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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Ceralasertib, AZD 6738


Image result for azd 6738

Image result for azd 6738

Image result for azd 6738

AZD-6738, Ceralasertib

  • Molecular Formula C20H24N6O2S
  • Average mass 412.509 Da
CAS 1352226-88-0 [RN]
1H-Pyrrolo[2,3-c]pyridine, 4-[4-[(3R)-3-methyl-4-morpholinyl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]-2-pyrimidinyl]-
4-{4-[(3R)-3-Methyl-4-morpholinyl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]-2-pyrimidinyl}-1H-pyrrolo[2,3-c]pyridine
1H-Pyrrolo(2,3-b)pyridine, 4-(4-(1-((S(R))-S-methylsulfonimidoyl)cyclopropyl)-6-((3R)-3-methyl-4-morpholinyl)-2-pyrimidinyl)-
imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane
85RE35306Z
AZD-6738
UNII:85RE35306Z
CAS : 1352226-88-0 (free base)   1352280-98-8 (formic acid)   1352226-97-1 (racemic)
  • 4-[4-[1-[[S(R)]-S-Methylsulfonimidoyl]cyclopropyl]-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinyl]-1H-pyrrolo[2,3-b]pyridine
  • AZD 6738
  • Ceralasertib
  • Originator AstraZeneca; University of Pennsylvania
  • Class Antineoplastics; Morpholines; Pyrimidines; Small molecules
  • Mechanism of Action ATR protein inhibitors
  • Phase II Breast cancer; Gastric cancer; Non-small cell lung cancer; Ovarian cancer
  • Phase I/II Chronic lymphocytic leukaemia; Solid tumours
  • Phase I Non-Hodgkin’s lymphoma
  • Preclinical Diffuse large B cell lymphoma
  • No development reported B-cell lymphoma; Lymphoid leukaemia
  • 26 Mar 2019 National Cancer Institute plans a phase II trial for Cholangiocarcinoma (Combination therapy, Second-line therapy or greater) and Solid tumours (Combination therapy, Second-line therapy or greater) in March 2019 (NCT03878095)
  • 18 Mar 2019 Royal Marsden NHS Foundation Trust and AstraZeneca re-initiate the phase I PATRIOT trial in Solid tumours (Second-line therapy or greater) in United Kingdom (NCT02223923)
  • 25 Dec 2018 University of Michigan Cancer Center plans the phase II TRAP trial for Prostate cancer (Combination therapy; Metastatic disease; Second-line therapy or greater) in February 2019 (NCT03787680)

Inhibits ATR kinase.

Ceralasertib, also known as AZD6738, is an orally available morpholino-pyrimidine-based inhibitor of ataxia telangiectasia and rad3 related (ATR) kinase, with potential antineoplastic activity. Upon oral administration, ATR kinase inhibitor Ceralasertib selectively inhibits ATR activity by blocking the downstream phosphorylation of the serine/threonine protein kinase CHK1. This prevents ATR-mediated signaling, and results in the inhibition of DNA damage checkpoint activation, disruption of DNA damage repair, and the induction of tumor cell apoptosis.

ATR (also known as FRAP-Related Protein 1; FRP1; MEC1; SCKL; SECKL1) protein kinase is a member of the PI3 -Kinase like kinase (PIKK) family of proteins that are involved in repair and maintenance of the genome and its stability (reviewed in Cimprich K.A. and Cortez D. 2008, Nature Rev. Mol. Cell Biol. 9:616-627). These proteins co-ordinate response to DNA damage, stress and cell-cycle perturbation. Indeed ATM and ATR, two members of the family of proteins, share a number of downstream substrates that are themselves recognised components of the cell cycle and DNA-repair machinery e.g. Chkl, BRCAl, p53 (Lakin ND et al,1999, Oncogene; Tibbets RS et al, 2000, Genes & Dev.). Whilst the substrates of ATM and ATR are to an extent shared, the trigger to activate the signalling cascade is not shared and ATR primarily responds to stalled replication forks (Nyberg K.A. et al., 2002, Ann. Rev.

Genet. 36:617-656; Shechter D. et al. 2004, DNA Repair 3:901-908) and bulky DNA damage lesions such as those formed by ultraviolet (UV) radiation (Wright J. A. et al, 1998, Proc. Natl. Acad. Sci. USA, 23:7445-7450) or the UV mimetic agent, 4-nitroquinoline-1-oxi-e, 4NQO (Ikenaga M. et al. 1975, Basic Life Sci. 5b, 763-771). However, double strand breaks (DSB) detected by ATM can be processed into single strand breaks (SSB) recruiting ATR; similarly SSB, detected by ATR can generate DSB, activating ATM. There is therefore a significant interplay between ATM and ATR.

Mutations of the ATR gene that result in complete loss of expression of the ATR protein are rare and in general are not viable. Viability may only result under heterozygous or hypomorphic conditions. The only clear link between ATR gene mutations and disease exists in a few patients with Seckel syndrome which is characterized by growth retardation and microcephaly (O’Driscoll M et al, 2003 Nature Genet. Vol3, 497-501). Cells from patients with hypomorphic germline mutations of ATR (seckel syndrome) present a greater susceptibility to chromosome breakage at fragile sites in presence of replication stress compared to wild type cells (Casper 2004). Disruption of the ATR pathway leads to genomic instability. Patients with Seckel syndrome also present an increased incidence of cancer,suggestive of the role of ATR in this disease in the maintenance of genome stability .

Moreover, duplication of the ATR gene has been described as a risk factor in rhabdomyosarcomas (Smith L et al, 1998, Nature Genetics 19, 39-46). Oncogene-driven tumorigenesis may be associated with ATM loss-of- function and therefore increased reliance on ATR signalling (Gilad 2010). Evidence of replication stress has also been reported in several tumour types such as colon and ovarian cancer, and more recently in glioblastoma, bladder, prostate and breast (Gorgoulis et al, 2005; Bartkova et al. 2005a; Fan et al., 2006; Tort et al, 2006; Nuciforo et al, 2007; Bartkova et al., 2007a). Loss of Gl checkpoint is also frequently observed during tumourigenesis. Tumour cells that are deficient in Gl checkpoint controls, in particular p53 deficiency, are susceptible to inhibition of ATR activity and present with premature chromatin condensation (PCC) and cell death (Ngheim et al, PNAS, 98, 9092-9097).

ATR is essential to the viability of replicating cells and is activated during S-phase to regulate firing of replication origins and to repair damaged replication forks (Shechter D et al, 2004, Nature cell Biology Vol 6 (7) 648-655). Damage to replication forks may arise due to exposure of cells to clinically relevant cytotoxic agents such as hydroxyurea (HU) and platinums (O’Connell and Cimprich 2005; 118, 1-6). ATR is activated by most cancer chemotherapies (Wilsker D et al, 2007, Mol. Cancer Ther. 6(4) 1406-1413). Biological assessment of the ability of ATR inhibitors to sensitise to a wide range of chemotherapies have been evaluated. Sensitisation of tumour cells to chemotherapeutic agents in cell growth assays has been noted and used to assess how well weak ATR inhibitors (such as Caffeine) will sensitise tumour cell lines to cytotoxic agents. (Wilsker D .et al, 2007, Mol Cancer Ther. 6 (4)1406-1413; Sarkaria J.N. et al, 1999, Cancer Res. 59, 4375-4382). Moreover, a reduction of ATR activity by siRNA or ATR knock-in using a dominant negative form of ATR in cancer cells has resulted in the sensitisation of tumour cells to the effects of a number of therapeutic or experimental agents such as antimetabolites (5-FU, Gemcitabine, Hydroxyurea, Metotrexate, Tomudex), alkylating agents (Cisplatin, Mitomycin C, Cyclophosphamide, MMS) or double-strand break inducers (Doxorubicin, Ionizing radiation) (Cortez D. et al. 2001, Science, 294:1713-1716; Collis S.J. et al, 2003, Cancer Res. 63:1550-1554; Cliby W.A. et al, 1998, EMBO J. 2:159-169) suggesting that the combination of ATR inhibitors with some cytotoxic agents might be therapeutically beneficial.

An additional phenotypic assay has been described to define the activity of specific ATR inhibitory compounds is the cell cycle profile (PJ Hurley, D Wilsker and F Bunz, Oncogene, 2007, 26, 2535-2542). Cells deficient in ATR have been shown to have defective cell cycle regulation and distinct characteristic profiles, particularly following a cytotoxic cellular insult. Furthermore, there are proposed to be differential responses between tumour and normal tissues in response to modulation of the ATR axis and this provides further potential for therapeutic intervention by ATR inhibitor molecules (Rodnguez-Bravo V et al, Cancer Res., 2007, 67, 11648-11656).

Another compelling utility of ATR-specific phenotypes is aligned with the concept of synthetic lethality and the observation that tumour cells that are deficient in G1 checkpoint controls, in particular p53 deficiency, are susceptible to inhibition of ATR activity resulting in premature chromatin condensation (PCC) and cell death (Ngheim et al, PNAS, 98, 9092-9097). In this situation, S-phase replication of DNA occurs but is not completed prior to M-phase initiation due to failure in the intervening checkpoints resulting in cell death from a lack of ATR signalling. The G2/M checkpoint is a key regulatory control involving ATR (Brown E. J. and Baltimore D., 2003, Genes Dev. 17, 615-628) and it is the compromise of this checkpoint and the prevention of ATR signalling to its downstream partners which results in PCC. Consequently, the genome of the daughter cells is compromised and viability of the cells is lost (Ngheim et al, PNAS, 98, 9092-9097).

It has thus been proposed that inhibition of ATR may prove to be an efficacious approach to future cancer therapy (Collins I. and Garret M.D., 2005, Curr. Opin. Pharmacol., 5:366-373; Kaelin W.G. 2005, Nature Rev. Cancer, 5:689-698) in the appropriate genetic context such as tumours with defects in ATM function or other S-phase checkpoints. Until recently, There is currently no clinical precedent for agents targeting ATR, although agents targeting the downstream signalling axis i.e. Chk1 are currently undergoing clinical evaluation (reviewed in Janetka J.W. et al. Curr Opin Drug Discov Devel, 2007, 10:473-486). However, inhibitors targeting ATR kinase have recently been described (Reaper 2011, Charrier 2011).

In summary ATR inhibitors have the potential to sensitise tumour cells to ionising radiation or DNA-damage inducing chemotherapeutic agents, have the potential to induce selective tumour cell killing as well as to induce synthetic lethality in subsets of tumour cells with defects in DNA damage response.

PAPER

Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent

  • Kevin M. Foote
Cite This:J. Med. Chem.201861229889-9907
Publication Date:October 22, 2018
https://doi.org/10.1021/acs.jmedchem.8b01187
The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2(AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.
 ATR Inhibitors
4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (2)
2 (139 g, 42%) as a white crystalline solid.
1H NMR (400 MHz, DMSO-d6): 1.19 (3H, d), 1.29–1.50 (3H, m), 1.61–1.72 (1H, m), 3.01 (3H, s), 3.22 (1H, d), 3.43 (1H, td), 3.58 (1H, dd), 3.68–3.76 (2H, m), 3.87–3.96 (1H, m), 4.17 (1H, d), 4.60 (1H, s), 6.98 (1H, s), 7.20 (1H, dd), 7.55–7.58 (1H, m), 7.92 (1H, d), 8.60 (1H, d), 11.67 (1H, s).
13C NMR (176 MHz, DMSO-d6) 11.29, 12.22, 13.39, 38.92, 41.14, 46.48, 47.81, 65.97, 70.19, 101.54, 102.82, 114.58, 117.71, 127.21, 136.70, 142.21, 150.12, 161.88, 162.63, 163.20.
HRMS-ESI m/z 413.17529 [MH+]; C20H24N6O2S requires 413.1760.
Chiral HPLC: (HP1100 system 4, 5 μm Chiralpak AS-H (250 mm × 4.6 mm) column, eluting with isohexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf = 8.252, >99%. Anal. Found (% w/w): C, 58.36; H, 5.87; N, 20.20; S, 7.55; H2O, <0.14. C20H24N6O2S requires C, 58.23; H, 5.86; N, 20.37; S, 7.77.

Patent

WO 2011154737

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=CF8CA857FDD8BF59DA9F336056132BB7.wapp2nA?docId=WO2011154737&tab=PCTDESCRIPTION

Example 1.01

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[((R)-S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine

(R)-3-Methyl-4-(6-((R)-S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (98 mg, 0.18 mmol) was dissolved in MeOH (10 ml) and DCM (10 ml) and heated to 50 °C. Sodium hydroxide, 2M aqueous solution (0.159 ml, 0.32 mmol) was then added and heating continued for 5 hours. The reaction mixture was evaporated and the residue dissolved in DME: water :MeCN 2: 1 : 1 (4 ml) and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated and the residue trituated with Et2O

(1 ml) to afford the title compound (34.6 mg, 49%); 1HNMR (400 MHz, CDCl3) 1.40 (3H, d), 3.17 (3H, s), 3.39 (1H, tt), 3.62 (1H, td), 3.77 (1H, dd), 3.85 (1H, d), 4.08 (1H, dd), 4.18 (1H, d), 4.37 – 4.48 (2H, q), 4.51 (1H, s), 6.59 (1H, s), 7.35 (1H, t), 7.46 (1H, d), 8.06 (1H, d), 8.42 (1H, d), 10.16 (1H, s); m/z: (ES+) MH+, 387.19.

