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ORGANIC SPECTROSCOPY

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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XL 114, AUR 104 and XL 102, AUR 102 (NO CONCLUSIONS, ONLY PREDICTIONS)


File:Animated-Flag-India.gif - Wikimedia Commons
XL 102

XL 114

FOR BOTH, JUST PREDICTION

PREDICTIONS

or

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Figure imgf000002_0001
Figure imgf000024_0001

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

(2S)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2S)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

CAS 2305027-62-5

C12 H20 N6 O7, 360.32Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-, (2S,3ξ)-N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

ALSO SEE

Figure imgf000003_0002
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(2S,3R)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png

1673534-76-3C12 H20 N6 O7, 360.32
L-Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]
(2S,3R)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acidN-[[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-L-threonine

CAS 1673534-76-3

PD-1-IN-1 free base, EX-A1918, CS-6240NSC-799645CA-170 (AUPM-170)|PDL1 inhibitorHY-101093, PD-1-IN-1

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)[C@@H](C)O)CC(N)=O

XL 114, AUR 104

A novel covalent inhibitor of FABP5 for cancer therapy

XL 102,  AUR 102

A potent, selective and orally bioavailable inhibitor of cyclin-dependent kinase 7 (CDK7)

NO CONCLUSIONS, ONLY PREDICTIONS

PREDICTIONS MORE

(2R,3R)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2R,3R)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

C12H20N6O7, 360.32

(2S,3S)-2-[[(1S)-3-Amino-1-[3-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2S,3S)-2-[[(1S)-3-amino-1-[3-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

XL102, AUR 102

XL102 is a potent, selective and orally bioavailable covalent inhibitor of CDK7, which is an important regulator of the cellular transcriptional and cell cycle machinery. CDK7 helps regulate cell cycle progression, with overexpression observed in multiple cancers, such as breast, prostate and ovarian cancers. In preclinical studies, XL102 revealed potent anti-proliferative activity, induced cell death in a large panel of cancer cell lines and caused tumor growth inhibition and regression in xenograft models, demonstrating its potential as a targeted antitumor agent.

In late 2020, Exelixis exercised its option to in-license XL102 (formerly AUR102) from Aurigene per the companies’ July 2019 collaboration, option and license agreement. Exelixis has assumed responsibility for the future clinical development, manufacturing and commercialization of XL102. Aurigene retains limited development and commercial rights for India and Russia.

SYN

ABOUT Fatty acid-binding proteins (FABPs)

Fatty acid-binding proteins (FABPs) are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting them to the appropriate compartments in the cell. Epidermal fatty acid-binding protein (FABP5) is an intracellular lipid-binding protein that is abundantly expressed in adipocytes and macrophages. Previous studies have revealed that the FABP5 expression level is closely related to malignancy in various types of cancer. However, its precise functions in the metabolisms of cancer cells remain unclear. Here, we revealed that FABP5 knockdown significantly induced downregulation of the genes expression, such as hormone-sensitive lipase (HSL), monoacylglycerol lipase (MAGL), elongation of long-chain fatty acid member 6 (Elovl6), and acyl-CoA synthetase long-chain family member 1 (ACSL1), which are involved in altered lipid metabolism, lipolysis, and de novo FA synthesis in highly aggressive prostate and breast cancer cells. Moreover, we demonstrated that FABP5 induced inflammation and cytokine production through the nuclear factor-kappa B signaling pathway activated by reactive oxygen species and protein kinase C in PC-3 and MDA-MB-231 cells. Thus, FABP5 might regulate lipid quality and/or quantity to promote aggressiveness such as cell growth, invasiveness, survival, and inflammation in prostate and breast cancer cells. In the present study, we have revealed for the first time that high expression of FABP5 plays a critical role in alterations of lipid metabolism, leading to cancer development and metastasis in highly aggressive prostate and breast cancer cells.

Fatty acid-binding protein, epidermal is a protein that in humans is encoded by the FABP5 gene

Function

This gene encodes the fatty acid binding protein found in epidermal cells, and was first identified as being upregulated in psoriasis tissue. Fatty acid binding proteins are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. It is thought that FABPs roles include fatty acid uptake, transport, and metabolism.[6]

The phytocannabinoids (THC and CBD) inhibit endocannabinoid anandamide (AEA) uptake by targeting FABP5, and competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids.[7] Results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.[8]

Interactions

FABP5 has been shown to interact with S100A7.[

ABOUT CD47/SIRPa axis

CD47/SIRPa axis is established as a critical regulator of myeloid cell activation and serves as an immune checkpoint for macrophage mediated phagocytosis. Because of its frequent upregulation in several cancers, CD47 contributes to immune evasion and cancer progression. CD47 regulates phagocytosis primarily through interactions with SIRPla expressed on macrophages. Blockade of SIRPla/CD47 has been shown to dramatically enhance tumor cell phagocytosis and dendritic cells maturation for better antigen presentation leading to substantially improved antitumor responses in preclinical models of cancer (M. P. Chao et al. Curr Opin Immunol. 2012 (2): 225-232). Disruption of CD47-SIRPa interaction is now being evaluated as a therapeutic strategy for cancer with the use of monoclonal antibodies targeting CD47 or SIRPa and engineered receptor decoys.

CD47 is expressed on virtually all non-malignant cells, and blocking the CD47 or the loss of CD47 expression or changes in membrane distribution can serve as markers of aged or damaged cells, particularly on red blood cells (RBC). Alternatively, blocking SIRPa also allows engulfment of targets that are not normally phagocytosed, for those cells where pre-phagocytic signals are also present. CD47 is a broadly expressed transmembrane glycoprotein with a single Ig-like domain and five membrane- spanning regions, which functions as a cellular ligand for SIRPa with binding mediated through the NH2-terminal V-like domain of SIRPa. SIRPa is expressed primarily on myeloid cells, including macrophages, granulocytes, myeloid dendritic cells (DCs), mast cells, and their precursors, including hematopoietic stem cells.

CD47 is also constitutively upregulated on a number of cancers such as Non-Hodgkin Lymphoma (NHL), Acute myeloid leukemia (AML), breast, colon, glioblastoma, glioma, ovarian, bladder and prostate cancers, etc. Overexpression of CD47 by tumor cells, which efficiently helps them to escape immune surveillance and killing by innate immune cells. However, in most of the tumor types, blockade of the CD47-SIRPa interaction as a single agent may not be capable of inducing significant phagocytosis and antitumor immunity, necessitating the need to combine with other therapeutic agents. The concomitant engagement of activating receptors such as Fc-receptors (FcRs) or other prophagocytic receptors (collectively known as “eat-me” signals) may be necessary for exploiting the maximum potential of the CD-47-SIPRa pathway blockade.

The role of engagement of prophagocytic receptors is proved by inefficiency to trigger phagocytosis either by anti-CD47 F(ab) fragments, single chain variable fragments of CD-47 or non-Fc portion- containing SIRPa proteins in blocking of the CD47-SIRPa interaction. When activating prophagocytic receptors are engaged, as evident in the case of using Fc portion-containing blocking anti-CD47 antibodies, CD47- SIRPa blockade is able to trigger more efficient phagocytosis. Combining CD47-SIRPa blocking agents with therapeutic antibodies (Fc-containing) targeting tumor antigens stimulate activating Fc receptors (FcRs) leading to efficient phagocytosis. The Fc portion of therapeutic antibody targeting tumor antigen also induces antibody-dependent cellular cytotoxicity (ADCC), which also adds to the therapeutic efficacy. Hence antibodies selected from the group consisting of rituximab, herceptin, trastuzumab, alemtuzumab, bevacizumab, cetuximab and panitumumab, daratumumab due to its tumor targeting nature and ADCC, can trigger more efficient phagocytosis.

Earlier approaches to disrupt CD47- SIRPa interaction utilized monoclonal antibodies targeting CD47 or SIRPa and engineered receptor decoys fused to Fc fragment. However, a concern with this approach is that CD47 is highly expressed on both hematopoietic and non-hematopoietic normal cells. Hence along with tumor cells CD47-SIRPa blocking agents containing Fc-portion may also target many normal cells potentially leading to their elimination by macrophages. The interaction of blocking antibodies with normal cells is considered as a major safety issue resulting in anemia, thrombocytopenia, and leukopenia. These agents may also affect solid tissues rich in macrophages such as liver, lung, and brain. Hence it may be ideal to block the CD47- SIRPa interaction by agents devoid of Fc portion, such as small

molecules, peptides, Fab fragments etc. while activating prophagocytic receptors in tumor cells by appropriate combinations to induce efficient phagocytosis of tumor cells.

Apart from Fc Receptors, a number of other prophagocytic receptors are also reported to promote engulfment of tumor cells in response to CD47-SIRPa blockade by triggering the phagocytosis. These include receptors for SLAMF7, Mac-l, calreticulin and possibly yet to identified receptors. B cell tumor lines such as Raji and other diffuse large B cell lymphoma express SLAMF7 and are implicated in triggering prophagocytic signals during CD47-SIRPa blockade.

Therapeutic agents known to activate prophagocytic receptors are also therefore ideal partners for use in combination with CD47-SIRPa blocking agents to achieve efficient phagocytosis. These agents include proteasome inhibitors (bortezomib, ixazomib and carfilzomib), Anthracyclines (Doxorubicin, Epirubicin, Daunorubicin, Idarubicin, Mitoxantrone) Oxaliplatin, Cyclophosphamide, Bleomycin, Vorinostat, Paclitaxel, 5-Fluorouracil, Cytarabine, BRAF inhibitory drugs (Dabrafenib, Vemurafenib), PI3K inhibitor, Docetaxel, Mitomycin C, Sorafenib, Tamoxifen and oncolytic viruses.

Apart from the specific agents known to have effect on‘eat me’ signals other agents including Abiraterone acetate, Afatinib, Aldesleukin, Aldesleukin, Alemtuzumab, Anastrozole, Axitinib, Belinostat, Bendamustine, Bicalutamide, Blinatumomab, Bosutinib, Brentuximab, Busulfan, Cabazitaxel, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Clofarabine, Crizotinib, Dacarbazine, Dactinomycin, Dasatinib, Degarelix, Denileukin, Denosumab, Enzalutamide, Eribulin, Erlotinib, Everolimus, Exemestane, Exemestane, Fludarabine, Fulvestrant, Gefitinib, Goserelin, Ibritumomab, Imatinib, Ipilimumab, Irinotecan, Ixabepilone, Lapatinib, Lenalidomide, Letrozole, Leucovorin, Leuprolide, Lomustine, Mechlorethamine, Megestrol, Nelarabine, Nilotinib, Nivolumab, Olaparib, Omacetaxine, Palbociclib, Pamidronate, Panitumumab, Panobinostat, Pazopanib, Pegaspargase, Pembrolizumab, Pemetrexed Disodium, Pertuzumab, Plerixafor, Pomalidomide, Ponatinib, Pralatrexate, Procarbazine, Radium 223, Ramucirumab, Regorafenib, rIFNa-2b, Romidepsin, Sunitinib, Temozolomide, Temsirolimus, Thiotepa, Tositumomab, Trametinib, Vinorelbine, Methotrexate, Ibrutinib, Aflibercept, Toremifene, Vinblastine, Vincristine, Idelalisib, Mercaptopurine and Thalidomide could potentially have effect on‘eat me’ signal pathway on combining with CD-47-SIRPa blocking agents.

In addition to the therapeutic agents mentioned above, other treatment modalities that are in use in cancer therapy also activate prophagocytic receptors, and thus can be combined with CD47-SIRPa blocking agents to achieve efficient phagocytosis. These include Hypericin-based photodynamic therapy (Hyp-PDT), radiotherapy, High-hydrostatic pressure, Photofrin-based PDT and Rose Bengal acetate -based PDT.

However, there is an unmet need for combining small molecule CD-47-SIRPa pathway inhibitors with agents capable of stimulating activating receptors such as Fc-receptors (FcRs) or other prophagocytic receptors, or combining with other treatment modalities that are in use in cancer therapy to activate prophagocytic receptors for exploiting the maximum potential of the CD-47- SIRPa pathway blockade.

CLIP

Exelixis In-Licenses Second Anti-Cancer Compound from Aurigene Following FDA Acceptance of Investigational New Drug Application for Phase 1 Clinical Trial in Non-Hodgkin’s Lymphoma

– Robust preclinical data support Exelixis’ clinical development of XL114, with phase 1 trial in Non-Hodgkin’s lymphoma expected to begin in the coming months –

– Exelixis will make an option exercise payment of $10 million to Aurigene –

https://www.businesswire.com/news/home/20211014005549/en/Exelixis-In-Licenses-Second-Anti-Cancer-Compound-from-Aurigene-Following-FDA-Acceptance-of-Investigational-New-Drug-Application-for-Phase-1-Clinical-Trial-in-Non-Hodgkin%E2%80%99s-LymphomaOctober 14, 2021 08:00 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today announced that Exelixis has exercised its exclusive option under the companies’ July 2019 agreement to in-license XL114 (formerly AUR104), a novel anti-cancer compound that inhibits the CARD11-BCL10-MALT1 (CBM) signaling pathway, which promotes lymphocyte survival and proliferation. Exelixis has now assumed responsibility for the future clinical development, commercialization and global manufacturing of XL114. Following the U.S. Food and Drug Administration’s (FDA) recent acceptance of its Investigational New Drug (IND) application, Exelixis will soon initiate a phase 1 clinical trial evaluating XL114 monotherapy in patients with Non-Hodgkin’s lymphoma (NHL). At the American Association of Cancer Research Annual Meeting in April of this year, Aurigene presented preclinical data (Abstract 1266) demonstrating that XL114 exhibited potent anti-proliferative activity in a large panel of cancer cell lines ranging from hematological cancers to solid tumors with excellent selectivity over normal cells. In addition, oral dosing of XL114 resulted in significant dose-dependent tumor growth inhibition in diffuse large B-cell lymphoma (DLBCL) and colon carcinoma models.

“We are pleased that our agreement with Aurigene has generated a second promising compound that warrants advancement into clinical development and believe the collaboration will continue to play an important role in expanding our pipeline”

XL114 is the second molecule that Exelixis in-licensed from Aurigene under the companies’ July 2019 collaboration, option and license agreement. Exelixis previously exercised its option to in-license XL102, a potent, selective and orally bioavailable inhibitor of cyclin-dependent kinase 7 (CDK7), from Aurigene in December 2020 and initiated a phase 1 trial of XL102 as a single agent and in combination with other anti-cancer agents in patients with advanced or metastatic solid tumors in January 2021.

“We are pleased that our agreement with Aurigene has generated a second promising compound that warrants advancement into clinical development and believe the collaboration will continue to play an important role in expanding our pipeline,” said Peter Lamb, Ph.D., Executive Vice President, Scientific Strategy and Chief Scientific Officer, Exelixis. “XL114 has shown potent anti-proliferative activity in lymphoma cell lines that have aberrant activation of the CBM signaling pathway and may have a differentiated profile and potential as a best-in-class molecule that could improve outcomes for patients with Non-Hodgkin’s lymphoma and other hematologic cancers.”

XL114 was identified to have anti-proliferative activity in cell lines with constitutive activation of CBM signaling, including activated B-cell-like DLBCL (ABC-DLBCL), mantle cell lymphoma and follicular lymphoma cell lines. Further characterization of XL114 in cell-based assays demonstrated a functional role in B-cell (BCR) signaling pathways. Additionally, XL114 showed dose-dependent tumor growth inhibition in an ABC-DLBCL mouse xenograft tumor model. In preclinical development, XL114 also demonstrated a high degree of selectivity against a broad safety pharmacology panel of enzymes and receptors. While the precise molecular mechanism underlying XL114’s function in repressing BCR signaling and MALT1 activation has yet to be characterized, the fatty acid-binding protein 5 (FABP5) has been identified as a prominent XL114-binding target.

