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ORGANIC SPECTROSCOPY

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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MAX 40279


Thieno(3,2-d)pyrimidin-2-amine, 7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-(1-(4-piperidinyl)-1H-pyrazol-4-yl)-.png
2D chemical structure of 2070931-57-4

MAX 40279, EX-A4057

Max 4; MAX-40279; MAX-40279-001; MAX-40279-01

UNII-DL772G3NN7

2070931-57-4

C22H23FN6OS, 438.5

7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-(1-piperidin-4-ylpyrazol-4-yl)thieno[3,2-d]pyrimidin-2-amine

Thieno[3,2-d]pyrimidin-2-amine, 7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-

Structure of MAX-40279 HEMIFUMARATE
Unii-JU19P2M2KM.png

7-(4-FLUORO-2-METHOXYPHENYL)-6-METHYL-N-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL) THIENO (3,2-D)PYRIMIDIN-2-AMINE SEMI-FUMARATE CAS 2388506-43-0 

  • 7-(4-Fluoro-2-methoxyphenyl)-6-methyl-N-[1-(4-piperidinyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-2-amine
  • Originator Maxinovel Pharmaceuticals
  • ClassAntineoplastics
  • Mechanism of ActionFibroblast growth factor receptor antagonists; Fms-like tyrosine kinase 3 inhibitors
  • Orphan Drug StatusYes – Acute myeloid leukaemia
  • Phase IAcute myeloid leukaemia; Solid tumours

Most Recent Events

  • 28 Nov 2019Phase-I clinical trials in Solid tumours (Late-stage disease, Metastatic disease) in China (PO) (NCT04183764)
  • 16 Apr 2019Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) (NCT04187495)
  • 23 Jan 2019Guangzhou Maxinovel Pharmaceuticals plans a phase I trial in China (ChiCTR1900020971)
  • MaxiNovel Pharmaceuticals, Inc. Announces FDA Orphan Drug Designation for MAX-40279 for the Treatment of Acute Myeloid Leukemia (AML)
Jobs with Maxinovel Pharmaceuticals

March 29, 2018 11:24 AM Eastern Daylight Timehttps://www.businesswire.com/news/home/20180329005826/en/MaxiNovel-Pharmaceuticals-Inc.-Announces-FDA-Orphan-Drug-Designation-for-MAX-40279-for-the-Treatment-of-Acute-Myeloid-Leukemia-AML

GUANGZHOU, China–(BUSINESS WIRE)–MaxiNovel Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (“FDA”) has granted MaxiNovel Orphan Drug Designation for MAX-40279 in the treatment of Acute Myeloid Leukemia (AML).

AML is the most common acute leukemia which accounts for approximately 25% of all adult leukemias worldwide. Approximately one-third of AML patients have a FLT3 gene mutation. Such mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML. Inhibition of FLT3 mutation is of high importance in combating AML.

In the preclinical testing, MAX-40279 demonstrated potent inhibition of both FLT3 and FGFR with excellent drug concentration in the bone marrow. It is designed to overcome the observed drug resistance of the current FLT3 inhibitors due to the bone marrow FGF/FGFR pathway activation.

“We are very pleased to receive the ODD,” commented MaxiNovel’s Vice President Dr. Elizabeth Ashraf. “Our objective is to bring the best in class medicine to the patients worldwide.”

The FDA Office of Orphan Products Development grants orphan drug designation to novel drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. The designation allows manufacturers to qualify for various incentives including federal grants, tax credits for qualified clinical trials, a waiver of PDUFA filing fees and 7 years of market exclusivity upon regulatory approval.

About MaxiNovel Pharmaceuticals, Inc:

Maxinovel Pharmaceuticals, Inc. is a biotech company focusing on the discovery and development of Immuno-oncology therapy and targeted therapy. It will use its orally active Immuno-oncology product platform to bring effective combo product of multi-components in a single oral pill to the patients worldwide. For more info: www.maxinovel.com

The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signal pathway is a signal transduction pathway stimulated by cytokines discovered in recent years, and it participates in many important biology such as cell proliferation, differentiation, apoptosis and immune regulation. Process (Aaronson, D Set al. Science 2002, 296, 1653-1655; O’Shea, J Jet al. Nat. Rev. Drug Discovery 2004, 3, 555-564). Compared with other signal pathways, the transmission process of this signal pathway is relatively simple. It mainly consists of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT. JAK (Janus Kinase), a type of molecule in the cell, is rapidly recruited and activated on the receptor after receiving the signal from the upstream receptor molecule. The activated JAK catalyzes the receptor tyrosine phosphorylation, and the phosphorylation of tyrosine on the receptor molecule Amino acid is the recognition and binding site of a kind of signal molecule STAT SH2. Tyrosine phosphorylation occurs after STAT binds to the receptor. Tyrosine phosphorylated STAT forms a dimer and enters the nucleus. As an active transcription factor, dimeric STAT molecules directly affect the expression of related genes, thereby changing the proliferation or differentiation status of target cells.

The JAK-STAT pathway is widely present in various tissues and cells in the body, and has an important role in the differentiation, proliferation, and anti-infection of lymphocytes, and participates in the interaction of various inflammatory factors and signal transduction (Kiesseleva T. et al. . J. Gene, 2002, 285, 1-24). The abnormal activation of this pathway is closely related to a variety of diseases. Finding and screening JAK inhibitors can help in-depth study of the regulatory mechanism of JAK-STAT, thereby providing new drugs and methods for the prevention and treatment of related diseases

The occurrence, growth, invasion and metastasis of tumors are related to the JAK-STAT signal transduction pathway. In normal signal transduction, the activation of STATs is rapid and transient. The continuous activation of STATs is closely related to the process of malignant transformation of cells (Buettner R. et al. Clin. Cancer Res. 2002, 8(4), 945-954). STAT3 is the focus of multiple oncogenic tyrosine kinase signal channels such as EGFR, IL-6/JAK, Src, etc. It is activated in a variety of tumor cells and tissues, such as breast cancer, ovarian cancer, and head and neck squamous cells. Like cell carcinoma, prostate cancer, malignant melanoma, multiple myeloma, lymphoma, brain tumor, non-small cell lung cancer and various leukemias, etc. (Niu G. et al. Oncogene 2002, 21(13), 2000-2008 ). JAK-STAT pathway inhibitors belong to PTK inhibitors, and this enzyme is a member of the oncogene protein and proto-oncoprotein family, and plays an important role in the normal and abnormal cell proliferation. The occurrence and growth of tumors are inseparable from PTK. Therefore, JAK-STAT pathway inhibitors inhibit tumor growth by antagonizing PTK, and have obvious anti-tumor effects (Mora LBet al.J.Cancer Res.2002,62(22) , 6659-6666).