The (R)-3-methyl-4-(6-((R)-S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine, used as starting material, can be prepared as follows:

a) (R)-3-methylmorpholine (7.18 g, 71.01 mmol) and triethylamine (12.87 ml, 92.31 mmol) were added to methyl 2,4-dichloropyrimidine-6-carboxylate (14.70 g, 71.01 mmol) in DCM (100 ml). The resulting mixture was stirred at RT for 18 hours. Water (100 ml) was added, the layers separated and extracted with DCM (3 × 75 ml). The combined organics were

dried over MgSO4, concentrated in vacuo and the residue triturated with Et2O to yield (R)-methyl 2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (14.77 g, 77%); 1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.34 (1H, td), 3.55 (1H, td), 3.70 (1H, dd), 3.81 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.37 (1H, br s), 7.15 (1H, s); m/z: (ESI+) MH+, 272.43. The liquors were concentrated onto silica and purified by chromatography on silica eluting with a gradient of 20 to 40% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford (R)-methyl 2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (1.659 g, 9%); 1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.33 (1H, td), 3.55 (1H, td), 3.69 (1H, dd), 3.80 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.36 (1H, br s), 7.15 (1H, s); m/z: (ESI+) MH+, 272.43.

b) Lithium borohydride, 2M in THF (18 ml, 36.00 mmol) was added dropwise to (R)-methyl 2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (16.28 g, 59.92 mmol) in THF (200 ml) at 0°C over a period of 20 minutes under nitrogen. The resulting solution was stirred at 0 °C for 30 minutes and then allowed to warm to RT and stirred for a further 18 hours. Water (200 ml) was added and the THF evaporated. The aqueous layer was extracted with EtOAc (2 × 100 ml) and the organic phases combined, dried over MgSO4 and then evaporated to afford (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (14.54 g, 100%) which was used in the next step without purification; 1HNMR (400 MHz, CDCl3) 1.32 (3H, d), 2.65 (1H, br s), 3.25 – 3.32 (1H, m), 3.51 – 3.57 (1H, m), 3.67 – 3.70 (1H, m), 3.78 (1H, d), 3.98 – 4.09 (2H, m), 4.32 (1H, br s), 4.59 (2H, s), 6.44 (1H, s); m/z: (ESI+) MH+, 244.40.

c) Methanesulfonyl chloride (4.62 ml, 59.67 mmol) was added dropwise to (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (14.54 g, 59.67 mmol) and triethylamine (8.32 ml, 59.67 mmol) in DCM (250 ml) at 25 °C over a period of 5 minutes. The resulting solution was stirred at 25 °C for 90 minutes. The reaction mixture was quenched with water (100 ml) and extracted with DCM (2 × 100 ml). The organic phases were combined, dried over MgSO4, filtered and evaporated to afford (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (20.14 g, 105%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.13 (3H, s), 3.27 – 3.34 (1H, m), 3.51 -3.57 (1H, m), 3.66 – 3.70 (1H, m), 3.79 (1H, d), 3.99 – 4.03 (2H, m), 4.34 (1H, br s), 5.09 (2H, d) , 6.52 (1H, s); m/z: (ESI+) MH+, 322.83.

Alternatively, this step can be carried out as follows:

In a 3 L fixed reaction vessel with a Huber 360 heater / chiller attached, under a nitrogen atmosphere, triethylamine (0.120 L, 858.88 mmol) was added in one go to a stirred solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (161 g, 660.68 mmol) in DCM (7.5vol) (1.2 L) at 20°C (3°C exotherm seen). The mixture was cooled to 5°C and then methanesulfonyl chloride (0.062 L, 792.81 mmol) was added dropwise over 15 minutes, not allowing the internal temperature to exceed 15°C. The reaction mixture was stirred at 15°C for 2 hours and then held (not stirring) overnight at RT under a nitrogen atmosphere. Water (1.6 L, 10 vol) was added and the aqueous layer was separated and then extracted with DCM (2 × 1.6 L, 2 × 10 vol). The organics were combined, washed with 50% brine / water (1.6 L, 10 vol), dried over magnesium sulphate, filtered and then evaporated to afford a mixture of

approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (216 g) which was used in the next step without further purification, d) Lithium iodide (17.57 g, 131.27 mmol) was added to (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (19.2 g, 59.67 mmol) in dioxane (300 ml) and heated to 100 °C for 2 hours under nitrogen. The reaction mixture was quenched with water (200 ml) and extracted with EtOAc (3 × 200 ml). The organic layers were combined and washed with 2M sodium bisulfite solution (400 ml), water (400 ml), brine (400 ml) dried over MgSO4 and then evaporated. The residue was triturated with Et2O to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (13.89 g, 66%); 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 -4.02 (2H, m), 4.21 (2H, s), 4.29 (1H, br s), 6.41 (1H, s); m/z: (ESI+) MH+ 354.31.

The mother liquors were concentrated down and triturated with Et2O to afford a further crop of (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (2.46 g, 12%); 1HNMR (400 MHz, CDCI3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 – 4.02 (2H, m), 4.21 (2H, s), 4.30 (1H, s), 6.41 (1H, s); m/z: (ESI+) MH+, 354.31.

Alternatively, this step can be carried out as follows:

(R)-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (80 g, 248.62 mmol) and lithium iodide (83 g, 621.54 mmol) were dissolved in dioxane (300 ml) and then heated at 107 °C for 1 hour. The reaction mixture was quenched with water (250 ml), extracted with EtOAc (3 × 250 ml), the organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and Et2O was added, the mixture was passed through silica (4 inches) and eluted with Et2O. Fractions containing product were evaporated and the residue was then triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (75 g, 86%) ; m/z: (ESI+) MH+, 354.27.

e) (R)-4-(2-Chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (17.0 g, 48.08 mmol) was dissolved in DMF (150 ml), to this was added sodium methanethiolate (3.37 g, 48.08 mmol) and the reaction was stirred for 1 hour at 25 °C. The reaction mixture was quenched with water (50 ml) and then extracted with Et2O (3 × 50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash

chromatography on silica, eluting with a gradient of 50 to 100% EtOAc in iso-hexane. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 96%); m/z: (ES+) MH+, 274.35.

Alternatively, (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine, may be prepared as follows:

In a 3 L fixed vessel, sodium thiomethoxide (21% in water) (216 g, 646.69 mmol) was added dropwise over 5 minutes to a stirred solution of a mixture of approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (130.2 g, 431 mmol) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1 L) at RT (temperature dropped from 20 °C to 18 °C over the addition and then in the next 5 minutes rose to 30 °C). The reaction mixture was stirred for 16 hours and then diluted with EtOAc (2 L), and washed sequentially with water (750 ml) and saturated brine (1 L). The organic layer was dried over MgSO4, filtered and then evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (108 g, 91%); 1H NMR (400 MHz, DMSO- d6) 1.20 (3H, d), 2.07 (3H, s), 3.11 – 3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92 – 4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s); m/z: (ES+) MH+, 274.36.

f) (R)-4-(2-Chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 46.13 mmol) was dissolved in DCM (100 ml), to this was added mCPBA (7.96 g, 46.13 mmol) in one portion and the reaction mixture was stirred for 10 minutes at 25 °C. An additional portion of mCPBA (0.180 g) was added. The reaction mixture was quenched with saturated Na2CO3 solution (50 ml) and extracted with DCM (3 × 50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was dissolved in DCM (80 ml) in a 150

ml conical flask which was placed into a beaker containing Et2O (200 ml) and the system covered with laboratory film and then left for 3 days. The obtained crystals were filtered, crushed and sonicated with Et2O. The crystallisation procedure was repeated to afford (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine as white needles (3.87 g, 29%); 1HNMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, s), 3.30 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 4.00 (1H, dd), 4.02 (1H, s), 4.32 (1H, s), 6.42 (1H, s).

The remaining liquour from the first vapour diffusion was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine as an orange gum (5.70 g, 43%); 1 HNMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, d), 3.29 (1H, td), 3.54 (1H, td), 3.68 (1H, dd), 3.73 – 3.82 (2H, m), 3.94 (1H, dd), 4.00 (2H, dd), 4.33 (1H, s), 6.42 (1H, s).

Alternatively, this step can be carried out as follows:

Sodium meta-periodate (64.7 g, 302.69 mmol) was added in one portion to (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (82.87 g, 302.69 mmol) in water (500 ml), EtOAc (1000 ml) and MeOH (500 ml). The resulting solution was stirred at 20 °C for 16 hours. Sodium metabisulfite (50 g) was added and the mixture stirred for 30 minutes. The reaction mixture was filtered and then partially evaporated to remove the MeOH. The organic layer was separated, dried over MgSO4, filtered and then evaporated. The aqueous layer was washed with DCM (3 x 500 ml). The organic layers were combined, dried over MgSO4, filtered and then evaporated. The residues were combined and dissolved in DCM (400 ml) and purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Fractions containing product were evaporated and the residue was dissolved in DCM (400 ml) and then divided into four 450 ml bottles. An aluminium foil cap was placed over the top of each bottle and a few holes made in each cap. The bottles were placed in pairs in a large dish containing Et2O (1000 ml), and then covered and sealed with a second glass dish and left for 11 days. The resultant white needles were collected by filtration and dried under vacuum. The crystals were dissolved in DCM (200 ml) and placed into a 450 ml bottle. An aluminium foil cap was placed over the top of the bottle and a few holes made in the cap. The bottle was placed in a large dish containing Et2O (1500 ml) and then covered and sealed with a second glass dish and left for 6 days. The resultant crystals were collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (16.53 g, 19%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.61 (3H, s),

3.29 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 3.99 (1H, dd), 4.02 (1H, s), 4.31 (1H, s), 6.41 (1H, s). Chiral HPLC: (HP1100 System 5, 20μm Chiralpak AD-H (250 mm × 4.6 mm) column eluting with Hexane/EtOH/TEA 50/50/0.1) Rf, 12.192 98.2%.

The filtrate from the first vapour diffusion was concentrated in vacuo to afford an approximate

5:2 mixture of (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine and (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (54.7 g, 62%).

Alternatively, this step can be carried out as follows:

Sodium meta-periodate (2.87 g, 13.44 mmol) was added in one portion to (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (3.68 g, 13.44 mmol) in water (10.00 ml), EtOAc (20 ml) and MeOH (10.00 ml). The resulting solution was stirred at 20 °C for 16 hours. The reaction mixture was diluted with DCM (60 ml) and then filtered. The DCM layer was separated and the aqueous layer washed with DCM (3 × 40 ml). The organics were combined, dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (2.72 g, 70%); 1H NMR (400 MHz, DMSO-d6) 1.22 (3H, d), 2.64 (3H, d), 3.14 – 3.26 (1H, m), 3.45 (1H, td), 3.59 (1H, dd), 3.73 (1H, d), 3.88 – 3.96 (2H, m), 4.00 (1H, d), 4.07 (1H, dt), 4.33 (1H, s), 6.81 (1H, s); m/z: (ESI+) MH+, 290.43.