“XL114 is the second molecule that Exelixis has opted to in-license under our July 2019 agreement, underscoring the significant potential of our approach to the discovery and preclinical development of innovative cancer therapies that target novel mechanisms of action,” said Murali Ramachandra, Ph.D., Chief Executive Officer, Aurigene. “Exelixis has a track record of success in the clinical development and commercialization of anti-cancer therapies that provide patients with important new treatment options, and we are pleased that the continued advancement of XL114 will be supported by the company’s extensive clinical, regulatory and commercialization infrastructure.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to obtain an exclusive license from Aurigene to three preexisting programs, including the compounds now known as XL102 and XL114. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for an additional upfront payment of $2.5 million per program. The collaboration was expanded in 2021 to include three additional early discovery programs. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all nine programs. Exelixis may exercise its option for a program at any time up until the first IND for the program becomes effective. Having exercised options on two programs thus far (XL102 and XL114), if and when Exelixis exercises a future option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. To exercise its option for XL114, Exelixis will make an option exercise payment to Aurigene of $10 million. Once Exelixis exercises its option for a program, Aurigene will be eligible for clinical development, regulatory and sales milestones, as well as royalties on future potential sales of the compound. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene Discovery Technologies Limited is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY, NSEIFSC: DRREDDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the U.S. and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of the Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. In November 2020, the company was named to Fortune’s 100 Fastest-Growing Companies list for the first time, ranking 17th overall and the third-highest biopharmaceutical company. For more information about Exelixis, please visit www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Dinesh Chikkanna

Dinesh Chikkanna

Director, Medicinal Chemistry Aurigene Discovery Technologies

Murali Ramachandra

Murali Ramachandra

CEO at Aurigene Discovery Technologies

str1

CLIP

https://cancerres.aacrjournals.org/content/81/13_Supplement/1266

Abstract 1266: Discovery and preclinical evaluation of a novel covalent inhibitor of FABP5 for cancer therapyDinesh Chikkanna, Leena Khare Satyam, Sunil Kumar Pnaigrahi, Vinayak Khairnar, Manoj Pothuganti, Lakshmi Narayan Kaza, Narasimha Raju Kalidindi, Vijaya Shankar Nataraj, Aditya Kiran Gatta, Narasimha Rao Krishnamurthy, Sandeep Patil, DS Samiulla, Kiran Aithal, Vijay Kamal Ahuja, Nirbhay Kumar Tiwari, KB Charamannna, Pravin Pise, Thomas Anthony, Kavitha Nellore, Sanjeev Giri, Shekar Chelur, Susanta Samajdar and Murali Ramachandra 
DOI: 10.1158/1538-7445.AM2021-1266 Published July 2021 
Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA

Abstract

Dysregulated fatty acid metabolism is thought to be a hallmark of cancer, wherein fatty acids function both as an energy source and as signals for enzymatic and transcriptional networks contributing to malignancy. Fatty acid-binding protein 5 (FABP5) is an intracellular protein that facilitates transport of fatty acids and plays a role in regulating the expression of genes associated with cancer progression such as cell growth, survival, and metastasis. Overexpression of FABP5 has been reported to contribute to an aggressive phenotype and a poor survival correlation in several cancers. Therefore, inhibition of FABP5 is considered as a therapeutic approach for cancers. Phenotypic screening of a library of covalent compounds for selective sensitivity of cancer cells followed by medicinal chemistry optimization resulted in the identification of AUR104 with desirable properties. Chemoproteomic-based target deconvolution revealed FABP5 as the cellular target of AUR104. Covalent adduct formation with Cys43 of FABP5 by AUR104 was confirmed by mass spectrometry. Target occupancy studies using a biotin-tagged AUR104 demonstrated potent covalent binding to FABP5 in both cell-free and cellular conditions. Ligand displacement assay with a fluorescent fatty acid probe confirmed the competitive binding mode of AUR104 with fatty acids. Binding at the fatty acid site and covalent bond formation with Cys43 were also demonstrated by crystallography. Furthermore, AUR104 showed a high degree of selectivity against a broad safety pharmacology panel of enzymes and receptors. AUR104 exhibited potent anti-proliferative activity in a large panel of cell lines derived from both hematological and solid cancers with a high degree of selectivity over normal cells. Anti-proliferative activity in lymphoma cell lines correlated with inhibition of MALT1 pathway activity, cleavage of RelB/Bcl10 and secretion of cytokines, IL-10 and IL-6. AUR104 displayed desirable drug-like properties and dose-dependent oral exposure in pharmacokinetic studies. Oral dosing with AUR104 resulted in dose-dependent anti-tumor activity in DLBCL (OCI-LY10) and NSCLC (NCI-H1975) xenograft models. In a repeated dose MTD studies in rodents and non-rodents, AUR104 showed good tolerability with an exposure multiple of >500 over cellular EC50 for up to 8 hours. In summary, we have identified a novel covalent FABP5 inhibitor with optimized properties that showed anti-tumor activity in in vitro and in vivo models with acceptable safety profile. The data presented here strongly support clinical development of AUR104.

Citation Format: Dinesh Chikkanna, Leena Khare Satyam, Sunil Kumar Pnaigrahi, Vinayak Khairnar, Manoj Pothuganti, Lakshmi Narayan Kaza, Narasimha Raju Kalidindi, Vijaya Shankar Nataraj, Aditya Kiran Gatta, Narasimha Rao Krishnamurthy, Sandeep Patil, DS Samiulla, Kiran Aithal, Vijay Kamal Ahuja, Nirbhay Kumar Tiwari, KB Charamannna, Pravin Pise, Thomas Anthony, Kavitha Nellore, Sanjeev Giri, Shekar Chelur, Susanta Samajdar, Murali Ramachandra. Discovery and preclinical evaluation of a novel covalent inhibitor of FABP5 for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1266.

Patent

US20200147054 – COMBINATION OF SMALL MOLECULE CD-47 INHIBITORS WITH OTHER ANTI-CANCER AGENTS

Muralidhara Ramachandra
Pottayil Govindan Nair Sasikumar
Girish Chandrappa Daginakatte
Kiran Aithal Balkudru

PATENT

WO 2020095256

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020095256

Example- 1: The synthetic procedures for the preparation of compounds described in the present invention were described in co-pending Indian provisional patent application 201841001438 dated 12* Jan 2018, which is converted as PCT application

PCT/IB2019/050219, the contents of which are hereby incorporated by reference in their entirety.

str1

PATENT

WO 2018178947https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018178947&tab=PCTDESCRIPTION

PATENT

WO 2019138367

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019138367

PATENT

WO 2019073399

https://patents.google.com/patent/WO2019073399A1/en

Priority to IN201741036169

Example 4 of WO 2015/033299

Figure imgf000002_0001
Figure imgf000003_0002

PATENT

https://patents.google.com/patent/BR112020014202A2/en

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PATENT

The present invention relates to substituted alkynylene compounds represented by compound of formula (I) pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the methods of preparation of compound of formula (I) and therapeutic uses thereof as anti-cancer agents.

Patent

Example 1

(((S)-4-amino-1-(3-((S)-1,5-diaminopentyl)-1,2,4-oxadiazol-5-yl)-4-oxobutyl)carbamoyl)-L-proline (Compound 1)


 (MOL) (CDX)

Synthesis of Compound 1 b


 (MOL) (CDX)
      Ethylchloroformate (2.47 mL, 25.9 mmol) and NMM (2.9 mL, 25.9 mmol) were added to a solution of compound 1a (6.0 g, 17.3 mmol) in THF (60 mL) and stirred at −20° C. for 20 min. After 20 minutes 25% of aq.ammonia (24 mL) was added to the active mixed anhydride resulting from the reaction and the reaction mass was stirred at 0-5° C. for 30 min. The completeness of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 5.6 g of compound 1 b. LCMS: 346.4 [M+H] +.

Synthesis of Compound 1C


 (MOL) (CDX)
      Trifluroacetic anhydride (6.85 mL, 48.6 mmol) was added to a solution of compound 1b (5.6 g, 16.2 mmol), pyridine (7.84 mL, 97.2 mmol) in DCM (60 mL) at 0° C. and stirred at room temperature for an hour. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and CH 2Cl 2. The organic layer was washed with NaHCO solution followed by citric acid and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 5.42 g of compound 1c, which was used for next step directly.

Synthesis of Compound 1d


 (MOL) (CDX)
      Hydroxylamine hydrochloride (3.43 g, 49.5 mmol), water (10 mL) and K 2CO (4.54 g, 32.9 mmol) were added to a solution of compound 1c (5.4 g, 16.5 mmol) in EtOH (60 mL) and stirred at room temperature for overnight. The completion of the reaction was confirmed by TLC analysis. After the completion of reaction, the compound from the water was extracted by using the CH 2Cl followed washing the organic layer with water, brine and concentrated under reduced pressure to yield 5.8 g of compound 1d. LCMS: 361.3 [M+H] +.

Synthesis of Compound 1f


 (MOL) (CDX)
      HOBt (3.24 g, 24.0 mmol) and DIC (3.36 mL, 24.0 mmol) were added to a solution of Fmoc-Gln(Trt)-OH (compound 1e) (9.83 g, 16.1 mmol) in DMF (100 mL) at 0° C. and stirred for 15 min. Compound 1d (5.8 g, 16.1 mmol) was added to the reaction mass at the same temperature and the resulting mixture was stirred for an hour at the same temperature, followed by stirring at room temperature for an additional 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice water; precipitated white solid was filtered; washed with water (150 mL) and dried under high under reduced pressure to yield 8.62 g of compound 1f. LCMS: 953.7 [M+H] +.

Synthesis of Compound 1g


 (MOL) (CDX)
      Acetic acid (5 mL) was added to a solution of compound 1f (5.0 g, 5.0 mmol) in acetonitrile (50 ml) at room temperature and the reaction mass was refluxed at 85° C. for 12 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain crude semi solid which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid and brine solution. The organic layer was dried over Na 2SO 4; filtered and evaporated under reduced pressure to obtain crude solid. Compound was purified using column chromatography to yield 4.3 g of title compound. LCMS: 935.6 [M+H] +.

Synthesis of Compound 1h


 (MOL) (CDX)
      Compound 1g (4.3 g, 4.5 mmol) was added to a solution of 20% piperidine in DMF (20 mL) at 0° C. and the reaction mass was stirred at same temperature for an hour. The completion of the reaction was confirmed by TLC analysis. After completion, the reaction mixture was quenched with ice-cold water and the resulting white precipitate was filtered and dried under vacuum. The crude product obtained was diluted with hexane, stirred and filtered to yield 3.0 g of compound 1h. LCMS: 713.4 [M+H] +.

Synthesis of Compound 1i


 (MOL) (CDX)
      Pyridine (0.33 mL, 4.2 mmol) was added to a solution of compound 1h (1.5 g, 2.1 mmol) in CH 2Cl (15 mL) and the resulting solution was stirred at room temperature for 10 min. 4-nitrophenyl chloroformate (0.84 g, 4.2 mmol) in CH 2Cl (15 mL) was added to the above mixture and the resultant mixture was stirred at room temperature for an hour. After completion of reaction (confirmed by TLC), it was diluted with CH 2Cl (50 mL) and washed with water (100 mL×2), 1N HCl (100 mL×2), water followed by brine solution (100 mL×2). The organic layer was dried over Na 2SO 4; filtered and evaporated under reduced pressure to yield 0.72 g compound 1i, which was taken to the next step without any further purification. LCMS: 878.9 [M-100].

Synthesis of compound 1j


 (MOL) (CDX)
      TEA (0.34 mL, 2.46 mm) was added to a solution of H-Pro-O tBu.HCl (0.21 g, 1.23 mmol) and compound 1i (0.72 g, 0.82 mmol) in THF (10 mL) at room temperature and stirred for 12 h. The volatiles were evaporated and portioned between ethyl acetate and water. The reaction mixture was diluted with ice cold water and extracted with EtOAc. The Organic layer was separated and dried over Na 2SO and concentrated under reduced pressure. The crude compound obtained was purified by column chromatography and compound elutes in 50% of ethyl acetate in hexane. Yield: 0.5 g of compound 1j. LCMS: 910.6 [M+H] +.

Synthesis of Compound 1


 (MOL) (CDX)
      Compound 1j (0.5 g, 0.55 mmol) was added to a cocktail mixture (10 m L) of TFA:TIPS:H 2O (95:2.5:2.5) and was stirred at room temperature for 3 h. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether and filtered to yield 0.2 g of crude compound 1. The crude solid material was purified by preparative HPLC method described under experimental conditions. LCMS: 412.2 [M+H] +. HPLC t (min): 9.6.

Example 2

(S)-4-(3-((S)-1-amino-4-guanidinobutyl)-1,2,4-oxadiazol-5-yl)-4-(3-((S)-1-carboxy-2-phenylethyl) ureido)butanoic acid (Compound 7)


 (MOL) (CDX)

Synthesis of Compound 2b


 (MOL) (CDX)
      Ethylchloroformate (1.75 mL, 18.23 mmol) and NMM (2.0 mL, 18.23 mmol) were added into a solution of compound 2a (8.0 g, 15.18 mmol) in THF (45 mL) and the resulting mixture was stirred at −20° C. for 20 min. After 20 minutes 25% of aqueous ammonia (25 mL) was added to the active mixed anhydride generated and stirred at 0-5° C. for 30 min. The completeness of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 7.1 g of compound 2b. LCMS: 526.3 [M+H] +.

Synthesis of Compound 2c


 (MOL) (CDX)
      Trifluroacetic anhydride (TFAA) (2.83 mL, 20.26 mmol) was added to a solution of compound 2b (7.1 g, 13.51 mmol) in pyridine (7.08 g, 87.80 mmol) and the resulting mixture was stirred at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with citric acid and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure. The crude solid was purified via column chromatography (60-120 silicagel) to yield 5.8 g of compound 2c. LCMS: 508.3 [M+H] +.

Synthesis of Compound 2d


 (MOL) (CDX)
      Hydroxylamine hydrochloride (1.56 g, 22.50 mmol), water (30 mL) and potassium carbonate (3.11 g, 11.25 mmol) were added to a solution of compound 2c (5.8 g, 11.25 mmol) in EtOH (60 mL) and stirred at 90° C. for 3 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with brine solution, dried over Na 2SO then filtered and evaporated under reduced pressure, the solid obtained was washed with 20% ethyl acetate to yield 6.1 g of compound 2d. LCMS: 541.3 [M+H] +.

Synthesis of Compound 2f


 (MOL) (CDX)
      HOBt (2.28 g, 16.9 mmol) and DIC (2.62 mL, 16.9 mmol) were added to a solution of Fmoc-Glu(O tBu)-OH (compound 2e) (4.0 g, 9.02 mmol) in DMF (60 mL) at 0° C. and the resulting mixture was stirred for 15 min. Then compound 2d (6.1 g, 11.28 mmol) was added to the above mixture at the same temperature and the reaction mixture was continued stirring for an hour and then at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice cold water, the precipitated white solid was filtered, washed with water (150 mL) and dried under high under reduced pressure. The solid was taken into 10% MeOH in DCM and washed the organic layer with 10% NaHCO 3, water and brine solution. The organic layer was dried over Na 2SO and concentrated under reduced pressure to yield 8.0 g of compound 2f. LCMS: 948.7 [M+H] +.

Synthesis of Compound 2g


 (MOL) (CDX)
      Acetic acid (7 mL) was added to a solution of compound 2f (7.0 g, 7.38 mmol) in THF (70 ml) at room temperature and the resulting mixture was refluxed at 70° C. for 12 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain crude semi solid which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO solution followed by brine solution. The organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to get crude solid. The compound was purified by column chromatography (60-120 silicagel) to yield 5.4 g of compound 2g. LCMS: 930.5 [M+H] +.

Synthesis of Compound 2h


 (MOL) (CDX)
      Compound 2g (5.4 g, 5.80 mmol) was added to a solution of 50% piperidine in DMF (20 mL) at 0° C. and stirred at same temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mass was quenched with water (100 mL), the resulted precipitate was filtered. The solid obtained was dissolved in ethyl acetate and washed the organic layer with 10% NaHCO 3, water and brine. The organic layer was dried over Na 2SO and concentrated under reduced pressure. The crude product obtained was diluted with hexane and the resulted precipitate was filtered followed by washing with hexane to obtain 3.0 g of compound 2h. LCMS 708.6 [M+H] +.

Synthesis of Compound 2i


 (MOL) (CDX)
      Pyridine (0.75 mL, 9.3 mmol) was added to a solution of H-Phe-O tBu.HCl (2.0 g, 7.75 mmol) in CH 2Cl (20 mL) was added pyridine and the resulting solution was stirred at room temperature for 10 min. To this reaction mixture a solution of 4-nitrophenyl chloroformate (1.87 g, 9.30 mmol) in CH 2Cl (20 mL) was added and the resultant mixture was stirred at room temperature for 3 h. After completion of reaction (confirmed by TLC) it was diluted with CH 2Cl (50 mL) and washed with water (100 mL×2), 10% citric acid (100 mL×2), water (100 mL), followed by brine solution (100 mL). The organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 1.7 g compound 2i, which was taken to the next step without any further purification.

Synthesis of Compound 2j


 (MOL) (CDX)
      TEA (0.29 mL, 2.1 mmol) was added to a solution of compound 2h (1.0 g, 1.41 mmol) and compound 2i (0.54 g, 1.41 mmol) in THF (10 mL) at room temperature and stirred for 3 h. The volatiles were evaporated and portioned between EtOAc and water. The reaction mixture was diluted with ice cold water and extracted with EtOAc followed by washing with 10% K 2CO (100 mL×4), water and brine solution. Organic layer separated and dried over Na 2SO and concentrated under reduced pressure. The crude product obtained was diluted with hexane and the resulted precipitate was filtered followed by washing with hexane yielded 0.98 g of compound 2j. LCMS: 955.6 [M+H] +.

Synthesis of Compound 7


 (MOL) (CDX)
      Compound 2j (0.5 g, 5.2 mmol) was added to cocktail mixture (5 m L) of trifluoroacetic: TIPS: water (95:2.5:2.5). The cleavage solution was stirred at room temperature for 3 h. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether and filtered to yield 0.34 g of crude compound 2. The crude solid material was purified by preparative HPLC method as described under experimental conditions. LCMS: 491.1 [M+H] +. HPLC t R: (min): 11.1

PATENT

WO 2015/033299

https://patents.google.com/patent/WO2015033299A1/en?oq=WO+2015%2f033299

Pottayil Govindan Nair SasikumarMuralidhara RamachandraSeetharamaiah Setty Sudarshan Naremaddepalli

Figure imgf000024_0001

Example 1: Synthesis of Compound 1

Figure imgf000019_0001

Step la:

Figure imgf000019_0002

Ethylchloroformate (1.5 g, 13.78 mniol) and N-Methylmorpholine ( 1.4 g, 13.78 mmol) were added to a solution of compound la (3 g, 11.48 mmol) in THE (30 mL) arid stirred at -20 °C. After 20 min. Liquid ammonia (0.77 g, 45.92 mmol) was added to the active mixed anhydride formed in- situ and stirred at 0-5 °C for 20 min. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCOs, citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure to get 2.9 g of compound lb (Yield: 96.3%). LCMS: 261.0 ( Vi+H ; .

Step lb:

Figure imgf000020_0001

1 b 1cTrifluroacetic anhydride (9.7 g, 46.0 mmol) was added to a solution of compound lb (8 g, 30.7 mmol) in pyridine (24.3 g, 307.0 mmol) and stirred at room temperature for 3 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCO?,, citric acid, brine solution, dried over Na2-S04 and evaporated under reduced pressure to afford 7 g of compound lc (Yield: 94.0%). LCMS: 187.2 (M-¾u )+.

Step lc:

Figure imgf000020_0002

1 c 1dHydroxylamine hydrochloride (3 g, 43.37 mmol) and potassium carbonate (6 g, 43.37 mmol) were added to a solution of compound lc (7 g, 28.91 mmol) in EtOH (70 m L) and stirred at 90 °C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with brine solution, dried over Na2S04 and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to get 4.2 g of compound Id (Yield: 52.8%). LCMS: 276.4 (M+H)+.Step Id:

Figure imgf000021_0001

Deoxo-Fluor® (1.83 g, 8.3 mmol) was added to a solution of Fmoc-Asn(Trt)-OH (4.5 g, 7.5 mmol) in CH2Q2 (50 mL) and stirred at 0 °C for 3 h. Then CH2CI2 was evaporated and triturated with hexane, decanted and evaporated under vacuum to get the corresponding acid fluoride. NMM (1.17 g, 1 1.6 mmol) and compound Id (1.6 g, 5.8 mmol) in THF were added to the acid fluoride and stirred at room temperature for 12 h. Then THF was evaporated and sodium acetate (0.72 g, 8.7 mmol) was added followed by EtOH (50 mL). The reaction mixture was stirred at 90 °C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCOa, citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure, which was further purified by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to afford 2.8 g of compound le (Yield: 44.4%). LCMS: 836.4 (M+Hf .Step le:

Ph3

Figure imgf000021_0002

To compound le (2.3 g, 2.7 mmol) in CH2CI2 (10 mL) diethyiarnine (10 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The resulting solution was concentrated in vacuum to get gummy residue. The crude compound was purified by neutral alumina column chromatography (Eluent: 0-50% ethyl acetate in hexane then 0-5% methanol in chloroform) to get 1.4 g of If (Yield: 90 %). LCMS: 636.5 (M+Na)+.

Figure imgf000022_0001

1f 1To a solution of compound If (0.45 g) in CH2CI2 (5 mL), trifluoroacetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred for 3 h at room temperature to remove the acid sensitive protecting groups. The resulting solution was concentrated in vacuum to afford 0.29 g of crude compound 1 which was purified using prep-HPLC method described under experimental conditions. \H NMR (DMSQ-d6, 400 MHz): δ 2.58 (m, 2H), 3.53 (m, 3H), 3.91 (t, 1H), 4.36 (t, 1H), 6.91 (s, 1H), 7.45 (s, 1H); 1 C NMR (DMSO-de, 400 MHz): δ 20.85, 45.71 , 50.23, 65.55, 171.03, 171 .41, 181.66. LCMS: 216.2 (Μ+ΗΓ; HPLC: tR = 13.1 min.Example 2: Synthesis of Co

Figure imgf000022_0002

Step 2a:

Figure imgf000022_0003

1f2a

The urea linkage was carried out by the coupling compound If (2.7 g, 4.39 mmoi) in THF (30 mL) at room temperature with compound 2b (1.67 g, 4.39 mmoi). The coupling was initiated by the addition of TEA (0.9 g, 8.78 mmoi) in THF (10 m L) and the resultant mixture was stirred at room temperature. After completion of 20 h, THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2S04 and evaporated under reduced pressure to get compound 2a, which was further purified by silica gel column chromatography (Fluent: 0-50% ethyl acetate in hexane) to afford 3.46 g of compound 2a (Yield: 92.10%). LCMS 857.4 (M+H)+.

Figure imgf000023_0001

2aTo a solution of compound 2a (0.22 g, 0.25 mmol) in 0¾ί¾ (5 m L), trifluoroaeetic acid (5 mL) and catalytic amount of triisopropyisilane were added and stirred for 3h at room, temperature. The resulting solution was concentrated under reduced pressure to obtain 0.35 g of crude compound. The crude solid material was purified using preparative- HPLC method described under experimental conditions. LCMS: 347.1 (M+H)+; HPLC: tR = 12.9 min.

Synthesis of

Figure imgf000023_0002

2bTo the compound H-Ser(tBu)-OiBu (2 g, 9.2 mmol) in C I I■(.{■ (20 mL), triethylamine (1.39 g, 13.8 mmol) was added and the solution was stirred at room temperature for 5-10 min. To this mixture, solution of 4-Nitrophenyl chioro formate (2.22 g, 11.04 mmol) in CH2CI2 was added and the resultant mixture was stirred at room temperature for 30 min. The completion of the reaction was confirmed by TLC analysis. After completion of reaction, reaction mixture was diluted with CH2CI2 and washed with water and 5.0 M citric acid solution, dried over Na2SC>4 and evaporated under reduced pressure to get crude compound 2b, which was further purified by silica gel column chromatography (Eiuent: 0-20% ethyl acetate in hexane) to yield 2.1 g (58.9%) of 2b.Example 3: Synthesis of Compound 3

Figure imgf000023_0003

The compound was synthesised using similar procedure as depicted in Example 1 (compound 1) and D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH (compound la, Example 1) and Fmoc-D- Asn(trt)-OH in place of Fmoc-Asn(trt)-OH to yield 0.15 g crude material of the title compound 3. LCMS: 230.1 (M+H)+.Example 4: Synthesis of Co

Figure imgf000024_0001

The compound was synthesised using similar procedure as depicted in Example 2 for synthesising compound 2 using

Figure imgf000024_0002

instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.35 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.2 (M+H)+, HPLC: tR = 12.19 min.Example 5: Synthesis of

Figure imgf000024_0003

The compound was synthesised using similar procedure as depicted in Example 4 (compound 4) using D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH, Fmoc-D-Asn(trt)-OH in place of Fmoc-Asn(trt)- OH and H-D-Ser(‘Bu)-0’Bu was used in place of H-Thr^Bu^O’Bu to yield 0.3 g crude material of the title compound. The cmde solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.3 (M+H)+. HPLC: tR = 13.58 min.Example 6: Synthesis of Compound 6

Figure imgf000024_0004

The compound was synthesised using similar procedure as depicted in Example 2 by using H-Thr(‘Bu)-OMe instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.2 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 375.1 (M+H)+, HPLC: tR = 1.84 min.Example 7: Synthesis of Compound 7

Figure imgf000025_0001

Step 7a:

Figure imgf000025_0002

1f7aThe compound 7a was synthesised using similar procedure as for compound 2a (Example 2, step 2a) using H-Thr(‘Bu)-OMe instead of H-Ser(‘Bu)-OtBu to get crude material which was further purified by silica gel column chromatography (Eluent: 0-50% ethyl acetate in he ane) to get 2.0 g of compound 7a (Yield: 74 %). LCMS: 829.2 (M+H)+.Step 7b:

Figure imgf000025_0003

7a 7bTo a solution of compound 7a (0.35 g, 4.0 mmol) in THF (5 mL) was added lithium hydroxide (0.026 g, 0.63 mmol) at 0 °C and the mixture was stirred for 2 h at room temperature. The completion of the reaction was confirmed by TLC analysis. THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure to afford 7b, which was further purified by silica gel column chromatography (Eluent: 0-5% methanol in DCM) to get 0.3 g of product 7b (Yield: 86.7%). LCMS 815.2 (M+H)+.

Step 7c:

Figure imgf000026_0001

7b 7Compound 7b (0.295 g, 0.39 mmol) was anchored to Rink amide resin (0.7 g, 0.55 mmol/g) using HOBT (0.072 g, 0.54 mmol) and DIC (0.068 g, 0.54 mmol) method in DMF (10 mL). The resin was stirred for 12 h at room temperature. The resin was washed with DCM, DMF and DCM and dried. The target compound was cleaved from the rink amide resin using TFA (5 mL) and catalytic amount of TIPS. The resin was allowed to remain at room temperature for 2 h with occasional stirring. After 2 h, TFA and TIPS were evaporated under nitrogen atmosphere and the resulting residue was washed with diethyl ether to yield 0.1 g crude material of the title compound 7. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 360.0 (M+H)+, HPLC: tR = 13.88 min.Example 8: Synthesis of

Figure imgf000026_0002

The compound was synthesised using similar procedure as depicted in Example 2 (compound 2) using Fmoc-Glu(0’Bu)-OH instead of Fmoc-Asn(Trt)-OH to get 0.4 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 362.1 (M+H)+. HPLC: tR = 13.27 min.

PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019061324&tab=FULLTEXT

Patenthttps://patents.google.com/patent/WO2019067678A1/enPATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019061324

PATENThttps://patents.google.com/patent/WO2018073754A1/en
PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019087087
PAPERSScientific Reports (2019), 9(1), 1-19. https://www.nature.com/articles/s41598-019-48826-6

figure1

Chemical structures of PD-L1 inhibitors developed by Aurigene (Aurigene-1) and Bristol-Meyers Squibb (BMSpep-57, BMS-103, and BMS-142). Chemical structures were generated using ChemDraw Professional 15. PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019087087

L-threonine’ mentioned in compound of formula (I) thereof can be represented by any one of the following formulae:

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EP-3041827-B11,2,4-oxadiazole derivatives as immunomodulators2013-09-062018-04-18
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EP-3363790-B11,2,4-oxadiazole derivatives as immunomodulators2013-09-062020-02-19
US-10173989-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062019-01-08
US-10590093-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062020-03-17
US-2015073024-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2017101386-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06
Publication NumberTitlePriority DateGrant Date
US-2018072689-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2019144402-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2020199086-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-9771338-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062017-09-26
WO-2015033299-A11,2,4-oxadiazole derivatives as immunomodulators2013-09-06

////////////Investigational New Drug Application,  Phase 1,  Clinical Trial, Non-Hodgkin’s Lymphoma, XL 114, AUR 104, aurigene, Exelixis 

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

https://patentscope.wipo.int/search/en/result.jsf?inchikey=HFOBENSCBRZVSP-WHFCDURNSA-N

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PATENT

The present invention relates to substituted alkynylene compounds represented by compound of formula (I) pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the methods of preparation of compound of formula (I) and therapeutic uses thereof as anti-cancer agents.

XL 102

EXELIXIS AND AURIGENE ANNOUNCE THAT PROMISING PRECLINICAL DATA TO BE PRESENTED AT THE ENA SYMPOSIUM SUPPORT THE CLINICAL DEVELOPMENT OF A NOVEL CDK7 INHIBITOR

https://www.aurigene.com/exelixis-and-aurigene-announce-that-promising-preclinical-data-to-be-presented-at-the-ena-symposium-support-the-clinical-development-of-a-novel-cdk7-inhibitor/

Exelixis and Aurigene Announce That Promising Preclinical Data to Be Presented at the ENA Symposium Support the Clinical Development of a Novel CDK7 Inhibitor

– Detailed characterization of an oral inhibitor of CDK7 demonstrates potent activity against multiple hematologic and solid tumor cell lines, as monotherapy and in combination with chemotherapies –

October 09, 2020 03:02 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today disclosed new preclinical data showing that AUR102 has potent anti-tumor activity in a large panel of cancer cell lines. AUR102 is a potent, selective, and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7), which is an important regulator of the cellular transcriptional and cell cycle machinery. Exelixis has an exclusive option for AUR102 under its July 2019 exclusive collaboration, option and license agreement with Aurigene. The new data will be presented in a poster (Abstract 170) at the 32nd EORTC-NCI-AACR (ENA) Symposium, which is being held virtually on October 24-25, 2020.

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy”

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy,” said Murali Ramachandra, Ph.D., Chief Executive Officer of Aurigene. “The data to be presented at ENA 2020 demonstrate that AUR102 effectively engages CDK7 and inhibits a key mediator of the cell cycle and transcription. The ability to inhibit CDK7 activity with an orally available therapeutic such as AUR102 holds great potential to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma.”

The abstract provides a summary of results from a detailed characterization of AUR102 in cancer cell lines and animal tumor models. Additional data will be presented in the poster. Key findings included in the abstract are:
• AUR102 exhibited potent anti-proliferative activity in a large panel of cell lines with induction of cell death in cell lines derived from multiple cancer types.
• The observed anti-proliferative activity correlated with cellular CDK7 target engagement and decreased levels of P-Ser5 RNAPII, a key mediator of transcription.
• AUR102 studies showed synergy when used in combination with multiple chemotherapies.
• Oral dosing with AUR102 resulted in dose-dependent anti-tumor activity, including complete tumor regression in diffuse large B-cell lymphoma, acute myeloid leukemia, and triple-negative breast cancer xenograft models.
• Inhibition of tumor growth was accompanied by complete target engagement as demonstrated in a parallel PK-PD study.
• AUR102 significantly impacts several pathways and key cancer driver and immune-response genes.

The study authors conclude that the data support clinical evaluation of AUR102 as a single agent and in combination with chemotherapies for the treatment of cancer.

“The exciting AUR102 data to be presented at ENA 2020 provide further validation of our partnering strategy, which gives us multiple opportunities to build a pipeline of best-in-class cancer therapies,” said Peter Lamb, Ph.D., Executive Vice President of Scientific Strategy and Chief Scientific Officer of Exelixis. “AUR102 could be the subject of an Investigational New Drug filing later this year, which would be an important value driver for the program itself and for our collaboration with Aurigene. We commend the Aurigene team on their ongoing success in building a robust body of data supporting the broad clinical potential of AUR102.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to license three preexisting programs from Aurigene. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for additional upfront option payments of $2.5 million per program. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all six programs. As the programs mature, Exelixis will have the opportunity to exercise an exclusive option for each program up until the time of Investigational New Drug (IND) filing acceptance. If Exelixis decides to exercise an option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. Aurigene will be eligible for clinical development, regulatory, and sales milestones, as well as royalties on sales. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/ VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the United States and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at http://www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

EXELIXIS AND AURIGENE ANNOUNCE THAT PROMISING PRECLINICAL DATA TO BE PRESENTED AT THE ENA SYMPOSIUM SUPPORT THE CLINICAL DEVELOPMENT OF A NOVEL CDK7 INHIBITOR

https://www.aurigene.com/exelixis-and-aurigene-announce-that-promising-preclinical-data-to-be-presented-at-the-ena-symposium-support-the-clinical-development-of-a-novel-cdk7-inhibitor/

Exelixis and Aurigene Announce That Promising Preclinical Data to Be Presented at the ENA Symposium Support the Clinical Development of a Novel CDK7 Inhibitor

– Detailed characterization of an oral inhibitor of CDK7 demonstrates potent activity against multiple hematologic and solid tumor cell lines, as monotherapy and in combination with chemotherapies –

October 09, 2020 03:02 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today disclosed new preclinical data showing that AUR102 has potent anti-tumor activity in a large panel of cancer cell lines. AUR102 is a potent, selective, and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7), which is an important regulator of the cellular transcriptional and cell cycle machinery. Exelixis has an exclusive option for AUR102 under its July 2019 exclusive collaboration, option and license agreement with Aurigene. The new data will be presented in a poster (Abstract 170) at the 32nd EORTC-NCI-AACR (ENA) Symposium, which is being held virtually on October 24-25, 2020.

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy”

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy,” said Murali Ramachandra, Ph.D., Chief Executive Officer of Aurigene. “The data to be presented at ENA 2020 demonstrate that AUR102 effectively engages CDK7 and inhibits a key mediator of the cell cycle and transcription. The ability to inhibit CDK7 activity with an orally available therapeutic such as AUR102 holds great potential to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma.”

The abstract provides a summary of results from a detailed characterization of AUR102 in cancer cell lines and animal tumor models. Additional data will be presented in the poster. Key findings included in the abstract are:
• AUR102 exhibited potent anti-proliferative activity in a large panel of cell lines with induction of cell death in cell lines derived from multiple cancer types.
• The observed anti-proliferative activity correlated with cellular CDK7 target engagement and decreased levels of P-Ser5 RNAPII, a key mediator of transcription.
• AUR102 studies showed synergy when used in combination with multiple chemotherapies.
• Oral dosing with AUR102 resulted in dose-dependent anti-tumor activity, including complete tumor regression in diffuse large B-cell lymphoma, acute myeloid leukemia, and triple-negative breast cancer xenograft models.
• Inhibition of tumor growth was accompanied by complete target engagement as demonstrated in a parallel PK-PD study.
• AUR102 significantly impacts several pathways and key cancer driver and immune-response genes.

The study authors conclude that the data support clinical evaluation of AUR102 as a single agent and in combination with chemotherapies for the treatment of cancer.

“The exciting AUR102 data to be presented at ENA 2020 provide further validation of our partnering strategy, which gives us multiple opportunities to build a pipeline of best-in-class cancer therapies,” said Peter Lamb, Ph.D., Executive Vice President of Scientific Strategy and Chief Scientific Officer of Exelixis. “AUR102 could be the subject of an Investigational New Drug filing later this year, which would be an important value driver for the program itself and for our collaboration with Aurigene. We commend the Aurigene team on their ongoing success in building a robust body of data supporting the broad clinical potential of AUR102.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to license three preexisting programs from Aurigene. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for additional upfront option payments of $2.5 million per program. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all six programs. As the programs mature, Exelixis will have the opportunity to exercise an exclusive option for each program up until the time of Investigational New Drug (IND) filing acceptance. If Exelixis decides to exercise an option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. Aurigene will be eligible for clinical development, regulatory, and sales milestones, as well as royalties on sales. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/ VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the United States and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at http://www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Exelixis Forward-Looking Statements

This press release contains forward-looking statements, including, without limitation, statements related to: Exelixis’ and Aurigene’s plans to present preclinical data in support of the continued development of AUR102 in a poster as part of the 32nd ENA Symposium; the potential for AUR102 to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma; the potential for AUR102 to be the subject of an Investigational New Drug filing later in 2020; Exelixis’ potential future financial and other obligations under the exclusive collaboration, option and license agreement with Aurigene; and Exelixis’ plans to reinvest in its business to maximize the potential of the company’s pipeline, including through targeted business development activities and internal drug discovery. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; the level of costs associated with Exelixis’ commercialization, research and development, in-licensing or acquisition of product candidates, and other activities; uncertainties inherent in the drug discovery and product development process; Exelixis’ dependence on its relationship with Aurigene, including Aurigene’s adherence to its obligations under the exclusive collaboration, option and license agreement and the level of Aurigene’s assistance to Exelixis in completing clinical trials, pursuing regulatory approvals or successfully commercializing partnered compounds in the territories where they may be approved; the continuing COVID-19 pandemic and its impact on Exelixis’ research and development operations; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ and Aurigene’s continuing compliance with applicable legal and regulatory requirements; Exelixis’ and Aurigene’s ability to protect their respective intellectual property rights; market competition; changes in economic and business conditions; and other factors affecting Exelixis and its product pipeline discussed under the caption “Risk Factors” in Exelixis’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 6, 2020, and in Exelixis’ future filings with the SEC. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.

Exelixis, the Exelixis logo, CABOMETYX, COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a registered Japanese trademark.

Voxtalisib, SAR-245409, XL-765


Voxtalisib

SAR-245409, XL-765

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

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

C13 H14 N6 O . Cl H, 306.751

934493-76-2

INNOVATOR Exelixis Inc,, LICENSE SANOFI

PHASE 2, Malignant neoplasms

0.2H2O

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

SAR245409 (XL765)

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

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

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

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

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

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

PATENT

WO 2014058947

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

Example 1. Synthesis of Compound (1)

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

Figure imgf000015_0001

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

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

PATENT

WO 2007044813

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

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

Figure imgf000060_0001

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

Figure imgf000060_0002

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

Figure imgf000060_0003

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

Figure imgf000061_0001

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

Figure imgf000061_0002

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

Figure imgf000061_0003

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

Figure imgf000062_0001

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

Figure imgf000062_0002

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

Figure imgf000063_0001

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

References:

1. P. W. Yu, et al., Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway, Mol Cancer Ther, May 2014 13; 1078-91
2. K. P. Papadopoulos, et al., Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors, Clin Cancer Res, May 1, 2014 20; 2445
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WO2007044813A1 9 Oct 2006 19 Apr 2007 Exelixis Inc PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kα
WO2012054748A2 * 20 Oct 2011 26 Apr 2012 Seattle Genetics, Inc. Synergistic effects between auristatin-based antibody drug conjugates and inhibitors of the pi3k-akt mtor pathway
WO2012065019A2 * 11 Nov 2011 18 May 2012 Exelixis, Inc. Pyridopyrimidinone inhibitors of p13k alpha
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////////////Voxtalisib hydrochloride, Exelixis, SANOFI, PHASE 2, Malignant neoplasms, SAR-245409, XL-765

 

 

 

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


XL 388

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

Benzoxazepine-Containing Kinase Inhibitor

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone
 [7-​(6-​amino-​3-​pyridinyl)​-​2,​3-​dihydro-​1,​4-​benzoxazepin-​4(5H)​-​yl]​[3-​fluoro-​2-​methyl-​4-​(methylsulfonyl)​phenyl]​-Methanone,
(7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone
MW 455.50, CAS 1251156-08-7, MF C23 H22 F N3 O4 S
Exelixis, Inc. INNOVATOR, IND Filed
½H2O
C23H22FN3O4S.½H2O ,  Molecular Weight: 464.51
MONO HYDROCHLORIDE…..CAS 1777807-51-8, [7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)
TLC Rf = 0.33 (Dichloromethane:Methanol [95:5])
Potent and selective mTOR inhibitor (IC50 = 9.9 nM). Inhibits mTOR activity in an ATP-competitive manner. Exhibits >300-fold selectivity for mTOR over PI 3-K and a range of other kinases. Displays antitumor activity in athymic nude mice implanted with tumor xenografts.
SYNTHESIS
 
 CLICK ON IMAGE FOR CLEAR VIEW……………..
 
Tyrosine kinases are important enzymes for signal transduction in cells. Therefore, they are often targets for the treatment of diseases that are caused by dysregulation of cellular processes, such as cancers. Mammalian target of rapamycin (mTOR) is a kinase in the phosphatidylinositol-3-kinase (PI3K) family of enzymes and is implicated in the regulation of cell growth and proliferation. Various inhibitors of mTOR have been explored as possible agents for treatment of various cancers
The mammalian target of rapamycin (mTOR) is a large protein kinase that integrates both extracellular and intracellular signals of cellular growth, proliferation, and survival. Both extracellular mitogenic growth factor signaling from cell surface receptors and intracellular signals that convey hypoxic stress, energy, and nutrient status converge at mTOR. mTOR exists in two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
mTORC1 is a key mediator of translation and cell growth, via its substrates p70S6 kinase (p70S6K) and eIF4E binding protein 1 (4E-BP1), and promotes cell survival via the serum and glucocorticoid-activated kinase (SGK), whereas mTORC2 promotes activation of prosurvival kinase AKT. mTORC1, but not mTORC2, can be inhibited by an intracellular complex between rapamycin and FK506 binding protein (FKBP). However, rapamycin–FKBP may indirectly inhibit mTORC2 in some cells by sequestering mTOR protein and thereby inhibiting assembly of mTORC2.
Given the role of mTOR signaling in cellular growth, proliferation, and survival as well as its frequent deregulation in cancers, several rapamycin analogues (rapalogues) that are selective allosteric mTORC1 inhibitors have been extensively evaluated in a number of cancer clinical trials.
Demonstrated clinical efficacy for rapalogues is currently limited to patients with advanced, metastatic renal cell carcinoma (RCC) despite extensive development efforts.
This result is likely attributed not only to a lack of inhibition of mTORC2 by rapalogues that leads to upregulation of Akt through a negative feedback loop, but also to only partial inhibition of mTORC1.Therefore, ATP-competitive mTOR inhibitors that should simultaneously inhibit both mTORC1 and mTORC2 may offer a clinical advantage over rapalogues.
As a key component of the phosphoinositide 3-kinase-related kinase (PIKK) family, which is comprised of phosphoinositide 3-kinases (PI3Ks), DNA-PK, ATM, and ATR, mTOR shares the highly conserved ATP binding pockets of the PI3K family with sequence similarity of 25% in the kinase catalytic domain.
In light of this fact, it is not surprising that many of the first reported ATP-competitive mTOR inhibitors such as BEZ235 and GDC-0980 also inhibited PI3Ks. PI3Ks are responsible for the production of 3-phosphoinositide lipid second messengers such as phosphatidylinositol 3,4,5-triphosphate (PIP3), which are involved in a number of critical cellular processes, including cell proliferation, cell survival, angiogenesis, cell adhesion, and insulin signaling.
Therefore, the development of ATP-competitive mTOR inhibitors that are selective over PI3Ks may offer an improved therapeutic potential relative to rapalogues as well as dual PI3K/mTOR inhibitors. Recently, several selective ATP-competitive mTOR inhibitors such as Torin 2 and AZD8055  have been reported with sufficient promise to warrant clinical trials.

PATENT

WO 2010118208

Example 2:

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

Figure imgf000250_0001

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

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

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

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

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

MS (EI) C23H22FN3O4S: 456 (MH+).

PAPER

Journal of Medicinal Chemistry (2013), 56(6), 2218-2234.
J. Med. Chem., 2013, 56 (6), pp 2218–2234
DOI: 10.1021/jm3007933
Abstract Image

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

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

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

PATENT

    SYNTHETIC EXAMPLES
      Reference Example 13-Fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride

    • Figure US20100305093A1-20101202-C01052
    • 1-Bromo-3,4-difluoro-2-methylbenzene. To a stirred mixture of 2,3-difluorotoluene (1.9 g, 14.8 mmol) and iron (82.7 mg, 1.48 mmol) in chloroform (10 mL) at rt was added bromine (76 μL, 14.8 mmol) over 2 h. The resulting mixture was stirred at rt overnight. Excess water (10 mL) was added and the reaction mixture was diluted with ether (20 mL). The separated organic layer was washed with aqueous sodium thiosulfate, brine, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was distilled to give the desired product (2.49 g, 81%) as a colorless oil.
    • 3,4-Difluoro-2-methylbenzoic acid. To a stirred solution of 1-bromo-3,4-difluoro-2-methylbenzene (940 mg, 4.54 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium bromide (3.0 mL, 6.0 mmol) over 1 h at 0° C. The resulting mixture was stirred at rt for 24 h. Carbon dioxide (CO2), generated from dry ice, was introduced to the reaction mixture over 2 h and the resulting mixture was stirred for an additional 30 min. The reaction mixture was quenched with addition of an excess amount of water (5 mL) and the tetrahydrofuran was removed on a rotary evaporator. The resulting aqueous layer was diluted with water (5 mL) and acidified with concentrated hydrochloric acid to pH 1-2. The white precipitate was filtered and washed with water and cold hexanes and dried under high vacuum to give the desired product (630 mg, 81%) as a white powder. MS (EI) for C8H6F2O2: 171 (MH).
    • 3-Fluoro-2-methyl-4-(thiomethyl)benzoic acid. To a stirred solution of acid 3,4-difluoro-2-methylbenzoic acid (700 mg, 4.1 mmol) in dimethylsulfoxide (5 mL) was added powdered potassium hydroxide (274 mg, 4.9 mmol) and the mixture was stirred at rt for 30 min. Sodium thiomethoxide (342 mg, 4.9 mmol) was added to the mixture and the resulting mixture was stirred at 55-60° C. for 4 h. Additional powdered potassium hydroxide (70 mg, 1.2 mmol), sodium thiomethoxide (60 mg, 0.8 mmol), and dimethylsulfoxide (2 mL) were added to the reaction mixture. After stirring for 4 h, the mixture was cooled to 0° C. and quenched with excess water (10 mL). The resulting suspension was acidified at 0° C. with concentrated hydrochloric acid to pH 1-2. The white precipitate was collected by suction filtration, washed with water and dried under vacuum overnight to give the desired product (870 mg, 100%). The intermediate sulfide was used in the next step without further purification. MS (EI) for C9H9FO2S: 199.1 (MH).
    • 3-Fluoro-2-methyl-4-(methylsulfonyl)benzoic acid. To a stirred suspension of 3-fluoro-2-methyl-4-(thiomethyl)benzoic acid in an acetone/water (1 mL/10 mL) mixture was added sodium hydroxide (330 mg, 8.25 mmol) and sodium bicarbonate (680 mg, 8.1 mmol). Oxone (˜4 g) was added portionwise to the reaction mixture at 0° C. over 2 h. The reaction was monitored by LC/MS. Concentrated hydrochloric acid was added to adjust the pH 2-3 and the white precipitate was collected by suction filtration, washed with water, and dried under vacuum. Dried precipitate was suspended in water (10 mL), stirred vigorously at rt for 1 h, filtered, washed with water, and hexanes and dried under vacuum to give the desired product (886 mg, 94%) as a white powder. MS (EI) for C9H9FO4S: 231 (MH).
    • 3-Fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride. A mixture of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (860 mg, 3.7 mmol) in thionyl chloride (10 mL) was heated to reflux for 3 h. (the reaction mixture became homogenous). The reaction mixture was concentrated on a rotary evaporator to give the crude acid chloride. This acid chloride was triturated with dichloromethane (2 mL) and concentrated under reduced pressure. The trituration process was repeated 3 times until the product (900 mg, 98%) was obtained as a white powder.

