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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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Enzalutamide


str0

str0

4-(6-chloro-1-oxo-3-thioxo-9,9a-dihydro-1H-imidazo[1,5-a]indol-2(3H)-yl)-2-(trifluoromethyl)-benzonitrile

Drug Name:
Enzalutamide
Research Code:
MDV-3100
Trade Name:
Xtandi®
MOA:
Androgen receptor inhibitor
Indication:
Prostate cancer
Status:
Approved
Company:
Medivation (Originator) , Astellas
Sales:
$2,100.8 Million (Y2015); 
$1,247.3 Million (Y2014);
$546 Million (Y2013);
$148.8 Million (Y2012);
ATC Code:
L01
Approved Countries or AreaUpdate Date:2015-07-29

Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2012-08-31 Marketing approval Xtandi Prostate cancer Capsule, Liquid filled 40 mg Astellas Priority
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2013-06-21 Marketing approval Xtandi Prostate cancer Capsule 40 mg Astellas
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2014-03-24 Marketing approval Xtandi Prostate cancer Capsule 40 mg Astellas

WILL BE UPDATED………

Enzalutamide was approved by the U.S. Food and Drug Administration (FDA) on August 31, 2012, then approved by European Medicine Agency (EMA) on June 21, 2013, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on March 24, 2014. It was developed by Medivation and Astellas and marketed as Xtandi® by Astellas.

Enzalutamide is an androgen receptor inhibitor that decreases proliferation and induces death of prostate cancer cells. It is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

Xtandi® is available as capsule for oral use, containing 40 mg of free Enzalutamide, and the recommended doe is 160 mg once daily.

Prostate cancer, one of the most malignant tumors worldwide, is the second leading cause of cancer deaths among men in America . Although androgen deprivation therapy (ADT) has been proved to be effective initially, the tumor will eventually progress and develop into the lethal castration resistant prostate cancer (CRPC) . The androgen receptor (AR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily and plays a critical role in the progression of normal prostate cells. However, overexpression of AR was found in most CRPC, which is essential for CRPC to adapt to the low levels of androgens. As AR contributes significantly to the resistance to castration, it has been recognized as an attractive target for the treatment of CRPC

Reagents and conditions: (i) HNO3 , H2SO4 , -5 oC, 3 h; (ii) SOCl2 , MeOH, reflux, 12 h; (iii) H2 , Pd/C, MeOH, rt, 12 h; (iv) (CH3CO)2O, TEA, 50 oC, 6 h; (v) H2 , Pd/C, MeOH, rt, 12 h; (vi) acetone, HCl (6 mol/L), -10 oC, 0.5 h, NaNO2 , H2O, -10 oC, 1 h, CuCl/CuBr/KI, 0 oC, 3 h; (vii) HCl, 50 oC, 3 h; (viii) SOCl2 , MeOH, reflux, 12 h; (ix) 2, DMF, TEA, 60 oC, 1 h.

4-(6-chloro-1-oxo-3-thioxo-9,9a-dihydro-1H-imidazo[1,5-a]indol-2(3H)-yl)-2-(trifluoromethyl)-benzonitrile (48c). It was obtained as a yellow solid

m.p. 220-222 oC;

1H-NMR (300 MHz,DMSO-d6): δ 8.40 (d, J = 8.1 Hz, 1H, Ar-H), 8.19 (s, 1H, Ar-H), 8.02-7.92 (m, 2H, Ar-H), 7.49-7.46 (m, 1H, Ar-H), 7.34-7.32 (m, 1H, Ar-H), 5.56 (t, J = 9.6 Hz, 1H, -CH-), 3.58 (d, J = 9.6 Hz, 2H, -CH2-) ppm;

13C-NMR (75 MHz, DMSO-d6): δ 184.1, 172.1, 142.3, 138.5, 136.8, 134.7, 131.9, 131.5, 128.0, 126.1 (q, J = 267.9 Hz, CF3), 117.2, 115.4, 66.9, 39.9 ppm;

IR (KBr): 3094, 2232, 1763, 1607, 1499, 1270, 1136, 1052, 998, 786 cm-1;

HRMS (ESI): m/z, calculated for C18H9ClF3N3OS 408.0180 (M + H)+ , found 408.0173.