In addition, the latest research shows that: organ transplant rejection, psoriasis, tissue and organ fibrosis, bronchial asthma, ischemic cardiomyopathy, heart failure, myocardial infarction, blood system diseases, and immune system diseases are all related to JAK-STAT signaling. The pathway is closely related. This signaling pathway is not only important for maintaining the normal physiological functions of cells, but also has an important regulatory role for the occurrence and development of diseases.

The Fibroblast Growth Factor Receptor family belongs to a new type of receptor kinase family, which includes four receptor subtypes (FGFR-1,2,3) encoded by four closely related genes. And 4) and some heterogeneous molecules, which form a ternary complex with fibroblast growth factor (FGF) and heparan sulfate, and then trigger a series of signal transduction pathways to participate in the regulation of physiological processes in the organism. FGFR has a wide range of physiological and pathological effects in the body: (1) Embryo development. Studies have shown that during embryonic development, FGFR signal transduction is essential for most organ development and the formation of embryonic patterns. (2) Cell division, migration and differentiation. FGFR stimulates cell proliferation and participates in the regulation of cell transformation in the pathological process. There are many parallel pathways to achieve FGFR-mediated cell division signal transduction, which has been confirmed by many studies (JKWang et al., Oncogene 1997, 14, 1767 -1778.). (3) Bone diseases. The growth and differentiation of bones are also regulated by the FGF family, and mutations in FGFR can cause bone deformities (R. Shang et al., Cell 1994, 78, 335-342.). (4) The occurrence of tumors. FGFR can promote the migration, proliferation and differentiation of endothelial cells, and plays an important role in the regulation of angiogenesis and angiogenesis. Uncontrolled angiogenesis can lead to the occurrence of tumors and the growth of metastases (J.Folkman.Nat.Med.1995) ,1,27-31.).

FMS-like tyrosine kinase 3 (FMS-like tyrosine kinase 3, FLT3) belongs to the type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member, it is composed of extracellular domain, intracellular domain and The transmembrane region is composed of 3 parts, which are first expressed in human hematopoietic stem cells. FLT3 interacts with its ligand FL to stimulate or act on stem cells, which is of great significance to the growth and differentiation of stem cells. FLT3 kinase has wild-type FLT3-WT and its main activation mutant FLT3-ITD and FLT3-D835Y. FLT3 is mainly expressed in the precursors of normal myeloid cells, but its abnormal expression is also found in a large part of acute myeloid leukemia (AML) cells. 

In recent years, many large-scale studies have confirmed that activating mutations of FLT3 play a very important pathological role in the occurrence and progression of acute myeloid leukemia. FLT3 has become an important target for the treatment of acute myeloid leukemia.

rc family kinase (SFK) is a family of non-receptor tyrosine kinases, including c-Src, LYN, FYN, LCK, HCK, FGR, BLK, YES and YRK, among which LYN kinase has LYNα and LYNβ Both subtypes, LYN kinase and its two subtypes can cause similar intracellular tyrosine phosphorylation. According to the amino acid sequence, SFK can be divided into two sub-families: one family is c-Src, FYN, YES and FGR, which are widely expressed in different tissues; the other family is LCK, BLK, LYN and HCK, which are closely related to hematopoietic cells. SFK is connected to multiple signal transduction pathways in the body, and can be activated by growth factors, cytokines and immune cell receptors, G protein-coupled receptors, integrins and other cell adhesion molecules, and then activate the corresponding signal transduction pathways , Causing a variety of physiological effects of cells. The activity of SFK mainly includes the regulation of cell morphology, cell movement, cell proliferation and survival. The abnormal activation and expression of these kinases leads to the occurrence and development of a wide range of diseases, such as a large number of solid tumors, various hematological malignancies and some neuronal pathologies. Therefore, looking for SFK inhibitors is a promising research topic in the field of medicinal chemistry.

wdt-13

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$10.00

Patent

CN106366093A

PATENT

WO 2017012559

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017012559Example 31
N-[7-(4-Fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidin-4-yl)- 1H-pyrazole-4-amine (Compound 31)