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

  • Figure US20100305093A1-20101202-C01053
  • 4-(ethoxycarbonyl)phenylboronic acid (22.16 g, 114 mmol), tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-carboxylate (34.08 g, 104 mmol), prepared as described in Reference Example 4, Pd(dppf)Cl2 and TEA (21 g, 208 mmol) were combined in a mixture of dioxane (200 mL) and water (20 mL). The reaction mixture was heated to 90° C. for 2 h, then cooled and the solvent removed. Purification of the residue by silica chromatography gave the desired product ester (31.3 g, 69% yield).
  • To the solution of tert-butyl 7-(4-(ethoxycarbonyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10.3 g, 25.93 mmol) in MeOH (120 mL) was added a solution of 4 N HCl in dioxane (50 mL). The reaction mixture was heated to 50° C. for 3 h (monitored by LC/MS). The reaction mixture was allowed to cool to rt. Ethyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate as the hydrochloride salt (8.8 g, 99% yield) was collected by suction filtration.
      Reference Example 4tert-Butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

    • Figure US20100305093A1-20101202-C01055
    • tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate. Commercially-available 5-bromo-2-hydroxybenzaldehyde (4.0 g, 10 mmol) and 2-aminoethanol were combined in THF/MeOH (100 mL, 10:1) and sodium borohydride (0.76 g, 2.0 mmol) was added with stirring. The resulting reaction mixture was stirred at 40° C. for 4 h, concentrated on a rotary evaporator then diluted with EtOAc (50 mL) and saturated NaHCO3 (30 mL). To this suspension was added di-tert-butyl dicarbonate (2.83 g, 13 mmol). The mixture was stirred at rt overnight. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was filtered to obtain the desired product (6.8 g, 98%) as a white solid. MS (EI) for C14H20BrNO4, found 346 (MH+).
    • tert-Butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate (3.46 g, 10 mmol) and triphenylphosphine (3.96 g, 15 mmol) were combined in DCM (100 mL) and diisopropyl azodicarboxylate (3.03 g, 15 mmol) was added. The resulting reaction mixture was stirred at rt for 12 h. The reaction mixture was washed with water, dried, filtered, and concentrated on a rotary evaporator. The resulting crude product was purified via silica gel chromatography eluting with 8:2 hexane/ethyl acetate to give the desired product (1.74 g, 53%) as a white solid. MS (EI) for C14H18BrNO3, found 328 (MH+).

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

  • Figure US20100305093A1-20101202-C01056
  • To a stirred solution of tert-butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10 g, 30.5 mmol), prepared as described in Reference Example 4, and triisopropylborate (9.1 mL, 40 mmol) in dry tetrahydrofuran (100 mL) was added dropwise n-butyllithium in tetrahydrofuran (1.6 M, 25 mL, 40 mmol) while maintaining the temperature below −60° C. Upon completion of addition, the reaction mixture was stirred for 30 min, then quenched with 1 N aqueous hydrochloric acid (35 mL) and allowed to warm to rt. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was stirred for 1 h and filtered to obtain 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (8.6 g, 95%) as a white solid. MS (EI) for C14H20BNO5: 194 (M-Boc).
    Example 2[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone

  • Figure US20100305093A1-20101202-C01076
  • tert-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. To a mixture of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol %) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77%) as an off-white solid. MS (EI) for C19H23N3O3: 342 (MH+).
  • 5-(2,3,4,5-Tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5% methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96%). MS (EI) for C14H15N3O: 242 (MH+).
  • [7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone. To a stirred suspension of 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0° C. for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.24-8.03 (dd, 1H), 7.79-7.71 (m, 1H), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, 1H), 7.05-7.01 (dd, 1H), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, 1H), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36 (d, 3H), 2.12-1.77 (d, 3H). MS (EI) C23H22FN3O4S: 456 (MH+).

PAPER

Org. Process Res. Dev., 2015, 19 (7), pp 721–734
DOI: 10.1021/acs.oprd.5b00037

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

Abstract Image

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

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

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

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

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

1·HCl as a white solid (7.81 kg, 95%, 99.7% purity by AN-HPLC).
Analyses: OVI: DMF < 100 ppm, DMC < 100 ppm, acetone = 3081 ppm, MTBE < 100 ppm, iPAc < 100 ppm, THF < 100 ppm. Heavy metals: Pd ≤ 0.2 ppm, others < 20 ppm (USP ⟨231⟩). 1H NMR (400 MHz, DMSO-d6), equimolar amounts of two rotamers: δ 8.20–8.40 (br s, 2H), 8.33 (s, 0.5H), 8.31 (d, J = 2.8 Hz, 0.5H), 8.15 (d, J = 2.0 Hz, 0.5H), 7.96 (dd, J = 9.7, 2.0 Hz, 0.5H), 7.70–7.78 (m, 1.5H), 7.55–7.57 (m, 0.5H), 7.51–7.55 (m, 0.5H), 7.28 (d, J = 8.6 Hz, 0.5H), 7.17 (d, J = 3.1 Hz, 0.5H), 7.15 (d, J = 5.1 Hz, 0.5H), 7.05–7.11 (m, 1.5H), 6.83 (d, J = 2.7 Hz, 0.5H), 4.86–4.99 (m, 1H), 4.29–4.56 (m, 1H), 4.10–4.27 (m, 2H), 3.93–4.04 (m, 0.5H), 3.45–3.65 (m, 1.5H), 3.37 (s, 1.5 H), 3.35 (s, 1.5H), 2.12 (d, J = 2.0 Hz, 1.5H), 1.76 (d, J = 2.0 Hz, 1.5H). 13C NMR (100 MHz, DMSO-d6), equimolar amounts of two rotamers: δ 168.1, 167.5, 159.4, 159.2, 159.1, 156.6, 153.9, 153.8, 144.6, 142.9, 142.3, 133.0, 132.7, 130.0, 129.9, 129.7, 129.5, 129.1, 129.0, 128.9, 128.8, 128.5, 127.7, 127.6, 127.5, 127.1, 126.9, 124.4, 124.3, 124.1, 122.7, 122.1, 121.6, 114.4, 71.2, 51.7, 51.3, 47.9, 46.9, 44.3, 44.2, 11.7, 11.4.

REFERENCES

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

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

US20100305093

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

PROFILE

Sriram Naganathan

Sriram Naganathan

Senior Director

Chemical Development at Dermira, Inc.

Lives San jose caifornia

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

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

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

snaganat@exelixis.com, sriramrevathi@yahoo.com

sriram.naganathan@dermira.com

Summary

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

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

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

Experience

Senior Director, Chemical Development

Dermira, Inc.

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

Consultant

Intarcia Therapeutics

December 2014 – January 2015 (2 months)

Senior Director

Exelixis

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

Exelixis , Inc. 

210 E. Grand Ave

South San Francisco , California 94080
United States
Company Description: Exelixis, Inc. (Exelixis) is developing therapies for cancer and other serious diseases. Through its drug discovery and development activities, the Company is…   more

Director

Exelixis, Inc

July 2008 – February 2013 (4 years 8 months)

Senior Scientist II

Exelixis

August 2004 – January 2008 (3 years 6 months)

Associate Director

CellGate, Inc.

2000 – 2004 (4 years)

Research Scientist

Roche Bioscience

1997 – 2000 (3 years)

Research Scientist

Cultor

1995 – 1997 (2 years)

Research Scientist

Pfizer

1994 – 1997 (3 years)

Research Assistant Professor

University of Pittsburgh

April 1992 – October 1994 (2 years 7 months)

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

Education

Vivekananda College (University of Madras), India

Bachelor of Science (B.Sc.), Chemistry

1980 – 1983

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

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

snaganathan

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dermira

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

CEO TOM WIGGANS, LEFT AND CMO GENE GAUER, RIGHT

Map of Dermira

Exelixis, Inc.

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

Directions to Exelixis, Inc.

101 Northbound from San Francisco Airport:

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

101 Southbound from San Francisco:

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

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

CS 3150, angiotensin II receptor antagonist, for the treatment or prevention of such hypertension and heart disease


 

CS-3150,  (XL550)

CS 3150, angiotensin II receptor antagonist,  for the treatment or prevention of such hypertension and heart disease similar to olmesartan , losartan, candesartan , valsartan,  irbesartan,  telmisartan, eprosartan,

 Cas name 1H-​Pyrrole-​3-​carboxamide, 1-​(2-​hydroxyethyl)​-​4-​methyl-​N-​[4-​(methylsulfonyl)​phenyl]​-​5-​[2-​(trifluoromethyl)​phenyl]​-​, (5S)​-

CAS 1632006-28-0 for S conf

MF C22 H21 F3 N2 O4 S

MW 466.47

(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

CAS 1632006-28-0 for S configuration

1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(+/-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, CAS 880780-76-7

(+)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-82-4

(-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-83-5

WO 2014168103

WO 2008126831

WO2008 / 126831 (US Publication US2010-0093826)http://www.google.co.in/patents/EP2133330A1?cl=en

WO 2015012205

WO 2006012642..compound A;..http://www.google.com/patents/WO2006012642A2?cl=en

WO2006 / 012642 (US Publication US2008-0234270)

WO 2015030010…http://www.google.com/patents/WO2015030010A1?cl=en

 

 

JAPAN PHASE 2……….Phase 2 Study to Evaluate Efficacy and Safety of CS-3150 in Patients with Essential Hypertension

http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-121921

Phase II Diabetic nephropathies; Hypertension

  • 01 Jan 2015 Daiichi Sankyo initiates a phase IIb trial for Diabetic nephropathies in Japan (NCT02345057)
  • 01 Jan 2015 Daiichi Sankyo initiates a phase IIb trial for Hypertension in Japan (NCT02345044)
  • 01 May 2013 Phase-II clinical trials in Diabetic nephropathies in Japan (PO)
  •  Currently, angiotensin II receptor antagonists and calcium antagonists are widely used as a medicament for the treatment or prevention of such hypertension or heart disease.
     Mineralocorticoid receptor (MR) (aldosterone receptor) has been known to play an important role in the control of body electrolyte balance and blood pressure, spironolactone having a steroid structure, MR antagonists such as eplerenone, are known to be useful in the treatment of hypertension-heart failure.
     Renin – angiotensin II receptor antagonists are inhibitors of angiotensin system is particularly effective in renin-dependent hypertension, and show a protective effect against cardiovascular and renal failure. Also, the calcium antagonists, and by the function of the calcium channel antagonizes (inhibits), since it has a natriuretic action in addition to the vasodilating action, is effective for hypertension fluid retention properties (renin-independent) .
     Therefore, the MR antagonist, when combined angiotensin II receptor antagonists or calcium antagonists, it is possible to suppress the genesis of multiple hypertension simultaneously, therapeutic or prophylactic effect of the stable and sufficient hypertension irrespective of the etiology is expected to exhibit.
     Also, diuretics are widely used as a medicament for the treatment or prevention of such hypertension or heart disease. Diuretic agent is effective in the treatment of hypertension from its diuretic effect. Therefore, if used in combination MR antagonists and diuretics, the diuretic effect of diuretics, it is possible to suppress the genesis of multiple blood pressure at the same time, shows a therapeutic or prophylactic effect of the stable and sufficient hypertension irrespective of the etiology it is expected.
     1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (hereinafter, compound ( I)) is, it is disclosed in Patent Documents 1 and 2, hypertension, for the treatment of such diabetic nephropathy are known to be useful.

CS-3150 (XL550) is a small-molecule antagonist of the mineralocorticoid receptor (MR), a nuclear hormone receptor implicated in a variety of cardiovascular and metabolic diseases. MR antagonists can be used to treat hypertension and congestive heart failure due to their vascular protective effects. Recent studies have also shown beneficial effects of adding MR antagonists to the treatment regimen for Type II diabetic patients with nephropathy. CS-3150 is a non-steroidal, selective MR antagonist that has the potential for the treatment of hypertension, congestive heart failure, or end organ protection due to vascular damage.

Useful as a mineralocorticoid receptor (MR) antagonist, for treating hypertension, cardiac failure and diabetic nephropathy. It is likely to be CS-3150, a non-steroidal MR antagonist, being developed by Daiichi Sankyo (formerly Sankyo), under license from Exelixis, for treating hypertension and diabetic nephropathy (phase 2 clinical, as of March 2015). In January 2015, a phase II trial for type 2 diabetes mellitus and microalbuminuria was planned to be initiated later that month (NCT02345057).

Exelixis discovered CS-3150 and out-licensed the compound to Daiichi-Sankyo. Two phase 2a clinical trials, one in hypertensive patients and the other in type 2 diabetes with albuminuria, are currently being conducted in Japan by Daiichi-Sankyo.

 

Mineralocorticoid receptor (MR) (aldosterone receptor) has been known to play an important role in the control of body electrolyte balance and blood pressure, spironolactone having a steroid structure, MR antagonists such as eplerenone, are known to be useful in the treatment of hypertension-heart failure.

CS-3150 (XL550) is a small-molecule antagonist of the mineralocorticoid receptor (MR), a nuclear hormone receptor implicated in a variety of cardiovascular and metabolic diseases. MR antagonists can be used to treat hypertension and congestive heart failure due to their vascular protective effects. Recent studies have also shown beneficial effects of adding MR antagonists to the treatment regimen for Type II diabetic patients with nephropathy. CS-3150 is a non-steroidal, selective MR antagonist that has the potential for the treatment of hypertension, congestive heart failure, or end organ protection due to vascular damage.

Exelixis discovered CS-3150 and out-licensed the compound to Daiichi-Sankyo. Two phase 2a clinical trials, one in hypertensive patients and the other in type 2 diabetes with albuminuria, are currently being conducted in Japan by Daiichi-Sankyo.

Daiichi Sankyo (formerly Sankyo), under license from Exelixis, is developing CS-3150 (XL-550), a non-steroidal mineralocorticoid receptor (MR) antagonist, for the potential oral treatment of hypertension and diabetic nephropathy, microalbuminuria ,  By October 2012, phase II development had begun ; in May 2014, the drug was listed as being in phase IIb development . In January 2015, a phase II trial for type 2 diabetes mellitus and microalbuminuria was planned to be initiated later that month. At that time, the trial was expected to complete in March 2017 .

Exelixis, following its acquisition of X-Ceptor Therapeutics in October 2004 , was investigating the agent for the potential treatment of metabolic disorders and cardiovascular diseases, such as hypertension and congestive heart failure . In September 2004, Exelixis expected to file an IND in 2006. However, it appears that the company had fully outlicensed the agent to Sankyo since March 2006 .

Description Small molecule antagonist of the mineralocorticoid receptor (MR)
Molecular Target Mineralocorticoid receptor
Mechanism of Action Mineralocorticoid receptor antagonist
Therapeutic Modality Small molecule

In January 2015, a multi-center, placebo-controlled, randomized, 5-parallel group, double-blind, phase II trial (JapicCTI-152774;  NCT02345057; CS3150-B-J204) was planned to be initiated later that month in Japan, in patients with type 2 diabetes mellitus and microalbuminuria, to assess the efficacy and safety of different doses of CS-3150 compared to placebo. At that time, the trial was expected to complete in March 2017; later that month, the trial was initiated in the Japan

By October 2012, phase II development had begun in patients with essential hypertension

By January 2011, phase I trials had commenced in Japan

Several patents WO-2014168103,

WO-2015012205 and WO-2015030010

XL-550, claimed in WO-2006012642,

………………………………………………………………….

http://www.google.co.in/patents/EP2133330A1?cl=en

(Example 3)(+/-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

  • After methyl 4-methyl-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxylate was obtained by the method described in Example 16 of WO 2006/012642 , the following reaction was performed using this compound as a raw material.
  • Methyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.4 g, 4.9 mmol) was dissolved in methanol (12 mL), and a 5 M aqueous sodium hydroxide solution (10 mL) was added thereto, and the resulting mixture was heated under reflux for 3 hours. After the mixture was cooled to room temperature, formic acid (5 mL) was added thereto to stop the reaction. After the mixture was concentrated under reduced pressure, water (10 mL) was added thereto to suspend the resulting residue. The precipitated solid was collected by filtration and washed 3 times with water. The obtained solid was dried under reduced pressure, whereby 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (1.1 g, 83%) was obtained as a solid. The thus obtained solid was suspended in dichloromethane (10 mL), oxalyl chloride (0.86 mL, 10 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 hours. After the mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), and 4-(methylsulfonyl)aniline hydrochloride (1.0 g, 4.9 mmol) and N,N-diisopropylethylamine (2.8 mL, 16 mmol) were sequentially added to the solution, and the resulting mixture was heated under reflux for 18 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and acetonitrile (10 mL) and 3 M hydrochloric acid (100 mL) were added to the residue. A precipitated solid was triturated, collected by filtration and washed with water, and then, dried under reduced pressure, whereby 4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (1.4 g, 89%) was obtained as a solid.
    1H-NMR (400 MHz, DMSO-d6) δ11.34 (1H, brs,), 9.89 (1H, s), 7.97 (2H, d, J = 6.6 Hz), 7.87-7.81 (3H, m), 7.73 (1H, t, J = 7.4 Hz), 7.65-7.61 (2H, m), 7.44 (1H, d, J = 7.8 Hz), 3.15 (3H, s), 2.01 (3H, s).
  • Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl -N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60°C for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained.
    1H-NMR (400 MHz, CDCl3) δ: 7.89-7.79 (m, 6H), 7.66-7.58 (m, 2H), 7.49 (s, 1H), 7.36 (d, 1H, J = 7.4Hz), 3.81-3.63 (m, 4H), 3.05 (s, 3H), 2.08 (s, 3H).
    HR-MS (ESI) calcd for C22H22F3N2O4S [M+H]+, required m/z: 467.1252, found: 467.1246.
    Anal. calcd for C22H21F3N2O4S: C, 56.65; H, 4.54; N, 6.01; F, 12.22; S, 6.87. found: C, 56.39; H, 4.58; N, 5.99; F, 12.72; S, 6.92.

(Example 4)

Optical Resolution of Compound of Example 3

  • Resolution was performed 4 times in the same manner as in Example 2, whereby 74 mg of Isomer C was obtained as a solid from a fraction containing Isomer C (tR = 10 min), and 71 mg of Isomer D was obtained as a solid from a fraction containing Isomer D (tR = 11 min).
  • Isomer C: (+)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
    [α]D 21: +7.1° (c = 1.0, EtOH) .
    1H-NMR (400 MHz, CDCl3) δ: 7.91 (s, 1H), 7.87-7.79 (m, 5H), 7.67-7.58 (m, 2H), 7.51 (s, 1H), 7.35 (d, 1H, J = 7.0 Hz), 3.78-3.65 (m, 4H), 3.05 (s, 3H), 2.07 (s, 3H).
    HR-MS (ESI) calcd for C22H22F3N2O4S [M+H]+, required m/z: 467.1252, found: 467.1260.
    Retention time: 4.0 min.
  • Isomer D: (-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
    [α]D 21: -7.2° (c = 1.1, EtOH) .
    1H-NMR (400 MHz, CDCl3) δ: 7.88-7.79 (m, 6H), 7.67-7.58 (m, 2H), 7.50 (s, 1H), 7.36 (d, 1H, J = 7.5 Hz), 3.79-3.65 (m, 4H), 3.05 (s, 3H), 2.08 (s, 3H).
    HR-MS (ESI) calcd for C22H22F3N2O4S [M+H]+, required m/z: 467.1252, found: 467.1257.
    Retention time: 4.5 min.

……………………………………………….

WO 2014168103

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014168103

 

 Step B: pyrrole derivative compounds (A ‘)
[Of 16]
(Example 1) 2-bromo-1- [2- (trifluoromethyl) phenyl] propan-1-one
[Of 19]
 1- [2- (trifluoromethyl) phenyl] propan-1-one 75 g (370 mmol) in t- butyl methyl ether (750 mL), and I was added bromine 1.18 g (7.4 mmol). After confirming that the stirred bromine color about 30 minutes at 15 ~ 30 ℃ disappears, cooled to 0 ~ 5 ℃, was stirred with bromine 59.13 g (370 mmol) while keeping the 0 ~ 10 ℃. After stirring for about 2.5 hours, was added while maintaining 10 w / v% aqueous potassium carbonate solution (300 mL) to 0 ~ 25 ℃, was further added sodium sulfite (7.5 g), was heated to 20 ~ 30 ℃. The solution was separated, washed in the resulting organic layer was added water (225 mL), to give t- butyl methyl ether solution of the title compound and the organic layer was concentrated under reduced pressure (225 mL).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.91 (3H, D, J = 4.0 Hz), 4.97 (1H, Q, J = 6.7 Hz), 7.60 ~ 7.74 (4H, M).
(Example 2) 2-cyano-3-methyl-4-oxo-4- [2- (trifluoromethyl) phenyl] butanoate
[Of 20]
 2-bromo-1- [2- (trifluoromethyl) phenyl] propan-1 / t- butyl methyl ether solution (220 mL) in dimethylacetamide (367 mL), ethyl cyanoacetate obtained in Example 1 53.39 g (472 mmol), potassium carbonate 60.26 g (436 mmol) were sequentially added, and the mixture was stirred and heated to 45 ~ 55 ℃. After stirring for about 2 hours, 20 is cooled to ~ 30 ℃, water (734 mL) and then extracted by addition of toluene (367 mL), washed by adding water (513 mL) was carried out in the organic layer (2 times implementation). The resulting organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (220 mL).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.33 ~ 1.38 (6H, M), 3.80 ~ 3.93 (2H, M), 4.28 ~ 4.33 (2H, M), 7.58 ~ 7.79 (4H, M).
(Example 3) 2-chloro-4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl
[Of 21]
 The 20 ~ 30 ℃ 2-cyano-3-methyl-4-oxo-4 was obtained [2- (trifluoromethyl) phenyl] butanoate in toluene (217 mL) by the method of Example 2 ethyl acetate (362 mL) Te, after the addition of thionyl chloride 42.59 g (358 mmol), cooled to -10 ~ 5 ℃, was blown hydrochloric acid gas 52.21 g (1432 mmol), further concentrated sulfuric acid 17.83 g (179 mmol) was added, and the mixture was stirred with hot 15 ~ 30 ℃. After stirring for about 20 hours, added ethyl acetate (1086 mL), warmed to 30 ~ 40 ℃, after the addition of water (362 mL), and the layers were separated. after it separated organic layer water (362 mL) was added for liquid separation, and further 5w / v% was added for liquid separation aqueous sodium hydrogen carbonate solution (362 mL).
 Subsequently the organic layer was concentrated under reduced pressure, the mixture was concentrated under reduced pressure further added toluene (579 mL), was added toluene (72 mL), and cooled to 0 ~ 5 ℃. After stirring for about 2 hours, the precipitated crystals were filtered, and washed the crystals with toluene which was cooled to 0 ~ 5 ℃ (217 mL). The resulting wet goods crystals were dried under reduced pressure at 40 ℃, the title compound was obtained (97.55 g, 82.1% yield).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.38 (3H, t, J = 7.1 Hz), 2.11 (3H, s), 4.32 (2H, Q, J = 7.1 Hz), 7.39 (1H, D, J = 7.3 Hz), 7.50 ~ 7.62 (2H, m), 7.77 (1H, d, J = 8.0 Hz), 8.31 (1H, br).
(Example 4) 4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl
[Of 22]
 Example obtained by the production method of the three 2-chloro-4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylate 97.32 g (293 mmol) in ethanol (662 mL), tetrahydrofuran (117 mL), water (49 mL), sodium formate 25.91 g (381 mmol) and 5% palladium – carbon catalyst (water content 52.1%, 10.16 g) was added at room temperature, heated to 55 ~ 65 ℃ the mixture was stirred. After stirring for about 1 hour, cooled to 40 ℃ less, tetrahydrofuran (97 mL) and filter aid (KC- flock, Nippon Paper Industries) 4.87 g was added, the catalyst was filtered and the residue using ethanol (389 mL) was washed. The combined ethanol solution was used for washing the filtrate after concentration under reduced pressure, and with the addition of water (778 mL) was stirred for 0.5 hours at 20 ~ 30 ℃. The precipitated crystals were filtered, and washed the crystals with ethanol / water = 7/8 solution was mixed with (292 mL). The resulting wet goods crystals were dried under reduced pressure at 40 ℃, the title compound was obtained (86.23 g, 98.9% yield).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.35 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 4.29 (2H, M), 7.40 ~ 7.61 (4H, M), 7.77 (1H, d, J = 7.9 Hz), 8.39 (1H, br).
(Example 5) (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl
[Of 23]
 N to the fourth embodiment of the manufacturing method by the resulting 4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylate 65.15 g (219 mmol), N- dimethylacetamide ( 261 mL), ethylene carbonate 28.95 g (328.7 mmol), 4- dimethylaminopyridine 2.68 g (21.9 mmol) were sequentially added at room temperature, and heated to 105 ~ 120 ℃, and the mixture was stirred. After stirring for about 10 hours, toluene was cooled to 20 ~ 30 ℃ (1303 mL), and the organic layer was extracted by adding water (326 mL). Subsequently, was washed by adding water (326 mL) to the organic layer (three times). The resulting organic layer was concentrated under reduced pressure, ethanol (652 mL) was added, and was further concentrated under reduced pressure, ethanol (130 mL) was added to obtain an ethanol solution of the title compound (326 mL).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.35 (3H, t, J = 7.1 Hz), 1.84 (1H, Broad singlet), 2.00 (3H, s), 3.63 ~ 3.77 (4H, M), 4.27 (2H , m), 7.35 ~ 7.79 (5H, m).
(Example 6) (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid
[Of 24]
 Obtained by the method of Example 5 (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl / ethanol (321 mL) solution in water (128.6 mL), was added at room temperature sodium hydroxide 21.4 g (519 mmol), and stirred with heating to 65 ~ 78 ℃. After stirring for about 6 hours, cooled to 20 ~ 30 ℃, after the addition of water (193 mL), and was adjusted to pH 5.5 ~ 6.5, while maintaining the 20 ~ 30 ℃ using 6 N hydrochloric acid. was added as seed crystals to the pH adjustment by a liquid (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid 6.4 mg , even I was added to water (193mL). Then cooled to 0 ~ 5 ℃, again, adjusted to pH 3 ~ 4 with concentrated hydrochloric acid and stirred for about 1 hour. Then, filtered crystals are precipitated, and washed the crystals with 20% ethanol water is cooled to 0 ~ 5 ℃ (93 mL). The resulting wet product crystals were dried under reduced pressure at 40 ℃, to give the title compound (64.32 g, 95.0% yield). 1 H NMR (400 MHz, DMSO-D 6 ) delta: 1.87 (3H, s), 3.38 ~ 3.68 (4H, M), 7.43 ~ 7.89 (5H, M).
(Example 7)
(S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid quinine salt 
(7-1) (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid quinine salt 
obtained by the method of Example 6 the (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid 50.00 g (160 mmol), N, N- dimethylacetamide (25 mL), ethyl acetate (85 mL) was added and dissolved at room temperature (solution 1).
 Quinine 31.05 g (96 mmol) in N, N- dimethylacetamide (25 mL), ethyl acetate (350 mL), was heated in water (15 mL) 65 ~ 70 ℃ was added, was added dropwise a solution 1. After about 1 hour stirring the mixture at 65 ~ 70 ℃, and slowly cooled to 0 ~ 5 ℃ (cooling rate standard: about 0.3 ℃ / min), and stirred at that temperature for about 0.5 hours. The crystals were filtered, 5 ℃ using ethyl acetate (100 mL) which was cooled to below are washed crystals, the resulting wet product crystals was obtained and dried under reduced pressure to give the title compound 43.66 g at 40 ℃ (Yield 42.9%). Furthermore, the diastereomeric excess of the obtained salt was 98.3% de. 1 H NMR (400 MHz, DMSO-D 6 ) delta: 1.30 ~ 2.20 (10H, M), 2.41 ~ 2.49 (2H, M), 2.85 ~ 3.49 (6H, M), 3.65 ~ 3.66 (1H, M), 3.88 (3H, s), 4.82 (1H, broad singlet), 4.92 ~ 5.00 (2H, m), 5.23 ~ 5.25 (1H, m), 5.60 (1H, br), 5.80 ~ 6.00 (1H, m), 7.36 ~ 7.92 (9H, M), 8.67 (1H, D, J = 4.6 Hz) (7-2) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3 diastereomeric excess of the carboxylic acid quinine salt HPLC measurements (% de)  that the title compound of about 10 mg was collected, and the 10 mL was diluted with 50v / v% aqueous acetonitrile me was used as a sample solution.

