes-fiery discussions in the lab, and further solidified in my post-doc years. I learned that every “blip-in-the-baseline” cannot to be ignored, and is part of the whole story.

As a process chemist in the pharma industry, I can attribute much of my success to lessons about careful and critical evaluation of primary data and thorough knowledge of reaction mechanisms. I am currently Director, Chemical Development, at Exelixis.NOW DERMIRA.

My primary responsibility involves the manufacture and potential commercialization of our primary product, cabozantinib. It was only natural that I developed a strong interest in the science of cooking and food. I have been pursuing this avenue since moving to Northern California.

I am also an avid gardener, experimenting with growing interesting varieties of chilies, tomatoes and then combining those with all sorts of alliums. It does help that I live close enough to Gilroy, CA, that I can often smell what they are famous for as I walk out of the front door!! I have shared my knowledge in several lectures at the Tech Museum (San Jose, CA) where I was a volunteer exhibit explainer.

My family (my wife Revathi and our two high-school-age daughters Swetha and Sandhya) like to travel and also enjoy the outdoor recreation so abundant in Northern California. We try to take in a new country each year and accomplish personal challenges. After many interesting years in the tech-industry, Revathi is a full-time mom. She is also a fitness instructor at the Y. Swetha and Sandhya are part of the water polo and swim teams at their school.

Swetha is very active in a leadership role for the robotics team, and Sandhya belongs to the quiz team. Revathi and I climbed Half Dome (Yosemite) a few years ago and I just completed a 100-mile bicycle ride around Lake Tahoe.

I remain a highly-opinionated baseball and college basketball fan (favorite teams: in order, Kansas, North Carolina and whoever happens to be playing Missouri and Duke). I am still an avid photographer, although I spend no money on film (I thought I was going to be the last guy on the planet still shooting film!!). I greatly value the many friendships developed during my stay in Albany and keep in touch with many.

In fact, one of my roommates from the SUNY days was instrumental in me getting my present position. Of course, this also means that I have lost touch with several friends during the past decades. If you are reading this and haven’t contacted me in a few years, please do, via e-mail.

We enjoy entertaining guests who drop by – so now you have no excuse not to contact us, especially when you visit the SF Bay Area.

OLD PROFLE……Dr Sriram Naganathan received his Ph.D. from SUNY-Albany where he studied organosulfur chemistry. He is currently an Associate Director at CellGate, Inc. located in Sunnyvale, California. CellGate is involved in the commercialization of novel medicines by utilizing proprietary transporter technology, based on oligomers of arginine, to enhance the therapeutic potential of existing drugs. His responsibilities include process development, scale-up and GMP production of clinical candidates, as well some basic research. He previously held positions at Pfizer Central Research and Roche Bioscience.

Dermira

Thomas G. Wiggans | Founder & Chief Executive Officer……..http://dermira.com/about-us/management-team/

CEO TOM WIGGANS, LEFT AND CMO GENE GAUER, RIGHT

Map of Dermira

Exelixis, Inc.

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

Directions to Exelixis, Inc.

101 Northbound from San Francisco Airport:

Take 101 North toward San Francisco.
Take the Grand Avenue exit, exit 425A, toward So San Francisco.
Turn right onto East Grand Ave.
210 East Grand Ave is on your right-hand side.

101 Southbound from San Francisco:

Take 101 South.
Take the Grand Avenue exit. Turn left at the first light.
Immediately turn left at the first light onto Grand Avenue (which will become East Grand Avenue)
210 East Grand Ave is on your right-hand side.

////////////mTOR inhibitor, Exelixis, Inc., PI3K, phosphatidylinositol-3-kinase, XL 388, XL388, IND Filed

IPI 504, Retaspamycin, Retaspimycin

October 27, 2015 4:55 am / Leave a comment

IPI 504, Retaspamycin, Retaspimycin

CAS 857402-63-2

Cas 857402-23-4 ( Retaspimycin); 857402-63-2 ( Retaspimycin HCl).

MF C31H45N3O8 BASE

MW: 587.32067 BASE

Infinity Pharmaceuticals Inc, INNOVATOR

[(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-6,20,22-trihydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16-oxo-21-(prop-2-enylamino)-17-azabicyclo[16.3.1]docosa-1(22),8,12,14,18,20-hexaen-10-yl] carbamate;hydrochloride

17-Allylamino-17-demethoxygeldanamycin Hydroquinone Hydrochloride

UNII-928Q33Q049
SEE………http://www.biotechduediligence.com/retaspamycin-hcl-ipi-504.html

Retaspimycin hydrochloride; 8,21-didehydro-17-demethoxy-18,21-dideoxo-18,21-dihydroxy-17-(2-propenylamino)-geldanamycin monohydrochloride
Application:	A novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90)
Molecular Weight:	624.17 ……….HCl salt
Molecular Formula:	C₃₁H₄₆ClN₃O_{8……….HCl salt}

Introduction

IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90).

Orphan drug designation was assigned to the compound by the FDA for the treatment of gastrointestinal stromal cancer (GIST).

Retaspimycin Hydrochloride is the hydrochloride salt of a small-molecule inhibitor of heat shock protein 90 (HSP90) with antiproliferative and antineoplastic activities. Retaspimycinbinds to and inhibits the cytosolic chaperone functions of HSP90, which maintains the stability and functional shape of many oncogenic signaling proteins and may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which may result in the induction of apoptosis.

Phase I study of Retaspimycin: A phase 1 study of IPI-504 (retaspimycin hydrochloride) administered intravenously twice weekly for 2 weeks at 22.5, 45, 90, 150, 225, 300 or 400 mg/m(2) followed by 10 days off-treatment was conducted to determine the safety and maximum tolerated dose (MTD) of IPI-504 in patients with relapsed or relapsed/refractory multiple myeloma (MM). Anti-tumor activity and pharmacokinetics were also evaluated. Eighteen patients (mean age 60.5 years; median 9 prior therapies) were enrolled. No dose-limiting toxicities (DLTs) were reported for IPI-504 doses up to 400 mg/m(2).

The most common treatment-related adverse event was grade 1 infusion site pain (four patients). All other treatment-related events were assessed as grade 1 or 2 in severity. The area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2-4 h for IPI-504 and its metabolites. Four patients had stable disease, demonstrating modest single-agent activity in relapsed or relapsed/refractory MM. (source: Leuk Lymphoma. 2011 Dec;52(12):2308-15.)

Figure Hsp90 protein partners and clients destabilized by Hsp90 inhibition (Jackson et al., 2004).

In a different approach, Infinity Pharmaceuticals has developed IPI504 (retaspimycin or 17-AAG hydroquinone, Figure 4) (Adams et al., 2005; Sydor et al., 2006), a new GA analogue, in which the quinone moiety was replaced by a dihydroquinone one. Indeed, the preclinical data suggested that the hepatotoxicity of 17-AAG was attributable to the ansamycin benzoquinone moiety, prone to nucleophilic attack.

Furthermore, it was recently reported that the hydroquinone form binds Hsp90 with more efficiency than the corresponding quinone form (Maroney et al., 2006). In biological conditions, the hydroquinone form can interconvert with GA, depending on redox equilibrium existing in cell. It has been recently proposed, that NQ01 (NAD(P)H: quinone oxidoreductase) can produce the active hydroquinone from the quinone form of IPI504 (Chiosis, 2006).

However, Infinity Pharmaceuticals showed that if the overexpression of NQ01 increased the level of hydroquinone and cell sensitivity to IPI504, it has no significant effect on its growth inhibitory activity. These results suggest that NQ01 is not a determinant of IPI504 activity in vivo (Douglas et al., 2009).

Figure 4: GA, 17-AAG, 17-DMAG and IPI504.

PATENT

http://www.google.com/patents/EP2321645A1?cl=en

Geldanamycin (IUPAC name ([18S-(4E,5Z,8R*.9R*.10E,12R*.13S*,14R*,l6S*)]- 9- [(aminocarbonyl)oxy]- 13- hydroxy- 8,14,19- trimetoxy- 4,10,12,16- tetramethyl- 2- azabicyclo[16.3.1.]docosa- 4,6.10,18,21- pentan- 3.20,22trion) is a benzoquinone ansamycin antibiotic which may be produced by the bacterium Streptorayces hygroscopicus. Geldanamycin binds specifically to HSP90 (Heat Shock Protein 90) and alters its function.

While Hsp90 generally stabilizes folding of proteins and, in particular in tumor cells, folding of overexpressed/mutant proteins such as v-Src. Bcr-Abl and p53. the Hsp90 inhibitor Geldanamycin induces degradation of such proteins.