Synthesis of compound 31-e
2,4-Dichloro-6-methylthiophene [3,2-d] pyrimidine (10g, 45.6mmol) was dissolved in tetrahydrofuran (100mL) and ethanol (100mL), and the reaction solution was cooled to 0°C and divided Sodium borohydride (12.5 g, 198 mmol) was added in batches. The reaction solution was raised to room temperature and continued to stir for 16 hours, diluted with water (500 mL), and then adjusted to pH=7 with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (150 mL×3). The organic phase was washed sequentially with water (100mL×3) and saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 31-e (7.5g, yield: 88%). The product does not require further purification. LC-MS(ESI): m/z=187[M+H] + .[0492]Synthesis of compound 31-d[0493]Compound 31-e (7.5 g, 40 mmol) was dissolved in chloroform (300 mL) at 0°C, active manganese dioxide (35 g, 400 mmol) was added, the reaction solution was raised to room temperature and stirring was continued for 16 hours. The reaction solution was filtered through Celite, and the filter cake was washed with chloroform (100 mL×3). The combined filtrates were concentrated under reduced pressure to obtain white solid 31-d (6.6 g, yield: 89%), which did not require further purification. LC-MS(ESI): m/z=185[M+H]+.[0494]Synthesis of compound 31-c[0495]Compound 31-d (3.1g, 16.8mmol) was dissolved in trifluoroacetic acid (30mL) at 0℃, N-iodosuccinimide (5.7g, 25.3mmol) was added in batches, and the reaction solution was raised to Keep stirring at room temperature for 1 hour. Water (50 mL) was added to the reaction solution to quench the reaction, and it was extracted with dichloromethane (50 mL×3). The organic phase was washed successively with water (50mL×3) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 31-c (4.9g, yield: 94%). The product does not require further purification. LC-MS(ESI): m/z=311[M+H] + .[0496]Synthesis of compound 31-b[0497]Compound 31-c (615mg, 1.98mmol), 2-methoxy-4-fluorophenylboronic acid (405mg, 2.38mmol) and sodium carbonate (630mg, 5.94mmol) were suspended in dioxane (5mL) water (5mL) ), add [1,1′-bis(diphenylphosphorus)ferrocene]dichloropalladium dichloromethane complex (163mg, 0.2mmol). Replace with nitrogen 3 times, and heat to 80°C to react for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was partitioned with dichloromethane (50mL) and water (50mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum Ether: dichloromethane=1:1) to obtain a white solid 31-b (240 mg, yield: 39%). LC-MS(ESI): m/z=309[M+H] + .[0498]Synthesis of compound 31-a[0499]Compound 31-b (240mg, 0.78mmol) and compound 32-c (208mg, 0.78mmol) were dissolved in N,N-dimethylformamide (3mL), potassium carbonate (323mg, 2.34mmol) was added, 2- Dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (112 mg, 0.24 mmol) and tris(dibenzylideneacetone) dipalladium (134 mg, 0.24 mmol). Under the protection of nitrogen, heat to 110°C to react for 16 hours. After cooling to room temperature, the reaction solution was partitioned with dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography preparation plate (petroleum Ether: ethyl acetate = 1:1) to obtain a yellow viscous oil 31-a (190 mg, yield: 45%). LC-MS(ESI): m/z=539[M+H] + .[0500]Synthesis of compound 31[0501]31-a (190 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was layered with ethyl acetate (50mL) and 1N aqueous hydrochloric acid (50mL). The aqueous phase was adjusted to pH=10 with saturated aqueous potassium carbonate solution. 3) Washing and vacuum drying the solid to obtain a light yellow solid 31 (22 mg, yield: 14%). LC-MS(ESI): m/z=439[M+H] + .[0502]1 H-NMR (400MHz, MeOD) δ: 8.78 (d, J = 5Hz, 1H), 7.87 (s, 1H), 7.48 (s, 1H), 7.35 (m, 1H), 7.05 (dd, J = 11Hz) ,J = 2Hz, 1H), 6.91 (m, 1H), 4.10 (m, 1H), 3.79 (s, 3H), 3.22 (m, 2H), 2.77 (m, 2H), 2.47 (s, 3H), 2.03(m,2H),1.73(m,2H)ppm

PATENT

WO 2019228171

Example 1 Preparation of fumarate of fused ring pyrimidine compound as shown in formula 2
Weigh the compound N-[7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidine-4- Base)-1H-pyrazol-4-amine (synthesized according to Example 31 of patent CN106366093A) 100mg (0.228mmol, 1eq) into the vial, add 10mL 88% acetone-water solution, add the vial at about 50°C and stir until dissolved clear. 1.1 mL of fumaric acid with a concentration of 0.25 mol/L in ethanol (0.275 mmol, 1.2 eq) was slowly added dropwise to the free base solution of fused ring pyrimidine compounds, and stirred at 50 ℃ for 1 hour, and then the solution was The rate of 5°C/h was slowly reduced to room temperature, and the solid was collected and dried under vacuum at 40°C overnight.
1 H-NMR (400MHz, DMSO-d 6 ) δ: 9.45 (s, 1H), 8.94 (s, 1H), 7.75 (s, 1H), 7.78-7.33 (m, 2H), 7.15 (d, J = 6.4Hz, 1H), 6.99 (dd, J = 7.6 Hz, J = 7.2 Hz, 1H), 6.42 (s, 1H), 4.10 (m, 1H), 3.73 (s, 3H), 3.17 (d, J = 12.4 Hz, 2H), 2.77 (dd, J = 12.4 Hz, J = 11.6 Hz, 2H), 2.40 (s, 3H), 1.94 (d, J = 11.6 Hz, 2H), 1.73 (m, 2H) ppm.

PATENT

WO2021175155

7-(4-Fluoro-2-methoxyphenyl)-6-methyl-N-(1-piperidin-4-yl)-1hydro-pyrazol-4-yl)thieno[3,2 -D]pyrimidine-2-amino is a strong JAK, FGFR, FLT3 kinase inhibitor, and has a good application prospect in the treatment of tumors, immune system diseases, allergic diseases and cardiovascular diseases. This compound is described in patent CN106366093A and has the following chemical structure:

CN106366093A discloses the preparation method of the compound:

In the above synthetic route, NaBH 4 is sodium borohydride, MnO 2 is manganese dioxide, NIS is N-iodosuccinimide, TFA is trifluoroacetic acid, and Pd(dppf)Cl 2 is [1,1′- Bis(diphenylphosphino)ferrocene]palladium dichloride, DIAD is diisopropyl azodicarboxylate, PPh 3 is triphenylphosphine, Pd/C is palladium on carbon, Pd 2 (dba) 3 is Tris(dibenzylideneacetone)dipalladium, RuPhos is 2-bicyclohexylphosphine-2′,6′-diisopropoxybiphenyl.

However, the above method has the problems of a large number of reaction steps, low yield, and requires column chromatography for separation and purification, and is not suitable for industrial scale-up production. Therefore, it is necessary to improve its preparation method.

The present invention provides a method for preparing a compound represented by formula B, which comprises the following steps: under a protective gas atmosphere, in a solvent, in the presence of a catalyst and a base, a compound represented by formula C is combined with a compound represented by formula K The compound can be subjected to the coupling reaction shown below; the catalyst includes a palladium compound and a phosphine ligand;

The preparation method of the compound represented by formula B may further include the following steps: in an organic solvent, in the presence of a base, the compound represented by formula E and the compound represented by formula D are subjected to the substitution reaction shown below, To obtain the compound represented by formula C;

The present invention provides a method for preparing a compound represented by formula C, which comprises the following steps: in an organic solvent, in the presence of a base, a compound represented by formula E and a compound represented by formula D are subjected to the following steps: Substitution reaction is enough;

Example 1: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
Into a 500L reactor, add 10% palladium on carbon (4.6Kg), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (24.2Kg, 109.5mol), and tetrahydrofuran (150Kg) in sequence And N,N-diisopropylethylamine (17.0Kg, 131.5mol). Fill the kettle with hydrogen, and control the hydrogen pressure at 0.5 MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 120 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (58Kg) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (60Kg) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 360Kg of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was separated out, centrifuged, and the filter cake was vacuum dried to obtain the product 2-chloro-6-methylthieno[3,2-D]pyrimidine 18.94Kg, yield: 93.2%. LC-MS(ESI): m/z=185.1[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.30 (s, 1H), 7.34 (s, 1H), 2.73 (s, 3H). 
Example 2: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
To a 100mL reaction flask, add 10% palladium on carbon (0.17g), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (2g, 9.2mmol), tetrahydrofuran (40mL) and N,N-Diisopropylethylamine (1.412 g, 10.9 mmol). Fill the bottle with hydrogen and control the hydrogen pressure at 0.5MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 20 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (2.1 g) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (2.2g) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 13.3g of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was precipitated, centrifuged, and the filter cake was vacuum dried to obtain 2.4 g of 2-chloro-6-methylthieno[3,2-D]pyrimidine as a product, with a yield of 82%. The LC-MS and 1 H NMR are the same as in Example 1. 
Example 3: 7-Bromo 2-chloro-6-methylthieno[3,2-D]pyrimidine (Compound E) 
Add trifluoroacetic acid (150Kg) and 2-chloro-6-methylthieno[3,2-D]pyrimidine (18.90Kg, 102.4mol) into a 500L enamel reactor. Add N-bromosuccinimide (18.33Kg, 103.0mol) under temperature control at 15±5℃. After the addition, the temperature is controlled at 25±5℃ to react for 2 hours. Sampling to monitor the reaction, there is still a small amount of raw materials remaining. Additional N-bromosuccinimide (1.0 Kg, 5.6 mol) was added, stirring was continued for 1 hour, sampling and monitoring showed that the reaction was complete. Control the temperature at 10±5°C, and add 274Kg of water dropwise. After the addition, stir at 10±5°C for 2 hours. After centrifugation, the solid was vacuum-dried to obtain the product, 7-bromo-2-chloro-6-methylthieno[3,2-D]pyrimidine, 24.68Kg, yield: 91.4%. LC-MS(ESI): m/z=265.0[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.33 (s, 1H), 2.64 (s, 3H). 
Example 4: 4-(p-toluenesulfonyl)-piperidine-1-tert-butyl carbonate (Compound G) 
Add pyridine (176Kg) and N-BOC-4-hydroxypiperidine (36.00Kg, 178.9mol) to a 500L enamel reactor. Add p-toluenesulfonyl chloride (50.5Kg, 264.9mol) in batches under temperature control at 10±10°C. After the addition, the temperature is controlled at 25±5°C to react for 18 hours. The reaction solution was transferred to a 1000L reactor, the temperature was controlled at 15±5°C, and 710Kg of water was added dropwise. After the addition, stir at 15±5°C for 2 hours. After filtration, the solid was washed with water and dried in vacuum to obtain the product 4-(p-methylbenzenesulfonyl)-piperidine-1-carbonate tert-butyl ester, 59.3Kg, yield: 93.3%. LC-MS(ESI): m/z=378.0[M+Na] + . 
Example 5: 4-(4-Nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound F) 
Add N,N-dimethylformamide (252Kg), 4-(p-methylbenzenesulfonyl)-piperidine-1-carbonate tert-butyl ester (59.3Kg, 166.8mol), 4-nitro to the reaction kettle Pyrazole (21.5Kg, 190.1mol), and anhydrous potassium carbonate (34.3Kg, 248.2mol). The temperature was controlled at 80±5°C and the reaction was stirred for 18 hours. Cool down to 15±5°C, add 900Kg of water dropwise, control the dropping rate, and keep the temperature at 15±5°C. After the addition, stir at 5±5°C for 2 hours. After filtering, the solid was washed twice with water and dried in vacuum to obtain the product 4-(4-nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 39.92Kg, yield: 80.8%. LC-MS (ESI): m/z=319.1 [M+Na] + . 
1 H NMR (400MHz, d 6 -DMSO): δ8.96(s,1H), 8.27(s,1H), 4.44-4.51(m,1H), 4.06-4.08(m,2H), 2.75-2.91( m, 2H), 2.04-2.07 (m, 2H), 1.80-1.89 (m, 2H), 1.41 (s, 9H). 
Example 6: 4-(4-Amino-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound D) 
Add 10% palladium-carbon (2.00Kg), 4-(4-nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (39.94Kg, 134.09mol) to the reaction kettle, nothing Water ethanol (314Kg) and ammonia (20.0Kg, 134.09mol). Fill the kettle with hydrogen, and control the hydrogen pressure at 0.2MPa. Turn on the stirring and keep the temperature at 45±5°C to react for 4 hours. Filter, collect the filtrate, and concentrate the filtrate under reduced pressure. Add ethyl acetate (40Kg) and n-heptane (142Kg) to the concentrate, stir at 25±5°C for 1 hour, and then lower the temperature to 5±5°C and stir for 2 hours. After filtration, the solid was vacuum dried to obtain the product 4-(4-amino-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 31.85Kg, yield: 88.6%. LC-MS(ESI): m/z=267.2[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ7.06 (s, 1H), 6.91 (s, 1H), 4.08-4.15 (m, 1H), 3.98-4.01 (m, 2H), 3.81 (brs, 2H), 2.83-2.87 (m, 2H), 1.88-1.91 (m, 2H), 1.63-1.72 (m, 2H), 1.41 (s, 9H). 
Example 7: 4-(4-(7-Bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1hydro-pyrazol-1-yl)piperidine-1 -Tert-butyl carbonate (compound C) 
Add n-butanol (117Kg), N,N-diisopropylethylamine (15.00Kg, 116.06mol), 4-(4-amino-1hydro-pyrazol-1-yl)piperidine to the reaction kettle 1-tert-butyl carbonate (32.02Kg, 120.22mol) and 7-bromo-2-chloro-6-methylthieno[3,2-D]pyrimidine (24.68Kg, 93.65mol). Turn on the stirring and keep the temperature at 100±5°C to react for 42 hours. Concentrate under reduced pressure. Methanol was added to the concentrate to be beaten. The solid was filtered and dried under vacuum to obtain the product 4-(4-(7-bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1hydro-pyrazol-1-yl ) Piperidine-1-tert-butyl carbonate 37.26Kg, yield: 80.6%. LC-MS(ESI): m/z=493.1[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.73 (s, 1H), 8.97 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 4.30-4.36 (m, 1H) ,4.01-4.04(m,2H),2.87-2.93(m,2H),2.53(s,3H),2.00-2.03(m,2H),1.70-1.80(m,2H),1.41(s,9H) . 
Example 8: 4-(4-((7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1 Hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound B) 
Add purified water (113Kg), dioxane (390Kg), 4-(4-(7-bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino) into the reactor -1H-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (37.26Kg, 93.65mol), 2-methoxy-4-fluorophenylboronic acid pinacol ester (23.05Kg, 120.22mol) , Anhydrous potassium carbonate (20.95Kg, 151.8mol), palladium acetate (0.18Kg, 0.80mol) and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.90Kg, 1.89mol). Under the protection of nitrogen, the temperature is controlled at 70±5℃ to react for 4 hours. Cool down to 40±5°C, add ammonia water (68Kg), and stir for 8 hours. Cool down to 20±5°C and dilute with water (1110Kg). Dichloromethane extraction twice (244Kg, 170Kg). Combine the organic phases, wash sequentially with water and then with saturated brine. Add 3-mercaptopropyl ethyl sulfide-based silica (4.0Kg, used to remove heavy metal palladium) into the organic phase, and stir at 40±5°C for 20 hours. After filtration, the filtrate was concentrated under reduced pressure. The remainder was slurried sequentially with methyl tert-butyl ether and ethanol. Filter and dry in vacuo to obtain 4-(4-((7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-D]pyrimidin-2-yl)amino) -1H-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 34.6Kg, yield: 68.6%. LC-MS(ESI): m/z=539.3[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.46 (s, 1H), 8.94 (s, 1H), 7.76 (s, 1H), 7.38 (s, 1H), 7.33 to 7.35 (m, 1H) ,7.08-7.11(m,1H),6.91-6.95(m,1H),4.03-4.12(m,3H),3.73(s,3H),2.85-2.89(m,2H),2.39(s,3H) ,1.90-1.93(m,2H),1.55-1.60(m,2H),1.41(s,9H). 
Comparative Example 1: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
Into a 100mL reaction flask, add 10% palladium on carbon (0.1g), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (2g, 9.2mmol), methanol (40mL) and N,N-Diisopropylethylamine (1.412 g, 10.9 mmol). Fill the bottle with hydrogen and control the hydrogen pressure at 0.5MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 21 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (2.1 g) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (2.2g) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 13.3g of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was precipitated, centrifuged, and the filter cake was vacuum dried to obtain 1.6 g of 2-chloro-6-methylthieno[3,2-D]pyrimidine as a product, with a yield of 54%. Methoxy substituted impurities in 20% yield.
Comparative Example 2: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
After replacing the solvent tetrahydrofuran in Example 2 with ethyl acetate, the solubility of 2-chloro-6-methylthieno[3,2-D]pyrimidine in ethyl acetate was poor, and only a small amount of product was formed, which was not calculated Specific yield. 
Comparative example 3: 4-(p-toluenesulfonyl)-piperidine-1-tert-butyl carbonate (Compound G) 
Triethylamine (25mL), N-BOC-4-hydroxypiperidine (5g) were added to a 100mL reaction flask. P-toluenesulfonyl chloride (7.1g) was added in batches while controlling the temperature at 10±10°C. After the addition, the temperature is controlled at 25±5℃ to react for 25 hours. Monitoring by LC-MS showed a large amount of unreacted raw materials and the reaction liquid was black and red. 