The (3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (2.7 g, 9.32 mmol) was purified by preparative chiral chromatography on a Merck 100 mm 20 μm Chiralpak AD column, eluting isocratically with a 50:50:0.1 mixture of iso-Hexane:EtOH:TEA as eluent. The fractions containing product were evaporated to afford (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (1.38 g, 51%) as the first eluting compound; 1HNMR (400 MHz, CDCl3) 1.29 (3H, dd), 2.56 (3H, s), 3.15 – 3.33 (1H, m), 3.46 (1H, tt), 3.55 – 3.83 (3H, m), 3.85 – 4.06 (3H, m), 4.31 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 System 6, 20μm Chiralpak AD (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/TEA 50/50/0.1) Rf, 7.197 >99%.

and (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (1.27 g, 47 %) as the second eluting compound; 1H NMR (400 MHz, CDCl3) 1.28 (3H, d), 2.58 (3H, s),

3.26 (1H, td), 3.48 (1H, td), 3.62 (1H, dt), 3.77 (2H, dd), 3.88 – 4.13 (3H, m), 4.28 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 System 6, 20μm Chiralpak AD (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/TEA 50/50/0.1) Rf, 16.897 >99%.

g) Iodobenzene diacetate (18.98 g, 58.94 mmol) was added to (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (17.08 g, 58.94 mmol), 2,2,2-trifluoroacetamide (13.33 g, 117.88 mmol), magnesium oxide (9.50 g, 235.76 mmol) and rhodium(II) acetate dimer (0.651 g, 1.47 mmol) in DCM (589 ml) under air. The resulting suspension was stirred at 20 °C for 24 hours. Further 2,2,2-trifluoroacetamide (13.33 g, 117.88 mmol), magnesium oxide (9.50 g, 235.76 mmol), iodobenzene diacetate (18.98 g, 58.94 mmol) and rhodium(II) acetate dimer (0.651 g, 1.47 mmol) were added and the suspension was stirred at 20 °C for 3 days. The reaction mixture was filtered and then silica gel (100 g) added to the filtrate and the solvent removed in vacuo. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to afford N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-(R)-sulfanylidene]-2,2,2-trifluoroacetamide (19.39 g, 82%); 1H NMR (400 MHz, DMSO-d6) 1.22 (3H, d), 3.17 – 3.27 (1H, m), 3.44 (1H, td), 3.59 (1H, dd), 3.62 (3H, s), 3.74 (1H, d), 3.95 (1H, dd), 4.04 (1H, br s), 4.28 (1H, s), 5.08 (2H, q), 6.96 (1H, s); m/z: (ESI+) MH+, 401.12 and 403.13.

h) Dichlorobis(triphenylphosphine)palladium(II) (8.10 mg, 0.01 mmol) was added in one portion to N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-(R)-sulfanylidene]-2,2,2-trifluoroacetamide (185 mg, 0.46 mmol), 2M aqueous Na2CO3 solution (0.277 ml, 0.55 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (193 mg, 0.48 mmol) in DME:water 4: 1 (5 ml) at RT. The reaction mixture was stirred at 90 °C for 1 hour, filtered and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to afford (R)-3-methyl-4-(6-((R)-S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (102 mg, 41%); 1HNMR (400 MHz, CDCl3) 1.33 (3H, d), 3.21 – 3.38 (1H, m), 3.42 (3H, d), 3.45 – 3.57 (1H, m), 3.61 – 3.70 (1H, m), 3.78 (1H, d), 4.01 (1H, dd), 3.90 -4.15 (1H, br s), 4.30 (1H, s), 4.64 (1H, dd), 4.84 (1H, dd), 6.49 (1H, d); m/z: (ESI+) MH+, 541.35

The 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, used as starting material, can be prepared as follows:

a) To a 3L fixed vessel was charged 3-chlorobenzoperoxoic acid (324 g, 1444.67 mmol) portionwise to 1H-pyrrolo[2,3-b]pyridine (150 g, 1244.33 mmol) in DME (750 ml) and heptane (1500 ml) at 20°C over a period of 1 hour under nitrogen. The resulting slurry was stirred at 20 °C for 18 hours. The precipitate was collected by filtration, washed with DME / heptane (1/2 5 vol) (750 ml) and dried under vacuum at 40°C to afford 1H-pyrrolo[2,3-b] pyridine 7-oxide 3-chlorobenzoate (353 g, 97%) as a cream solid, which was used without further purification; 1H NMR (400 MHz, DMSO-d6) 6.59 (1H, d), 7.07 (1H, dd), 7.45 (1H, d), 7.55 (1H, t), 7.65 (1H, dd), 7.70 (1H, ddd), 7.87 – 7.93 (2H, m), 8.13 (1H, d), 12.42 (1H, s), 13.32 (1H, s).

b) A 2M solution of potassium carbonate (910 ml, 1819.39 mmol) was added dropwise to a stirred slurry of 1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate (352.6 g, 1212.93 mmol) in water (4.2 vol) (1481 ml) at 20°C, over a period of 1 hour adjusting the pH to 10. To the resulting slurry was charged water (2 vol) (705 ml) stirred at 20 °C for 1 hour. The slurry was cooled to 0°C for 1 hour and the slurry filtered, the solid was washed with water (3 vol 1050ml) and dried in a vacuum oven at 40°C over P2O5 overnight to afford 1H-pyrrolo[2,3-b] pyridine 7-oxide (118 g, 73%); 1H NMR (400 MHz, DMSO-d6) 6.58 (1H, d), 7.06 (1H, dd), 7.45 (1H, d), 7.64 (1H, d), 8.13 (1H, d), 12.44 (1H, s); m/z: (ES+) (MH+MeCN)+, 176.03. c) To a 3L fixed vessel under an atmosphere of nitrogen was charged methanesulfonic anhydride (363 g, 2042.71 mmol) portionwise to 1H-pyrrolo[2,3-b]pyridine 7-oxide (137 g, 1021.36 mmol), and tetramethylammonium bromide (236 g, 1532.03 mmol) in DMF (10 vol) (1370 ml) cooled to 0°C over a period of 30 minutes under nitrogen. The resulting suspension was stirred at 20 °C for 24 hours. The reaction mixture was quenched with water (20 vol, 2740 ml) and the reaction mixture was adjusted to pH 7 with 50% sodium hydroxide (approx 200 ml). Water (40 vol, 5480 ml) was charged and the mixture cooled to 10°C for 30 minutes. The solid was filtered, washed with water (20 vol, 2740 ml) and the solid disssolved into

DCM/methanol (4: 1, 2000 ml), dried over MgSO4 and evaporated to provide a light brown solid. The solid was taken up in hot methanol (2000 ml) and water added dropwise until the solution went turbid and left overnight. The solid was filtered off and discarded, the solution was evaporated and the solid recrystallised from MeCN (4000 ml). The solid was filtered and washed with MeCN to afford 4-bromo-1H-pyrrolo[2,3-b]pyridine (68.4 g, 34%) as a pink

solid; 1H NMR (400 MHz, OMSO-d6) 6.40 – 6.45 (1H, m), 7.33 (1H, d), 7.57 – 7.63 (1H, m), 8.09 (1H, t), 12.02 (1H, s); m/z: (ES+) MH+, 198.92. The crude mother liquors were purified by Companion RF (reverse phase CI 8, 415g column), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents (starting at 26% upto 46% MeCN). Fractions containing the desired compound were evaporated to afford 4-bromo-1H-pyrrolo[2,3-b]pyridine (5.4 g, 3%) as a pink solid; 1H NMR (400 MHz, DMSO-d6) 6.43 (1H, dd), 7.33 (1H, d), 7.55 – 7.66 (1H, m), 8.09 (1H, d), 12.03 (1H, s); m/z: (ES+) MH+, 199.22.

d) Sodium hydroxide (31.4 ml, 188.35 mmol) was added to 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.03 g, 50.91 mmol), tosyl chloride (19.41 g, 101.81 mmol) and

tetrabutylammonium hydrogensulfate (0.519 g, 1.53 mmol) in DCM (250 ml) at RT. The resulting mixture was stirred at RT for 1 hour. The reaction was quenched through the addition of saturated aqueous NH4Cl, the organic layer removed and the aqueous layer further extracted with DCM (3 × 25 ml). The combinbed organics were washed with brine (100 ml), dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to afford 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (14.50 g, 81%); 1H NMR (400 MHz, CDCl3) 2.38 (3H, s), 6.64 (1H, d), 7.28 (2H, d), 7.36 (1H, d), 7.78 (1H, d), 8.06 (2H, d), 8.22 (1H, d); m/z: (ES+) MH+, 353.23.

e) 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (3.37 g, 4.13 mmol) was added in one portion to 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (14.5 g, 41.28 mmol), bis(pinacolato)diboron (20.97 g, 82.57 mmol) and potassium acetate (12.16 g, 123.85 mmol) in anhydrous DMF (300 ml) at RT. The resulting mixture was stirred under nitrogen at 90 °C for 24 hours. After cooling to RT, 1N aqueous NaOH was added untill the aqueous layer was taken to pH 10. The aqueous layer was washed with DCM (1L), carefully acidified to pH 4 with 1 N aqueous HCl, and then extracted with DCM (3 × 300 ml). The organic layer was concentrated under reduced pressure to afford a dark brown solid. The solid was triturated with diethyl ether, filtered and dried to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7.058 g, 43%); 1H NMR (400 MHz, CDCl3) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.22 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, m), 8.42 (1H, d); m/z: (ES+) MH+, 399.40. The mother liquors were concentrated in vacuo and the residue triturated in isohexane, filtered and dried to afford a further sample of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (3.173 g, 19%); 1H NMR (400 MHz,

CDCI3) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.23 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, d), 8.42 (1H, d); m/z: (ES+) MH+, 399.40.

Example 2.01 and example 2.02

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-blpyridine, and

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-blpyridine


(3R)-3-Methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (1.67 g, 2.95 mmol) was dissolved in DME:water 4: 1 (60 ml) and heated to 50 °C. Sodium hydroxide, 2M aqueous solution (2.58 ml, 5.16 mmol) was then added and heating continued for 18 hours. The reaction mixture was acidified with 2M H Cl (~2 ml) to pH5. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc (250 ml), and washed with water (200 ml). The organic layer was dried over MgSO4, filtered and evaporated onto silica gel (10 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions were evaporated and the residue was purified by preparative chiral chromatography on a Merck 50mm, 20μm ChiralCel OJ column, eluting isocratically with 50% isohexane in EtOH/MeOH (1 : 1) (modified with TEA) as eluent. The fractions containing the desired compound were evaporated to dryness to afford the title compound: 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (0.538g, 44%) as the first eluting compound; 1H NMR (400 MHz,

DMSO-d6) 1.29 (3H, d), 1.51 (3H, m), 1.70 – 1.82 (1H, m), 3.11 (3H, s), 3.28 (1H, m, obscured by water peak), 3.48 – 3.60 (1H, m), 3.68 (1H, dd), 3.75 – 3.87 (2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.60 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.51 – 7.67 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.76 (1H, s); m/z: (ES+) MH+, 413.12. Chiral HPLC: (HP1100 System 4, 5μm Chiralcel OJ-H (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf, 9.013 >99%. Crystals were grown and isolated by slow evaporation to dryness in air from EtOAc. These crystals were used to obtain the structure shown in Fig 1 by X-Ray diffraction (see below). Example 2.02: 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (326 mg, 0.79 mmol) was dissolved in DCM (3 ml). Silica gel (0.5 g) was added and the mixture concentrated in vacuo. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness and the residue was crystallized from EtOAc/n-heptane to afford 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (256 mg, 79%) as a white crystalline solid; 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.39 – 1.60 (3H, m), 1.71 – 1.81 (1H, m), 3.10 (3H, d), 3.21 – 3.29 (1H, m), 3.52 (1H, td), 3.67 (1H, dd), 3.80 (2H, t), 4.01 (1H, dd), 4.19 (1H, d), 4.59 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.54 – 7.62 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.75 (1H, s). DSC (Mettler-Toledo DSC 820, sample run at a heating rate of 10°C per minute from 30°C to 350°C in a pierced aluminium pan) peak, 224.1 FC.

and the title compound: 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (0.441 g, 36%) as the second eluting compound; 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40 – 1.58 (3H, m), 1.70 – 1.80 (1H, m), 3.10 (3H, d), 3.23 – 3.27 (1H, m), 3.51 (1H, dt), 3.66 (1H, dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54 – 7.61 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.75 (1H, s); m/z: (ES+) MH+, 413.12. Chiral HPLC: (HP1100 System 4, 5μm Chiralcel OJ-H (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf, 15.685 >99%. Example 2.01 : 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (66.5 mg) was purified by crystallisation from EtOH/water to afford 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (0.050 g); 1H NMR (400 MHz, CDCl3) 1.40 (3H, d), 1.59 (2H, s), 1.81 (2H, s), 2.41 (1H, s), 3.16 (3H, s), 3.39 (1H, td), 3.59 – 3.67 (1H, m), 3.77 (1H, dd), 3.86 (1H, d), 4.07 (1H, dd), 4.17 (1H, d), 4.54 (1H, s), 6.91 (1H, s), 7.34 (1H, t), 7.43 (1H, t), 8.05 (1H, d), 8.41 (1H, d), 9.14 (1H, s).

Scheme 1. Medicinal Chemistry Route to AZD6738

Reagent and conditions:

(a) (3R)-3-methylmorpholine, TEA, DCM, 77%;

(b) LiBH4, THF, 100%;

(c) MsCl, TEA, DCM, 100%;

(d) LiI, dioxane, 78%;

(e) NaSMe, DMF, 96%;

(f) m-CPBA, DCM;

(g) crystallization or chromatography, 40% (two steps);

(h) IBDA, trifluoroacetamide, MgO, DCM, Rh2(OAc)4 82%;

(i) 1,2-dibromoethane, sodium hydroxide, TOAB, 2-MeTHF, 47%;

(j) TsCl, tetrabutylammonium hydrogen sulfate, sodium hydroxide, DCM, 92%;

(k) bis(pinacolato)diboron, potassium acetate, 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II), DMF, 62%;

(l) Pd(II)Cl2(PPh3)2, Na2CO3, DME, water, 80%;

(m) 2 N NaOH, DME, water, 92%.

Foote, K. M. N.Johannes, W. M.Turner, P.Morpholino Pyrimidines and their use in therapyWO 2011/154737 A1, 15 December 2011.