Paper

A series of indoline thiohydantoin derivatives were synthesized and evaluated in vitro.The most potent compound 48c shows comparable ability with enzalutamide in proliferation inhibition of LNCaP cells.Compound 48c has less cytotoxic to AR-negative cells compared with Enzalutamide.

The bicalutamide-resistant mechanism was clarified and overcome by compound 48c.


Abstract

A novel scaffold of indoline thiohydantoin was discovered as potent androgen receptor (AR) antagonist through rational drug designation. Several compounds showed good biological profiles in AR binding and higher selective toxicity than enzalutamide toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient). In addition, the docking studies supported the rationalization of the biological evaluation. Among these compounds, the representative compound 48c exhibited the strongest inhibitory effect on LNCaP growth and also acted as a competitive AR antagonist. Further preliminary mechanism study confirmed that 48c exerted its AR antagonistic activity through impairing AR nuclear translocation. All these results indicated that the novel scaffold compounds demonstrated AR antagonistic behaviour and promising candidates for future development were identified.


Graphical abstract

Image 1

Available online 22 October 2016

Design and synthesis of indoline thiohydantoin derivatives based on enzalutamide as antiproliferative agents against prostate cancer
  • Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China
  • zhiyuli@cpu.edu.cn

http://www.sciencedirect.com/science/article/pii/S0223523416309114

http://dx.doi.org/10.1016/j.ejmech.2016.10.049

Paper

Chinese Chemical Letters

Volume 28, Issue 2, February 2017, Pages 426-430
An improved and practical route for the synthesis of enzalutamide and potential impurities study
An improved and practical route for the synthesis of enzalutamide and  potential impurities study - ScienceDirect
An improved and practical route for the synthesis of enzalutamide and  potential impurities study - ScienceDirect

SYN 1

. WO2006124118A1.

2. WO2007127010A2 / US8110594B2.

3. J. Med. Chem. 201053, 2779-2796.

4. WO2013087004A1 / US20140371284A1.

SYN 2

WO2011106570A1 / US20130190507A1.

2. WO2014041487A2.

3. CN103980141A.

4. CN104016924A.

SYN 3

WO2011106570A1 / US20130190507A1.

SYN 4

CN103910679A.

2. Fine Chem. Intermed. 201242, 34-36.

CHINA PATENTS

////////Prostate cancer, Androgen receptor, Antagonist, Indoline thiohydantoin derivatives, indoline thiohydantoin derivatives, enzalutamide, antiproliferative agents, prostate cancer

c1c(cc(c(c1)C#N)C(F)(F)F)N2C(C3Cc4ccc(cc4N3C2=S)Cl)=O

ENZALUTAMIDE


Enzalutamide, MDV-3100
MDV3100 is an orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. MDV3100 (Enzalutamide) blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Early preclinical studies also suggest that MDV3100 inhibits breast cancer cell growth.
1H NMR FROM THE NET

1H NMR PREDICT AND 13 C NMR PREDICT BELOW

COSY PREDICT

Synthesis pics

……………………..