Publication Number TitlePriority Date Grant Date
WO-2019228171-A1Salt of fused ring pyrimidine compound, crystal form thereof and preparation method therefor and use thereof2018-05-31 
AU-2016295594-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
AU-2016295594-B2Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212020-04-16
EP-3354653-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
EP-3354653-B1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212019-09-04
Publication Number TitlePriority Date Grant Date
JP-2018520202-AFused ring pyrimidine compounds, intermediates, production methods, compositions and applications thereof2015-07-21 
KR-20180028521-ACondensed ring pyrimidine-based compounds, intermediates, methods for their preparation, compositions and applications2015-07-21 
US-10494378-B2Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212019-12-03
US-2018208604-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
WO-2017012559-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21
CTID TitlePhaseStatusDate
NCT03412292MAX-40279 in Subjects With Acute Myelogenous Leukemia (AML)Phase 1Recruiting2021-05-21

///////////////Orphan Drug, Acute myeloid leukaemia, MAX 40279, EX-A4057, Max 4,  MAX-40279, MAX-40279-001, MAX-40279-01, PHASE 1, Maxinovel Pharmaceuticals

CC1=C(C2=NC(=NC=C2S1)NC3=CN(N=C3)C4CCNCC4)C5=C(C=C(C=C5)F)OC

AKN 028


img

AKN-028
CAS 1175017-90-9
Chemical Formula: C17H14N6
Molecular Weight: 302.33

N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine

N2-(1H-indol-5-yl)-6-(pyridin-4-yl)pyrazine-2,3-diamine

  • Originator Swedish Orphan Biovitrum
  • Developer Akinion Pharmaceuticals
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Fms-like tyrosine kinase 3 inhibitors; Proto oncogene protein c-kit inhibitors
  • Phase I/II Acute myeloid leukaemia
  • 01 Mar 2016 Akinion Pharmaceuticals terminates phase I/II trial in Acute myeloid leukaemia in Czech Republic, Poland, Sweden and United Kingdom (NCT01573247)
  • 17 Sep 2015 AKN 028 is still in phase I/II trials for Acute myeloid leukaemia in Czech Republic, Poland and Sweden
  • 09 Apr 2014 AKN 028 is still in phase I/II trials for Acute myeloid leukaemia in Czech Republic, Poland and Sweden

AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC(50)=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC(50) 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. (source: Blood Cancer J. 2012 Aug 3;2:e81. doi: 10.1038/bcj.2012.28.)

SYN

WO 2013/089636

Clip

Development of a Synthesis of Kinase Inhibitor AKN028

 R&D DepartmentMagle Chemoswed, P.O. Box 839, SE 201 80 Malmö, Sweden
 Recipharm OT ChemistryVirdings Allé 32 B, SE 754 50 Uppsala, Sweden
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00092
*Telephone: +46 704473035. E-mail: johan.docera@gmail.com
Abstract Image

The novel tyrosine kinase inhibitor AKN028 has demonstrated promising results in preclinical trials. An expedient protocol for the synthesis of the compound at kilogram scale is described, including an SNAr reaction with high regioselectivity and a Suzuki coupling. Furthermore, an efficient method for purification and removal of residual palladium is described.

yellow or faint-orange powder. Mp 300 °C (dec.);

IR 3133 broad, 1689, 1597, 1554, 1480 cm–11H NMR (DMSO-d6) δ 11.01 (s, 1H), 8.62–8.50 (m, 2H), 8.22 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.89–7.82 (m, 2H), 7.39 (d, J = 2.0 Hz, 2H), 7.32 (t, J = 2.7 Hz, 1H), 6.77 (s, 2H), 6.42 (dd, J1 = 8.7 Hz, J2 = 2.0 Hz, 1H);

13C NMR (DMSO-d6) δ 149.9, 145.2, 145.0, 139.6, 132.8, 132.4, 132.2, 128.4, 127.6, 125.6, 118.7, 116.1, 111.2, 111.0, 101.0.

PATENT

 WO 2009095399

https://patentscope.wipo.int/search/ko/detail.jsf;jsessionid=074E97C06EF8C2088428DECCA2CD2EBA.wapp1nB?docId=WO2009095399&recNum=208&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22%26fq%3DDP%3A2009&sortOption=Pub+Date+Desc&maxRec=3425

PATENT

WO 2013089636

https://patents.google.com/patent/WO2013089636A1/ko

Protein kinases are involved in the regulation of cellular metabolism, proliferation, differentiation and survival. The FLT-3 (fms-like tyrosine kinase) receptor is a member of the class III subfamily of receptor tyrosine kinases and has been shown to be involved in various disorders such as haematological disorders, proliferative disorders, autoimmune disorders and skin disorders.

In order to function effectively as an inhibitor, a kinase inhibitor needs to have a certain profile regarding its target specificity and mode of action. Depending on factors such as the disorder to be treated, mode of administration etc. the kinase inhibitor will have to be designed to exhibit suitable properties. For instance, compounds exhibiting a good plasma stability are desirable since this will provide a pharmacological effect of the compounds extending over time. Another example is oral administration of the inhibitor which may require that the inhibitor is transformed into a prodrug in order to improve the bioavailability.

WO 2009/095399 discloses pyrazine compounds acting as inhibitors of protein kinases, especially FTL3, useful in the treatment of haematological disorders, proliferative disorders, autoimmune disorders and skin disorders. This document discloses methods for manufacturing such compounds. However these methods are not suitable for large scale processes and the chemical yields are moderate. Furthermore, the compounds obtained by these methods are in amorphous form.

n one aspect of the invention, there is provided a process for preparing a compound of formula (I)

said process comprises the steps of:

a) reacting a compound of formula (1) with a compound of formula (2) in an inert solvent and in the presence of an (C1-6alkyl)3amine, providing a compound of formula (3):


, b) Suzuki coupling of a compound of formula (3) and a compound of formula (4) in an inert solvent and in the presence of a palladium catalyst and a base, providing a crude product comprising a compound of formula (I) and palladium

and

c) removing the palladium from the crude product in step b).

The compound of formula (I) may be obtained in amorphous or crystalline form using the processes outlined below.

Step 1:

Reaction of 2-amino-3,5-dibromopyrazine (1) and 5-aminoindole (2) in a

nucleophilic substitution reaction in the presence of a C1-6alkylamine and an inert polar solvent yields 3-bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3-diamine (3). Examples of inert polar solvents are DMSO, water and NEP. Examples of (C1-6alkyl)3amine are triethylamine, trimethylamine and tributylamine. The reaction may be performed at reflux temperature or at about 100-130°C.

Step 2:

A Suzuki coupling of 3-bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3-diamine) (3) and 4- pyridyl-boronic acid (4) in an inert polar solvent in the presence of a palladium catalyst and a base yields N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine (I) in amorphous form. Examples of inert solvents are DMF, water and DMA. Examples of palladium catalysts are Pd(dppf) and Pd(OAc)2-DTB-PPS. Example of a base is

K2CO3 The reaction may be performed under inert and oxygen-free atmosphere such as nitrogen or argon.

Heating may take place during step 1 and/or step 2. Steps 1 and 2 may be performed at reflux or in a temperature range of from 100 to 140°C, such as from 105 to 135°C, such as from 110 to 130°C, such as from 130-135°C, such as from 110-115ºC.

Step 3:

A compound of formula (I), also denominated N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine, in amorphous form may be dissolved in acetic acid (HOAc) after which potassium hydroxide (KOH) is added. The compound of formula (I) in amorphous form may be obtained from the process outlined in steps 1 and 2.

Alternatively, the compound of formula (I) may be obtained according to the process described in WO 2009/095399. The obtained crystalline form is removed from the slurry by, for instance, filtration. Step 3 may be repeated. Step 3 may be performed at a temperature of about 40°C followed by cooling to room temperature.

The process for preparing a compound according to formula (I) may comprise an additional step (step i) between step 2 and step 3 in order to remove palladium from the crude product of the compound of formula (I). The step comprises; forming a slurry comprising an acid and the compound according to formula (I) in a solvent, adding a siloxane compound to said slurry, removing the solvent from the slurry and adding an organic solvent, such as DMF and/or toluene, to the solid formed whereby a mixture is formed and then potassium hydroxide is added to the formed mixture, Alternatively, palladium may be removed from the crude product comprising (I) using a palladium scavenger such as TMT and/or 3-mercaptopropyl ethyl sulfide silica.

The crystalline form of the compound according to formula (I) may also be prepared from an amorphous form of the compound according to formula (I) by dissolving said amorphous form of the compound in a solvent mixture of

dichloromethane/methanol followed by evaporation of the solvent in a rotary evaporator. The amorphous form of the compound of formula (I) may obtained using the process disclosed in WO 2009/095399.

Example 1. Preparation of 5-Bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3-diamine (compound 3)

DMSO (10 L, 11 kg), 2-amino-3,5-dibromopyrazine (1) (4.5 kg, 17.8 mol, 1 eq.), 5- amino indole (2) (3.06 kg, 23.15 mol, 1.3 eq.) and triethylamine (7.4 L, 5.4 kg, 53.36 mol, 3 eq.) were charged to a reactor. The reaction mixture was heated to 95°C while agitated. After 12 hours, the heating was discontinued and the conversion was 88% of 2-amino-3,5-dibromopyrazine. The reaction was heated again to 95°C and

agitated for an additional 2.5 hours. There was no improvement in conversion. The reaction mixture was agitated at ambient temperature overnight. Triethylamine (3.5 kg) was removed under vacuum and the remaining reaction mixture was transferred to a stainless steel container from which it was charged into another reactor.

Subsequently, 18.4 kg of 50% acetic acid (aq.) was introduced over a period of 20 minutes under agitation, followed by purified water (61 L) charged over a period time of 60 minutes. The slurry was then filtered and the isolated material was washed with 2 x 20 L of 1% acetic acid (aq.).

The isolated 3-bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3-diamine) (3) was transferred to a drying cabinet and dried to invariable weight at 40 ±3°C, (19 hours), to afford 4.36 kg, 14.34 mol, 81 % yield, with a purity of 96% by HPLC.

The reaction temperature in the batch record was set to be 130-135°C. However, at 95°C the reaction mixture was at reflux.

Example 2. Preparation of N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3- diamine (compound I)

To a reactor was charged N,N-dimethylformamide (46.7 L, 45 kg), 4-pyridylboronic acid (4) (2.64 kg, 21.5 mol, 1.5 eq.) and 5-bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3- diamine (3) (4.36 kg, 14.3 mol). The reactor was then flushed with nitrogen prior to the charging of Pd(dppf)Cl2-catalyst (0.47 kg, 0.55 mol, 0.04 eq.). To reactor was then charged, over a period of 20 minutes, 24.9 kg of a 2 M solution of potassium carbonate (aq.). The reactor was flushed with nitrogen and heated under agitation to 110-115°C for 1.5 hours, after which 98.3% conversion of (3) was showed. The reaction mixture was quenched by addition of purified water (180 L) under vigorous agitation. The precipitated material was isolated on a hastalloy filter and washed with purified water (50 L), The isolated material was transferred to a drying cabinet and dried to invariable weight at 40 ±3°C (18 hours), to afford a compound of formula (5), i.e. a compound of formula (!) also denominated N-3-(1H-lndol-5-yl)-5-pyhdin-4-yl-pyrazine-2,3-diamine, (3.64 kg, 12.1 mol, 85 % yield).

During the process precipitated material was observed in the solutions, after the reactions, in both steps not previously seen in lab-scale. These impurities were not removed.

Example 3. Purification and crystallisation

In order to remove residual solvents from the material, two consecutive re-precipitations of the material from acetic acid were performed. This also gave crystallinity of the isolated substance. The purification is performed in order to remove palladium.

Purification

To a 1 L round bottomed flask was added 37.8 g of a compound according to formula (I) followed by 600 mL 2 M HOAc (aq.). The material was stirred at RT until a clear, dark red solution was obtained. To the solution was added 30 g Hyflo Super Celite and the slurry was filtered. The filter cake was washed with 25 mL 2 M HOAc

(aq) and 2×35 mL purified water. The obtained filtrate was transferred to a 2 L round bottomed flask containing 950 mL of Me-THF. The mixture was then stirred and heated to 40°C for 30 minutes. To the solution was then added 290 mL 8 M KOH (aq.) at 40°C and pH in the solution was 14.

The aqueous phase was removed and the organic phase washed with 2×100 mL of purified water. The remaining organic phase was then transferred to a 2 L round bottomed flask, followed by 95 mL of DMF, 20 g scavenger 3-Mercaptopropyl ethyl sulphide silica, Phosphonics LTD and 20 g scavenger 2-Mercaptoethyl ethyl sulfide silica purchased from Phosphonics LTD. The solution was vigorously stirred and heated at 60°C. A sample was withdrawn from the slurry after 12 hours, and showed 6 ppm of palladium remaining in the solution. The mixture was allowed to cool and was then filtered to remove the scavenger. The round bottomed flask and filter were rinsed with a mixture of 90 mL Me-THF and 10 mL DMF. Me-THF was then removed on a rotary evaporator and the remaining slurry was azeotropically dried with two portions of 100 mL toluene. To the remaining slurry was then added 85 mL of DMF to a total of 185 mL DMF (5ml DMF/g substance). To the clear solution was then added, slowly, while agitated, 1500 mL of toluene which produced a heavy precipitate. The slurry was filtered off and washed with 2×50 mL of toluene where after the material was dried overnight at 35°C under vacuum to afford 30.9 g of a compound according to formula (I) in a yield of 82%.

Crystallisation:

Example i

1. First re-precipitation

The N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine material (30.9 g) was added to a 1 L round bottomed flask and 450 mL 2 M HOAc (aq.) was added. The slurry was agitated and heated to 40°C for 1 hour, until the material had dissolved. To the solution was then added 158 mL 8 M KOH (aq.) at 40°C. The pH in the solution was 11.4. The slurry was then allowed to cool to 25°C and filtered. The filter cake was washed with 3x 80 mL of purified water and the material was dried overnight at 95°C under vacuum to afford 28.7g N-3-(1H-indol-5-yl)-5-pyridin-4-yl- pyrazine-2,3-diamine in a yield of 93%.

2. Second re-precipitation

N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine material (28.7 g) was added to a 1L round bottomed flask and 430 mL 2 M HOAc (aq) was added. The slurry was agitated and heated to 40°C for 1 hour, until the material had dissolved. To the solution was then added 15 mL 8M KOH (aq) at 40°C. The pH in the solution was 12.3. The slurry was then allowed to cool to 25°C and filtered. The filter cake was washed with 5×50 mL of purified water, and the solid was then dried overnight at 95°C under vacuum to afford 28.3 g N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3- diamine in a yield of 99%.

Example ii

The N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine material (2.1 kg, 7 mol) was added to a reactor, followed by 2M HOAc (aq.) (59.6 L, 60.2 kg) . The solution in the reactor was then heated to 40°C and stirred for 20 minutes. To the clear solution was then charged, slowly, 30% KOH (aq.) (25 kg) under vigorous agitation. The slurry was agitated for 15 minutes. pH in the solution was 6.2, and a total of 1.5 kg 30% KOH (aq.) was then added to the solution to give pH 12.1. The precipitated material was isolated on a Hastelloy filter and washed with purified water (5×30 L). The solid was then transferred to a drying cabinet and dried to invariable weight at 85 ±3°C under vacuum (16 hours; a sample was withdrawn after 16 hours, showing 1400 ppm HOAc and 75 ppm DMF), to afford N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine (2.0 kg, 7 mol, 95 % yield).

Hence, N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine is obtained in an uniform crystalline form, which was achieved by precipitating the product from aqueous acetic acid by introduction of aqueous potassium hydroxide.

Example 5. Synthesis of 5-Bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3-diamine (compound 3)

2-Amino-3,5-dibromopyrazine (45 g, 1.0 eq.), 5-aminoindole (30,6 g, 1.3 eq.), 67.5 mL NEP, i.e. 1-ethyl-2-pyrrolidone, and 74.5 mL triethylamine were added to a 250 mL reactor. The jacket temperature was set to 130°C and the reaction mixture was stirred for 22 h. HPLC after 22 h showed 87% conversion of the 2-amino-3,5-dibromopyrazine. After 24 h HPLC showed 92% conversion and the reaction slurry was cooled to 80°C and quenched by addition of addition of 50% HOAc(aq) and water. The obtained slurry was then allowed to cool to room temperature over night while agitated. The material was isolated on a glass filter funnel and was washed with water. The material was dried at 80 °C under vacuum until dry to afford 71% of the compound 5-bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3-diamine as a dark brown powder. The purity was 99.8% as measured by HPLC.

Example 6. Synthesis of N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine (Compound I)

5-Bromo-N-3-(1H-indol-5-yl)-pyrazine-2,3-diamine (15.0 g, 49 mmol, 1.0 eq.), 4-pyridyl boronic acid (6.6 g, 59 mmol, 1.2 eq.), Pd(OAc)2 (166 mg, 0.74 mmol, 0.015 eq.), DTB-PPS, i.e. 3-(di-tert-butylphosphino)propane-1-sulfonic acid, (199 mg, 0.74 mmol, 0.015 eq.), and DMA, i.e. N,N-dimethylacetamide, (75 mL) were added to a three-necked round-bottomed flask equipped with a mechanical stirrer,

thermometer, and a nitrogen atmosphere. Through a septa was added 2M K2CO3 (aq) (27 ml, 54 mmol, 1.1 eq.) with a syringe. The temperature was increased to 100 °C. Samples for HPLC-analysis of the conversion were drawn and when the conversion had reached 100% the temperature was cooled to 25 °C. At that temperature a water solution of 0.5 M L-cysteine (150 ml) was added by a syringe pump over 1 hour with a rate of 2.5 mL/minute. After 3 hours maturing time at room temperature the material was isolated on a glass filter funnel and was washed with water. The material was dried at 40 °C under vacuum over the weekend, and 15 grams of N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine (101%) were obtained as a brown powder.

Example 7. Purification of N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine (Compound I)

The crude (7.0 g, 23 mmol) and 2M HOAc (98 mL) was added to a 250 mL round-bottomed flask. To this was added TMT, i.e. trithiocyanuric acid, (1.4 g) and SPM32, i.e. 3-mercaptopropyl ethyl sulfide silica, (1.4 g). The mixture was stirred in room temperature for 24 hours. After 24 hour a polish filtration through hyflo super cel was performed. To the clear filtrate was added 50 mL 5 M KOH(aq) under 15 minutes to precipitate the product. After 18 hours maturing time at room temperature the material was isolated on a glass filter funnel and was washed with 2×20 mL water. The first was being a slurry wash and the second a displacement wash. The material was dried at 40 °C under vacuum over the weekend, and 3.9 grams (56%) was obtained as a light yellow powder. The Pd content was 3.7 ppm.

PATENT

US 8436171

PATENT

WO 2016008433

PATENT

WO 2016015604

PATENT

WO 2016015597

PATENT

WO 2016015605

PATENT

WO 2016015598

PATENT

WO 2017146794

PATENT

WO 2017146795

https://patents.google.com/patent/WO2017146795A1/en

PATENT

US 20180071302

REFERENCES

1: Eriksson A, Hermanson M, Wickström M, Lindhagen E, Ekholm C, Jenmalm Jensen A, Löthgren A, Lehmann F, Larsson R, Parrow V, Höglund M. The novel tyrosine kinase  inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia. Blood Cancer J. 2012 Aug 3;2:e81. doi: 10.1038/bcj.2012.28. PubMed PMID: 22864397; PubMed Central PMCID: PMC3432483.

////////////AKN028 , AKN-028 , AKN 028, phase 2, Swedish Orphan Biovitrum,  Akinion Pharmaceuticals,  Acute myeloid leukaemia

NC1=NC=C(C2=CC=NC=C2)N=C1NC3=CC4=C(NC=C4)C=C3

Phase 3-Volasertib for acute myeloid leukaemia in patients ineligible for intensive induction therapy


Volasertib (BI 6727) for  Acute myeloid leukaemia. is a cell cycle kinase inhibitor of polo-like kinases 1, 2 and 3. Volasertib inhibits cancer growth by disrupting cell division and inducing cell death. Volasertib is administered as a 350mg one hour intravenous (IV) infusion on days 1 and 15 of a 28 day cycle in combination with low-dose cytarabine (LDAC), administered via subcutaneous injection (SC) at 20mg twice daily on days 1-10 of a 28 day cycle.

Acute myeloid leukaemia (AML): previously untreated; patients considered ineligible for intensive remission induction therapy – first line; in combination with low-dose cytarabine

volasertib (also known as BI 6727) is a small molecule inhibitor of the PLK1 (polo-like kinase 1) protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.

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