 Column: DAICEL CHIRALPAK IC-3 (4.6 mmI.D. × 250 mm, 3 μm) 
mobile phase A: 0.02mol / L phosphorus vinegar buffer solution (pH 3) 
mobile phase B: acetonitrile 
solution sending of mobile phase: mobile phase A and I indicates the mixing ratio of mobile phase B in Table 1 below.
[Table 1]
  Detection: UV 237 nm 
flow rate: about 0.8 mL / min 
column temperature: 30 ℃ constant temperature in the vicinity of 
measuring time: about 20 min 
Injection volume: 5 μL 
diastereomeric excess (% de), the title compound (retention time about 12 min), was calculated by the following equation using a peak area ratio of R-isomer (retention time of about 13 min). 
% De = {[(the title compound (S body) peak area ratio) – (R body peak area ratio)] ÷ [(the title compound (S body) peak area ratio) + (R body peak area ratio)]} × 100
(Example 8)
(S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxamide (Compound (A)) 
(8-1) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole -3 – carboxylic acid 
obtained by the method of Example 7 (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid (8α, 9R) -6′- methoxycinnamate Conan-9-ol 40.00 g (63 mmol) in ethyl acetate (400 mL), was added 2N aqueous hydrochloric acid (100 mL) was stirred at room temperature and separated . The resulting organic layer was concentrated under reduced pressure (120 mL), and added ethyl acetate (200 mL), and further concentrated under reduced pressure to obtain a solution containing the title compound (120 mL).
(8-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl 
ethyl acetate (240 mL), was mixed tetrahydrofuran (80 mL) and oxalyl chloride 20.72 g (163 mmol), and cooled to 10 ~ 15 ℃ was. Then the resulting solution was added while keeping the 10 ~ 15 ℃ Example (8-1) and stirred for about 1 hour by heating to 15 ~ 20 ℃. After stirring, acetonitrile (120 mL) and pyridine 2.46 g (31 mmol) was added and the reaction mixture was concentrated under reduced pressure (120 mL), acetonitrile (200 mL) was added and further concentrated under reduced pressure (120 mL).
 After completion concentration under reduced pressure, acetonitrile (200 mL) was added and cooled to 10 ~ 15 ℃ (reaction 1).
 Acetonitrile (240mL), pyridine 12.39 g (157 mmol), 4- were successively added (methylsulfonyl) aniline 26.85 g (157 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.
 The resulting reaction solution in acetonitrile (40 mL), 2 N hydrochloric acid water (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. Again, 2N aqueous hydrochloric acid to the organic layer (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. After filtering the resulting organic layer was concentrated under reduced pressure (400 mL). Water (360 mL) was added to the concentrated liquid, after about 1 hour stirring, the crystals were filtered, washed with 50v / v% aqueous acetonitrile (120 mL), wet product of the title compound (undried product, 62.02 g) and obtained. 1 H NMR (500 MHz, DMSO-D 6 ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H) 
(8-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A))  ( the resulting wet product crystals 8-2), t- butyl methyl ether (200 mL), acetonitrile (40 mL), 48w / w potassium hydroxide aqueous solution (16 g) and water (200 mL) was added, I was stirred for about 2 hours at 25 ~ 35 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (120 mL), ethanol (240 mL) was added and further concentrated under reduced pressure (120 mL). After completion concentration under reduced pressure, ethanol (36 mL), and heated in water (12 mL) was added 35 ~ 45 ℃, while maintaining the 35 ~ 45 ℃ was added dropwise water (280 mL), and was crystallized crystals. After cooling the crystal exudates to room temperature, I was filtered crystal. Then washed with crystals 30v / v% aqueous ethanol solution (80 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystalline (26.26 g, 89.7% yield). Moreover, the enantiomers of the resulting crystals was 0.3%. 
1 H NMR (400 MHz, CDCl 3 ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, M), 7.77 ~ 7.90 (6H, M). 
(8-4) (S)-1-(2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole -3- HPLC method for measuring the amount enantiomer carboxamide (%)  and collected the title compound of about 10 mg is, what was the 10 mL was diluted with 50v / v% aqueous acetonitrile to obtain a sample solution.
see
(Example 12) (S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxamide (Compound (A)) Preparation of 2 
(12-1) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H – pyrrole-3-carboxylic acid 
obtained by the method of Example 7 (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxylic acid (8α, 9R) -6′- methoxycinnamate Conan-9-ol 10.00 g (16 mmol) in t- butyl methyl ether (90 mL), water (10 mL) 36w / w% aqueous hydrochloric acid ( 5 mL) was added and stirring at room temperature and separated. The resulting organic layer was concentrated under reduced pressure (30 mL), was added ethyl acetate (50 mL), and further concentrated under reduced pressure to obtain a solution containing the title compound (30 mL). 
(12-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl 
ethyl acetate (50 mL), was mixed with tetrahydrofuran (20 mL) and oxalyl chloride 5.18 g (41 mmol), and cooled to 0 ~ 5 ℃ was.Then the resulting solution was added in Examples while maintaining the 0 ~ 5 ℃ (12-1), and the mixture was stirred for 6 hours at 0 ~ 10 ℃. After stirring, acetonitrile (30 mL) and pyridine 0.62 g (8 mmol) was added and the reaction mixture was concentrated under reduced pressure (30 mL), acetonitrile (50 mL) was added, and further concentrated under reduced pressure (30 mL).
 After concentration under reduced pressure end, is added acetonitrile (10 mL) and oxalyl chloride 0.10 g (1 mmol), and cooled to 0 ~ 5 ℃ (reaction 1).
 Acetonitrile (30mL), pyridine 3.15 g (40 mmol), 4- were successively added (methylsulfonyl) aniline 6.71 g (39 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.
 Insolubles from the resulting reaction solution was filtered, washed with acetonitrile (10 mL), and stirred for about 2 hours the addition of water (15 mL), followed by dropwise addition of water (75 mL) over about 1 hour . After about 1 hour stirring the suspension was filtered crystals were washed with 50v / v% aqueous acetonitrile (20 mL), wet product of the title compound (undried product, 15.78 g) to give a. 1 H NMR (500 MHz, DMSO-D 6 ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H) 
(12-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A))  ( the resulting wet product crystals 12-2), t- butyl methyl ether (50 mL), acetonitrile (10 mL), 48w / w potassium hydroxide aqueous solution (4 g) and water (50 mL) was added, 15 I was about 2 hours of stirring at ~ 25 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (30 mL), was added ethanol (60 mL), was further concentrated under reduced pressure (30 mL). After completion concentration under reduced pressure, ethanol (14 mL), after addition of water (20 mL), was added a seed crystal, and was crystallized crystals. After dropwise over about 1 hour water (50 mL), and about 1 hour stirring, and crystals were filtered off. Then washed with crystals 30v / v% aqueous ethanol solution (10 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystal (6.36 g, 87.0% yield). Moreover, the enantiomers of the resulting crystals was 0.05%. Enantiomers amount, I was measured by the method of (Example 8-4). 1 H NMR (400 MHz, CDCl 3 ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, m), 7.77 ~ 7.90 (6H, m).

………………………………………………

 

Patent literature

Patent Document 1: International Publication WO2006 / 012642 (US Publication US2008-0234270) 
Patent Document 2: International Publication WO2008 / 056907 (US Publication US2010-0093826) 
Patent Document 3: Pat. No. 2,082,519 JP (US Patent No. 5,616,599 JP) 
Patent Document 4: Pat. No. 1,401,088 JP (US Pat. No. 4,572,909) 
Patent Document 5: US Pat. No. 3,025,292

Angiotensin II receptor 桔抗 agent

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015012205&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Angiotensin II receptor 桔抗 agent used as the component (A), olmesartan medoxomil, olmesartan cilexetil, losartan, candesartan cilexetil, valsartan, biphenyl tetrazole compounds such as irbesartan, biphenyl carboxylic acid compounds such as telmisartan, eprosartan, agile Sultan, and the like, preferably, a biphenyl tetrazole compound, more preferably, olmesartan medoxomil, is losartan, candesartan cilexetil, valsartan or irbesartan, particularly preferred are olmesartan medoxomil, losartan or candesartan cilexetil, Most preferably, it is olmesartan medoxomil.
 Olmesartan medoxomil, JP-A-5-78328, US Patent No. 5,616,599 
is described in Japanese or the like, its chemical name is (5-methyl-2-oxo-1,3-dioxolen-4-yl ) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1 – in [2 ‘(1H- tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate, Yes, olmesartan medoxomil of the present application includes its pharmacologically acceptable salt.
Olmesartan.pngOLMESARTAN
 Losartan (DUP-753) is, JP 63-23868, is described in US Patent No. 5,138,069 JP like, and its chemical name is 2-butyl-4-chloro-1- [2 ‘ – The (1H- tetrazol-5-yl) biphenyl-4-ylmethyl] -1H- is imidazol-5-methanol, application of losartan includes its pharmacologically acceptable salt (losartan potassium salt, etc.).
Skeletal formula
 LOSARTAN
 Candesartan cilexetil, JP-A-4-364171, EP-459136 JP, is described in US Patent No. 5,354,766 JP like, and its chemical name is 1- (cyclohexyloxycarbonyloxy) ethyl-2 ethoxy-1- [2 ‘one (1H- tetrazol-5-yl) -4-Bife~eniru ylmethyl] -1H- benzimidazole-7-carboxylate is a salt application of candesartan cilexetil, which is a pharmacologically acceptable encompasses.
 Valsartan (CGP-48933), the JP-A-4-159718, are described in EP-433983 JP-like, and its chemical name, (S) -N- valeryl -N- [2 ‘- (1H- tetrazol – It is a 5-yl) biphenyl-4-ylmethyl) valine, valsartan of the present application includes its pharmacologically acceptable ester or a pharmacologically acceptable salt thereof.
 Irbesartan (SR-47436), the Japanese Patent Publication No. Hei 4-506222, is described in JP WO91-14679 publication, etc., its chemical name, 2-N–butyl-4-spiro cyclopentane-1- [2′ The (tetrazol-5-yl) biphenyl-4-ylmethyl] -2-imidazoline-5-one, irbesartan of the present application includes its pharmacologically acceptable salts.
 Eprosartan (SKB-108566) is described in US Patent No. 5,185,351 JP etc., the chemical name, 3- [1- (4-carboxyphenyl-methyl) -2-n- butyl – imidazol-5-yl] The 2-thienyl – methyl-2-propenoic acid, present in eprosartan, the carboxylic acid derivatives, pharmacologically acceptable ester or a pharmacologically acceptable salt of a carboxylic acid derivative (eprosartan mesylate, encompasses etc.).
 Telmisartan (BIBR-277) is described in US Patent No. 5,591,762 JP like, and its chemical name is 4 ‘- [[4 Mechiru 6- (1-methyl-2-benzimidazolyl) -2 – is a propyl-1-benzimidazolyl] methyl] -2-biphenylcarboxylic acid, telmisartan of the present application includes its carboxylic acid derivative, a pharmacologically acceptable ester or a pharmacologically acceptable salt thereof of carboxylic acid derivatives .
 Agile Sultan, is described in Patent Publication No. 05-271228 flat JP, US Patent No. 5,243,054 JP like, and its chemical name is 2-ethoxy-1 {[2 ‘- (5-oxo-4,5-dihydro 1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl} -1H- benzo [d] imidazole-7-carboxylic acid (2-Ethoxy-1 {[2 ‘- (5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] is a methyl} -1H-benzo [d] imidazole-7-carboxylic acid).

Foretinib (Exelixis, GlaxoSmithKline, XL-880)


Foretinib.svg

Foretinib (Exelixis, GlaxoSmithKline) (XL-880)

CAS No.:849217-64-7, 937176-80-2
Formula:C34H34F2N4O6
M.Wt:632.24

GSK1363089, XL880

1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Foretinib is an experimental drug candidate for the treatment of cancer.[1] It was discovered by Exelixis and is under development by GlaxoSmithKline.[2] It is currently in Phase II clinical trials.[3] As of December 2012 no phase III trials are registered.[3]

Foretinib is an inhibitor of the kinase enzymes c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2).[4]

Foretinib is an orally bioavailable small molecule with potential antineoplastic activity. MET/VEGFR2 inhibitor GSK1363089 binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers. VEGFR2 is found on endothelial and hematopoietic cells and mediates the development of the vasculature and hematopoietic cells through VEGF signaling.

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

 

Foretinib.png

 

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Patent Submitted Granted
Preparation of a Quinolinyloxydiphenylcyclopropanedicarboxamide [US2010081805] 2010-04-01
C-Met Modulators and Method of Use [US2012022065] 2012-01-26
C-Met Modulators and Method of Use [US2011077233] 2011-03-31
c-Met modulators and methods of use [US7579473] 2009-07-02 2009-08-25
c-MET MODULATORS AND METHODS OF USE [US8067436] 2009-04-23 2011-11-29
C-MET MODULATORS AND METHOD OF USE [US8178532] 2007-09-27 2012-05-15
Method of Treating Cancer using a cMet and AXL Inhibitor and an ErbB Inhibitor [US2009274693] 2009-11-05
c-MET MODULATORS AND METHOD OF USE [US2007244116] 2007-10-18
c-Met modulators and methods of use [US2007054928] 2007-03-08

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http://www.google.com/patents/WO2014067417A1?cl=en

Foretinib (GSK1363089, XL880) quinoline compounds are, an oral c-Met and VEGFR / KDR kinase inhibitor of c-Met kinase and KDR kinase IC 5Q Wo port respectively 0.4 0.8 nM, the current has entered Phase II clinical study (WO2010036831Al). Clinical studies have shown that, Foretinib variety of people, such as human lung cancer cells, human gastric cancer cells and other tumor cell lines showed a significant inhibitory effect, an IC 50 value of 0.004 g / mL.

Figure imgf000004_0001

 

 

 

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http://www.google.com/patents/WO2014145693A1?cl=en

Accordingly, small-molecule compounds that specifically inhibit, regulate, and/or modulate the signal transduction of kinases, particularly including Ret, c-Met, and VEGFR2 described above, are particularly desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. One such small-molecule is XL880, known variously as N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide and alternatively as foretimb. Foretimb has the chemical structure:

[0007] WO 2005/030140 describes the synthesis of foretinib (Example 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate, and/or modulate the signal transduction of kinases (Assays, Table 4, entry 312). Example 44 begins at paragraph [0349] in WO 2005/030140.

Figure imgf000034_0001

 

 

Figure imgf000032_0001

……………………………………

 

WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases

Figure imgf000020_0003
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
 http://www.google.com/patents/WO2012044577A1?cl=en

In another embodiment, the compound of Formula I is Compound 1 :
Figure imgf000005_0001
Compound 1
or a pharmaceutically acceptable salt thereof. Compound I is known as N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide. WO 2005/030140 describes the synthesis of N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in WO 2005/030140.
[0013] In another embodiment, the compound of Formula I is Compound 2:
Figure imgf000005_0002
Compound 2
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)
or a pharmaceutically acceptable salt thereof. Compound 2 is known as is N-[3-fluoro-4- ({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4- fluorophenyl)cyc!opropane- 1,1 -dicarboxamide. WO 2005-030140 describes the synthesis of Compound (I) (Examples 25, 30, 36, 42, 43 and 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 312). Compound 2 has been measured to have a c-Met IC50 value of about 0.6 nanomolar (nM). PC1YUS09/064341, which claims priority to U.S. provisional application 61/199,088, filed November 13, 2008, describes a scaled-up synthesis of Compound I.

Scheme 2

Preparation of 4-Chloro-6,7-dimethoxy-quinoIine

[00173] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).

Preparation of -(6, 7 -Dimethoxy-quinoline- -yloxy)-phenylamine

[00174] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 21 1.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg). Alternative Preparation of 4-(6, 7-Dimethoxy-quinoIine-4-yloxy)-phenylamine

[00175] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenoI (30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a reactor, followed by N(N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated to 105-1 15 °C for approximately 9 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-25 °C and water (315 kg) was added over a two hour period while maintaining the temperature between 20-30 °C. The reaction mixture was then agitated for an additional hour at 20-25 °C. The crude product was collected by filtration and washed with a mixture of 88kg water and 82.1 kg DMA, followed by 175 kg water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1 percent w/w.

[00176] In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used and the reaction temperature was increased from 1 10-120 °C. In addition , the cool down temperature was increased to 35-40 °C and the starting temperature of the water addition was adjusted to 35-40 °C, with an allowed exotherm to 45 °C.

Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

[00177] Triethylamine (19.5 kg) was added to a cooled (approximately 5 °C) solution of cyclopropane-l,l-dicarboxylic acid (24.7 kg) in THF (89.6 kg) at a rate such that the batch temperature did not exceed 5 °C. The solution was stirred for approximately 1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, the solution was stirred for approximately 4 hours keeping temperature below 10 °C. A solution of 4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 10 hours after which the reaction was deemed complete. The reaction mixture was then diluted with isopropyl acetate (218.1 kg). This solution was washed sequentially with aqueous sodium hydroxide (10.4 kg, 50 percent dissolved in 1 19 L of water) further diluted with water (415 L), then with water (100 L) and finally with aqueous sodium chloride (20.0 kg dissolved in 100 L of water). The organic solution was concentrated by vacuum distillation (100 L residual volume) below 40 °C followed by the addition of n- heptane (171.4 kg), which resulted in the precipitation of solid. The solid was recovered by filtration and washed with n-heptane ( 102.4 kg), resulting in wet, crude l-(4-fluoro- phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). The crude, l-(4-fluoro- phenylcarbamoy -cyclopropanecarboxylic acid was dissolved in methanol (139.7 kg) at approximately 25 °C followed by the addition of water (320 L) resulting in slurry which was recovered by filtration, washed sequentially with water (20 L) and n-heptane (103.1 kg) and then dried on the filter at approximately 25 °C under nitrogen to afford the title compound (25.4 kg).