The respectiv e formula of geldanamycin is given herein below:

E\en though geldanamycin is a potent antitumor agent, the use of geldanamycin also shows some negathe side-effects (e.g. hepatotoxicity) which led to the dev elopment of geldanamycin analogues/derivatives, in particular analogues/deriv atives containing a derivatisation at the 17 position. Without being bound by theory , modification at the 17 position of geldanamycin may lead to decreases hepatotoxicity.

Accordingly geldanamycin analogues/derivatives which are modified at the 17 position, such as 17-AAG (17-N-Allylamino-17-demethoxygeldanamycin), are preferred in context of the present invention. Also preferred herein are geldanamycin derivatives to be used in accordance with the present invention which are water-soluble or which can be dissoh ed in water completely (at least 90 %. more preferably 95 %. 96 %. 97 %, 98 % and most preferably 99 %). 17-AAG ([QS.5S,6RJS$EΛ0R,l \SΛ2E,14E)-2\- (allylamino)-6-hydroxy-5.11-diraethoxy-

3.7.9,15-tetramethyl-16.20.22-trioxo-17-azabicyclo[16.3.1]docosa-8,12.14,18,21-pentaen-10- yl] carbamate) is. as mentioned above a preferred derivative of geldanamycin. 17- AAG is commercially available under the trade name “Tanespimycin^“ (also known as KOS-953) for example from Kosan Biosciences Incorporated (Acquired by Bristol-Myers Squibb Company). Tanespimycin is presently studied in phase II clinical trials for multiple myeloma and breast cancer and is usually administered intravenously.

The respective formula of 17- AAG is given herein below:

Preferred geldanamycin-derh ative (HSP90 inhibitor) to be used in context of the present invention are IPI-504 (also known as retaspiimcin or Mcdi-561 : lnfinin Pharmaceuticals (Medlmmunc/ Astra Zeneca)). Clinical trials on the use of IPI-504 (which is usually administered intravenously) in the treatment of non-small cell lung cancer (NSCLC) and breast cancer are performed. Also alvespimycin hy drochloride (Kosan Biosciences Incorporated Acquired By : Bristol-Myers Squibb Company) is a highly potent, water-soluble and orally acti\e derivative of geldanamycin preferably used in context of the present invention.

IPI-504

PATENT

WO 2005063714

http://www.google.co.ug/patents/WO2005063714A1?cl=en

Example 24

Preparation of Air-stable Hydroquinone Derivatives of the Geldanamycin Family of Molecules

17-Allylamino-17-Demethoxygeldanamycin (10.0 g, 17.1 mmol) in ethyl acetate

(200 mL) was stirred vigorously with a freshly prepared solution of 10% aqueous sodium hydrosulfite (200 mL) for 2 h at ambient temperature. The color changed from dark purple to bright yellow, indicating a complete reaction. The layers were separated and the organic phase was dried with magnesium sulfate (15 g). The drying agent was rinsed with ethyl acetate (50 mL). The combined filtrate was acidified with 1.5 M hydrogen chloride in ethyl acetate (12 mL) to pH 2 over 20 min. The resulting slurry was stirred for 1.5 h at ambient temperature. The solids were isolated by filtration, rinsed with ethyl acetate (50 mL) and dried at 40 °C, 1 mm Hg, for 16 h to afford 9.9 g (91%) of off-white solid. Crude hydroquinone hydrochloride (2.5 g) was added to a stirred solution of 5% 0.01 N aq. hydrochloric acid in methanol (5 mL). The resulting solution was clarified by filtration then diluted with acetone (70 mL). Solids appeared after 2-3 min. The resulting slurry was stirred for 3 h at ambient temperature, then for 1 h at 0-5 °C. The solids were isolated by filtration, rinsed with acetone (15 mL) and dried

PAPER

J. Med. Chem., 2006, 49 (15), pp 4606–4615

DOI: 10.1021/jm0603116

http://pubs.acs.org/doi/abs/10.1021/jm0603116

17-Allylamino-17-demethoxygeldanamycin (17-AAG)¹ is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.

17-Allylamino-17-demethoxygeldanamycin Hydroquinone Hydrochloride Ia

17-AAG hydroquinone hydrochloride (1a) as an off-white solid (11 g, 18 mmol, 80% yield). HPLC purity: 99.6%;

IR (neat): 3175, 2972, 1728, 1651, 1581, 1546, 1456, 1392, 1316, 1224, 1099, 1036 cm^-1;

¹H NMR (CDCl₃:d₆-DMSO, 6:1, 400 MHz):

δ 10.20 (1H, br), 9.62 (2H, br), 8.53 (1H, s), 8.47 (1H, s), 7.74 (1H, s), 6.72 (1H, d, J= 11.6 Hz), 6.28 (1H, dd, J = 11.6, 11.2 Hz), 5.73 (1H, dddd, J = 17.2, 10.0, 3.2, 2.4 Hz), 5.53 (1H, d, J = 10.4 Hz), 5.49 (1H, dd, J = 10.8, 10.0 Hz), 5.32 (2H, s), 5.04 (1H, d, J = 4.8 Hz), 5.02 (1H, d, J = 16.0 Hz), 4.81 (1H, s), 4.07 (1H, d, J = 9.6 Hz), 3.67 (2H, d, J = 6.4 Hz), 3.31 (1H, d,J = 8.8 Hz), 3.07 (3H, s), 3.07−3.04 (1H, m), 2.99 (3H, s), 2.64 (1H, m), 2.52−2.49 (1H, m), 1.76 (3H, s), 1.61−1.39 (3H, m), 0.78 (3H, d, J = 6.4 Hz), 0.64 (3H, d, J = 7.2 Hz);

¹³C NMR (CDCl₃:d₆-DMSO, 6:1, 100 MHz): δ 167.3, 155.8, 143.3, 136.3, 135.0, 134.2, 132.9, 132.1, 128.8, 127.6, 125.9, 125.3, 123.7, 123.0, 115.1, 104.5, 80.9, 80.7, 80.1, 72.5, 56.2, 56.2, 52.4, 34.6, 33.2, 31.1, 27.2, 21.6, 12.1, 12.1, 11.7;

HRMS calculated for C₃₁H₄₅N₃O₈ (M⁺ + H): 588.3285, Found 588.3273.

POSTER

Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90

MEDI 210

James R. Porter, jporter@ipi.com, Jie Ge, Emmanuel Normant, Janid Ali, Marlene S. Dembski, Yun Gao, Asimina T. Georges, Louis Grenier, Roger Pak, Jon Patterson, Jens R. Sydor, Jim Wright, Julian Adams, and Jeffrey K. Tong.

Infinity Pharmaceuticals, Inc, 780 Memorial Drive, Cambridge, MA 02139

IPI-504 is the hydroquinone hydrochloride salt of 17-allylamino-17-demethoxy-geldanamycin (17-AAG), an Hsp90 inhibitor that is currently in clinical trials for the treatment of cancer.

IPI-504 demonstrates high aqueous solubility (>200 mg/mL). Interestingly, in vitro and in vivo IPI-504 interconverts with 17-AAG and exists in a pH and enzyme-mediated redox equilibrium. This occurs due to oxidation of the hydroquinone (IPI-504) to the quinone (17-AAG) at physiological pH and the reduction of 17-AAG by quinone reductases such as NQO1 to IPI-504.

Here we report the design and synthesis of the stabilized hydroquinone IPI-504 and its inhibitory effect against Hsp90 and Grp94. Although IPI-504 was originally designed to be a soluble prodrug of 17-AAG, the hydroquinone is more potent than the quinone in the biochemical Hsp90 binding assay.

Various hydroquinone analogs have been prepared to investigate the structure activity relationship of hydroquinone binding to Hsp90. Hydroquinone and quinone forms of 17-AAG metabolites show comparable binding affinities for Hsp90 and in cancer cell lines, hydroquinone analogs elicit specific responses consistent with Hsp90 inhibition.

