New Drug Approvals

Home » Phase3 drugs » Masitinib

Masitinib

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

PAYPAL DONATIONS

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,309,803 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

add to any

Share

Masitinib

Masitinib; 790299-79-5; Masivet; AB1010; AB-1010;

CLASS:Immunomodulator
TARGET:KIT (a stem cell factor, also called c-KIT) receptor as well as select other tyrosine kinases
STATUS FOR MS:Phase III
COMMERCIAL:Under development by AB Science..Ab Science
4-((4-Methylpiperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)-1,3-thiazol-2-yl)amino)phenyl)benzamide
AB 1010
UNII-M59NC4E26P

4-((4-Methylpiperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)-1,3-thiazol-2-yl)amino)phenyl)benzamide

Regulatory and Commercial Status

STATUS FOR MS:Phase III
HIGHEST STATUS ACHIEVED (FOR ANY CONDITION):
Marketing Authorization Application for the treatment of pancreatic cancer has been filed with the European Medicines Agency (16 October 2012)
Marketing Authorization Application for the conditional approval in the treatment of pancreatic cancer has been accepted by the European Medicines Agency (30 October 2012)

Masitinib.png

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs.[1][2] Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.

Masitinib is being studied for several human conditions including cancers. It is used in Europe to fight orphan diseases.[3]

Mechanism of action

Masitinib inhibits the receptor tyrosine kinase c-Kit which is displayed by various types of tumour.[2] It also inhibits the platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).

 

http://www.google.com/patents/WO2012136732A1?cl=en

In a preferred embodiment of the above-depicted treatment, the active ingredient masitinib is administered in the form of masitinib mesilate; which is the orally bioavailable mesylate salt of masitinib – CAS 1048007-93-7 (MsOH); C28H30N6OS.CH3SO3H; MW 594.76:

Figure imgf000031_0001

 

http://www.google.com/patents/WO2004014903A1?cl=en

Figure imgf000021_0001

003 : 4-(4-Methyl-piperazin-l-ylmethyl)-N-[3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl] -benzamide

4-(4-Methyl-piperazin-l-yl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)- phenyl] -benzamide

Figure imgf000053_0001

beige brown powder mp : 128-130°C

1H RMN (DMSO-d6) δ = 2.15 (s, 3H) ; 2.18 (s, 3H) ; 2.35-2.41 (m, 4H) ; 3.18-3.3.24 (m, 4H) ; 6.94 (d, J = 8.9 Hz, 2H) ; 7.09 (d, J = 8.4 Hz, IH) ; 7.28-7.38 (m, 3H) ; 7.81 (d, J = 8.9 Hz, 2H) ; 8.20-8.25 (m, IH) ; 8.40 (dd, J = 1.6 Hz, J = 4.7 , IH) ; 8.48 (d, J = 1.9 Hz, IH) ; 9.07 (d, J = 1.5 Hz, IH) ; 9.35 (s, IH) ; 9.84 (s, IH)

……………

http://www.google.com/patents/WO2008098949A2?cl=en

EXAMPLE 4 N- [4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide derivatives

Method A In a reactor and under low nitrogen pressure, add 4-Methyl-N3-(4-pyridin-3-yl-thiazol- 2-yl)-benzene-l,3-diamine (95 g, 336.45 mmol), dichloromethane (2 L). To this suspension cooled to temperature of 5°C was added dropwise 2M/n-hexane solution of trimethylaluminium (588 mL). The reaction mixture was brought progressively to 15°C, and maintained for 2 h under stirring. 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 mL) was added for 10 minutes. After 1 h stirring at room temperature, the reaction mixture was heated to reflux for 20 h and cooled to room temperature. This solution was transferred dropwise via a cannula to a reactor containing 2N NaOH (2.1 L) cooled to 5°C. After stirring for 3 h at room temperature, the precipitate was filtered through Celite. The solution was extracted with dichloromethane and the organic layer was washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated under vacuum. The brown solid obtained was recrystallized from /-Pr2O to give 130.7 g (78%) of a beige powder.