PAPER

Development and Scale-up of a Route to ATR Inhibitor AZD6738

  • William R. F. Goundry et al
Cite This:Org. Process Res. Dev.2019XXXXXXXXXX-XXX
Publication Date:June 21, 2019
https://doi.org/10.1021/acs.oprd.9b00075
AZD6738 is currently being tested in multiple phase I/II trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine, and an azaindole, make it a challenging molecule to synthesize on a large scale. We describe the evolution of the chemical processes, following the manufacture of AZD6738 from the initial scale-up through to multikilos on plant scale. During this evolution, we developed a biocatalytic process to install the sulfoxide with high enantioselectivity, followed by introduction of the cyclopropyl group first in batch, then in a continuous flow plate reactor, and finally through a series of continuous stirred tank reactors. The final plant scale process to form AZD6738 was operated on 46 kg scale with an overall yield of 18%. We discuss the impurities formed throughout the process and highlight the limitations of this route for further scale-up.
Abstract Image
imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane (1) (30.0 g) were added at 75 °C, and the reaction mixture was held for 2 h. The mixture was cooled to 20 °C, and n-heptane (141.9 kg) was added at the rate of 40 kg/h. The solid was collected by filtration, washed with a mixture of 1-butanol and n-heptane (9.3 and 22.4 kg respectively), and then given a further wash with n-heptane (32.2 kg). The solid was dried at 40 °C to give imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane (1) as a whit  solid (41.4 kg, 92% yield): Assay (HPLC) 99.9%; Assay (NMR) 99% wt/wt.

REFERENCES

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2: Wallez Y, Dunlop CR, Johnson TI, Koh SB, Fornari C, Yates JWT, Bernaldo de Quirós Fernández S, Lau A, Richards FM, Jodrell DI. The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression. Mol Cancer Ther. 2018 Jun 11. doi: 10.1158/1535-7163.MCT-18-0010. [Epub ahead of print] PubMed PMID: 29891488.

3: Fròsina G, Profumo A, Marubbi D, Marcello D, Ravetti JL, Daga A. ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration. Radiat Oncol. 2018 Apr 23;13(1):76. doi: 10.1186/s13014-018-1020-3. PubMed PMID: 29685176; PubMed Central PMCID: PMC5914052.

4: Zhang J, Dulak AM, Hattersley MM, Willis BS, Nikkilä J, Wang A, Lau A, Reimer C, Zinda M, Fawell SE, Mills GB, Chen H. BRD4 facilitates replication stress-induced DNA damage response. Oncogene. 2018 Jul;37(28):3763-3777. doi: 10.1038/s41388-018-0194-3. Epub 2018 Apr 11. PubMed PMID: 29636547.

5: Jin J, Fang H, Yang F, Ji W, Guan N, Sun Z, Shi Y, Zhou G, Guan X. Combined Inhibition of ATR and WEE1 as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. Neoplasia. 2018 May;20(5):478-488. doi: 10.1016/j.neo.2018.03.003. Epub 2018 Mar 30. PubMed PMID: 29605721; PubMed Central PMCID: PMC5915994.

6: Henssen AG, Reed C, Jiang E, Garcia HD, von Stebut J, MacArthur IC, Hundsdoerfer P, Kim JH, de Stanchina E, Kuwahara Y, Hosoi H, Ganem NJ, Dela Cruz F, Kung AL, Schulte JH, Petrini JH, Kentsis A. Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. Sci Transl Med. 2017 Nov 1;9(414). pii: eaam9078. doi: 10.1126/scitranslmed.aam9078. PubMed PMID: 29093183; PubMed Central PMCID: PMC5683417.

7: Jones BC, Markandu R, Gu C, Scarfe G. CYP-Mediated Sulfoximine Deimination of AZD6738. Drug Metab Dispos. 2017 Nov;45(11):1133-1138. doi: 10.1124/dmd.117.077776. Epub 2017 Aug 23. PubMed PMID: 28835442.

8: Dunne V, Ghita M, Small DM, Coffey CBM, Weldon S, Taggart CC, Osman SO, McGarry CK, Prise KM, Hanna GG, Butterworth KT. Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy. Radiother Oncol. 2017 Sep;124(3):475-481. doi: 10.1016/j.radonc.2017.06.025. Epub 2017 Jul 8. PubMed PMID: 28697853.

9: Kiesel BF, Shogan JC, Rachid M, Parise RA, Vendetti FP, Bakkenist CJ, Beumer JH. LC-MS/MS assay for the simultaneous quantitation of the ATM inhibitor AZ31 and the ATR inhibitor AZD6738 in mouse plasma. J Pharm Biomed Anal. 2017 May 10;138:158-165. doi: 10.1016/j.jpba.2017.01.055. Epub 2017 Feb 4. PubMed PMID: 28213176; PubMed Central PMCID: PMC5357441.

10: Ma J, Li X, Su Y, Zhao J, Luedtke DA, Epshteyn V, Edwards H, Wang G, Wang Z, Chu R, Taub JW, Lin H, Wang Y, Ge Y. Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells. Sci Rep. 2017 Feb 8;7:41950. doi: 10.1038/srep41950. PubMed PMID: 28176818; PubMed Central PMCID: PMC5296912.

11: Vendetti FP, Leibowitz BJ, Barnes J, Schamus S, Kiesel BF, Abberbock S, Conrads T, Clump DA, Cadogan E, O’Connor MJ, Yu J, Beumer JH, Bakkenist CJ. Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Sci Rep. 2017 Feb 1;7:41892. doi: 10.1038/srep41892. PubMed PMID: 28145510; PubMed Central PMCID: PMC5286430.

12: Min A, Im SA, Jang H, Kim S, Lee M, Kim DK, Yang Y, Kim HJ, Lee KH, Kim JW, Kim TY, Oh DY, Brown J, Lau A, O’Connor MJ, Bang YJ. AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells. Mol Cancer Ther. 2017 Apr;16(4):566-577. doi: 10.1158/1535-7163.MCT-16-0378. Epub 2017 Jan 30. PubMed PMID: 28138034.

13: Dillon MT, Barker HE, Pedersen M, Hafsi H, Bhide SA, Newbold KL, Nutting CM, McLaughlin M, Harrington KJ. Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei. Mol Cancer Ther. 2017 Jan;16(1):25-34. doi: 10.1158/1535-7163.MCT-16-0239. Epub 2016 Nov 9. PubMed PMID: 28062704; PubMed Central PMCID: PMC5302142.

14: Kim H, George E, Ragland R, Rafial S, Zhang R, Krepler C, Morgan M, Herlyn M, Brown E, Simpkins F. Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models. Clin Cancer Res. 2017 Jun 15;23(12):3097-3108. doi: 10.1158/1078-0432.CCR-16-2273. Epub 2016 Dec 19. PubMed PMID: 27993965; PubMed Central PMCID: PMC5474193.

15: Kim HJ, Min A, Im SA, Jang H, Lee KH, Lau A, Lee M, Kim S, Yang Y, Kim J, Kim TY, Oh DY, Brown J, O’Connor MJ, Bang YJ. Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. Int J Cancer. 2017 Jan 1;140(1):109-119. doi: 10.1002/ijc.30373. Epub 2016 Oct 21. PubMed PMID: 27501113.

16: Biskup E, Naym DG, Gniadecki R. Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation. J Dermatol Sci. 2016 Dec;84(3):239-247. doi: 10.1016/j.jdermsci.2016.09.010. Epub 2016 Sep 16. PubMed PMID: 27743911.

17: Checkley S, MacCallum L, Yates J, Jasper P, Luo H, Tolsma J, Bendtsen C. Corrigendum: Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738. Sci Rep. 2016 Feb 9;6:16545. doi: 10.1038/srep16545. PubMed PMID: 26859465; PubMed Central PMCID: PMC4747154.

18: Kwok M, Davies N, Agathanggelou A, Smith E, Oldreive C, Petermann E, Stewart G, Brown J, Lau A, Pratt G, Parry H, Taylor M, Moss P, Hillmen P, Stankovic T. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood. 2016 Feb 4;127(5):582-95. doi: 10.1182/blood-2015-05-644872. Epub 2015 Nov 12. PubMed PMID: 26563132.

19: Vendetti FP, Lau A, Schamus S, Conrads TP, O’Connor MJ, Bakkenist CJ. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget. 2015 Dec 29;6(42):44289-305. doi: 10.18632/oncotarget.6247. PubMed PMID: 26517239; PubMed Central PMCID: PMC4792557.

20: Karnitz LM, Zou L. Molecular Pathways: Targeting ATR in Cancer Therapy. Clin Cancer Res. 2015 Nov 1;21(21):4780-5. doi: 10.1158/1078-0432.CCR-15-0479. Epub 2015 Sep 11. Review. PubMed PMID: 26362996; PubMed Central PMCID: PMC4631635.

//////AZD6738AZD-6738AZD 6738, AstraZeneca,  University of Pennsylvania, Phase II,  Breast cancer, Gastric cancer, Non-small cell lung cancer, Ovarian cancer, Ceralasertib
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USFDA approval to Lumoxiti (moxetumomab pasudotoxtdfk) a new treatment for hairy cell leukemia


Image result for moxetumomab pasudotox tdfk

USFDA approval to Lumoxiti is a new treatment for hairy cell leukemia

On September 13, 2018, the U.S. Food and Drug Administration approved Lumoxiti (moxetumomab pasudotoxtdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory Hairy Cell Leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog 1. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL. The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent. The FDA granted this application Fast Track and Priority Review designations. Lumoxiti also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals. About Hairy Cell Leukemia HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cells that fight infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

About Lumoxiti2 Lumoxiti (moxetumomab pasudotox) is a CD22-directed cytotoxin and a first-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min). It comprises the CD22 binding portion of an antibody fused to a truncated bacterial toxin; the toxin inhibits protein synthesis and ultimately triggers apoptotic cell death.

September 13, 2018

Release

The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent.

Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Women who are breastfeeding should not be given Lumoxiti.

The FDA granted this application Fast Track and Priority Review designations. Lumoxiti also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals.

1 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620448.htm

2 https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-approves-lumoxiti-moxetumomab-pasudotox-tdfk-for-certain-patientswith-relapsed-or-refractory-hairy-cell-leukaemia.html

/////////// Lumoxiti, moxetumomab pasudotoxtdfk, FDA 2018, Fast Track,  Priority Review ,  Orphan Drug, AstraZeneca

AZD 9567


SCHEMBL17643955.png

str1

AZD 9567

CAS 1893415-00-3

1893415-64-9  as MONOHYDRATE

2,2-Difluoro-N-[(1R,2S)-3-methyl-1-[[1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl]oxy]-1-phenylbutan-2-yl]propanamide

Propanamide, N-[(1S)-1-[(R)-[[1-(1,6-dihydro-1-methyl-6-oxo-3-pyridinyl)-1H-indazol-5-yl]oxy]phenylmethyl]-2-methylpropyl]-2,2-difluoro-

2,2-difluoro-N-[(1R,2S)-3-methyl-1-[1-(1-methyl-6-oxopyridin-3-yl)indazol-5-yl]oxy-1-phenylbutan-2-yl]propanamide

2,2-difluoro- V-[(lR,25)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide

MF C27 H28 F2 N4 O3, MF 494.533

AstraZeneca INNOVATOR

AZD-9567, a glucocorticoid receptor modulator, is in early clinical development at AstraZeneca in healthy male volunteers.

Phase I Rheumatoid arthritis

  • Originator AstraZeneca
  • Class Antirheumatics
  • Mechanism of Action Glucocorticoid receptor modulators
    • 01 Sep 2016 AstraZeneca completes a phase I trial (In volunteers) in Germany (NCT02512575)
    • 24 May 2016 Phase-I clinical trials in Rheumatoid arthritis (In volunteers) in United Kingdom (PO) (NCT02760316)
    • 24 May 2016 AstraZeneca initiates a phase I trial in Rheumatoid arthritis (In volunteers) in Germany (PO) (NCT02760316)
     
Inventors Lena Elisabeth RIPA, Karolina Lawitz, Matti Juhani Lepistö, Martin Hemmerling, Karl Edman, Antonio Llinas
Applicant Astrazeneca

Warning: Chancellor George Osborne told Scotland it could be forced to give up the pound if it became independent of the rest of the UK. He is pictured yesterday with Jan Milton-Edwards during a visit to the Macclesfield AstraZeneca site in Cheshire

Macclesfield AstraZeneca site in Cheshire

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Glucocorticoids (GCs) have been used for decades to treat acute and chronic inflammatory and immune conditions, including rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (“COPD”), osteoarthritis, rheumatic fever, allergic rhinitis, systemic lupus erythematosus, Crohn’s disease, inflammatory bowel disease, and ulcerative colitis. Examples of GCs include dexamethasone, prednisone, and

prednisolone. Unfortunately, GCs are often associated with severe and sometimes irreversible side effects, such as osteoporosis, hyperglycemia, effects on glucose metabolism (diabetes mellitus). skin thinning, hypertension, glaucoma, muscle atrophy. Cushing’s syndrome, fluid homeostasis, and psychosis (depression ). These side effects can particularly limit the use of GCs in a chronic setting. Thus, a need continues to exist for alternative therapies that possess the beneficial effects of GCs, but with a reduced likel ihood of side effects.

GCs form a complex with the GC receptor ( GR ) to regulate gene transcription. The GC-GR complex translocates to the cell nucleus, and then binds to GC response elements (GREs) in the promoter regions of various genes. The resulting GC-GR- GRE complex, in turn, activates or inhibits transcription of proximally located genes. The GC-GR complex also (or alternatively) may negatively regulate gene transcription by a process that does not involve DNA binding. In this process, termed transrepression, the GC-GR complex enters the nucleus and directly interacts (via protein-protein interaction) with other transcription factors, repressing their ability to induce gene transcription and thus protein expression.