The desirable pharmacological properties as well as in vitro and in vivo activity of our lead compound, IPI-504, has led to the initiation of Phase I clinical trials in multiple myeloma.

http://oasys2.confex.com/acs/231nm/techprogram/P945016.HTM

Geldanamycin and Beyond: Progress Toward the Development of HSP90 Inhibitors
8:30 AM-12:05 PM, Wednesday, 29 March 2006 Georgia World Congress Center — Georgia Ballroom 1, OralDivision of Medicinal Chemistry The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006

References

Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90
231st Am Chem Soc (ACS) Natl Meet (March 26-30, Atlanta) 2006, Abst MEDI 210

Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90
J Med Chem 2006, 49(15): 4606

http://www.biotechduediligence.com/retaspamycin-hcl-ipi-504.html

///////////////////Hsp90, IPI-504, infinity pharma, Retaspamycin, Retaspimycin

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

October 26, 2015 2:04 pm / Leave a comment

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

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

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

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

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

Mavatrep, JNJ 39439335,

October 25, 2015 9:10 am / Leave a comment

Mavatrep; UNII-F197218T99; Mavatrep (USAN); JNJ-39439335; 956274-94-5;

2-(2-(2-(2-(4-trifluoromethylphenyl)vinyl)-1H-benzimidazol-5-yl)phenyl)propan-2-ol

(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

(E)-2-(2-(2-(4-(Trifluoromethyl)styryl)-1H-benzo[d]imidazol-5-yl)phenyl)-propan-2-ol Hydrochloride

Phase I Musculoskeletal pain; Pain

01 Mar 2013 Janssen Research and Development completes a phase I trial in Japanese and Caucasian adult male volunteers in the US (NCT01631487)
01 Mar 2013 Janssen completes enrolment in its phase I trial for Pain (in volunteers) in the USA (NCT01631487)
05 Feb 2013 Janssen Research and Development initiates enrolment in a phase I trial for Pain (Japanese and Caucasian volunteers) in USA (NCT01631487)

Originator Johnson & Johnson Pharmaceutical Research & Development
Developer Janssen Research & Development
Class Analgesics; Benzimidazoles; Small molecules
Mechanism of Action TRPV1 receptor antagonists

ChemSpider 2D Image | Mavatrep | C25H21F3N2O

PHASE 1 Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Public title:	A Clinical Study to Investigate the Effect on Pain Relief of a Single Dose of JNJ-39439335 in Patients With Chronic Osteoarthritis Pain of the Knee

http://clinicaltrials.gov/ct2/show/NCT01006304
http://apps.who.int/trialsearch/trial.aspx?trialid=NCT00933582

http://www.ama-assn.org/resources/doc/usan/mavatrep.pdf SEE STRUCTURE IN THIS FILE

MAVATREP IS JNJ-39439335
—

(E)-2-(2-(2-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol hydrochloride

956282-89-6 CAS NO OF HCl SALT

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00271, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00271

The process development of Mavatrep (1), a potent transient receptor potential vanilloid-1 (TRPV1) antagonist, is described. The two key synthetic transformations are the synthesis of (E)-6-bromo-2-(4-(trifluoromethyl)styryl)1H-benzo[d]imidazole (4) and the Suzuki coupling of 4 with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (5). Compound 1a was prepared in four chemical steps in 63% overall yield.

HCl SALT

1a as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.35 (d, J = 16.6 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.80 (dd, J = 8.1, 1.3 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 6.6 Hz, 1H), 7.43 (dd,J = 8.4, 1.5 Hz, 1H), 7.39 (ddd, J = 8.1, 7.4, 1.5 Hz, 1H), 7.27 (ddd, J = 7.4, 7.4, 1.3 Hz, 1H), 7.04 (dd, J = 7.5, 1.5, 1H), 1.29 (s, 6H); ¹³C NMR (DMSO-d₆, 125 MHz) δ 147.7 (C), 147.4 (C), 142.3 (C), 140.3 (CH), 139.0 (C), 138.0 (C), 131.7 (CH), 131.1 (C), 130.5 (C), 130.2 (C), 128.7 (2CH), 128.3 (CH), 127.4 (CH), 126.2 (CH), 126.2 (CH), 125.8 (2CH), 124.0 (CF₃), 114.3 (CH), 113.2 (CH), 112.4 (CH), 71.6 (C), 32.4 (2CH₃); Anal. Calcd for C₂₅H₂₂F₃ClN₂O·1.2H₂O: C, 62.49; H, 5.12; Cl, 7.38; F, 11.86; N, 5.83. Found: C, 62.34; H, 4.93; Cl, 7.24; F, 11.61; N, 5.78. Water wt % calcd, 4.50%; found, 4.52% (determined by KF analysis).

Patent

http://www.google.st/patents/US20110190344

CLICK ON IMAGE FOR CLEAR VIEW

Example 10 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol(Cpd 18)

Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0278]

A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 μL piperidine (5.75 mmol) in 30 mL of pyridine was stirred at 70° C. for 18 h. The reaction solution was cooled to room temperature. Water (300 mL) was added and the resulting mixture was acidified to pH 4 (litmus) using concentrated hydrochloric acid to give a precipitate. The solid was filtered, and washed with water until the filtrate was neutral. The solid product was dried in vacuo to give the title Compound 10a as a white powder (11.2 g, 90%). ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.70 (d, 1H, J=16.0 Hz).
[0000]

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0279]

A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous methylene chloride (200 mL) was treated with oxalyl chloride (16.6 mL, 190 mmol) and “3 drops” of anhydrous dimethylformamide. The resulting solution was stirred at room temperature under an argon atmosphere for 18 h. The solvent was concentrated to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a solid, which was used without further purification in the next step.
[0280]

To a solution of 4-bromo-benzene-1,2-diamine (16.1 g, 86.7 mmol) in acetic acid (100 mL) was added dropwise a solution of Compound 10b (assumed 95.4 mmol) in acetic acid (100 mL). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and a mixture of ethyl acetate and hexanes 3:7 (500 mL) was added. The mixture was triturated at room temperature for 3 h to give a precipitate. The solid was filtered, and dried in vacuo to give the title Compound 10c (23.2 g, 73%). ¹H NMR (400 MHz, DMSO-d₆/CDCl₃) δ (ppm): 8.45 (d, 1H, J=16.7 Hz), 7.84-7.90 (m, 1H), 7.74 (d, 2H, J=8.3
[0281]

Hz), 7.56-7.62 (m, 3H), 7.50-7.52 (m, 1H), 7.34 (d, 1H, 16.7 Hz).
[0000]

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0282]

To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H).
[0000]

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0283]

To a solution of n-BuLi (166 mL, 2.6 M, 432 mmol) in 200 mL of THF at −78° C. under argon was slowly added a solution of Compound 10d (42.2 g, 196 mmol) in 60 mL of THF at a rate that the internal temperature remained below −70° C. The mixture was stirred at −75° C. for 2 h. To the reaction mixture was then added triisopropylborate (59 mL, 255 mmol) in three portions. The mixture was allowed to warm slowly to room temperature overnight. The mixture was then cooled to 0° C., and was carefully quenched with dilute hydrochloric acid (250 mL, 2N). The mixture was then stirred at room temperature for 1 h. The pH of the mixture was checked and adjusted to acidic using additional 2N HCl if prophetic. The two layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined, and dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a pale yellow oil. The residue was then diluted with ethyl acetate (400 mL) and, washed with 1N sodium hydroxide solution (150 mL×3). The basic aqueous layers were combined and acidified with 2N HCl. The clear solution turned cloudy when the acid was added. The mixture was extracted with ether (150 mL×3). The organic layers were combined and dried with magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield the title Compound 10e as a colorless oil (26.2 g, 82%) which was used without further purification in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.00 (s, 1H), 7.66 (dm, 1H, J=7.3 Hz), 7.45 (dt, 1H, J=1.1, 7.7 Hz), 7.40 (dm, 1H, J=7.6 Hz), 7.31 (dt, 1H, J=1.2, 7.1 Hz), 1.44 (s, 6H).
[0000]

Step E. (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

[0284]

To a mixture of Compound 10e (11.7 g, 71 mmol), Compound 10c (19.9 g, 54 mmol), sodium carbonate (46 g, 435 mmol) and PdCl₂(dppf).CH₂Cl₂(8.9 g, 11 mmol) in a 1 L round bottom flask equipped with water condenser was added 400 mL of anhydrous DME and 200 mL of water. The mixture was evacuated and filled with Argon three times. The mixture was heated to 100° C. for 20 h. The mixture was then cooled to room temperature. The biphasic system was transferred to a 1 L separatory funnel and the two layers were separated. The organic layer was washed with brine (2×300 mL). The aqueous layers were combined and extracted with ethyl acetate once (about 300 mL). The organic layers were combined, dried with sodium sulfate, and filtered. The volume of the filtrate was reduced to about 170 mL under reduced pressure. The mixture was then filtered through a pad of silica gel and the pad was washed with ethyl acetate until the filtrate did not contain any product. After concentration, a light pink/beige solid was obtained. The solid was triturated with 50 mL ethyl acetate, and the mixture was heated to 85° C. for 5 min. The mixture was slowly cooled to r.t., then cooled at 0° C. for 0.5 h. The mixture was filtered, and the solid was washed with cold ethyl acetate twice, and dried under vacuum at 40° C. to yield the title Compound 18 as a light beige solid (7.58 g, 33%). RP-HPLC 95% pure.
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.73 (m, 1H,), 7.90 (d, 2H, J=8.2 Hz), 7.85 (dd, 1H, J=8.0, 0.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.74 (d, 1H, J=16.8 Hz), 7.59-7.47 (m, 1H), 7.41 (s, 1H), 7.37-7.32 (m, 2H), 7.21 (dt, 1H, J=1.2, 7.4 Hz), 7.06 (s, 1H), 7.02 (d, 1H, J=7.4 Hz), 4.85 (s, 1H), 1.21 (s, 6H).
Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3.
m.p. (uncorr.) 250-251° C.