Method B Preparation of the acid chloride

To a mixture of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid dihydrochloride (1.0 eq), dichloromethane (7 vol) and triethylamine (2.15 eq), thionyl chloride (1.2 eq) was added at 18-28°C . The reaction mixture was stirred at 28-32°C for 1 hour. Coupling of acid chloride with amino thiazole To a chilled (0-50C) suspension of 4-Methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene- 1,3-diamine (0.8 eq) and thiethylamine (2.2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) was maintaining the temperature below 5°C. The reaction mixture was warmed to 25-300C and stirred at the same temperature for 1O h. Methanol (2 vol) and water (5 vol) were added to the reaction mixture and stirred. After separating the layers, methanol (2 vol), dihloromethane (5 vol) and sodium hydroxide solution (aqueous, 10%, till pH was 9.5-10.0) were added to the aqueous layer and stirred for 10 minutes. The layers were separated. The organic layer was a washed with water and saturated sodium chloride solution. The organic layer was concentrated and ethanol (2 vol) was added and stirred. The mixture was concentrated. Ethanol was added to the residue and stirred. The product was filtered and dried at 50-550C in a vaccum tray drier. Yield = 65-75%.

Method C

To a solution of 4-methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene-l,3-diamine (1.0 eq) in DMF (20 vol) were added successively triethylamine (5 eq), 2-chloro-l- methylpyridinium iodide (2 eq) and 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid (2 eq). The reaction mixture was stirred for 7 h at room temperature. Then, the mixture was diluted in diethyl ether and washed with water and saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using an elution of 100% EtOAc to give a yellow solid.

Yield = 51%.

1H NMR (CDCl3) : δ = 9.09 (IH, s, NH); 8.52 (IH, br s); 8.27 (IH, s); 8.13 (IH, s);

8.03 (IH, s); 7.85 (2H, d, J= 8.3Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (IH, s);

3.56 (2H, s); 2.50 (8H, br s); 2.31 (6H, br s).

MS (CI) m/z = 499 (M+H)+.

An additional aspect of the present invention relates to a particular polymorph of the methanesulfonic acid salt of N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide of formula (IX).

Figure imgf000023_0001

(VI)

Hereinafter is described the polymorph form of (IX) which has the most advantageous properties concerning processability, storage and formulation. For example, this form remains, dry at 80% relative humidity and thermodynamically stable at temperatures below 2000C.

The polymorph of this form is characterized by an X-ray diffraction pattern illustrated in FIG.I, comprising characteristic peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degrees θ, and is also characterized by differential scanning calorimetry (DSC) illustrated in FIG.II, which exhibit a single maximum value at approximately 237.49 ± 0.3 0C. X-ray diffraction pattern is measured using a Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) is measured using a Perking Elmer Precisely (Diamond DSC).

This polymorph form can be obtained by treatement of 4-(4-Methyl-piperazin-l- ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide with 1.0 to 1.2 equivalent of methanesulfonic acid, at a suitable temperature, preferably between 20-800C.

The reaction is performed in a suitable solvent especially polar solvent such as methanol or ethanol, or ketone such as acetone, or ether such as diethylether or dioxane, or a mixture therof. This invention is explained in example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Preparation of the above-mentioned polymorph form of 4-(4-Methyl-piperazin-l- ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide methanesulfonate .

4-(4-Methyl-piperazin- 1 -ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino) phenyl] -benzamide (1.0 eq) was dissolved in ethanol (4.5 vol) at 65-700C. Methanesulfonic acid (1.0 eq) was added slowly at the same temperature. The mixture was cooled to 25-300C and maintained for 6 h. The product was filtered and dried in a vacuum tray drier at 55-600C. Yield = 85-90%. Starting melting point Smp = 236°C.