Some of the side effects of GCs are believed to be the result of cross-reactivity with other steroid receptors (e.g., progesterone, androgen, mineralocorticoid, and estrogen receptors), which have somewhat homologous ligand binding domains; and/or the inability to selectively modulate gene expression and downstream signaling. Consequently, it is believed that an efficacious selective GR modulator (SGRM), which binds to GR with greater affinity relative to other steroid hormone receptors, would provide an alternative therapy to address the unmet need for a therapy that possesses the beneficial, effects of GCs, while, at the same time, having fewer side effects.

A range of compounds have been reported to have SGRM activity. See, e.g., WO2007/0467747, WO2007/114763, WO2008/006627, WO2008/055709, WO2008/055710, WO2008/052808, WO2008/063116, WO2008/076048,

WO2008/079073, WO2008/098798, WO2009/065503, WO2009/142569,

WO2009/142571, WO2010/009814, WO2013/001294, and EP2072509. Still, there continues to be a need for new SGRMs that exhibit, for example, an improved potency, efficacy, effectiveness in steroid-insensitive patients, selectivity, solubility allowing for oral administration, pharmacokinetic profile allowing for a desirable dosing regimen, stability on the shelf {e.g., hydro lytic, thermal, chemical, or photochemical stability), crystallinity, tolerability for a range of patients, side effect profile and/or safety profile.

PATENT

WO 2016046260

Scheme 1 below illustrates a general protocol for making compounds described in this specification, using either an Ullman route or an aziridine route.

Scheme 1

In Scheme 1, Ar is

[182] The amino alcohol reagent used in Scheme 1 may be made using the below Scheme 2.

Scheme 2

The Grignard reagent (ArMgBr) used in Scheme 2 can be obtained commercially, or, if not, can generally be prepared from the corresponding aryl bromide and Mg and/or iPrMgCl using published methods.

[183] The iodo and hydroxy pyridone indazole reagents used in Scheme 1 may be made using the below Scheme 3A or 3B, respectively.

Scheme 3A

[184] Scheme 4 below provides an alternative protocol for making compounds described in this specification.

Scheme 4

Example 1. Preparation of 2,2-difluoro- V-[(lR,2S)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide.

[199] Step A. Preparation of 5-[5-[(te^butyldimethylsilyl)oxy]-lH-indazol-l-yl]-l-methyl-l,2-dihydropyridin-2-one.

Into a 2 L 4-necked, round-bottom flask, purged and maintained with an inert atmosphere of N2, was placed a solution of 5-[(tert-butyldimethylsilyl)oxy]-lH-indazole (805 g, 3.2 mol) in toluene (8 L), 5 -iodo-1 -methyl- 1 ,2-dihydropyridin-2-one (800 g, 3.4 mol) and

K3PO4 (1.2 kg, 5.8 mol). Cyclohexane-l,2-diamine (63 g, 0.5 mol) was added followed by the addition of Cul (1.3 g, 6.8 mmol) in several batches. The resulting solution was stirred overnight at 102°C. The resulting mixture was concentrated under vacuum to yield 3.0 kg of the title compound as a crude black solid. LC/MS: m/z 356 [M+H]+.

[200] Step B. Preparation of 5-(5-hydroxy-lH-indazol-l-yl)-l-methylpyridin-2(lH)-one.

Into a 2 L 4-necked, round-bottom flask was placed 5-[5-[(fert-butyldimethylsilyl)oxy]-lH-indazol-l-yl]-l-methyl-l,2-dihydropyridin-2-one (3.0 kg, crude) and a solution of HCl (2 L, 24 mol, 36%) in water (2 L) and MeOH (5 L). The resulting solution was stirred for 1 hr at 40°C and then evaporated to dryness. The resulting solid was washed with water (4 x 5 L) and ethyl acetate (2 x 0.5 L) to afford 480 g (61%, two steps) of the title product as a brown solid. LC/MS: m/z 242 [M+H]+. 1HNMR (300 MHz, DMSO-d6): δ 3.52 (3H, s),6.61 (lH,m),7.06 (2H,m),7.54 (lH,m), 7.77 (lH,m), 8.19 (2H, m) 9.35 (lH,s).

[201] Ste C. Preparation of tert-butyl((lR,25)-l-hydroxy-3-methyl-l-phenylbutan-2-yl)carbamate.

(S)-tert-butyl 3 -methyl- l-oxo-l-phenylbutan-2-ylcarbamate (1.0 kg, 3.5 mol) was dissolved in toluene (4 L). Afterward, 2-propanol (2 L) was added, followed by triisopropoxyaluminum (0.145 L, 0.73 mol). The reaction mixture was heated at 54-58°C for 1 hr under reduced pressure (300-350 mbar) to start azeothropic distillation. After the collection of 0.75 L condensate, 2-propanol (2 L) was added, and the reaction mixture was stirred overnight at reduced pressure to afford 4 L condensate in total. Toluene (3 L) was added at 20°C, followed by 2M HC1 (2 L) over 15 min to keep the temperature below 28°C. The layers were separated (pH of aqueous phase 0-1) and the organic layer was washed successively with water (3 L), 4% NaHCCte (2 L) and water (250 mL). The volume of the organic layer was reduced from 6 L at 50°C and 70 mbar to 2.5 L. The resulting mixture was heated to 50°C and heptane (6.5 L) was added at 47-53°C to maintain the material in solution. The temperature of the mixture was slowly decreased to 20°C, seeded with the crystals of the title compound at 37°C (seed crystals were prepared in an earlier batch made by the same method and then evaporating the reaction mixture to dryness, slurring the residue in heptane, and isolating the crystals by filtration), and allowed to stand overnight. The product was filtered off, washed with heptane (2 x 1 L) and dried under vacuum to afford 806 g (81%) of the title compound as a white solid. 1HNMR (500 MHz, DMSO-d6): δ 0.81 (dd, 6H), 1.16 (s, 8H), 2.19 (m, 1H), 3.51 (m, 1H), 4.32 (d, 1H), 5.26 (s, 1H), 6.30 (d, 1H), 7.13 – 7.2 (m, 1H), 7.24 (t, 2H), 7.3 – 7.36 (m, 3H).

[202] Step D. Preparation of (lR,2S)-2-amino-3-methyl-l-phenylbutan-l-ol hydrochloride salt.

To a solution of HC1 in propan-2-ol (5-6 N, 3.1 L, 16 mol) at 20°C was added tert-butyl((li?,25)-l-hydroxy-3-methyl-l-phenylbutan-2-yl)carbamate (605 g, 2.2 mol) in portions over 70 min followed by the addition of MTBE (2 L) over 30 min. The reaction mixture was cooled to 5°C and stirred for 18 hr. The product was isolated by filtration and dried to afford 286 g of the title compound as an HC1 salt (61% yield). The mother liquor was concentrated to 300 mL. MTBE (300 mL) was then added, and the resulting precipitation was isolated by filtration to afford additional 84 g of the title compound as a HC1 salt (18% yield). Total 370 g (79%). 1HNMR (400 MHz, DMSO-d6): δ 0.91 (dd, 6H), 1.61 – 1.81 (m, 1H), 3.11 (s, 1H), 4.99 (s, 1H), 6.08 (d, 1H), 7.30 (t, 1H), 7.40 (dt, 4H), 7.97 (s, 2H).

[203] Step E. Preparation of (2S,35)-2-isopropyl-l-(4-nitrophenylsulfonyl)-3-phenylaziridine.

(li?,25)-2-Amino-3-methyl-l-phenylbutan-l-ol hydrochloride (430 g, 2.0 mol) was mixed with DCM (5 L) at 20°C. 4-Nitrobenzenesulfonyl chloride (460 g, 2.0 mol) was then added over 5 min. Afterward, the mixture was cooled to -27°C. Triethylamine (1.0 kg, 10 mol) was slowly added while maintaining the temperature at -18°C. The reaction mixture was cooled to -30°C, and methanesulfonyl chloride (460 g, 4.0 mol) was added slowly while maintaining the temperature at -25 °C. The reaction mixture was then stirred at 0°C for 16 hr before adding triethylamine (40 mL, 0.3 mol; 20 mL ,0.14 mol and 10 mL, 0.074 mol) w at 0°C in portions over 4 hr. Water (5 L) was subsequently added at 20°C, and the resulting layers were separated. The organic layer was washed with water (5 L) and the volume reduced to 1 L under vacuum. MTBE (1.5 L) was added, and the mixture was stirred on a rotavap at 20°C over night and filtered to afford 500 g (70%) of the title product as a solid. 1HNMR (400 MHz, CDCls): δ 1.12 (d, 3H), 1.25 (d, 3H), 2.23 (ddt, 1H), 2.89 (dd, 1H), 3.84 (d, 1H), 7.08 – 7.2 (m, 1H), 7.22 – 7.35 (m, 4H), 8.01 – 8.13 (m, 2H), 8.22 – 8.35 (m, 2H)

[204] Step F. Preparation of V-((lR,2S)-3-methyl-l-(l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yloxy)-l-phenylbutan-2-yl)-4-nitrobenzenesulfonamide.

[205] (25′,35)-2-Isopropyl-l-(4-nitrophenylsulfonyl)-3-phenylaziridine (490 g, 1.3 mol) was mixed with 5-(5-hydroxy-lH-indazol-l-yl)-l-methylpyridin-2(lH)-one (360 g, 1.4 mol) in acetonitrile (5 L) at 20°C. Cesium carbonate (850 g, 2.6 mol) was added in portions over 5 min. The reaction mixture was then stirred at 50°C overnight. Water (5 L) was added at 20°C, and the resulting mixture was extracted with 2-methyltetrahydrofuran (5L and 2.5 L). The combined organic layer was washed successively with 0.5 M HC1 (5 L), water (3 x 5L) and brine (5L). The remaining organic layer was concentrated to a thick oil, and then MTBE (2 L) was added. The resulting precipitate was filtered to afford 780 g (purity 71% w/w) of the crude title product as a yellow solid, which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 0.93 (dd, 6H), 2.01 -2.19 (m, 1H), 3.50 (s, 3H), 3.74 (s, 1H), 5.00 (d, 1H), 6.54 (d, 1H), 6.78 (d, 1H), 6.95 -7.15 (m, 4H), 7.23 (d, 2H), 7.49 (d, 1H), 7.69 (dd, 1H), 7.74 (d, 2H), 8.00 (s, 1H), 8.08 (d, 2H), 8.13 (d, 2H).

[206] Step G. Preparation of 2,2-difluoro- V-[(lR,25)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide.

[207] N-((lR,2S)-3-Methyl- 1 -(1 -(1 -methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)- \H-indazol-5-yloxy)-l-phenylbutan-2-yl)-4-nitrobenzenesulfonamide (780 g, 71%w/w) was mixed with DMF (4 L). DBU (860 g, 5.6 mol) was then added at 20°C over 10 min. 2-Mercaptoacetic acid (170 g, 1.9 mol) was added slowly over 30 min, keeping the temperature at 20°C. After 1 hr, ethyl 2,2-difluoropropanoate (635 g, 4.60 mol) was added over 10 min at 20°C. The reaction mixture was stirred for 18 hr. Subsequently, additional ethyl 2,2-difluoropropanoate (254 g, 1.8 mol) was added, and the reaction mixture was stirred for an additional 4 hr at 20°C. Water (5 L) was then slowly added over 40 min, maintaining the temperature at 20°C. The water layer was extracted with isopropyl acetate (4 L and 2 x 2 L). The combined organic layer was washed with 0.5M HC1 (4 L) and brine (2 L). The organic layer was then combined with the organic layer from a parallel reaction starting from 96 g of N-((li?,25)-3-methyl-l-((l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)- lH-indazol-5-yl)oxy)- 1 -phenylbutan-2-yl)-4-nitrobenzenesulfonamide, and concentrated to approximate 1.5 L. The resulting brown solution was filtered. The filter was washed twice with isopropyl acetate (2 x 0.5 L). The filtrate was evaporated until a solid formed. The solid was then co evaporated with 99.5% ethanol (1 L), affording 493 g (77%, two steps) of an amorphous solid.

[208] The solid (464 g, 0.94 mol) was dissolved in ethanol/water 2: 1 (3.7 L) at 50°C. The reaction mixture was then seeded with crystals () of the title compound (0.5 g) at 47°C, and a slight opaque mixture was formed. The mixture was held at that temperature for 1 hr. Afterward, the temperature was decreased to 20°C over 7 hr, and kept at 20°C for 40 hr. The solid was filtrated off, washed with cold (5°C) ethanol/water 1 :2 (0.8 L), and dried in vacuum at 37°C overnight to afford 356 g (0.70 mol, 74%, 99.9 % ee) of the title compound as a monohydrate. LC/MS: m/z 495 [M+H]+. ‘HNMR (600 MHz, DMSO-d6) δ 0.91 (dd, 6H), 1.38 (t, 3H), 2.42 (m, 1H), 3.50 (s, 3H), 4.21 (m, 1H), 5.29 (d, 1H), 6.53 (d, 1H), 7.09 (d, 1H), 7.13 (dd, 1H), 7.22 (t, 1H), 7.29 (t, 2H), 7.47 (d, 2H), 7.56 (d, 1H), 7.70 (dd, 1H), 8.13 (d, 1H), 8.16 (d, 1H), 8.27 (d, 1H).