Example 10.1 Scale Up Preparation of (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Cpd 18) Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0286]

A 2-L 4-neck round bottom flask equipped with an air condenser/argon inlet, mechanical stirrer, thermocouple and a stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL). An exotherm developed (about 38-40° C.), which was maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added to the reaction and a second exotherm developed (T_maxabout 42° C. after about 10 min.). The reaction was stirred for 30 min and then heated to 60° C. for 18 h (overnight). The reaction appeared to be complete by TLC, and was cooled to about 40° C., diluted into water (2 L; done to prevent reaction freezing), cooled to room temperature, and further diluted with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0 with concentrated hydrochloric acid (about 675-700 mL). The material was stirred for 30 min., and a white solid was collected by filtration. The filter cake was washed with water until the filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a Buchner funnel for 2 h, and then further dried in a vacuum oven at 60° C. overnight to provide 300.5 g (96%) of the title Compound 10a as a white solid.

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0287]

To a 5-L 4-neck round bottom flask equipped with a magnetic stirrer, argon inlet-argon outlet to a carbonate scrub, two stoppers, and a room temperature water bath was charged with 4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and dichloromethane (3.15 L) to give a slurry. To the slurry was added oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57 mmol). Upon addition of DMF, gas evolution commenced, and the reaction was continued for about 3 h during which time a solution developed. When the reaction was complete (LC-MS), it was concentrated to dryness to give 342.4 g of 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b (>100%) as a yellow oily solid.
[0288]

A 5-L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, air condenser with argon inlet, and a stopper was charged with 4-bromo-benzene-1,2-diamine (244 g, 1.27 mol) and acetic acid (2.13 L). To this solution was added a solution of Compound 10b (327 g, 1.39 mol) in toluene (237 mL). After this addition, the temperature spiked to 45° C. in about 30 seconds and then subsided. The reaction was then heated to 90° C. for 16 h (overnight). The reaction was cooled to 40° C., and poured into a mixed solution of EtOAc and heptane (about 1:3, 5.75 L) and a precipitate occurred. The resulting slurry was stirred for 3 h, and the solid was collected by filtration, washed with EtOAc:heptane (1:3, 3 L), and then dried in a vacuum oven (60° C.) to give 324.3 g (65%) of the title Compound 10c as a partial acetate salt.

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0289]

A 12-Liter 4-neck flask equipped with a thermocouple, condenser, septum, addition funnel and overhead mechanical stirrer under argon was charged with methyl-2-bromobenzoate (226.5 g, 1.05 mol) and THF (1.6 L, 19.66 mol). The mixture was cooled to a temperature between 2 and 5° C. with stirring and held for 30 min. To the solution was slowly added methyl magnesium bromide in diethyl ether (3M, 1.05 L; 3.15 mol) via the addition funnel at a rate to maintain the reaction temperature below 15° C. An exotherm was observed during the addition, the reaction temperature warmed from 3 to 15° C. The addition of 1.05 L Grignard was complete in 4 h (approximate feed rate was 4.17 mL/min). The reaction mixture appeared to be off-white/yellow slurry. The reaction was allowed to warm to room temperature and stirred overnight (15 h). The reaction was sampled by HPLC/TLC and showed no starting material present. The ice bath was again applied to the reaction flask and a 0.5 M HCl solution (4.5 L; 2.25 mol) was slowly added over a period of 2 h. The temperature increased dramatically from 0 to 15° C. After the quench was complete, the reaction was stirred at room temperature for 30 min. Additional 2 N HCl (500 mL; 1.00 mol) was slowly added to maintain a pH less than 6. MTBE (1 L) was added to help with the phase split. The reaction was stirred at room temperature for 1 to 2 h to dissolve the solid material into the aqueous phase (most likely Mg(OH)₂which is very basic). The pH must be checked and adjusted with additional acid when necessary. The phases were separated and the aqueous layer was washed with an additional 1 L MTBE (2×500 mL). The organic phases were combined, washed with NaHCO₃solution (2×300 mL), dried over MgSO₄, filtered and the filtrate was concentrated under vacuum to yield the title Compound 10d (220.83 g, 97.48% yield) as a clear yellow oil.

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0290]

A 12-Liter 4-neck round bottom flask equipped with a thermocouple, condenser, addition funnel and overhead mechanical stirrer under dry Argon was charged with anhydrous THF, (3 L) and chilled to −70 to −78° C. via a dry ice/acetone bath. n-Butyl lithium (2.5N in hexanes, 860 mL, 2.15 mol) was slowly added via addition funnel. An exotherm was observed as the temperature rose from −78 to −70° C. To the addition funnel was added a solution of Compound 10d (220 g, 979.97 mmol) in anhydrous THF (1 L). The 2-(2-bromophenyl)propan-2-ol solution was slowly added to the n-BuLi solution. The addition took 90 min in order to maintain a reaction temperature below −70° C. After the addition was complete, the reaction mixture was stirred at −70 to −75° C. for 30 min. The triethylborate (230 mL, 1.35 mol) was quickly added in 3 portions at −70° C. An exotherm was observed, the batch temperature rose from −70 to −64° C. The reaction was stirred at −70° C. and slowly warmed to room temperature over night. After the reaction was cooled to 0-5° C., the reaction was slowly quenched with 2 M HCl (1 L, 2.00 mol) added via the addition funnel while maintaining the batch temperature 0-5° C. The reaction mixture was stirred for 1 h. The aqueous phase pH was 9-10. The pH was then adjusted to acidic (4-5) with 2 M HCl (200 mL). The two phases were separated and the aqueous layer was extracted with MTBE (2×500 mL). The combined organic phases were dried with anhydrous magnesium sulfate. The solution was filtered and concentrated to yield a yellow oil. The yellow oil was diluted with MTBE (1.5 L) and washed with 1M NaOH (3×500 mL). The product containing basic aqueous phases were combined and acidified with 2 M HCl (800 mL) (the clear solution turns turbid with the addition of acid). After stirring the turbid solution for 15 min (pH=4-5) (Note 1), it was extracted with MTBE (2×500 mL). The organic phases were combined and dried over MgSO₄. The solution was filtered and the filtrate was concentrated to yield the title Compound 10e as a clear yellow oil (121.78 grams, 77% yield).

Step E. (E)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

A 5-L 4-neck flask equipped with a thermocouple controller, condenser, overhead mechanical stirrer, Firestone Valve® and a nitrogen inlet/outlet was charged with dimethoxyethane (2 L), DI water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution was degassed and purged with N₂three times. Compound 10e (71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added to the degassed solution. The solution was degassed and purged with N₂three times. PdCl₂(dppf) (44.48 g, 54.4 mmol) was added to the solution, and the solution was degassed and purged with N₂three times. The resulting two-phase suspension was heated to reflux for 18 h, and then cooled to room temperature. The reaction mixture was transferred to a 12-L separatory funnel, and the layers were separated. The organic layer was washed with brine (1 L). The two aqueous layers were combined and extracted with EtOAc (1 L). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated to an oil. Two separate 100 g coupling reactions were combined and purified by chromatography in 10 successive chromatography runs on an ISCO preparative chromatography system (10×1.5 Kg SiO2, 5 column volumes of EtOAc, 250 mL/min flow rate). The combined fractions were transferred to two 22 L 4-neck round bottom flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was added to each solution. The solutions were warmed to 40° C. and aged for 1 h. The solutions were filtered thru a medium glass funnel and washed with EtOAc (4 L) and combined. The filtrate was evaporated to a semi solid, which was transferred to a 2 L round bottom flask, to which EtOAc (0.4 L) was added. The resulting white precipitate slurry was cooled to −5° C. and stirred for 1 h. The slurry was filtered and washed twice with cold EtOAc (100 mL). The solids were dried in a vacuum oven at 40° C. for 40 h to afford 84.0 g (36.5% yield, 98.8 area % purity) of the title Compound 18 as a white solid. Anal. Calcd for C₂₅H₂₁N₂OF₃.0.04% H₂O.0.15 mol MeOH: C, 70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N, 6.18; F, 13.33