References

  1. Hahn, K.A.; Oglivie, G.; Rusk, T.; Devauchelle, P.; Leblanc, A.; Legendre, A.; Powers, B.; Leventhal, P.S.; Kinet, J.-P.; Palmerini, F.; Dubreuil, P.; Moussy, A.; Hermine, O. (2008). “Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors”. Journal of Veterinary Internal Medicine 22 (6): 1301–1309. doi:10.1111/j.1939-1676.2008.0190.x. ISSN 0891-6640.
  2.  Information about Masivet at the European pharmacy agency website
  3.  Orphan designation for Masitinib at the European pharmacy agency website
WO2004014903A1 Jul 31, 2003 Feb 19, 2004 Ab Science 2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
WO2008098949A2 Feb 13, 2008 Aug 21, 2008 Ab Science Process for the synthesis of 2-aminothiazole compounds as kinase inhibitors
EP1525200B1 Jul 31, 2003 Oct 10, 2007 AB Science 2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
US7423055 Aug 1, 2003 Sep 9, 2008 Ab Science 2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases
US20080207572 * Jul 13, 2006 Aug 28, 2008 Ab Science Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma
Masitinib.svg
Systematic (IUPAC) name
4-[(4-Methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)benzamide
Clinical data
Trade names Masivet, Kinavet
AHFS/Drugs.com International Drug Names
Identifiers
790299-79-5
L01XE22
PubChem CID 10074640
ChemSpider 8250179
ChEMBL CHEMBL1908391
Chemical data
Formula C28H30N6OS
498.64 g/mol
Patent Submitted Granted
2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases [US7423055] 2004-06-10 2008-09-09
2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors [US2005239852] 2005-10-27
Use of C-Kit Inhibitors for Treating Fibrosis [US2007225293] 2007-09-27
Use of Mast Cells Inhibitors for Treating Patients Exposed to Chemical or Biological Weapons [US2007249628] 2007-10-25
Use of c-kit inhibitors for treating type II diabetes [US2007032521] 2007-02-08
Use of tyrosine kinase inhibitors for treating cerebral ischemia [US2007191267] 2007-08-16
Use of C-Kit Inhibitors for Treating Plasmodium Related Diseases [US2008004279] 2008-01-03
Tailored Treatment Suitable for Different Forms of Mastocytosis [US2008025916] 2008-01-31
2-(3-AMINOARYL) AMINO-4-ARYL-THIAZOLES AND THEIR USE AS C-KIT INHIBITORS [US2008255141] 2008-10-16
Use Of C-Kit Inhibitors For Treating Inflammatory Muscle Disorders Including Myositis And Muscular Dystrophy [US2008146585] 2008-06-19
Patent Submitted Granted
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8940894] 2013-05-10 2015-01-27
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8492545] 2012-03-08 2013-07-23
Patent Submitted Granted
Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma [US2008207572] 2008-08-28
PROCESS FOR THE SYNTHESIS OF 2-AMINOTHIAZOLE COMPOUNDS AS KINASE INHIBITORS [US8153792] 2010-05-13 2012-04-10
COMBINATION TREATMENT OF SOLID CANCERS WITH ANTIMETABOLITES AND TYROSINE KINASE INHIBITORS [US8227470] 2010-04-15 2012-07-24
Anti-IGF antibodies [US8580254] 2008-06-19 2013-11-12
COMBINATIONS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2009047243] 2008-07-17 2009-02-19
TREATMENTS OF B-CELL PROLIFERATIVE DISORDERS [US2009053168] 2008-07-17 2009-02-26
Anti-IGF antibodies [US8318159] 2009-12-11 2012-11-27
SURFACE TOPOGRAPHIES FOR NON-TOXIC BIOADHESION CONTROL [US2010226943] 2009-08-31 2010-09-09
EGFR/NEDD9/TGF-BETA INTERACTOME AND METHODS OF USE THEREOF FOR THE IDENTIFICATION OF AGENTS HAVING EFFICACY IN THE TREATMENT OF HYPERPROLIFERATIVE DISORDERS [US2010239656] 2010-05-10 2010-09-23
ANTI CD37 ANTIBODIES [US2010189722] 2008-08-08 2010-07-29
United States National Library of Medicine

Note: Compound name must be entered under “Substance Identification” and then “Names and Synonyms” selected to view synonyms.

Kocic I, Kowianski P, Rusiecka I, Lietzau G, Mansfield C, Moussy A, Hermine O, Dubreuil P
Naunyn Schmiedebergs Arch Pharmacol. 2014 Oct 26. Epub 2014 Oct 26. PMID: 25344204.Abstract
 AB SCIENCE HEADQUARTER
3, Avenue George V
75008 PARIS – FRANCE
Tel. : +33 (0)1 47 20 00 14
Fax. : +33 (0)1 47 20 24 11

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Paypal Donate

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: