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SKLB 1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl,



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SKLB 1028

IND Filed

A multi-targeted inhibitor potentially for the treatment of leukemia and non small cell lung cancer.


Si Chuan University, 四川大学

CAS 1350544-93-2

9-isopropyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-(pyridin-3-yl)-9H-purine- 2,8-diamine


9-Isopropyl-N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-(3-pyridyl)-9H-purine-2,8-diamine, 443.5474, C24H29N9, Preclinical

9-isopropyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-(pyridin-3-yl)-9H-purine- 2,8-diamine. Yield 65.6 %. HPLC>98.6%. 1H NMR(400 MHz, DMSO-d6): δ 9.22(s, 1H), 9.05(s, 1H), 8.94(d, J=2.8Hz, 1H), 8.39(s, 1H), 8.34(d, J=8.4Hz, 1H), 8.20(m, 1H), 7.63(d, J=8.8Hz, 2H), 7.37(m, 1H), 6.88 (d, J=8.8Hz, 2H), 4.88(m, 1H), 3.05(m, 4H), 2.45(m, 4H), 2.22(s, 3H), 1.69(s, 3H), 1.68(s, 3H)ppm。HRMS (ESI) m/z [M-H]- calcd for C24H29N9: 443.2546, found: 442.2538………..Leukemia (2012), 26(8)


WO 2011147066

Synthetic route is as follows:


Example reaction is as follows:




Preparation of chloro-4-amino-5-nitro pyrimidine of Example 12-

Was added dropwise 2,4-dichloro-5-nitro-pyrimidine (lO Aqueous ammonia (8.0ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml dichloromethane, 0 ° C when .Og) in dichloromethane (30ml) solution, after dropwise, maintaining the temperature of the reaction one hour, the precipitate was filtered off, the filter cake was recrystallized to give a yellow solid 8.1g, yield 90.1%

Product 1HNMR (400MHz, DMSO-i¾): δ 9.20 (s, 1H), 9.02 (s, 1H), 8.60 (s, lH) ppm

Preparation of pyrimidine

Isopropylamine (4.5ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml of dichloromethane, was added dropwise 2,4-dichloro-5-nitro-pyrimidine at 0 ° C ( lO.Og) in dichloromethane (30ml) solution, after dropwise, maintaining the reaction temperature for half an hour, and purified by column chromatography to give a light yellow solid was 10.1g, 90.4% yield of product 1H NMR (400 MHz, CDCl 3 ): [delta] 9.03 (s, 1H), 8.24 (s, 1H), 4.53 (m, 1H), 1.34 (d, J = 6.8 Hz, 6H) ppm 0


Example 16, 4-amino-2- (4- (4-methyl-piperazin-1-yl) anilino) -5-nitro-pyrimidin embodiment

4- (4-methylpiperazine) aniline (3.8g) was added to the compound 2-l (3.5g) in n-butanol (150ml) solution, the reaction for 4.5 hours at 90 ° C, cooled to room temperature, filtered , washed, and dried to give a red solid (5.2g), a yield of 79.5%. Product ‘H NMR (400 MHz, CDCl 3 ): [delta] 9.07 (s, 1H), 8.52 (s, 2H), 8.40 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.10 (m, 2H), 3.3 l (t, J = 4.8Hz, 4H), 2.81 (t, J = 4.8Hz, 4H), 2.30 (s, 3H) ppm.

Example 90,

9-isopropyl-2- (4- (4-methyl-piperazin-1-yl) anilino) -8- (pyridin-3-yl) -9H- purine

The compound 5- 7 (2.05g) was dissolved in dichloromethane (90ml), were added sequentially EDCI (2.3g), Ν, Ν- diisopropylethylamine (4.9ml), 3- pyridyl isothiocyanate ester (1.0g), stirred at room temperature for half an hour, then refluxed for 10 hours, TLC monitoring completion of the reaction the raw material 5-7 was cooled and purified by column chromatography to give a light red solid, yield 65.7%.

Product ESI-MS (m / z,%) 442.26 (MH) -. Ή NMR (400 MHz, DMSO-d 6 ): [delta] 9.38 (s, IH), 9.13 (s, IH), 8.99 (s, IH), 8.40 (s, IH), 8.36 (d, J = 8.4 Hz, IH), 8.20 (d, J = 4.4Hz, IH), 7.70 (d, J = 8.8Hz, 2H), 7.37 (m, IH), 6.96 (d, J = 8.8Hz, 2H), 4.97-4.92 ( m, IH), 3.35 (s, 6H), 2.80 (s, 3H): 2.53 (s, 2H), 1.69 (s, 6H) ppm.

/////////SKLB 1028, IND Filed, Preclinical



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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, 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...... , 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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