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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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Gedatolisib, гедатолисиб , غيداتوليسيب , 吉达利塞 ,


Image result for GedatolisibImage result for Gedatolisib

Gedatolisib

Pfizer

PF-05212384; PF-5212384; PKI-587

CAS 1197160-78-3
Chemical Formula: C32H41N9O4
Molecular Weight: 615.72

1-(4-{[4-(Dimethylamino)-1-piperidinyl]carbonyl}phenyl)-3-{4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}urea
3-{4-[bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-1-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea
N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N’-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea
гедатолисиб [Russian] [INN]
غيداتوليسيب [Arabic] [INN]
吉达利塞 [Chinese] [INN]
  • Phase III Acute myeloid leukaemia
  • Phase II Colorectal cancer; Non-small cell lung cancer
  • Phase I Breast cancer; Solid tumours
  • Discontinued Endometrial cancer

Most Recent Events

  • 22 Nov 2017Pfizer suspends patient enrolment in a phase I/II trial due to drug supply delay in Non-small cell lung cancer (Combination therapy, Inoperable/Unresectable, Metastatic disease, Late-stage disease) in USA (IV) (NCT02920450)
  • 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (IV, Infusion)
  • 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Italy (IV, Infusion)

Gedatolisib, also known as PKI-587 and PF-05212384, is an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Upon intravenous administration, PI3K/mTOR kinase inhibitor PKI-587 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K.

PKI-587 is a PI3K/mTOR inhibitor, currently being developed by Pfizer. The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. PKI-587  has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously.

PATENT

WO 2009143317

WO 2010096619

WO 2012148540

WO 2014151147

PATENT

US 20170119778

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2636-2645

http://pubs.acs.org/doi/abs/10.1021/jm901830p

Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor

 Chemical Sciences
 Oncology
§ Drug Metabolism
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965
J. Med. Chem.201053 (6), pp 2636–2645
DOI: 10.1021/jm901830p
Publication Date (Web): February 18, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: (845) 602-4023. Fax (845) 602-5561. E-mail: venkata@wyeth.com or venkata699@gmail.com.

Abstract

Abstract Image

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure−activity relationships and the in vitro and in vivo activity of analogues in this series are described.

Preparation of 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenyl]urea (26)

MS (ESI) m/z = 616.7. HRMS: calcd for C32H41N9O4 + H+, 616.335 43; found (ESI-FTMS, [M + H]+), 616.334 24. Purity by analytical HPLC 99.3%. (Prodigy ODS3, 0.46 cm × 15 cm, 20 min gradient acetonitrile in water, trifluoroacetic acid, detector wavelengths, 215 and 254 nm.) 1H NMR (DMSO-d6) δ 1.29−1.36 (m, 6H), 2.6 (m, 4H), 2.9 (m,1H), 3.3 (m, 4H), 3.6 (m, 8H), 3.7 (m, 8H), 7.3 (d, J = 8.3 Hz, 2H), 7.51−7.57 (m, 4H), 8.3 (d, J = 8.3 Hz 2H), 8.9 (s, 1H), 9.0 (s, 1H) ppm. Anal. Calcd for C32H41N9O4: C 62.42%, H 6.71%, N 20.47%. Found: C 62.34%, H 6.67%, N 20.39%.

PAPER

Bioorganic & Medicinal Chemistry Letters (2011), 21(16), 4773-4778.

http://www.sciencedirect.com/science/article/pii/S0960894X11008468

PAPER

New and Practical Synthesis of Gedatolisib

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00298

 College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China
 Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal University, 99 South Longkun Road, Haina 571158, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00298
*Fax: +86 21 67791214. E-mail: yongjun.mao@hotmail.com.

Abstract

Abstract Image

A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.

off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (brs, 2H), 1.89 (brs, 2H), 2.29 (s, 6H), 2.94 (brs, 2H), 3.76 (m, 8H), 3.89 (m, 8H), 7.09 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.48 (s, 1H). ESI-MS (m/z) 615.9 (M + H). HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 μm); Detection: 254 nm; Flow rate: 0.8 mL/min; Temperature: 30 °C; Injection load: 1 μL; Solvent: MeOH; Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 10; % of mobile phase B: 90; tR = 2.598 min, purity: 99.34%

  • ZhaoX.; TanQ.ZhangZ.ZhaoY. Med. Chem. Res. 2014235188– 5196 DOI: 10.1007/s00044-014-1084-z
  • KhafizovaG.PotoskiJ. R. PCT Int. Appl. WO 2010096619, 2010.
  • VenkatesanA. M.ChenZ.DehnhardtC. M.Dos SantosO.Delos SantosE. G.ZaskA.VerheijenJ. C.KaplanJ. A.RichardD. J.Ayral-KaloustianS.MansourT. S.GopalsamyA.CurranK. J.ShiM. PCT Int. Appl. WO 2009143317, 2009.

REFERENCES

1: Gedaly R, Galuppo R, Musgrave Y, Angulo P, Hundley J, Shah M, Daily MF, Chen C, Cohen DA, Spear BT, Evers BM. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J Surg Res. 2013 Nov;185(1):225-30. doi: 10.1016/j.jss.2013.05.016. Epub 2013 May 25. PubMed PMID: 23769634.

2: Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Evers BM. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. J Surg Res. 2012 Aug;176(2):542-8. doi: 10.1016/j.jss.2011.10.045. Epub 2011 Nov 21. PubMed PMID: 22261591.

3: Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, Yu K, Hollander I, Feldberg L, Lucas J, Mallon R. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21. PubMed PMID: 21763134.

4: Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PubMed PMID: 21325073.

5: Venkatesan AM, Chen Z, dos Santos O, Dehnhardt C, Santos ED, Ayral-Kaloustian S, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Chaudhary I, Mansour TS. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30. PubMed PMID: 20797855.

6: Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham RT, Chaudhary I, Mansour TS. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p. PubMed PMID: 20166697.

????????????PF 05212384, PF 5212384, PKI-587, PF-05212384; PF-5212384; PKI 587, gedatolisib, antitumor agent, PHASE 3, PFIZER, гедатолисиб غيداتوليسيب 吉达利塞 

O=C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C=C1)NC5=CC=C(C(N6CCC(N(C)C)CC6)=O)C=C5

 Journal of Medicinal Chemistry (2017), 60(17), 7524-7538 PQR 309

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