[209] The seed crystals may be prepared from amorphous compound prepared according to Example 2 using 2,2-difluoropropanoic acid, followed by purification on HPLC. The compound (401 mg) was weighed into a glass vial. Ethanol (0.4 mL) was added, and the vial was shaken and heated to 40°C to afford a clear, slightly yellow solution. Ethanol/Water (0.4 mL, 50/50% vol/vol) was added. Crystallization started to

occur within 5 min, and, after 10 min, a white thick suspension formed. The crystals were collected by filtration

/////////////AZD 9567, AstraZeneca, lucocorticoid receptor modulator, Rheumatoid arthritis, phase 1, Lena Elisabeth RIPA, Karolina Lawitz, Matti Juhani Lepistö, Martin Hemmerling, Karl Edman, Antonio Llinas

3rd speaker this afternoon in 1st time disclosures is Lena Ripa of @AstraZeneca on a glucocorticoid receptor modulator

str2

CC(F)(F)C(=O)N[C@@H](C(C)C)[C@H](Oc1cc2cnn(c2cc1)C=3C=CC(=O)N(C)C=3)c4ccccc4

AZD 7594


str1

str1

.

Picture credit….

SCHEMBL3273974.png

AZD 7594

‘s asthma candidate

AZ13189620; AZD-7594

Bayer Pharma Aktiengesellschaft, Astrazeneca Ab

Molecular Formula: C32H32F2N4O6
Molecular Weight: 606.616486 g/mol

3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-(oxolan-3-yl)benzamide

Benzamide, 3-​[5-​[(1R,​2S)​-​2-​[(2,​2-​difluoro-​1-​oxopropyl)​amino]​-​1-​(2,​3-​dihydro-​1,​4-​benzodioxin-​6-​yl)​propoxy]​-​1H-​indazol-​1-​yl]​-​N-​[(3R)​-​tetrahydro-​3-​furanyl]​-
Cas 1196509-60-0

AZD-7594 is in phase II clinical trials by AstraZeneca for the treatment of mild to moderate asthma.

It is also in phase I clinical trials for the treatment of chronic obstructive pulmonary disorder (COPD).

https://clinicaltrials.gov/ct2/show/NCT02479412

Company AstraZeneca plc
Description Inhaled selective glucocorticoid receptor (GCCR) modulator
Molecular Target Glucocorticoid receptor (GCCR)
  • Phase II Asthma
  • Phase I Chronic obstructive pulmonary disease
  • 01 Feb 2016 AstraZeneca completes a phase II trial in Asthma in Bulgaria and Germany (Inhalation) (NCT02479412)
  • 09 Jan 2016 AstraZeneca plans to initiate a phase I trial in Healthy volunteers in USA (IV and PO) (NCT02648438)
  • 01 Jan 2016 Phase-I clinical trials in Chronic obstructive pulmonary disease (In volunteers) in USA (PO, IV, Inhalation) (NCT02648438)

PATENT

http://www.google.com/patents/WO2009142569A1

PATENT

US20100804345

UNWANTED ISOMER

str1

str1

WANTED COMPD

str1

str1

str1

PATENT

WO 2009142571

Example 6

WANTED ISOMER

Figure imgf000053_0002

3-(5- { TC 1 R,2SV2-r(2,2-difluoropropanoyl)aminol- 1 -(2,3-dihydro-l ,4-benzodioxin-6-5 yDpropylioxy) – 1 H-indazol- 1 -ylVN-[(3R)-tetrahydrofuran-3-vnbenzamide. APCI-MS: m/z 607 [MH+] 1H NMR ^OO MHz, DMSOd6) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d). LC (method A) rt = 12.03 min LC (method B) rt = 11.13 min Chiral SFC (method B) rt = 4.71 min M.p. = 177 °C

UNWANTED

Figure imgf000053_0001

o 3-(5- { IY 1 R,2S V2-r(2,2-difluoropropanoyl)amino|- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6- yl)propyl]oxy } – 1 H-indazol- 1 -yP-N-IO S)-tetrahydrofuran-3 -yl|benzamide

APCI-MS: m/z 607 [MH+]

1H NMR (400 MHz, DMSO-J6) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s),

7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H,s m), 5.17 (IH, d), 4.48 (IH, m), 4.24 – 4.11 (5H, m), 3.90 – 3.81 (2H, m), 3.72 (IH, td), 3.61

(IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (Method A) rt = 12.02 min

LC (Method B) rt = 11.12 min

Chiral SFC (method B) rt = 5.10 min o M.p. = 175 0C

PATENT

WO 2011061527

http://www.google.com/patents/WO2011061527A1?cl=en

Intermediate 12

( 1 R,2S)-2-amino- 1 -(2,3 -dihydrobenzo b [ 1 ,41dioxin-6-yl)propan- 1 -ol hydrochloride. (12)

Figure imgf000036_0001

5-6 N HC1 in 2-propanol (8 mL, 40-48 mmol) was added to tert-butyl (lR,2S)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxypropan-2-ylcarbamate (I2a) (3.1 g, 10.02 mmol) in ethyl acetate (40 mL) at 40°C and stirred for 3 hours. The reaction mixture was allowed to reach r.t. and was concentrated by evaporation. Ether was added and the salt was filtered off and washed with ether. The salt was found to be hygroscopic. Yield 2.10 g (85%)

APCI-MS: m/z 210 [MH+-HC1]

1H-NMR (300 MHz, DMSO-^): δ 8.01 (brs, 3H), 6.87-6.76 (m, 3H), 5.93 (brd, 1H), 4.79 (brt, 1H), 4.22 (s, 4H), 3.32 (brm, 1H), 0.94 (d, 3H).

tert-butyl (1R,2S)- 1 -(2,3-dihvdrobenzorbl Γ 1 ,41dioxin-6-yl)- 1 -hvdroxypropan-2-ylcarbamate.

Figure imgf000036_0002

The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction was made by the method described by Jingjun Yin et. al. J. Org. Chem. 2006, 71, 840-843.

(S)-tert-butyl 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)- 1 -oxopropan-2-ylcarbamate (I2b) (3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and 2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) were stirred at 50°C under argon for 16 hours. The reaction mixture was poured into 1M HC1 (150 mL) and the mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with water (2×50 mL) and brine (100 mL), dried over Na2SC”4, filtered and concentrated. The crude product was purified by flash- chromatography on silica using ethyl acetate/hexane (1/2) as eluent. Fractions containing product were combined. Solvent was removed by evaporation to give the desired product as a colourless solid. Yield 3.19 g (84%) APCI-MS: m/z 236, 210, 192 [MH -tBu-18, MH -BOC, MH -BOC- 18]

1H NMR (300 MHz, DMSO-^): δ 6.80-6.70 (m, 3H), 6.51 (d, IH), 5.17 (d, IH), 4.36 (t, IH),

4.19 (s, 4H), 3.49 (m, IH), 1.31 (s, 9H), 0.93 (d, 3H).

(S)-tert-butyl 1 -(2,3-dihydrobenzo[bl [ 1 ,41dioxin-6-yD- 1 -oxopropan-2-ylcarbamate. (I2b)

Figure imgf000037_0001

A suspension of (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) was placed under a protective atmosphere of argon and cooled down to -15 to -20°C. Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol), was added keeping the temperature below -10°C. The temperature was allowed to reach 0°C. A freshly prepared solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature was allowed to reach r.t. overnight. The reaction mixture was poured into ice cooled IN HC1 (300 mL). TBME (300 mL) was added and the mixture was transferred to a separation funnel. The water phase was back extracted with TBME (200 mL). The ether phases were washed with water, brine and dried (Na2S04). The crude product was purified by flash chromatography using TBME /Heptane 1/2 as eluent. Fractions containing the product were combined and solvents were removed by evaporation to give the subtitle compound as a slightly yellow sticky oil/gum. Yield 3.76g

(95%)

APCI-MS: m/z 208 [MH+ – BOC]

1H NMR (300 MHz, DMSO-^): δ 7.50 (dd, IH), 7.46 (d, IH), 7.24 (d, IH), 6.97 (d, IH), 4.97 (m, IH), 4.30 (m, 4H), 1.36 (s, 9H), 1.19 (d, 3H).

Intermediate 13

(lR,2S)-2-amino-l-(4H-benzo[dl[l,31dioxin-7- l)propan-l-ol hydrochloride (13)

Figure imgf000037_0002

Tert-butyl ( 1 R,2S)- 1 -(4H-benzo[d] [ 1 ,3]dioxin-7-yl)- 1 -hydroxypropan-2-ylcarbamate (I3b) (403 mg, 1.30 mmol) was dissolved in ethyl acetate (5 mL) and 5-6 N HC1 solution in 2- propanol (1.5 mL, 7.5-9 mmol) was added. The mixture was stirred at 50 °C for 1.5 hours. The solvents was removed by evaporation. The residual sticky gum was treated with ethyl acetate and evaporated again to give a solid material that was suspended in acetonitrile and stirred for a few minutes. The solid colourless salt was collected by filtration and was found to be somewhat hygroscopic. The salt was quickly transferred to a dessicator and dried under reduced pressure. Yield 293 mg (92%)

APCI-MS: m/z 210 [MH+ -HC1]

1H NMR (300 MHz, DMSO-^) δ 8.07 (3H, s), 7.05 (IH, d), 6.92 (IH, dd), 6.85 (IH, d), 6.03 (IH, d), 5.25 (2H, s), 4.87 (3H, m), 3.42 – 3.29 (IH, m), 0.94 (3H, d).

(4S.5R -5-(4H-benzordiri.31dioxin-7-vn- -methyloxazolidin-2-one (I3a

Figure imgf000038_0001

A mixture of (lR,2S)-2-amino-l-(4H-benzo[d][l,3]dioxin-7-yl)propan-l-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at r.t. for 2 hours. The reaction mixture was concentrated by evaporation and the residual material was partitioned between ethyl acetate and water. The organic phase was washed with 10% NaHS04, dried over MgS04, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)

The relative cis conformation of the product was confirmed by comparing the observed 1H- NMR with the literature values reported for similar cyclised norephedrine (Org. Lett. 2005 (07), 13, 2755-2758 and Terahedron Assym. 1993, (4), 12, 2513-2516). In a 2D NOESY experiment a strong NOE cross-peak was observed for the doublet at 5.64 with the multiplet at 4.19 ppm. This also confirmed the relative czs-conformation.

APCI-MS: m/z 236 [MH+]

1H NMR (400 MHz, CDC13) δ 6.99 (d, J= 8.0 Hz, IH), 6.88 (dd, J= 8.0, 1.4 Hz, IH), 6.83 (s, IH), 5.81 (brs,lH), 5.64 (d, J= 8.0 Hz, IH), 5.26 (s, 2H), 4.91 (s, 2H), 4.19 (m, IH), 0.85 (d, J = 6.4 Hz, 3H). Tert-butyl ( 1 R,2S)- 1 -(4H-benzord1 Γ 1 ,31dioxin-7-yl)- 1 -hvdroxypropan-2-ylcarbamate (I3b)

Figure imgf000039_0001

A mixture (S)-tert-butyl l-(4H-benzo[d][l,3]dioxin-7-yl)-l-oxopropan-2-ylcarbamate (I3c) (680 mg, 2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3 mL, 38.9 mmol) in toluene (3 mL) was stirred at 65 °C for 15 hours. The reaction mixture was allowed to cool down, poured into 1M HC1 (50 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was washed with water, brine, dried over MgS04, filtered and solvents were removed by evaporation to afford a colourless solid. The crude product was purified by flash chromatography, (solvent A = Heptane, solvent B = EtOAc + 10% MeOH. A gradient of 10%B to 50%B in A was used). The obtained product was crystallised from DCM / heptane to afford the subtitle compound as colourless needles. Yield 414 mg (60%)

APCI-MS: m/z 210 [MH+ -BOC]

1H NMR (400 MHz, DMSO- ¾ δ 6.97 (1H, d), 6.88 (1H, d), 6.77 (1H, s), 6.56 (1H, d), 5.27 (1H, d), 5.22 (2H, s), 4.83 (2H, s), 4.44 (1H, t), 3.53 (1H, m), 1.32 (9H, s), 0.93 (3H, d). (S)-Tert-butyl 1 -(4H-benzord1 Γ 1 ,31dioxin-7-vD- 1 -oxopropan-2-ylcarbamate (I3c)

Figure imgf000039_0002

7-Bromo-4H-benzo[d][l,3]dioxine (1 g, 4.65 mmol) was dissolved in THF (5 mL) and added to magnesium (0.113 g, 4.65 mmol) under a protective atmosphere of argon. One small iodine crystal was added. The coloured solution was heated with an heat gun in short periods to initiate the Grignard formation. When the iodine colour vanished the reaction was allowed to proceed at r.t. for 1.5 hours.