Preparation of l-(4-Fluoro-phenyIcarbamoyl)-cyclopropanecarbonyl chloride

[00178] Oxalyl chloride ( 12.6 kg) was added to a solution of I -(4-fluoro- phenylcarbamoyD-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25 °C. This solution was used in the next step without further processing.

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

[00179] A reactor was charged with l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175kg THF. The reaction mixture was adjusted to 12-17 °C and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12-17 °C for 3 to 8 hours. This solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00180] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 °C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 °C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 °C and then at approximately 45 °C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD). Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoIine-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00181] A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a solution of 48.3 K2C03 in 169 kg water. The acid chloride solution of described in the

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cvclopropanecarbonyl chloride above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine while maintaining the temperature between 20-30 °C over a minimum of two hours. The reaction mixture was stirred at 20-25 °C for a minimum of three hours. The reaction temperature was then adjusted to 30-25 °C and the mixture was agitated. The agitation was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added 804 kg water. The reaction was left stirring at 15-25 °C for a minimum of 16 hours.

[00182] The product precipitated. The product was filtered and washed with a mixture of 179 kg water and 157.9 kg THF in two portions. The crude product was dried under a vacuum for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30-35 °C for approximately 30 minutes. 456 kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol denatured with methanol over two hours. The mixture was agitated at 15-25 °C fir at least 16 hours. The product was filtered and washed with a mixture of 143 kg water and 126.7 THF in two portions. The product was dried at a maximum temperature set point of 40 °C.

[00183] In an alternative procedure, the reaction temperature during acid chloride formation was adjusted to 10-15 °C. The recrystallization temperature was changed from 15-25 °C to 45-50 °C for 1 hour and then cooled to 15-25 °C over 2 hours.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide, malate salt

[00184] Cyclopropane- 1 , 1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1 133.2 kg) (approximate residual volume 71 1 L; KF < 0.5 % w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).

Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yIoxy)-phenyl]-amide (4-fluoro-phenyI)-amide, (L) malate salt

[00185] Cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor and the mixture was heated 50-55 °C for approximately 1-3 hours, and then at 55-60 °C for an addition al 4-5 hours. The mixture was clarified by filtration through a 1 μπι cartridge. The reactor temperature was adjusted to 20-25 °C and vacuum distilled with a vacuum at 150-200 mm Hg with a maximum jacket temperature of 55 °C to the volume range of 558-731 L.

[00186] The vacuum distillation was performed two more times with the charge of 380 kg and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the batch was adjusted to 18 v/w of cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide by charging 159.9 kg methyl ethyl ketone to give a total volume of 880L. An addition al vacuum distillation was carried out by adjusting 245.7 methyl ethyl ketone. The reaction mixture was left with moderate agitation at 20-25 °C for at least 24 hours. The product was filtered and washed with 415.1 kg methyl ethyl ketone in three portions. The product was dried under a vacuum with the jacket temperature set point at 45 °C.

[00187] In an alternative procedure, the order of addition was changed so that a solution of 17.7 kg L-malic acid dissolved in 129.9 kg water was added to cyclopropane- 1,1- dicarboxylic acid [4-(6,7-dimethoxy-quinoHne-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)- amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Preparation of Compound 2

[00188] Compound 2 was prepared as provided in Scheme 3 and the accompanying experimental examples. Scheme 3

Toluene

[00189] In Scheme 1, Xb is Br or CI. For the names of the intermediates described within the description of Scheme 1 below, Xb is referred to as halo, wherein this halo group for these intermediates is meant to mean either Br or CI.Preparation of l-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone

[00190] Water (70 L) was charged to the solution of l-[4-(3-halo propoxy)- 3-methoxy phenyl] ethanone (both the bromo and the chloro compound are commercially available). The solution was cooled to approximately 4 °C. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch temperature did not exceed approximately 18 °C. The resulting solution was cooled to approximately 5 °C and 70 percent nitric acid (75.8 kg) was added at a rate such that the batch temperature did not exceed approximately 10 °C. Methylene chloride, water and ice were charged to a separate reactor. The acidic reaction mixture was then added into this mixture. The methylene chloride layer was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride layers were washed with aqueous potassium bicarbonate solution and concentrated by vacuum distillation. 1- Butanol was added and the mixture was again concentrated by vacuum distillation. The resulting solution was stirred at approximately 20°C during which time the product crystallized. The solids were collected by filtration, washed with 1-butanol to afford compound the title compound, which was isolated as a solvent wet cake and used directly in the next step. ‘HNMR (400MHz, DMSO-d6): δ 7.69 (s, 1H), 7.24 (s, 1H); 4.23 (m, 2H), 3.94 (s, 3H), 3.78 (0-3.65 (t) (2H), 2.51 (s, 3H), 2.30-2.08 (m, 2H) LC/MS Calcd for [M(CI)+H]+ 288.1, found 288.0; Calcd for [M(Br)+H]+ 332.0, 334.0, found 331.9, 334.0.

Preparation of l-[5-methoxy-4-(3-morpholin-4-yl-propoxy)-2-nitro-phenyl]-ethanone

[00191] The solvent wet cake isolated in the previous step was dissolved in toluene. A solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) was added to this solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The resulting 2 phase mixture was heated to approximately 85°C for about 9 hours. The mixture was then cooled to ambient temperature. The organic layer was removed. The aqueous layer was back extracted with toluene. The combined toluene layers were washed sequentially with two portions of saturated aqueous sodium thiosulfate followed by two portions of water. The resulting solution of the title compound was used in the next step without further processing. ‘HNMR (400MHz, DMSO-d6): δ 7.64 (s, 1 H), 7.22 (s, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.57 (t, 4H), 2.52 (s, 3H), 2.44-2.30 (m, 6H), 1.90 (quin, 2H); LC/MS Calcd for [M+H]+ 339.2, found 339.2.

Preparation of l-[2-amino-5-methoxy-4-(3-morpholin-4-yl- propoxy)-phenyl]-ethanone

[00192] The solution from the previous step was concentrated under reduced pressure to approximately half of the original volume. Ethanol and 10 percent Pd C (50 percent water wet, 5.02 kg) were added; the resulting slurry was heated to approximately 48 °C and an aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. When the addition was complete and the reaction deemed complete by thin layer chromatography (TLC), water was added to dissolve the by-product salts. The mixture was filtered to remove the insoluble catalyst. The filtrate was concentrated under reduced pressure and toluene was added. The mixture was made basic (pH of about 10) by the addition of aqueous potassium carbonate. The toluene layer was separated and the aqueous layer was back extracted with toluene. The combined toluene phases were dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting solution was used in the next step without further processing. ‘HNMR (400MHZ, DMSO-d6): δ 7.1 1 (s, 1H)„ 7.01 (br s, 2H), 6.31 (s, 1H), 3.97 (t, 2H), 3.69 (s, 3H), 3.57 (t, 4H), 2.42 (s, 3H), 2.44-2.30 (m, 6H), 1.91 (quin, 2H LC/MS Calcd for [M+H]+ 309.2, found 309.1.

Preparation of 6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoiin- 4-ol, sodium salt

[00193] A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg) was added to the solution from the previous step. The mixture was warmed to approximately 44 °C for about 3 hours. The reaction mixture was cooled to approximately 25°C. Methyl t- butyl ether (MTBE) was added which caused the product to precipitate. The product was collected by filtration and the cake was washed with MTBE and dried under reduced pressure at ambient temperature. The dried product was milled through a mesh screen to afford 60.2 kg of the title compound. ‘HNMR (400MHz, DMSO-d6): δ 1 1.22 (br s, 1H), 8.61 (d, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.17 (d, 1H), 4.29 (t, 2 H), 3.99 (m, 2H), 3.96 (s, 3H), 3.84 (t, 2H), 3.50 (d, 2H), 3.30 (m, 2H), 3.1 1 (m, 2H), 2.35 (m, 2H), LC/MS Calcd for [M+H]+ 319.2, found 319.1.

Preparation of 4-chIor-6-methoxy-7-(3 morpholin-4-yl)-quinoline

[00194] Phosphorous oxychloride (26.32 kg) was added to a solution of 6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ol (5.00 kg) in acetonitrile that was heated to 50-55 °C. When the addition was complete, the mixture was heated to reflux (approximately 82 °C) and held at that temperature, with stirring for approximately 18 hours at which time it was sampled for in process HPLC analysis. The reaction was considered complete when no more than 5 percent starting material remained. The reaction mixture was then cooled to 20-25 °C and filtered to remove solids. The filtrate was then concentrated to a residue. Acetronitrile was added and the resulting solution was concentrated to a residue. Methylene chloride was added to the residue and the resulting solution was quenched with a mixture of methylene chloride and aqueous ammonium hydroxide. The resulting 2 phase mixture was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride solutions were dried over anhydrous magnesium sulfate, filtered and concentrated to a solid. The solids were dried at 30-40 °C under reduced pressure to afford the title compound (1.480 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.21 (t, 2 H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97 (quin, 2H) LC MS Calcd for [M+Hf 458.2, found 458.0.

Preparation of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morphoIin-4-yl

propoxy)quinoline

[00195] A solution of 4-chIoro-6-methoxy-7-(3 morpholin-4-yl)-quinoline (2.005 kg, 5.95 mol) and 2 fluoro-4-nitrophenol (1.169 kg, 7.44 mol) in 2,6-Iutidine was heated to 140-145 °C, with stirring, for approximately 2 hours, at which time it was sampled for in process HPLC analysis. The reaction was considered complete when less than 5 percent starting materia! remained. The reaction mixture was then cooled to approximately 75 °C and water was added. Potassium carbonate was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, washed with aqueous potassium carbonate, and dried at 55-60 °C under reduced pressure to afford the title compound (1.7 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.54 (d, 1H), 8.44 (dd, 1H), 8.18 (m, 1H), 7.60 (m, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 6.75 (d, 1H), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H]+ 337.1 , 339.1 , found 337.0, 339.0.

Preparation of 3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yIoxy]- phenylamine

[00196] A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4- yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20-25 °C for approximately 1 hour. The solids were collected by filtration, washed with water and dried at 50-60 °C under reduced pressure to afford the title compound (1.164 kg)._’H NMR (400MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for

[M+H]+ 428.2, found 428.1.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cycIopropanecarboxylic acid

[00197] Triethylamine (7.78 kg) was added to a cooled (approximately 4°C) solution of commercially available cyclopropanel.l-dicarboxylic acid (9.95 kg) in THF, at a rate such that the batch temperature did not exceed 10 °C. The solution was stirred for approximately 30 minutes and then thionyl chloride (9.14 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, a solution of 4 fluoroaniline (9.4 kg) in THF was added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate. The diluted solution was washed sequentially with aqueous sodium hydroxide, water, and aqueous sodium chloride. The organic solution was concentrated by vacuum distillation. Heptane was added to the concentrate. The resulting slurry was filtered by centrifugation and the solids were dried at approximately 35 °C under vacuum to afford the title compound (10.2 kg). Ή NMR (400 MHz, DMSO-d6): δ 13.06 (br s, 1H), 10.58 (s, 1H), 7.65-7.60 (m, 2H), 7.18-7.12 (m, 2H), 1.41 (s, 4H), LC/MS Calcd for [M+H]+ 224.1 , found 224.0.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

[00198] Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5°C) solution of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10°C. When the addition was complete, the batch was allowed to warm to ambient temperature and held with stirring for approximately 2 hours, at which time in process HPLC analysis indicated the reaction was complete. The solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarbox lic acid {3-fluoro-4-[6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluorophenyl)-amide

[00199] The solution from the previous step was added to a mixture of 3-fluoro-4-[6- methoxy-7-(3-mo holin-4-yl-propox )-quinolin-4-ylo y]-phenylamine (1 160 kg) and potassium carbonate (412.25 g) in THF and water at a rate such that the batch temperature was maintained at approximately 15-21 °C. When the addition was complete, the batch was warmed to ambient temperature and held with stirring for approximately 1 hour, at which time in process HPLC analysis indicated the reaction was complete. Aqueous potassium carbonate solution and isopropyl acetate were added to the batch. The resulting 2-phase mixture was stirred and then the phases were allowed to separate. The aqueous phase was back extracted with isopropyl acetate. The combined isopropyl acetate layers were washed with water followed by aqueous sodium chloride and then slurried with a mixture of magnesium sulfate and activated carbon. The slurry was filtered over Celite® and the filtrate was concentrated to an oil at approximately 30°C under vacuum to afford the title compound which was carried into the next step without further processing. Ή NMR (400MHz, DMSO- d6): δ 10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (m, 2H), 7.16 (t, 2H), 6.41 (d, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H), 1.47 (m, 4H). LC MS Calcd for [M+H]+ 633.2, found 633.1.

Preparation of the bisphosphate salt of cyclopropane-l,l-dicarboxylic acid {3-fluoro-4- [6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide (4-fluoro- phenyl)-amide

[00200] Cyclopropane- 1,1-dicarboxy lie acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluoro phenyl)-amide from the previous step was dissolved in acetone and water. Phosphoric acid (85%, 372.48 g) was added at a rate such that the batch temperature did not exceed 30 °C. The batch was maintained at approximately 15- 30 °C with stirring for 1 hour during which time the product precipitated. The solids were collected by filtration, washed with acetone and dried at approximately 60 °C under vacuum to afford the title compound (1.533 kg). The title compound has a c-Met IC50 value of less than 50 nM. The bisphosphate salt is not shown in scheme 1. Ή NMR (400

MHz, DMSO-d6): (diphosphate) δ 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1 H), 7.93 (dd, 1H), 7.65 (m, 2H), 7.53 (d, 2H), 7.42 (m, 2H), 7.17 (m, 2H), 6.48 (d, 1H), 5.6 (br s, 6H), 4.24 (t, 2H), 3.95 (s, 3H), 3.69 (bs, 4H), 2.73 (bs, 6H), 2.09 (t, 2H), 1.48 (d, 4H).

Foretinib
Foretinib.svg
Identifiers
CAS number 849217-64-7 Yes
ChemSpider 24608641
UNII 81FH7VK1C4
Jmol-3D images Image 1
Properties
Molecular formula C34H34F2N4O6
Molar mass 632.65 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

References

  1. Hedgethorne, K., Huang, P.H. (2010). “Foretinib. c-Met and VEGFR-2 inhibitor, Oncolytic”. Drugs Fut 35 (11): 893–901. doi:10.1358/dof.2010.35.11.1529012 (inactive 2014-03-22).
  2. “XL880 (GSK1363089)”. Exelixis, Inc.
  3. “Foretinib”. clinicaltrials.gov.
  4. Qian, F; Engst, S; Yamaguchi, K; Yu, P; Won, KA; Mock, L; Lou, T; Tan, J et al. (2009). “Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases”. Cancer Research 69 (20): 8009–16. doi:10.1158/0008-5472.CAN-08-4889. PMID 19808973.

 

CN102227164A * Sep 25, 2009 Oct 26, 2011 葛兰素史密斯克莱有限责任公司 Preparation of quinolinyloxydiphenylcyclopropanedicarboxamide
CN102977014A * Nov 5, 2012 Mar 20, 2013 沈阳药科大学 New quinoline compounds and uses thereof

Non-Patent Citations
Reference
1 * BAOHUI QI ET AL.: ‘Discovery and optimization of novel 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazones as c-Met Kinase Inhibitors.‘ BIOORGANIC & MEDICINAL CHEMISTRY. vol. 21, 19 June 2013, pages 5246 – 5260
2 * BAOHUI QI ET AL.: ‘Synthesis and Biological Evaluation of 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazone Scaffolds as Selective c-Met Inhibitors.‘ ARCH. PHARM. CHEM. LIFE SCI. vol. 346, no. 8, 2013, pages 596 – 609
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