Example 10.2 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol monosodium salt (Cpd 18)

A 5-L 4-neck flask equipped with a thermocouple controller, an overhead mechanical stirrer, and a nitrogen inlet/outlet was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (125.0 g, 0.510 mol) and MeOH (1.25 L). A solution of sodium methoxide in methanol (0.5 M, 592 mL, 0.3 mol) was added. The reaction was heated to 65° C. for 30 min and all solids dissolved. The solution was cooled and evaporated to dryness. The foam was collected by scraping it out of the flask. The solids were placed in vacuum oven for 24 h at 40° C. to afford 139 g (about 100% isolated yield) of the title Compound 18 monosodium salt as a yellowish solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.84 (m, 3H), 7.74 (d, 2H, J=8.59 Hz), 7.65 (d, 1H, J=16.4 Hz), 7.40-7.44 (m, 2H), 7.25-7.37 (m, 2H), 7.16-7.20 (m, 1H), 7.01-7.05 (m, 1H), 6.84-6.87 (m, 1H), 1.23 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3. m.p. (uncorr.) 258-259° C.

Example 10.3 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol hydrochloride salt (Cpd 18)

A 250-mL separatory funnel was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (1.0 g, 2.4 mmol) and EtOAc (20 mL). Aqueous HCl (1M, 20 mL) was added to the white slurry, and the separatory funnel was shaken. The solid product quickly dissolved, and a white precipitate started to form. The organic layer was transferred to a 100 mL round bottom flask equipped with a magnetic stir bar, and was stirred for 2 h. The thick slurry was filtered, rinsed with EtOAc (2×5 mL), and put into a vacuum oven at 40° C. for 36 h to afford 0.95 g (87.5%) of the title Compound 18 hydrochloride salt.

US7951829

Patent	Submitted	Granted
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190344]	2011-08-04
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190364]	2011-08-04
Benzimidazole Modulators of VR1 [US7951829]	2007-11-08	2011-05-31

////////////Phase I, Musculoskeletal pain, Pain, Mavatrep, JNJ 39439335,

FDA grants breakthrough status for Pfizer’s leukaemia drug inotuzumab ozogamicin

October 23, 2015 3:21 am / 2 Comments on FDA grants breakthrough status for Pfizer’s leukaemia drug inotuzumab ozogamicin

Inotuzumab ozogamicin
RN: 635715-01-4
UNII: P93RUU11P7

Pfizer Inc., Oncology Institute Of Southern Switzerland INNOVATOR

http://chem.sis.nlm.nih.gov/chemidplus/rn/635715-01-4

MF 1680.6764
Oncological Treatment

FDA grants breakthrough status for Pfizer’s leukaemia drug inotuzumab ozogamicin
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Pfizer’s investigational antibody-drug conjugate (ADC) inotuzumab ozogamicin to treat acute lymphoblastic leukaemia (ALL).

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Pfizer’s investigational antibody-drug conjugate (ADC) inotuzumab ozogamicin to treat acute lymphoblastic leukaemia (ALL).

The breakthrough status was based on data from the Phase III INO-VATE ALL trial, which enrolled 326 adult patients with relapsed or refractory CD22-positive ALL and compared inotuzumab ozogamicin to standard of care chemotherapy………….http://www.pharmaceutical-technology.com/news/newsfda-grants-breakthrough-status-pfizer-leukaemia-drug-inotuzumab-ozogamicin-4697877?WT.mc_id=DN_News

EVER SINCE POST WAS WRITTEN…..FGD APPROVAL Inotuzumab ozogamicin

PFIZER

Image result for inotuzumab ozogamicin

Besponsa		FDA 8/17/2017	To treat adults with relapsed or refractory acute lymphoblastic leukemia Press Release Drug Trials Snapshot

LINK….https://newdrugapprovals.org/2015/10/23/fda-grants-breakthrough-status-for-pfizers-leukaemia-drug-inotuzumab-ozogamicin/

Inotuzumab ozogamicin (CMC-544) is an antibody-drug conjugate for the treatment of cancers.^[1] It consists of the humanized monoclonal antibody inotuzumab (for CD22), linked to a cytotoxic agent from the class of calicheamicins (which is reflected by ‘ozogamicin‘ in the drug’s name).^[2]

This drug is being developed by Pfizer and UCB.

It is undergoing numerous clinical trials,^[3] including two phase II trials for Non-Hodgkin lymphoma (NHL).

A phase III trial in patients with follicular b-cell NHL has been terminated due to poor enrollment.^[4] A Phase III trial in patients with relapsed or refractory CD22+ aggressive non-Hodgkin lymphoma (NHL) who were not candidates for intensive high-dose chemotherapy was terminated for futility.^[5]

Monoclonal antibodies (mAbs) and derivatives are currently the fastest growing class of therapeutic molecules. More than 30 G-type immunoglobulins (IgG) and related agents have been approved over the past 25 years mainly for cancers and inflammatory diseases. In oncology, mAbs are often combined with cytotoxic drugs to enhance their therapeutic efficacy. Alternatively, small anti-neoplastic molecules can be chemically conjugated to mAbs, used both as carriers (increased half-life) and as targeting agents (selectivity). Potential benefits of antibody-drug conjugates (ADCs), strategies, and development challenges are discussed in this review. Several examples of ADCs are presented with emphasis on three major molecules currently in late clinical development as well as next generation thio-mAbs conjugates with improved therapeutic index.

PATENT

http://www.google.com/patents/WO2013088304A1?cl=en

Inotuzumab ozogamicin:

is described in U.S. Patent Application No. 10/428894

U.S. Patent Application No. 10/428894

References

Statement On A Nonproprietary Name Adopted By The Usan Council – Inotuzumab ozogamicin, American Medical Association.
Takeshita, A; Shinjo, K; Yamakage, N; Ono, T; Hirano, I; Matsui, H; Shigeno, K; Nakamura, S; Tobita, T; Maekawa, M (2009). “CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukaemia and lymphoma.”. British journal of haematology 146 (1): 34–43.doi:10.1111/j.1365-2141.2009.07701.x. PMID 19388933.
http://clinicaltrials.gov/ct2/results?term=Inotuzumab+ozogamicin
http://clinicaltrials.gov/ct2/show/NCT00562965
http://pfizer.newshq.businesswire.com/press-release/pfizer-discontinues-phase-3-study-inotuzumab-ozogamicin-relapsed-or-refractory-aggress
http://pubs.rsc.org/en/content/articlelanding/2008/np/b514294f#!divAbstract

Structure of inotuzumab ozogamicin. ABOVE

Inotuzumab ozogamicin^?
Monoclonal antibody
Type	Whole antibody
Source	Humanized (from mouse)
Target	CD22
Identifiers
CAS Registry Number	635715-01-4
ATC code	None
UNII	P93RUU11P7
KEGG	D08933
Chemical data
Formula	C₆₅₁₈H₁₀₀₀₂N₁₇₃₈O₂₀₃₆S₄₂
Molecular mass	150,000 Daltons

//////////

Regulation of Herbal (Traditional) Medicinal Products in the European Union

October 21, 2015 8:29 am / Leave a comment

Regulation of Herbal (Traditional) Medicinal Products in the European Union

Introduction

The European Union (EU) regulatory framework for medicinal products is complex and is based on the need of a marketing authorization before placing medicines in the market. The main objective is to protect public health by assuring quality, efficacy and safety. The requirements and procedures to obtain a marketing authorization are laid down in regulations, directives and scientific guidelines which are contained in the “Rules Governing Medicinal Products in the European Union”. Several volumes are included which are supported by other publications with complementary information such as scientific or Good Manufacturing Practice (GMP) guidelines, between others [1].

Medicinal plants have been used since Ancient times in all parts of the world. Nonetheless, regulation of herbal medicines in a legal environment was introduced in the 20^th century. The EU regulatory framework includes specific requirements for herbal medicinal products (HMP) which are independent from their legal status: traditional herbal medicinal product (THMP) or products based on clinical evidence – well established use (WEU).

Before a HMP is placed in the market, it must be approved by a MS or by the European Commission by one of the existing types of application: full marketing authorization application, well-established use marketing authorization application or Traditional use marketing registration (Table 1).

The applicant has to submit adequate quality, non-clinical and clinical documentation of the product, irrespectively of the procedure used. Quality requirements of the pharmaceutical product are the same, regardless of the type of application, while efficacy documentation differs between them. The full marketing application is chosen for new medicinal products (new chemical entity) and it has to be completed with the results of pharmaceutical tests (quality documentation), nonclinical (toxicological and pharmacological) studies and clinical trials. Safety data have to be of sufficient size according the existing guidelines; efficacy is demonstrated by results from the clinical trials which have to be in conformity with the guidelines of the corresponding therapeutic area. This type of application is open for HMP, but only a few examples of herbal products have obtained a marketing authorization in the EU in this way.

EU Pharmaceutical Legislation for Herbal Medicinal Products for Human Use

Quality requirements

The principles to assure quality of medicinal products are defined mainly in two Directives of volume 1: Directive 2001/83/EC (which was emended by Directive 2004/24/EC) and Directive 2003/63/EC.

The basic legislation lay down in Directive 2001/83/EC describes the general requirements and provides legal definitions of herbal substances, herbal preparations and herbal medicinal products (Table 2). These concepts are essential for setting quality standards for HMP, as they are by definition complex in nature and so quality requirements set for purified compounds are not suitable for herbal products.

According to the Directive 2001/83/EC, monographs in the European Pharmacopoeia (Eur. Ph.) are legally binding and applicable to all substances which are included in it. For substances which do not have a Eur. Ph. monograph, each Member State (MS) may apply its own national pharmacopoeia. Constituents which are not given in any pharmacopoeia shall be described in the form of a monograph under the same headings included in any monograph in the Eur. Ph., i.e., the name of the substance supplemented by any trade or scientific synonyms; the definition of the substance, set down in a form similar to that used in the European Pharmacopoeia; methods of identification and purity tests.

Moreover, all medicinal products have to be manufactured according to the principles and guidelines of GMP for medicinal products. GMP are applicable to both finished HMP and active substances and, according to Article 46 (f) of Directive 2001/83/EC as amended, marketing authorization holders are required to use as starting materials only active substances which have been manufactured in accordance with the guidelines on the GMP for starting materials as adopted by the Community and distributed in accordance with good distribution practices for active substances.

Additional requirements are found in the Directive 2003/63/EC, as Herbal medicinal products differ substantially from conventional medicinal products in so far as they are intrinsically associated with the very particular notion of herbal substances and herbal preparations. It is therefore appropriate to determine specific requirements in respect of these products with regards to the standardized marketing authorization requirements. Then, detailed information on the herbal medicinal product, herbal substances and herbal preparations has to be included, such as the name, address and responsibility of each herbal substance supplier or description of the plant production process, geographical source or drying and storage conditions. The application dossier of a HMP should include specifications and details of all the analytical methods used for testing herbal substances and herbal preparations, results of batch analyses and analytical validation, together with the justification for the specifications.

Most of the quality requirements for HMP are laid down in soft laws (considered as EU measures such as scientific guidelines) which do not have legal force but provide practical harmonization between the MS and the European Medicines Agency (EMA).

The guideline on quality of HMP/THMP covers the general quality aspects of HMP for human and veterinary use, including THMP for human use (EMA, 2014) and indicates which information has to be included in the application dossier. It provides definitions to be taken in account such as genuine (native) herbal preparations, markers, drug to extract ratio (DER) and specifications. Which is more important, it states that the herbal substance or herbal preparation is considered as the whole active substance. In consequence, the quality control of these products has to include appropriate fingerprint analysis to cover not only the content of markers or constituents with known therapeutic activity but also a wider range of chemical constituents.

Efficacy requirements

Before a HMP is placed in the market, it must be approved by a MS or by the European Commission by one of the existing types of application: full authorization application, well-established use authorization application or Traditional use registration (Table 3).

The applicant has to submit adequate quality, non-clinical and clinical documentation of the product, irrespectively of the procedure used. Quality requirements of the pharmaceutical product are the same, regardless of the type of application, while efficacy documentation differs between them. The full marketing application is chosen for new medicinal products (new chemical entity) and it has to be completed with the results of pharmaceutical tests (quality documentation), nonclinical (toxicological and pharmacological) studies and clinical trials. Safety data have to be of sufficient size according the existing guidelines; efficacy is demonstrated by results from the clinical trials which have to be in conformity with the guidelines of the corresponding therapeutic area. This type of application is open for HMP, but only a few examples of herbal products have obtained a marketing authorization in the EU in this way.

The well-established medicinal use (WEU) in the EU can be applied to medicinal products for which there exists a wide clinical experience within the EU (not only HMP). The assessment may be based in published controlled clinical trials, non-clinical studies and epidemiological studies. In this type of application, there are no limitations to the therapeutic indication, as this will be derived from the available documentation.

(Traditional) Herbal Medicinal Products

Under the Traditional use registration for herbal medicinal product (article 16e), there exist some herbal products that not fulfill the efficacy requirements for a marketing authorization but are endorsed with a long tradition of use. In this case, no clinical trials on these products have been conducted and the efficacy is based on the long-standing use and experience. This simplified registration procedure is limited to products which are intended for use without medical supervision, with a specified strength and posology, to be used by oral, external or inhalation ways, and which can demonstrate a period of use equal or superior to 30 years, including at least 15 years within the EU. In this case, therapeutic indications are limited to those which can be considered safe for use without the supervision of a physician such as minor disorders or symptoms that are benign or self- limiting. In case the applicant should consider another kind of indication, the product must be documented with results of clinical and non-clinical studies, so a full application would be necessary.

Simplified registration of THMP is described in Chapter 2a of Directive 2004/24/EC with three main objectives: a) to protect public health by allowing access to safe and high-quality HMP; b) to allow European citizens the access to medicines of their choice, even those HMP with a long tradition of use and which efficacy hasn’t been proved by clinical trials performed according the modern standards; c) to facilitate movement of medicinal products on the European market.

Directive 2004/24/EC has two different dimensions: the evaluation by National Competent Authorities (NCA) of applications submitted by companies at any MS in the EU and at the EMA, and the establishment of advisory scientific opinions on the medicinal use of herbal substances or preparations. The directive on THMP also established a new scientific committee, the Herbal Medicinal Products Committee (HMPC) at the EMA in London, in 2004, to replace the previous Working Party on Herbal Medicinal Products (CPMP) with the following aims: to elaborate Community monographs and List entries for herbal substances/preparations; to publish scientific guidelines useful for the application of European legal framework; to publish its scientific opinion on questions related to herbal medicinal products and coordinate its work with the European Quality group. The HMPC is made up by 33 members, one member (and one alternate) nominated by each MS of the EU and by Iceland and Norway (the EFAEFTA states). Among them, also five experts are included, representing specific fields of expertise as clinical and non-clinical pharmacology, toxicology or pediatrician medicine.

The guidelines and the monographs developed and approved by the HMPC are accepted by both companies and NCAs and are used for TUR and WEU marketing authorizations. This committee plays a key role in the harmonization of the regulation of HMP whereby Community herbal monographs have a fundamental role.

Usage of Community herbal monographs in the EU regulation of traditional HMP

These documents are established for HMP with regards to bibliographic applications (art. 10 a Directive 2001/83/EC) as well as THPMs. Community monographs reflect the scientific opinion of the HMPC on safety and efficacy data concerning a herbal substance. Any single plant or herbal preparation is assessed individually, according to the available information and includes qualitative and quantitative composition, pharmaceutical form(s), therapeutic indication(s), posology and method of administration, contraindications, special warnings and precautions of use, interactions, use in special population (pregnancy, lactation), effects on ability to drive and use machines, undesirable effects, overdose, pharmacological,pharmacodynamics, pharmacokinetic properties and preclinical safety data.

Community list entry

In the EU, a community list of herbal substances, preparations and combinations thereof for use in THMPs has been established. This list is based in the proposals form HMPC and is gradually developed. Substances or preparations which are included in the list have the main advantage that applicants do not need to provide evidence on the safe or traditional use for its registration at the NCA in the intended use and indication.

A Public statement for one herbal substance/preparation is published because of safety reasons or lack of data to comply with the conditions in the Directive 2004/24/EC (the assessment work didn’t allow a monograph to be published) [2].

Community monographs are published by the EMA while list entries are approved and published by the European Commission because they are endorsed with a wider legal status: list entries are legally binding and NCAs should not request additional data on safety and traditional use.

The establishment of monographs and list entries is based on the assessment of the published scientific data, together with the existing products in the market. Most of the assessment work is developed by the Monograph and List Working Party (MLWP) at the HMPC, which was established in 2006. In this working group, a member is designed as rapporteur and is responsible of drafting a monograph and/or list entry which will be later on considered and approved by the HPC and then, by the EMA. The documents are published on the EMA website: Community monographs have to be taken in account by the MS when assessing the application of any company. Monographs are note legally binding and MS are not obliged to follow the monographs.

More than 100 species are included in the priority list with the following data: a) scientific data being assessed (R- Rapporteur assigned); b) evaluation report in progress and discussion in the MLWP (D- Draft under discussion); c) scientific opinion under public consultation (PDraft Published); d) comments after public consultation period being evaluated (PF- Assessment close to finalization – pre-final); e) final opinion adopted (F- Final opinion adopted).

MLWP is also responsible of developing guidelines related to legal requirements for TU and WEU, as well as evaluating hazards and problems related to HMP. For the latter, coordination is established with the Safety Working Party (SWP) from the Committee for Medicinal Products for Human Use (CHMP).

Community herbal monographs to support HMPC authorization

A community monograph reflects the scientific opinion from the HMPC in relation to safety and efficacy of one herbal substance/ preparation for medicinal use. AS stated before, a community monograph may be used by a company for a TU or WEU application. That’s the reason why monographs are divided in to two columns: Well Established Use and Traditional Use (simplified application) (Figure 1). WEU is based in the existence of safety data of sufficient size and efficacy data derived from good-quality clinical trials. Traditional use is accepted for those applications which fulfill the criteria shown in the Directive 2004/24/EC.

Each herbal substance/preparation is assessed individually, as the available information may be different for each one. As a result, some substances/preparations may be included in the WEU side, while others will be included in the TU side. If no enough data are available for the substance/preparation, it won’t be included in the monograph.

The approved draft art he HMPC is published for public consultation for 3 month at the EMA website. Comments received are discussed and taken in account when necessary to achieve the final version of the monograph which will be finally published at the MA website.

By the end of 2014, 126 monographs have been adopted and published by the EMA: 104 of them for TU only; 9 of the monographs refer only to WEU (Aloe vera, Cimicifuga racemosa, Rhamnus frangula, Plantago ovata – seed and tegumentum-, Plantago afra, Rheum palmatum, Cassia senna – leaves and fruits-.among them 13 monograph include both TU and WEU.

The main application of a community monograph is to serve as a reference material for the marketing application, both for TU or WEU. Simplified registration is carried on at a national level, so the company gives the dossier to the NCA. With the aim of improving harmonization, the other MSs should recognize the first authorization granted in the first MS, considering that this is based in the European list.

Directive 2004/24/CE established an adaptation period for those herbal products which were on the European market at the moment the Directive was approved. This seven-year period finalized last April 30^th, 2011 and implies that nowadays those herbal preparations that not fulfill the actual legislation will not be marketed any more.

In the public report form the EMA last June 2014, the status of updating the medicines registration in the EU was shown. The number Traditional use registrations (TUR) and Well-established use marketing authorizations (WEU) grouped for mono component and combination products has increased in the last years (Figure 2).

The European market for HMP is increasing during the last years and even exceeds prescription medicines. The indications approved cover a wide range of therapeutic areas, most of them characteristic of self-medication diseases: the main therapeutic areas are respiratory tract disorders (cough and cold), mental stress and mood disorders, urinary tract and gynecology disorders, sleep disorders and temporary insomnia (Figure 3). Most of the approved THMP until now were updates of existing authorizations and were based on Community monographs. The Summary of Product Characteristics (SoPC) reflects the items in the corresponding monograph [3].

A good correlation between the HMPC work and the evaluation of the dossiers from the companies was detected. The relevance of these documents (as shown by the accepted dossiers) is reflected in the HMPC working plan; as an example, last December 2012, 54 among the 56 species with more than 3 marketing authorizations were listed in the priority list.

Conclusión

European legal framework for medicinal products does also include herbal medicinal products to assure their quality, efficacy and safety. The specific characteristics of these products led to the development of a simplified procedure to assure pharmaceutical quality, while keeping safety and efficacy criteria according to marketing authorization granted.

Although the starting point was quite different for the MS, nowadays there exist Community monographs for most of the herbal substances/ preparations that are used in the European market and which form the basis for a harmonization scenario. Moreover, HMPC acts as an International Regulatory Body for herbal medicinal products in order to achieve global standards for this type of medicines, according to other International organization such as the International Conference on Harmonization (ICH). The main tasks the HMPC has to face are those related to herbal medicinal products which have been previously marketed abroad the EU and the increasing existence of combination products within the MS.

References

Kroes BH (2014) The legal framework governing the quality of (traditional) herbal medicinal products in the European Union. J of Ethnopharmacol 158: 449-453. Chinou I (2014) Monographs, list entries, public statements. J of Ethnopharmacol 158: 458-462. Peschel W (2014) The use of community herbal monographs to facilitate registrations and authorisations of herbal medicinal products in the European Union 2004-2012. J of Eth nopharmacol 158: 471-486.

	Main characteristics	Article n°
Full marketing authorisation	New medicinal product (new chemical substance) Quality documentation Non-clinical studies Clinical trials Efficacy demonstrated by results of clinical trials Adequate safety data	8 (3)
Well-established use	Medicinal products for which there is an extensive clinical experience Quality documentation Substantial clinical experience and scientific data available, so no new data on clinical trials No limitation for therapeutic indications	10 a
Traditional use	Products which not fulfill the efficacy requirements for a marketing authorization = simplified registration Efficacy plausible on the bases of long-standing use and experience Quality documentation Therapeutic indications considered to be safe for use without the supervision of a physician	16 a

Table 1: Types of applications for marketing authorization for a HMP in the EU according the Directive 2001/83/EC.

Herbal medicinal product	Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.
Herbal substances	All mainly whole, fragmented or cut plants, plant part, algae, fungi, lichen in an unprocessed,, usually dried, but sometimes fresh (…). Herbal substances are precisely defined by the planta part used and the botanical name according to the binomial system (genus, species, variety and author).
Herbal preparations	Preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.

Table 2: Definitions applicable to herbal medicinal products (Directive 2001/83/EC).

Herbal medicinal product	Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.
Herbal substances	All mainly whole, fragmented or cut plants, plant part, algae, fungi, lichen in an unprocessed,, usually dried, but sometimes fresh (…). Herbal substances are precisely defined by the planta part used and the botanical name according to the binomial system (genus, species, variety and author).
Herbal preparations	Preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.

Table 3: Definitions applicable to herbal medicinal products (Directive 2001/83/EC).

Figure 1: European Community Monograph for Valeriana officinalis L., radix, for WEU and TU

Ruiz-Poveda OMP^*

Department of Pharmacology, Faculty of Pharmacy, Universidad Complutense de Madrid, 28040 Madrid, Spain

Ruiz-Poveda OMP
Department of Pharmacology, Faculty of Pharmacy
Universidad Complutense de Madrid, Madrid
Ciudad Universitaria s/n. 28040 Madrid, Spain
Tel: 913 941 767
Fax: 913 941 726
E-mail: olgapalomino@farm.ucm.es

Citation: Ruiz-Poveda OMP (2015) Regulation of Herbal (Traditional) Medicinal Products in the European Union. Pharmaceut Reg Affairs 4:142. doi: 10.4172/2167-7689.1000142

/////////Herbal medicines, Good manufacturing practices, Traditional uses

EMA: European Medicines Agency; DER: Drug to Extract Ratio; HMP: Herbal Medicinal Products; THMP: Traditional Herbal Medicinal Products

Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

October 21, 2015 8:25 am / 1 Comment on Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

Dr. Ashok Kumar

PRESIDENT – R&D (Chemical) at IPCA LABORATORIES LTD

LINKS

https://in.linkedin.com/pub/ashok-kumar/16/6a7/903

Intro

The 25-year process patent regime allowed a large number of generic companies in India to reap rich dividends, but there were few who believed in the need to go beyond the horizon of process development to tap into unexplored terrains.

In the year 2000, when Dr Ashok Kumar joined the board of Mumbai-based IPCA Labs, he was determined to implement a different strategy to accelerate IPCA’s R&D initiatives. Having seen IPCA grow from a 350-crore company to one clocking an annual turnover of over 2,500 crore, Dr Ashok Kumar, president- Center for Research and Development, IPCA Labs, is now leaving no stone unturned to exploit the biotech and drug discovery space.

Dr Kumar completed his M Sc in Chemistry from Kumaun University, now in Uttarakhand. He then decided to pursue his PhD in organic chemistry and joined Banaras Hindu University (BHU), but opted out three months later to do PhD from the Central Drug Research Institute (CDRI), Lucknow, under the guidance of the then director of the CDRI, Dr Nityanand.

Dr Kumar did his post doctoral studies from the University of Sussex, UK. “During the 1980s, jobs in scientific research were not available in India. It was always good to go for higher studies abroad,” he says about the reason for going abroad. “Dr Nityanand taught me to be explorative and think of new ways to approach a subject. I still follow that process,” he says. In 1984, Dr Kumar decided to return to India and took up a job at the Imperial Chemical Laboratories (ICI), Mumbai. In 1994, he joined Lupin Labs where he was once again involved in process development of small molecules.

In 2000, he joined IPCA Labs where he immediately focused on bringing about two changes – introducing a library and bringing in systems like a nuclear magnetic resonance (NMR), which at that time was the costliest instrument. “I understood the importance of high-end technologies since my PhD years at the CDRI (which housed a couple of NMRs) and then in the UK. You do not enjoy organic chemistry without an NMR. My main objective at IPCA was cost reduction along with process development.”

In the last few years, IPCA’s R&D team has brought out over 100 products. Under Dr Kumar, IPCA has an R&D center in Mumbai and another parallel R&D center in Ratlam, Madhya Pradesh. “In Mumbai, we have around 60 people. The Mumbai team takes care of basic chemistry and small-scale development. Scaling up is done in Ratlam,” he explains. IPCA is also coming up with a facility at Vadodara, Gujarat, that will look into large-scale manufacture of both organic and biotech drugs. The facility will have a strategic importance for the company. “We are growing at a rate of 20 per cent year-on-year and, next year, we intend to add 500 crore to our revenue. For that, we need more products to come to the market and more volume,” he adds.

Apart from organic chemistry, Dr Kumar is currently aligning his attention to two promising but high risk segments – fermentation-based products and biosimilars. “We are working on five-to-six molecules, mainly active metabolites that are intermediates or biotech drugs,” he adds. IPCA has also collaborated with two companies in India for the development of biosimilars. Currently, there are three biosimilar products in the pipeline.

The R&D team at IPCA ventured into drug discovery three years ago. It has two products in the pipeline; one anti-malarial and the other anti-thrombotic. “We will be filing the investigational new drug application for one molecule this year and for the other next year. The success rate here is 99 per cent,” adds Dr Kumar. IPCA has also joined hands with the CDRI and licensed two molecules in the anti-malarial space. One of these molecules is currently in phase-I stage.

Innogen summit India 2016, 18-19 Aug, Mumbai, India, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd………topic is Supergenerics, Innovation in Generics, commercialization, regulatory, other insights,

Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd, at Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — with DR ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

PANEL DISCUSSION, Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd , Dr. Nilima A. Kshirsagar, National Chair Clinical Pharmacology, ICMR Government of India, Yugal Sikri, Chairman – Pharmaceutical Management, School of Business Management, SVKM’s Narsee Monjee Institute of Management Studies — with Yugal Sikri,, Nilima A. Kshirsagarand ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

JOURNEY

2005…..PRESIDENT

In 2000, he joined IPCA Labs

1994, he joined Lupin Labs where he was once again involved in process development of small molecules.

1984 Dr Kumar decided to return to India and took up a job at the Imperial Chemical Laboratories (ICI), Mumbai.

Dr Kumar did his post doctoral studies from the University of Sussex, UK.

PhD in organic chemistry and joined Banaras Hindu University (BHU), but opted out three months later to do PhD from the Central Drug Research Institute (CDRI), Lucknow, under the guidance of the then director of the CDRI, Dr Nityanand.

Dr Kumar completed his M Sc in Chemistry from Kumaun University, now in Uttarakhand

DR NITYANAND

DIRECTOR, CDRI, LUCKNOW, INDIA

Experience

PRESIDENT – R&D

IPCA LABORATORIES LTD

2005 – Present (10 years)

Patent 1

chlorthalidone is 3-hydroxy-3-(3′-sulfamyI-4′- chlorophenyl)phtalimidine and is represented by the structural formula shown below.

http://www.google.co.in/patents/WO2005065046A2?cl=en

Chlorthalidone Formula 1

(Scheme 2). The starting material, 2-(4′-chlorobenzoyl) benzoic acid, of Formula (2) and its preparation was reported earlier for example in patents US 4500636, US 30555904, US4379092, US 3764664.

Formula 9 CIS0₃H

Chlorthalidone Formula 10 Formula 1

PATENT 2

https://www.google.co.in/patents/US7847094Quetiapine and its process for preparation is first disclosed in the patent specification EP0240228 and various other processes for the preparation are disclosed in EP0282236, WO0155125, WO9906381, WO2004076431.

PATENT 3

http://www.google.com/patents/US20080009635

. The chemical name of Ondansetron is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl)-1H-imidazole-1-yl)methyl]-4H-carbazol-4-one and is represented by the structural formula given below:

PATENT 4

http://www.google.im/patents/US20100081847

scheme 2.

AT A SEMIMAR

Chemical Research & Development Centre

123-AB, Kandivli Industrial Estate, Kandivli (West)
Mumbai 400 067, Maharashtra

+91 (22) 6647 4755 / 56

+91 (22) 6647 4757

Kumaun University

Imperial Chemical Laboratories (ICI), Mumbai

/////Dr. Ashok Kumar, PRESIDENT, R&D, IPCA LABORATORIES LTD

FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder

October 21, 2015 12:54 am / Leave a comment

FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder

10/20/2015

The U.S. Food and Drug Administration today approved Coagadex, Coagulation Factor X (Human), for hereditary Factor X (10) deficiency. Until today’s orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.

October 20, 2015

Release

In healthy individuals, the Factor X protein activates enzymes to help with normal blood clotting in the body. Factor X deficiency is an inherited disorder, affecting men and women equally, where the blood does not clot as it should. Patients with the disorder are usually treated with fresh-frozen plasma or plasma-derived prothrombin complex concentrates (plasma products containing a combination of vitamin K-dependent proteins) to stop or prevent bleeding. The availability of a purified Factor X concentrate increases treatment options for patients with this rare bleeding disorder.

“The approval of Coagadex is a significant advancement for patients who suffer from this rare but serious disease,” said Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research.

Coagadex, which is derived from human plasma, is indicated for individuals aged 12 and older with hereditary Factor X deficiency for on-demand treatment and control of bleeding episodes, and for perioperative (period extending from the time of hospitalization for surgery to the time of discharge) management of bleeding in patients with mild hereditary Factor X deficiency.

The safety and efficacy of Coagadex was evaluated in a multi-center, non-randomized study involving 16 participants (208 bleeding episodes) for treatment of spontaneous, traumatic and heavy menstrual (menorrhagic) bleeding episodes. Coagadex was demonstrated to be effective in controlling bleeding episodes in participants with moderate to severe hereditary Factor X deficiency. Coagadex was also evaluated in five participants with mild to severe Factor X deficiency who were undergoing surgery. The five individuals received Coagadex for perioperative management of seven surgical procedures. Coagadex was demonstrated to be effective in controlling blood loss during and after surgery in participants with mild deficiency. No individuals with moderate or severe Factor X deficiency received Coagadex for perioperative management of major surgery, and no safety concerns were identified in either study.

The FDA granted Coagadex orphan product designation for these uses. Orphan product designation is given to drugs intended to treat rare diseases in order to promote their development. Coagadex was also granted fast track designation and priority review.

Coagadex is manufactured by Bio Products Laboratory Limited in Elstree, Hertfordshire, United Kingdom.

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

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WO2012062687A1 *	7 Nov 2011	18 May 2012	F. Hoffmann-La Roche Ag	Triazole derivatives and their use for neurological disorders
WO2013122260A1	14 Feb 2013	22 Aug 2013	Takeda Pharmaceutical Company Limited	Tablet
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US8329691	14 Oct 2008	11 Dec 2012	Takeda Pharmaceutical Company Limited	Amide compounds and use of the same
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US8658639	24 Jun 2010	25 Feb 2014	Dainippon Sumitomo Pharma Co., Ltd	N-substituted-cyclic amino derivative
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

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