In a separate reaction tube (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2- ylcarbamate (1 g, 4.31 mmol) was suspended in THF (5 mL) and cooled in an ice/acetone bath to below -5 °C. Isopropylmagnesium chloride, 2M solution in THF (2.5 mL, 5.00 mmol) was slowly added to form a solution. To this solution was added the above freshly prepared Grignard reagent. The mixture was allowed to reach r.t. and stirred for 4 hours. The reaction mixture was slowly poured into ice-cold 150 mL 1M HC1. Ethyl acetate (150 mL) was added and the mixture was stirred for a few minutes and transferred to a separation funnel. The organic phase was washed with water and brine, dried over MgS04, filtered and concentrated. The obtained crude product was further purified by flash chromatography using a prepacked 70g silica column with a gradient of 10% TBME to 40% TBME in heptane as eluent. The subtitle compound was obtained as a colourless solid. Yield 790 mg (59%>)

APCI-MS: m/z 208 [MH+ -BOC]

1H NMR (400 MHz, DMSO-^) δ 7.53 (IH, dd), 7.39 (IH, s), 7.30 (IH, d), 7.22 (IH, d), 5.30 (2H, s), 4.98 (IH, m), 4.95 (2H, s), 1.35 (9H, s), 1.20 (3H, d).

Preparation 4

3-(5-([(lR,2S)-2-[(2,2-difluoropropanoyl)aminol-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy| – 1 H-indazol- 1 -yl)-N-[(3R)-tetrahydrofuran-3-yllbenzamide

Figure imgf000051_0001

TEA (2.0 g, 20.65 mmol) was added to a mixture of 3-(5-((lR,2S)-2-(2,2- difluoropropanamido)- 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)propoxy)-l H-indazol-1 – yl)benzoic acid (14) (3.6 g, 6.70 mmol), (R)-tetrahydrofuran-3 -amine hydrochloride (0.99 g, 8.0 mmol) and HBTU (2.65 g, 6.99 mmol) in DCM (15 mL). The reaction was stirred at r.t. for 3h, then quenched by addition of a mixture of water and ethyl acetate. The mixture was shaken and the organic layer was collected. The water phase was extracted twice with ethyl acetate. The combined organic layers were washed with a small portion of water and dried over magnesium sulphate. The product was purified by flash chromatography (silica, eluent: a gradient of ethyl acetate in heptane). The residue was crystallized by dissolving in refluxing acetonitrile (50 mL) and then allowing to cool to r.t. over night. The solid was collected by filtration, washed with a small volume of acetonitrile and dried at 40°C in vaccum to give the title compound (2.5 g, 61%).

APCI-MS: m/z 607 [MH+]

1H NMR (400 MHz, DMSO-d6) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (method A) rt = 12.03 min

LC (method B) rt = 11.13 min

Chiral SFC (method B) rt = 4.71 min

M.p. = 177 °C

Patent ID Date Patent Title
US2015080434 2015-03-19 PHENYL AND BENZODIOXINYL SUBSTITUTED INDAZOLES DERIVATIVES
US8916600 2014-12-23 Phenyl and benzodioxinyl substituted indazoles derivatives
US8211930 2012-07-03 Phenyl and Benzodioxinyl Substituted Indazoles Derivatives

REFERENCES

https://www.astrazeneca.com/content/dam/az/press-releases/2014/Q2/Pipeline-table.pdf

////////AZD 7594, AZ13189620, AZD-7594 , phase 2, astrazeneca, 1196509-60-0

c21cc(ccc1n(nc2)c3cc(ccc3)C(=O)NC4COCC4)O[C@H](c5cc6c(cc5)OCCO6)[C@@H](NC(=O)C(F)(F)C)C

CC(C(C1=CC2=C(C=C1)OCCO2)OC3=CC4=C(C=C3)N(N=C4)C5=CC=CC(=C5)C(=O)NC6CCOC6)NC(=O)C(C)(F)F

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AZD 2716


str1

AZD2716

CAS 1845753-81-2
MF C24 H23 N O3,   MW 373.44
[1,1′-Biphenyl]-3-propanoic acid, 2′-(aminocarbonyl)-α-methyl-5′-(phenylmethyl)-, (αR)-
Antiplaque candidate drug

AstraZeneca INNOVATOR

(R)-7(AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Chiral HPLC using a Chiralcel OJ 5 μm 20×250 mm
column with heptane/EtOH/formic acid ((10:90:0.1; 15 ml/min, 40 °C, 260 nm) as mobile
phase to yield (S)-7 and (R)-7

(R)-7:tR=5.8 min [α]D20 15.4 (c 0.5, ACN), 99.7 %ee. desired

(S)-7: tR=9.2 min. 99.0 % ee. undesired

LINK

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00188

SYNTHESIS

 

op-2015-00382y_0007.gif

1H NMR (400 MHz, DMSO-d6): δ 1.04 (d, J = 6.6 Hz, 3H), 2.55–2.68 (m, 2H), 2.95 (dd, J = 6.1, 12.8 Hz, 1H), 4.00 (s, 2H), 7.13–7.37 (m, 13H), 7.49–7.54 (m, 1H), 12.2 (s, br, 1H).

13C NMR (151 MHz, DMSO): δ 16.7, 39.1, 40.7, 41.0, 126.3, 126.4, 127.3, 127.8, 128.0, 128.2, 128.7, 128.9, 129.2, 130.3, 135.3, 139.2, 139.5, 140.5, 141.2, 142.7, 171.3, 177.1.

HRMS (ESI): [M + H]+ m/z calcd for C24H24NO3 374.1751, found 374.1748.

1H NMR

 

str1

str1

13C NMR

An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

CVMD iMed, Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden
SP Process Development, Box 36, SE-151 21 Södertälje, Sweden
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00382………..http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00382
STR1

A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

 

Paper

Abstract Image

Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7(AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease

Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit Departments of Medicinal Chemistry, Bioscience, §DMPK, Discovery Sciences Departments of Structure & Biophysics, Reagents and Assay Development, and #Screening Sciences and Sample Management, Astrazeneca, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00188
*(F.G.) Phone: +1-212-4780-822. E-mail: fabrizio.giordanetto@deshawresearch.com., *(D.P.) Phone: +46 31 7065 663. E-mail:daniel.pettersen@astrazeneca.com.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00188

STR1

str2

akenoic acid as a key step in the sysnthesis of AZD2716. Org. Proc. Res. Dev. 2016, 20(2),
262-269).

/////////atherosclerosis,  coronary artery disease,  fragment screening,  fragment-based drug discovery,   Secreted phospholipase A2,  sPLA2,  AZD2716, AZD-2716, AZD 2716, PRECLINICAL

c1c(cc(c(c1)C(=O)N)c2cccc(c2)CC(C(=O)O)C)Cc3ccccc3

Vandetanib


 

 

Vandetanib2DACS.svg

 

Vandetanib; 443913-73-3; Zactima; ZD6474; Caprelsa; ZD 6474; ch 331, azd 6474

cas 338992-00-0 free form
338992-48-6 HCl
338992-53-3 monotrifluoroacetate

N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-amine

Vandetanib (INN, trade name Caprelsa) is an anti-cancer drug that is used for the treatment of certain tumours of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), theepidermal growth factor receptor (EGFR), and the RET-tyrosine kinase.[1][2] The drug was developed by AstraZeneca.

Orphan drug designation has been assigned in the E.U. for the treatment of medullary thyroid carcinoma. In 2005, orphan drug designation was also assigned in the U.S. for several indications, including treatment of patients with follicular thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, and locally advanced and metastatic papillary thyroid carcinoma. In 2013, orphan drug designation has been assigned in Japan as well for the treatment of thyroid cancer.

 

Vandetanib.png

Approvals and indications

Vandetanib was the first drug to be approved by FDA (April 2011) for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.[3] Vandetanib was first initially marketed without a trade name,[4] and is being marketed under the trade name Caprelsa since August 2011.[5]

Vandetanib is an orally active vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) tyrosine kinase inhibitor, originally developed by AstraZeneca, which was filed for approval in the U.S. and the E.U. for the treatment of non-small cell lung cancer (NSCLC) in combination with chemotherapy, in patients previously treated with one prior anticancer therapy.

However, in late 2009 the company withdrew both the U.S and the EU applications. In 2010, AstraZeneca discontinued development of this compound for the treatment of NSCLC. In 2011, the FDA approved vandetanib for the treatment of medullary thyroid cancer. Also in 2011, a positive opinion was assigned to the regulatory application filed in the E.U. for this indication and in Japan was filed for approval.

Final EMA approval was granted in February 2012 and first E.U. launch took place in the U.K. in 2012.

2011 年 4 月 6 by the FDA-approved surgical resection can not be used for locally advanced or metastatic medullary thyroid cancer (medullary thyroid cancer, MTC) of the drug. Vandetanib is vascular endothelial growth factor receptors (vascular endothelial growth factor receptor, VEGFR) and epidermal growth factor receptor (epidermal growth factor receptor, EGFR) antagonists, tyrosine kinase inhibitors (tyrosine kinase inhibitor). Produced by AstraZeneca.

The synthetic route is as follows:

 

………………

 

 

………………………..

 ……….

Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors
J Med Chem 1999, 42(26): 5369

http://pubs.acs.org/doi/abs/10.1021/jm990345w

 

 

………………………

Radiosynthesis of [(11)C]Vandetanib and [(11)C]chloro-Vandetanib as new potential PET agents for imaging of VEGFR in cancer
Bioorg Med Chem Lett 2011, 21(11): 3222

Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors
J Med Chem 2002, 45(6): 1300

A novel approach to quinazolin-4(3H)-one via quinazoline oxidation: An improved synthesis of 4-anilinoquinazolines
Tetrahedron 2010, 66(4): 962

………………………………

CN 104098544

http://www.google.com/patents/CN104098544A?cl=en

Vandetanib is a synthetic Anilinoquinazoline, advanced medullary thyroid cancer can not be used for the treatment of surgical treatment (medullary thyroid cancer), chemical name: 4- (4-bromo-2- fluoroanilino) _6_ methoxy -7 – [(l- methylpiperidin-4-yl) methoxy] quinazoline, having the following structural formula I:

 

Figure CN104098544AD00031

[0004] The present method of synthesizing the compound are as follows:

[0005] US Patent US7173038 AstraZeneca announced the following methods:

[0006] Method One:

[0007]

Figure CN104098544AD00032

Method two:

 

Figure CN104098544AD00041

 A structure in which the synthesis of compounds of formula as follows:

 

Figure CN104098544AD00042

the process is cumbersome, long synthetic route, therefore a need to provide a new synthetic way to overcome these problems.

An aspect provides a compound having the structure of formula II:

 

Figure CN104098544AD00043

 Another aspect provides a process for preparing a compound of the structural formula II, a compound of formula III with a compound of formula IV in the presence of a base to give a compound of the structural formula II,

 

Figure CN104098544AD00051

where Μ for methylphenylsulfonyl, methylsulfonyl.

Example: 4- (4-bromo-2-fluoroanilino) -6_ methoxy-7 – [(1-formyl-4-yl) methoxy] quinazoline preparation

[0026] in 50mL two-neck flask was added 4- (4-bromo-2-fluoroanilino) -6-methoxy-7-hydroxy-quinazoline (3. 64g, 0 · Olmol), 1- formyl- 4-p methylsulfonyloxy- methylpiperazine steep (3. 56g, 0 · 012mol) and potassium carbonate (4. 14g, 0.03mol), yellow turbid solution was stirred and heated to 100 ° C, TLC detection to feed completion of the reaction. Down to room temperature, the reaction mixture was slowly poured into l〇〇mL water, stirred, filtered, then the filter cake was washed with 50mL water, 15mL of ethyl acetate and then slurried, filtered and dried to give a pale green solid 4- (4- bromo-2-fluoroanilino) -6-methoxy -7 – [(l- carboxylic acid piperidin-4-yl) methoxy] quinazoline 3. 9g, 80% yield.

[0027] ^ NMR (400Mz, DMS0): δ = 1 1〇-1 29 (m, 2H), δ = 1 40-1 43 (m, 2H), δ = 2 15 (s,….. 1H), δ = 2. 64-2. 73 (m, 1H), δ = 3. 06-3. 12 (m, 1H), δ = 3. 71-3. 74 (d, 1H), δ = 3. 95 (s, 3H), δ = 4 • 03-4. 05 (d, 2H), δ = 4. 20-4. 23 (d, 1H), δ = 7. 20 (s, 1H), δ = 7. 46-7. 48 (m, 1H), δ = 7. 51-7 • 53 (m, 1H), δ = 7. 65-7. 67 (d, 1H), δ = 7. 80 (s, 1H), δ = 8. 01 (s, 1H), δ = 8. 35 (s, 1H), δ = 9. 54 (s, 1H).

[0028] Example 2: Preparation of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7 – [(1-methyl-piperidin-4-yl) methoxy] quinazoline preparation

[0029] 4- (4-bromo-2-fluoroanilino) in 100mL three-necked flask, 6-methoxy-7 – [(1-formyl-4-yl) methoxy] quinoline oxazoline (0 · 98g, 2. Ommol), zinc (0 · 6g, 4. 4mmol) and tetrahydrofuran (20mL), stirred pale yellow turbid liquid. At room temperature was added portionwise sodium borohydride (0. 15g, 4. OmmoL), little change in the temperature. Heating
……………………………….