PATENT
http://www.google.com/patents/WO2015063720A1?cl=en

Enzalutamide is chemically described as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl] -5 ,5 -dimethyl-4-oxo-2-sulfanylideneimidazolidin- 1 -yl } -2-fluoro-N-methylbenzamide of Formula I.
FORMULA I
Processes for the preparation of enzalutamide are described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 and PCT Publication Nos. WO 2007/127010, WO 2006/124118, and WO 2011/106570.
PCT Publication No. WO 2011/106570 discloses that the processes described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 result in a 25% yield of enzalutamide in the final step, which accounts for a 15% overall yield. PCT Publication No. WO 2011/106570 further discloses that the known processes for preparing enzalutamide involve the use of extremely toxic reagents, for example, acetone cyanohydrin.
Acetone cyanohydrin is toxic and therefore its use as a reagent should be avoided for industrial production of a pharmaceutical ingredient. Thus, there is a need in the art to develop a process for the preparation of enzalutamide that avoids the use of acetone cyanohydrin as a reagent
Example 6: Process for the preparation of Enzalutamide (Formula I)
Ethyl N-[3-fluoro-4-(methylcarbamoyl)-phenyl]-2-methylalaninate (Formula IV; 0.2 g) and 4-isothiocyanato 2-(triflouromethyl)-benzonitrile (Formula V; 0.33 g) were added to dimethyl sulfoxide (0.2 mL) and isopropyl acetate (0.4 mL) and heated to 90°C to 95°C. The reaction mixture was cooled to 70°C followed by the addition of methanol (0.4 mL). The reaction mixture was stirred for 2 hours. Isopropyl acetate (4 mL) was added to the reaction mixture followed by washing with water (4 mL). The organic layer was concentrated at 35°C under vacuum to obtain an oily residue which was further purified using silica gel column to obtain the title compound.
Yield: 0.2 g

…………………………

PAPER

J Med Chem 2010, 53(7): 2779

http://pubs.acs.org/doi/full/10.1021/jm901488g
A structure−activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

N-Methyl-4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluorobenzamide, 92

………………………..and concentrated and the residue was purified with SiO2 column chromatography (dichloromethane/acetone, 95:5) to give92 (30 mg, 51%) as colorless crystals.
1H NMR (CDCl3, 400 MHz) δ 1.61 (s, 6H), 3.07 (d, 3H, J= 4.1 Hz), 6.71 (m, 1 H), 7.15 (dd, 1H, J = 11.7, 2.0 Hz), 7.24 (dd, 1H, J = 8.4, 2.0 Hz), 7.83 (dd, 1H, J = 8.2, 2.1 Hz), 7.95 (d, 1H, J = 2.1 Hz), 7.99 (d, 1H, J = 8.2 Hz), 8.28 (dd, 1H, J = 8.4, 8.4 Hz). 
13C NMR (CDCl3, 125 MHz) δ 23.8, 26.9, 66.5, 110.3, 114.6, 117.7, 117.9, 121.7 (q, J = 272.3 Hz), 126.1, 126.9 (q, J = 4.6 Hz), 132.0, 133.3, 133.6 (q, J = 33.4 Hz), 135.2, 136.7, 138.9 (d, J = 10.8 Hz), 160.3 (d, J = 248.6 Hz), 162.6 (d, J = 3.3 Hz), 174.3, 179.6. 
19F NMR (CDCl3, 100 MHz) δ −111.13, −62.58. 
HRMS: found 465.1023 [M + H]+, calculated for [C21H16F4N4O2S + H]+ 465.1003.
COMPARISON OF 1H NMR KNOWN VALUES WITH PREDICTED —-KNOWN IN RED
1H NMR VALUES NMRDB

REF

MEDIVATION PROSTATE THERAPEUTICS, INC.; JAIN, Rajendra, Parasmal; ANGELAUD, Remy; THOMPSON, Andrew; LAMBERSON, Carol; GREENFIELD, Scott Patent: WO2011/106570 A1, 2011 ; Location in patent: Page/Page column 46

Regents of the University of California Patent: US2007/254933 A1, 2007 ; Location in patent: Page/Page column 7 ;

WO2011/106570 A1,

J Med Chem 2010, 53(7): 2779

WO2013067151A1 * Nov 1, 2012 May 10, 2013 Medivation Prostate Therapeutics, Inc. Treatment methods using diarylthiohydantoin derivatives
WO2014041487A2 * Sep 11, 2013 Mar 20, 2014 Dr. Reddy’s Laboratories Limited Enzalutamide polymorphic forms and its preparation
WO2014066799A2 * Oct 25, 2013 May 1, 2014 Memorial Sloan-Kettering Cancer Center Modulators of resistant androgen receptor
WO2014167428A3 * Mar 5, 2014 Feb 19, 2015 Shilpa Medicare Limited Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide
EP2536708A2 * Feb 16, 2011 Dec 26, 2012 Aragon Pharmaceuticals, Inc. Androgen receptor modulators and uses thereof

