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ChemSpider 2D Image | Savolitinib | C17H15N9

Savolitinib

CAS 1313725-88-0, Molecular Formula, C17-H15-N9, Molecular Weight, 345.3685

1H-1,2,3-Triazolo(4,5-b)pyrazine, 1-((1S)-1-imidazo(1,2-a)pyridin-6-ylethyl)-6-(1-methyl-1H-pyrazol-4-yl)-

  • AZD-6094
  • AZD6094
  • HMPL-504
  • HMPL504
  • Savolitinib
  • Savolitinib [INN]
  • UNII-2A2DA6857R
  • Volitinib
  • HM 5016504
1H-1,2,3-Triazolo[4,5-b]pyrazine, 1-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-6-(1-methyl-1H-pyrazol-4-yl)-
1-[(1S)-1-(Imidazo[1,2-a]pyridin-6-yl)ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine [
2A2DA6857R
9935
Phase III, AstraZeneca
Hutchison China MediTech (Chi-Med), Cancer, kidney (renal cell carcinoma, papillary)

A c-Met kinase inhibitor with antineoplastic activity.

NCI: volitinib. An orally bioavailable inhibitor of the c-Met receptor tyrosine kinase with potential antineoplastic activity. Volitinib selectively binds to and inhibits the activation of c-Met in an ATP-competitive manner, and disrupts c-Met signal transduction pathways. This may result in cell growth inhibition in tumors that overexpress the c-Met protein. C-Met encodes the hepatocyte growth factor receptor tyrosine kinase and plays an important role in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis; this protein is overexpressed or mutated in a variety of cancers.(NCI Thesaurus)

Savolitinib is an experimental small molecule inhibitor of c-Met. It is being investigated for the treatment of cancer by AstraZeneca.[1] It is in phase II clinical trials for adenocarcinomanon-small cell lung cancer, and renal cell carcinoma.[2]

Savolitinib is a first-in-class inhibitor of c-Met in phase III clinical development at at Hutchison China MediTech (Chi-Med) and AstraZeneca for the treatment of patients with MET-driven, unresectable and locally advanced or metastatic papillary renal cell carcinoma. Phase II trials are also under way for the oral treatment of locally advanced or metastatic pulmonary sarcomatoid carcinoma. AstraZeneca is conducting phase II clinical trials for the treatment of non-small cell lung cancer. Phase I/II trials are ongoing at Samsung Medical Center for the second-line treatment of advanced gastric adenocarcinoma patients with MET amplification.

In 2011, the drug was licensed to AstraZeneca by at Hutchison China MediTech (Chi-Med) for worldwide codevelopment and marketing rights for the treatment of cancer.

Image result for EPITINIB

SYNTHESIS

PAPER

Journal of Organic Chemistry (2018),

Abstract Image

A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation and experimental design, process engineering, and solid-state chemistry is used to develop a large-scale (kilomole) Suzuki–Miyaura process. Working against clear criteria and targets, a full process investigation and optimization package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.

Process Design and Optimization in the Pharmaceutical Industry: A Suzuki–Miyaura Procedure for the Synthesis of Savolitinib

AstraZeneca Pharmaceutical Technology and Development, Macclesfield SK10 2NA, United Kingdom
J. Org. Chem., Article ASAP
DOI: 10.1021/acs.joc.8b02351
Publication Date (Web): October 23, 2018
Copyright © 2018 American Chemical Society
This article is part of the Excellence in Industrial Organic Synthesis 2019 special issue.
Savolitinib (1) were added, and the resulting suspension was cooled to 0 °C over 8 h. After stirring for a further 4 h at 0 °C, the solid was collected via filtration, washed twice with cold s-BuOH (150 kg, 186 L), and dried in vacuo at 40 °C to give Savolitinib (1) as a white crystalline solid (105 kg, 304 mol, 76%): mp 205.9–208.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.83 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.62–7.55 (m, 2H), 7.42 (dd, J = 1.7, 9.4 Hz, 1H), 6.45 (q, J= 7.1 Hz, 1H), 3.98 (s, 3H), 2.22 (d, J = 7.1 Hz, 3H); 13C {1H} NMR (DMSO-d6, 101 MHz) δ 147.9, 147.2, 143.9, 141.9, 138.5, 137.4, 133.7, 131.6, 125.4, 124.3, 123.9, 119.4, 117.1, 113.8, 55.5, 40.1, 39.1, 19.6 ppm; HRMS (ESI/Q-ToF) m/z [M + H – N2]+ calcd for C17H16N7 318.1462, found 318.1486.
NMR Summary S6 1H‐NMR
S7 13C‐NMR
S8 HSQC‐DEPT‐NMR
S9 COSY‐NMR
S10 HMBC‐13C/1H‐NMR
S11 NOESY‐NMR
S12 HRMS

PAPER

Journal of Medicinal Chemistry (2014), 57(18), 7577-7589

Abstract Image

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure–activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.

Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal–Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer

Hutchison MediPharma Limited, Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, 201203, Shanghai, China
J. Med. Chem.201457 (18), pp 7577–7589
DOI: 10.1021/jm500510f
Publication Date (Web): August 22, 2014
Copyright © 2014 American Chemical Society
*E-mail: weiguos@hmplglobal.com. Phone: (+86)-21-20673002.

Preparation of (S)-2-(4-(1-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (30) and (R)-2-(4-(1-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (31)

The racemic compound 44 (prepared by a procedure similar to that described for the synthesis of compound 2 using the corresponding 1-(pyrazolo[1,5-a]pyridin-5-yl)ethanamine instead of quinolin-6-ylmethanamine) (5 mg) was resolved by chiral HPLC to produce optically pure enantiomers 30 (1.0 mg) and 31 (1.9 mg). HPLC resolution conditions: Gilson system, Column: Dicel IA 20 × 250 mm; Mobile phase: n-Hexane/i-PrOH/DEA = 6/4/0.1; Flow rate: 8 mL/min; Detector: 254 nm). Compound 44: Purity: 95.8%, RT 9.28. MS (m/z): 376 (M + 1)+1H NMR (400 MHz, CD3OD) δ 9.07 (s, 1H), 8.49–8.47 (m, 2H), 8.26 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.01 (dd, J = 7.2, 2.0 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.47 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 3.95 (t, J = 4.2 Hz, 2H), 2.25 (d, J = 6.8 Hz, 3H). Compound 30: MS (m/z): 376 (M + 1)+1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.50 (s,1 H), 8.50 (d, J = 7.2 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.01(dd, J = 7.2, 2.0 Hz, 1H), 6.62 (d, J = 1.6 Hz, 1H), 6.48 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 3.95(t, J = 4.2 Hz, 2H), 2.26 (d, J = 6.8 Hz, 3H). Purity: 98.1%, RT 18.44, ee: 96%. Compound 31: MS (m/z): 376 (M + 1)+1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.01 (dd, J = 7.2, 2.0 Hz,1H), 6.62 (d, J = 2.0 Hz, 1H), 6.48 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 3.95 (t, J = 4.2 Hz, 2H), 2.26 (d, J = 6.8 Hz, 3H). Purity: 90.7%, RT 24.22, ee: 81%. HPLC analysis conditions: Gilson system, Column: Chiralpak Ia 4.6 mm I.D. × 25 cm L; Mobile phase: n-Hexane/i-PrOH/DEA = 6/4/0.1; Flow rate: 1 mL/min; Detector: 254 nm.

PATENT

WO 2018175251

WO 2018055029

WO 2018024608

WO 2016087680

WO 2016081773

PATENT

JP 2016069348

PATENT

CN 105503906

The present invention provides a triazolopyrazine derivatives, the chemical name (S) -1- (l_ (imidazo [l, 2_a] pyrazin-6-yl) ethane-yl) -6-α _ -1H- pyrazol-4-yl-methyl) -1Η- [1,2,3] triazolo [4,5-b] pyrazine, of formula (I), the

Figure CN105503906AD00041

[0005] This compound is an inhibitor of the activity c -Me t, may be used for treatment or prevention of inhibition of c -Me t sensitive cancers. In the Chinese patent CN 102906092A (W02011 / 079804), discloses the synthesis and use triazolopyrazine derivatives. Prepared by repeating the above patent, the compound powder obtained by detecting an amorphous state. As those skilled in the art, although amorphous higher solubility and dissolution rate than polymorph in most cases, but it is unstable, hygroscopic, readily converted to stable crystalline form.Thus, without the presence of processing stability and poor storage stability shaped, and in the production process, the smaller the bulk density of the particles of amorphous, high surface free energy, are likely to cause aggregation, poor flowability, and a series of powerful elastic deformation of the formulation problem seriously affecting the clinical value of amorphous Drug triazolopyrazine derivatives.

PATENT

CN 105503905

PATENT

WO 2014174478

CN 102127096

PATENT

WO 2011079804

References

Savolitinib
Savolitinib.svg
Clinical data
Synonyms Volitinib
Identifiers
CAS Number
ChemSpider
KEGG
Chemical and physical data
Formula C17H15N9
Molar mass 345.37 g·mol−1
3D model (JSmol)

///////////////Savolitinib, Phase III, AZD-6094, AZD6094, HMPL-504, HMPL504, UNII-2A2DA6857R, Volitinib, HM 5016504

C[C@@H](c1ccc2nccn2c1)n3c4c(ncc(n4)c5cnn(c5)C)nn3

In some embodiments, the c-Met inhibitor is ARQ197 (Tivantinib). Tivantinib has the IUPAC name (3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-pyrrolidinedione and the following chemical structure:

[0058] In some embodiments, the c-Met inhibitor is EMD1214063 (MSC2156119J; Tepotinib).

Tepotinib has the IUPAC name 3-(1-(3-(5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-1,6-dihydro-6-oxopyridazin-3-yl)benzonitrile and the following chemical structure:

[0059] In some embodiments, the c-Met inhibitor is GSK/1363089/XL880 (Foretinib). Foretinib has the IUPAC name N1’-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0060] In some embodiments, the c-Met inhibitor is XL184 (Cabozantinib). Cabozantinib has the IUPAC name N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0061] In some embodiments, the c-Met inhibitor is HMPL-504/AZD6094/volitinib (Savolitinib). Volitinib has the IUPAC name (S)-1-(1-(imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine and the following chemical structure:

[0062] In some embodiments, the c-Met inhibitor is MSC2156119J (EMD 1214063, Tepotinib).

Tepotinib has the IUPAC name Benzonitrile, 3-[1,6-dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]- and the following chemical structure:

[0063] In some embodiments, the c-Met inhibitor is LY2801653 (Merestinib). Merestinib has the IUPAC name N-(3-fluoro-4-{[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5 yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide and the following chemical structure:

[0064] In some embodiments, the c-Met inhibitor is AMG 337. AMG 337 has the IUPAC name 7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine and the following chemical structure:

[0065] In some embodiments, the c-Met inhibitor is INCB28060 (Capmatinib). Capmatinib has the IUPAC name 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and the following chemical structure:

[0066] In some embodiments, the c-Met inhibitor is AMG 458. AMG 458 has the IUPAC name 1-(2-hydroxy-2-methylpropyl)-N-(5-((7-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide and the following chemical structure:

[0067] In some embodiments, the c-Met inhibitor is PF-04217903. PF-04217903 has the IUPAC name 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol and the following chemical structure:

[0068] In some embodiments, the c-Met inhibitor is PF-02341066 (Crizotinib). Crizotinib has the IUPAC name (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and the following chemical structure:

[0069] In some embodiments, the c-Met inhibitor is E7050 (Golvatinib). Golvatinib has the IUPAC name N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0070] In some embodiments, the c-Met inhibitor is MK-2461. MK-2461 has the IUPAC name N-((2R)-1,4-Dioxan-2-ylmethyl)-N-methyl-N’-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide and the following chemical structure:

[0071] In some embodiments, the c-Met inhibitor is BMS-777607. BMS-777607 has the IUPAC name N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide and the following chemical structure:

[0072] In some embodiments, the c-Met inhibitor is JNJ-38877605. JNJ-38877605 has the IUPAC name 6-(difluoro(6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline and the following chemical structure:

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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