CN 104211649

http://www.google.com/patents/CN104211649A?cl=en

Pharmacokinetics

Vandetanib is well absorbed from the gut, reaches peak blood plasma concentrations 4 to 10 hours after application, and has a half-life of 120 hours days on average, per Phase I pharmacokinetic studies. It has to be taken for about three months to achieve a steady-state concentration. In the blood, it is almost completely (90–96%) bound to plasma proteins such as albumin. It is metabolised to N-desmethylvandetanib via CYP3A4 and to vandetanib-N-oxide via FMO1 and 3. Both of these are active metabolites. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites.[2][9][10]

Metabolites of vandetanib (top left): N-desmethylvandetanib (bottom left, via CYP3A4), vandetanib-N-oxide (bottom right, via FMO1 andFMO3), both pharmacologically active, and a minor amount of aglucuronide.[10]

Clinical trials

Non-small cell lung cancer

The drug underwent clinical trials as a potential targeted treatment for non-small-cell lung cancer. There have been some promising results from a phase III trial withdocetaxel.[11] There have also been ambivalent results when used with pemetrexed.[12] Another trial with docetaxel was recruiting in July 2009.[13]

AstraZeneca withdrew EU regulatory submissions for vandetanib (under the proposed trade name Zactima) in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy.[14]

References

  1.  “Definition of vandetanib”. NCI Drug Dictionary. National Cancer Institute.
  2.  “Vandetanib Monograph”. Drugs.com. Retrieved 29 August 2012.
  3. “FDA approves new treatment for rare form of thyroid cancer”. Retrieved 7 April 2011.
  4.  “FDA approves orphan drug vandetanib for advanced medullary thyroid cancer” (Press release). AstraZeneca. Retrieved 2011-08-17.
  5.  “AstraZeneca announces trade name CAPRELSA® for vandetanib” (Press release). AstraZeneca. Retrieved 2011-08-17.
  6.  Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.”. Drug Metabol Drug Interact.0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID 24643910.
  7. Haberfeld, H, ed. (2012). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  8.  Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11.doi:10.1515/dmdi-2014-0014. PMID 24807167.
  9.  Martin, P.; Oliver, S.; Kennedy, S. J.; Partridge, E.; Hutchison, M.; Clarke, D.; Giles, P. (2012). “Pharmacokinetics of Vandetanib: Three Phase I Studies in Healthy Subjects”.Clinical Therapeutics 34 (1): 221–237. doi:10.1016/j.clinthera.2011.11.011.PMID 22206795.
  10. “Clinical Pharmacology Review: Vandetanib” (PDF). US Food and Drug Administration, Center for Drug Evaluation and Research. 20 August 2010. Retrieved29 August 2012.
  11.  “Vandetanib Shows Clinical Benefit When Combined With Docetaxel For Lung Cancer”. ScienceDaily. 3 June 2009.
  12.  “IASLC: Vandetanib Fails to Improve NSCLC Outcomes with Pemetrexed”. Medpage today. 5 Aug 2009.
  13.  Clinical trial number NCT00687297 for “Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer” at ClinicalTrials.gov
  14.  “Zactima”. European Medicines Agency.

External links

 

 

Vandetanib
Vandetanib2DACS.svg
Systematic (IUPAC) name
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
Clinical data
Trade names Caprelsa
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a611037
Licence data US FDA:link
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Protein binding 90–96%
Metabolism CYP3A4, FMO1, FMO3
Biological half-life 120 hours (mean)
Excretion 44% faeces, 25% urine
Identifiers
CAS Registry Number 443913-73-3 
ATC code L01XE12
PubChem CID: 3081361
IUPHAR/BPS 5717
DrugBank DB08764 Yes
ChemSpider 2338979 Yes
UNII YO460OQ37K Yes
ChEBI CHEBI:49960 Yes
ChEMBL CHEMBL24828 Yes
Synonyms ZD6474
Chemical data
Formula C22H24BrFN4O2
Molecular mass 475.354 g/mol

//////

AZD 3264 an IKK2 Inhibitor from Astra Zeneca


 

 

 

Figure

AZD 3264

MW 441.50

CAS 1609281-86-8

MF C21 H23 N5 O4 S
3-​Thiophenecarboxamide​, 2-​[(aminocarbonyl)​amino]​-​5-​[4-​(3,​5-​dimethyl-​4-​isoxazolyl)​-​2-​[(3S)​-​3-​pyrrolidinyloxy]​phenyl]​-
2-(Carbamoylamino)-5-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(3S)-pyrrolidin-3-yloxy]phenyl]thiophene-3-carboxamide

Inhibition of IkB-kinase IKK2 has been identified as one of the novel pathways to treat inflammatory conditions such as asthma, chronic pulmonary obstructive disorder (COPD) and rheumatoid arthritis

Astrazeneca Ab,

……………………..

PATENT

WO 2003010158

https://www.google.com/patents/WO2003010158A1?cl=en

 

Figure

 

The synthesis began with the aromatic nucleophilic substitution reaction of 2-fluorobromobenzene (2) with (S)-N-Boc-3-pyrrolidinol 3 to give the bromo intermediate 4, which was borylated via halogen metal exchange using n-hexLi in THF followed by treatment with triisopropyl borate and acidic work-up to give the boronic acid intermediate 5. Suzuki coupling of the boronic acid 5 with bromothiophene 6(2)afforded the intermediate 7. Intermediate 7 was subjected to regioselective bromination using bromine in acetic acid. This reaction was nonregioselective and yielded 17% of the required isomer 8. The bromo compound 8 was coupled with isoxazole boronate ester 9 by another Suzuki reaction to get the title compound. The overall yield of the synthesis was <6%.

 

 

………………………..

PAPER

Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op500105n

http://pubs.acs.org/doi/full/10.1021/op500105n

 

Abstract Image

An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially available fragments.

AZD3264 (1)

A stirred solution of tert-butyl (3S)-3-[2-(4-carbamoyl-5-methyl-2-thienyl)-5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-carboxylate (16) (2.65 kg, 4.63 mol) in tetrahydrofuran (25 L) w……………………………………………………title compound in 91% yield.
Purification

To a stirred suspension of crude AZD3264 (1) (1.75 kg, 3.98 mol) in methanol (23.75 L) and water (2.64 L) was added formic acid (0.24 kg, 5.18 mol), and the mixture was heated to 40 °C for 1.5 h, cooled to 25 °C, and basified with aqueous ammonia (12.29 M in water, 1.62 L, 19.92 mol). The product was isolated by filtration.
 1H NMR (DMSO-d6, 400 MHz): δ 1.92–2.10 (m, 2H), 2.28 (s, 3H), 2.46 (s, 3H), 2.75–2.82 (m, 1H), 3.00–3.12 (m, 3H), 5.11–5.12 (m, 1H), 6.90 (br, 2H), 7.00–7.03 (m, 2H), 7.30 (br, 1H), 7.70–7.72 (m, 2H), 7.83 (s, 1H), 10.93 (s, 1H).
 13C NMR (DMSO-d6, 100.6 MHz): δ 10.54, 11.42, 32.94, 45.51, 53.00, 79.37, 111.76, 114.17, 115.66, 120.70, 121.20, 122.77, 125.39, 126.92, 128.84, 150.12, 152.54, 154.50, 158.13, 165.14, 167.06.
DEPT NMR (DMSO-d6, 100.6 MHz): δ 10.54, 11.43, 32.94, 45.51, 53.01, 79.35, 114.17, 120.70, 121.20, 126.92.
HRMS calcd for C21H24N5O4S (M + H)+: 442.1543, found 442.1554.
[α]25D −13.80 (c 0.5, DMSO)
 
Journal of Medicinal Chemistry (2013), 56(18), 7232-7242 reports similar analogues

Daiichi partners with AZ to sell Movantik in US…….Pharmatimes, Selina McKee


Naloxegol.svg
Naloxegol
Daiichi partners with AZ to sell Movantik in US 
March 19, 2015

Selina McKee

News editor, Selina McKee

Selina McKee

Qualified from King’s College London with BSc (hons) in Human Biology in 1999 with an interest in medical journalism. Has since held positions as a database analyst managing a portfolio of companies at Evaluate Pharma, and as news editor at Pharma Marketletter. Fluent German speaker, interests include music, piano, reading, astronomy, photography and Formula 1.

Daiichi partners with AZ to sell Movantik in US

AstraZeneca has chosen Daiichi Sankyo to help sell its novel constipation drug Movantik (naloxegol) in the US, as the firm gears up for its launch in April.

First-in-class Movantik was cleared in the US last September for the treatment of opioid-induced constipation in adults with chronic non-cancer pain, for which there is still significant unmet need.

PharmaTimes Magazine and Digital offer a unique blend of news stories, interviews, features, case studies, analysis and comment on the critical issues facing the pharma and healthcare sectors. Our wide editorial lens combined with our editorial philosophy to deliver sharp, informed and entertaining coverage from the perspective of the industry, the payer and the patient, allows PharmaTimes to help kickstart conversations that matter most to our audience of decision makers within pharma and the healthcare profession.PharmaTimes Competitions are a critical facet of our business, providing a unique opportunity for industry to showcase its most talented people in marketing, communications, sales and clinical research. No other competitions offer entrants the chance to compete head-to-head in real-life challenges devised by independent industry and healthcare experts, to test their skill sets against their peers in real time, and receive feedback to ensure the whole experience is a valuable learning process.

 Selina McKee

Selina McKee

Editor, UK News at PharmaTimes

London, United Kingdom
Pharmaceuticals
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EMA approves AstraZeneca’s lesinurad to treat gout patients


EMA approves AstraZeneca’s lesinurad to treat gout patients
British-Swedish drugmaker AstraZeneca has received approval from European Medicines Agency (EMA) for its lesinurad 200mg tablets to treat gout patients. READ AT…..[LINK]

 

 

SYNTHESIS………..https://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/

“The company submitted a MAA based on data from the Clear1, Clear2 and Crystal pivotal Phase III combination therapy studies.”

AstraZeneca’s subsidiary Ardea Biosciences carried out Clear1, Clear2 and Crystal trials.

 

LESINURAD

SYNTHESIS………..https://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/

Lesogaberan


Lesogaberan.svg

Lesogaberan

AZD-3355, AZD3355, [(2R)-3-amino-2-fluoropropyl]phosphinic acid, 344413-67-8
Molecular Formula: C3H8FNO2P+
Molecular Weight: 140.073285 g/mol
[(2R)-3-amino-2-fluoropropyl]-hydroxy-oxophosphanium

Lesogaberan (AZD-3355) was[1] an experimental drug candidate developed by AstraZeneca for the treatment of gastroesophageal reflux disease (GERD).[2] As a GABAB receptor agonist,[3] it has the same mechanism of action as baclofen, but is anticipated to have fewer of the central nervous system side effects that limit the clinical use of baclofen for the treatment of GERD.[4]

http://pubs.acs.org/doi/abs/10.1021/jm701425k

J. Med. Chem., 2008, 51 (14), pp 4315–4320
DOI: 10.1021/jm701425k
Abstract Image

We have previously demonstrated that the prototypical GABAB receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABAB agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABAB agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABAB agonists devoid of classical GABAB agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (R)-7 (AZD3355) that is presently being evaluated in man.

(2R)-(3-Amino-2-fluoropropyl)phosphinic Acid ((R)-7)

(R)-7 as a white solid (3.12 g, 24%):
mp = 183−185 °C;
1H NMR (300 MHz, D2O) δ 7.90 (s, 0.5 H), 6.15 (s, 0.5 H), 5.12−5.29 (m, 0.5 H), 4.92−5.10 (m, 0.5 H), 3.12−3.42 (m, 2H), 1.74−2.26 (m, 2H);
[α]D25 −4.0° (c 1.0, H2O);
APIMS m/z 142 [M + H]+. Anal. (C3H9FNO2P·0.25H2O) C, H, N.

Lesogaberan.png

References

  1. AstraZeneca. “AZD3355”. Retrieved 30 December 2011.
  2. Bredenoord, Albert J. (2009). “Lesogaberan, a GABAB agonist for the potential treatment of gastroesophageal reflux disease”. IDrugs 12 (9): 576–584. PMID 19697277.
  3. Alstermark, et al.; Amin, K; Dinn, SR; Elebring, T; Fjellström, O; Fitzpatrick, K; Geiss, WB; Gottfries, J et al. (2008). “Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors”. Journal of Medicinal Chemistry 51 (14): 4315–4320. doi:10.1021/jm701425k. PMID 18578471.
  4. Brian E. Lacy, Robert Chehade, and Michael D. Crowell (2010). “Lesogaberan”. Drugs of the Future 35 (12): 987–992. doi:10.1358/dof.2010.035.012.1540661.
Lesogaberan
Lesogaberan.svg
Identifiers
CAS number 344413-67-8 Yes=  Yes
PubChem 9833984
ChemSpider 23254384 
UNII 4D6Q6HGC7Z Yes
ChEMBL CHEMBL448343 
Jmol-3D images Image 1
Properties
Molecular formula C3H9FNO2P
Molar mass 141.08 g mol−1
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