Fine赞顶顶顶路过顶灌水顶顶开心顶赞灌水路过

From 2-fluoro-4-bromo – benzoic acid s-1, firstly the carboxylic acid is converted to acid chloride with SOCl2 s-2, and then methylamine to give the enamine compound s-3, and s-3 bromide aminoisobutyric acid Ullmann (Goldberg) in CuCl catalyzed reaction to give the compound s-4, followed by reaction of the carboxylic acid and methyl iodide to give the corresponding methyl ester compound s-5.
Aniline compound s-6 in the sulfur phosgene primary amine is converted to the isothiocyanate s-7.
Finally, the nitrogen atom of the compound s-5 attack isothiocyanate s-7, followed by transesterification ring closure to give the final Xtandi (Enzalutamide, uh miscellaneous Lu amine). Scheme: WO2011106570A1

//////////

UK launch for Astellas’ prostate cancer drug


UK launch for Astellas' prostate cancer drug

http://www.pharmatimes.com/Article/13-07-19/UK_launch_for_Astellas_prostate_cancer_drug.aspx

UK patients with advanced prostate cancer have been given access to a new treatment that could prolong survival following the launch of Astella’s Xtandi in the country.

Xtandi (enzalutamide) was licensed in Europe this month for the treatment of men with advanced prostate cancer whose disease has become resistant to first-line hormonal treatments and has progressed following docetaxel chemotherapy.

Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide.

The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S. The structural formula is:

XTANDI® (enzalutamide) Structural Formula Illustration

Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.

XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.

Astellas’ Xtandi approved in EU for prostate cancer


enzalutamide

XTANDI

Regulators in European have given the green light to Astellas Pharma and Medivation’s oral prostate cancer drug Xtandi.

Specifically, the European Commission has approved Xtandi (enzalutamide) capsules for the treatment of men with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy. The thumbs-up comes a couple of months after the European Medicines Agency’s Committee for Human Medicinal Productsissued a positive recommendation on the treatment….. READ ALL AT

http://www.pharmatimes.com/Article/13-06-24/Astellas_Xtandi_approved_in_EU_for_prostate_cancer.aspx

Enzalutamide (marketed as Xtandi and formerly known as MDV3100) is an androgen receptor antagonist drug developed by the pharmaceutical company Medivation for the treatment of metastatic castration-resistant prostate cancer. Medivation has reported up to an 89% decrease in prostate specific antigen serum levels after a month of taking the medicine. Early preclinical studies also suggest that enzalutamide inhibits breast cancer cell growth. In August of 2012, the U.S. Food and Drug Administrationapproved enzalutamide for the treatment of castration-resistant prostate cancer.


Enzalutamide was discovered by Charles Sawyers who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung at UCLA.

 

Embedded Image

A model of the interaction between the prostate cancer drug enzalutamide and the androgen receptor

Astellas Pharma and Medivation have announced the submission of application for marketing approval of enzalutamide in Japan for the treatment of prostate cancer


enzalutamide

read all at

http://regulatoryaffairs.pharmaceutical-business-review.com/news/astellas-submits-marketing-application-of-enzalutamide-in-japan-270513

Enzalutamide, 20128.31FDA-approved treatment for advanced prostate cancer drugs. Enzalutamide the androgen receptor antagonist for the treatment of castration resistant prostate cancer (castration-ressitant prostate cancer). Enzalutamide Medivation developed by the trade name Xtandi.
Enzalutamide synthesis of amino acids by the compounds 1 and 2 obtained by the Ullmann coupling with methyl esterification of 3,3 isothiocyanate 4 (can be retrieved by the corresponding aniline and phosgene prepared sulfur) cyclization Enzalutamide

Prostate cancer is a threat to men’s health killer, according to incomplete statistics, their deaths after lung cancer. Metastatic prostate cancer refers to cancer cells by the prostate and surrounding tissue spread to other tissues or organs. Metastatic prostate cancer is usually divided into two phases: hormone sensitive period (the hormone-sensitive state) and castration tolerant phase (the castration-resistant state). Testosterone (testosterone) and other male hormones can provide nourishment prostate cancer cell growth.

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