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Infigratinib phosphate

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Infigratinib phosphate (USAN).png
Infigratinib.png
Structure of INFIGRATINIB PHOSPHATE

Infigratinib phosphate

FDA APPR Truseltiq 2021/5/28

インフィグラチニブリン酸塩;

3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylurea;phosphoric acid

  • BGJ 398
  • BGJ-398
  • BGJ398
  • NVP-BGJ398
  • WHO 10032

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Infigratinib acetate03D0789NYP1310746-17-8XHCQHOGMMJKLRU-UHFFFAOYSA-N
Infigratinib hydrochlorideWY8VD4RV771310746-15-6VBAIJSJSFCXDJB-UHFFFAOYSA-N
Infigratinib mesylateE223Z0KWCC1310746-12-3BXJJFNXYWJLBOS-UHFFFAOYSA-N
Infigratinib phosphate58BH47BV6S1310746-10-1GUQNHCGYHLSITB-UHFFFAOYSA-N

International/Other BrandsTruseltiq (BridgeBio Pharma, Inc.)

FormulaC26H31Cl2N7O3. H3PO4
CAS1310746-10-1FREE form 872511-34-7
Mol weight658.4706
  • Originator Novartis
  • Developer Array BioPharma; Novartis; Novartis Oncology; QED Therapeutics
  • Class Aniline compounds; Antineoplastics; Chlorobenzenes; Methylurea compounds; Phenyl ethers; Piperazines; Pyrimidines; Small molecules
  • Mechanism of Action Type 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type 4 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists
  • Orphan Drug Status Yes – Cholangiocarcinoma
  • RegisteredCholangiocarcinoma
  • Phase IIIBladder cancer; Urogenital cancer
  • Phase IIAchondroplasia; Head and neck cancer
  • Phase IBreast cancer
  • Phase 0Glioblastoma
  • DiscontinuedHaematological malignancies; Malignant melanoma; Solid tumours
  • 31 May 2021Clinical development is ongoing in Bladder cancer (QED Therapeutics pipeline, May 2020)
  • 28 May 2021Registered for Cholangiocarcinoma (Second-line therapy or greater, Metastatic disease, Inoperable/Unresectable, Late-stage disease) in USA (PO) – First global approval (under Project Orbis using RTOR program)
  • 28 May 2021Efficacy and safety data from a phase II trial in Cholangiocarcinoma released by QED Therapeutics

Infigratinib, sold under the brand name Truseltiq, is an anti-cancer medication used to treat cholangiocarcinoma (bile duct cancer).[1][2]

Infigratinib is a receptor tyrosine kinase inhibitor (and more specifically an inhibitor of the fibroblast growth factor receptors FGFR1FGFR2FGFR3).[3][1][2] It was designated an orphan drug by the U.S. Food and Drug Administration (FDA) in 2019,[4] and it was approved for medical use in the United States in May 2021.[2]

Infigratinib is a pan-fibroblast growth factor receptor (FGFR) kinase inhibitor. By inhibiting the FGFR pathway, which is often aberrated in cancers such as cholangiocarcinoma, infigratinib suppresses tumour growth.1 Cholangiocarcinoma is the most common primary malignancy affecting the biliary tract and the second most common primary hepatic malignancy.2 Infitratinib is a pan-FGFR inhibitor, as it is an ATP-competitive inhibitor of all four FGFR receptor subtypes.1

On May 28, 2021, the FDA granted accelerated approval to infigratinib – under the market name Truseltiq – for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test.5 This approval follows pemigatinib, another FGFR inhibitor approved by the FDA for the same therapeutic indication.

Infigratinib is indicated for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test.4

Medical uses

Infigratinib is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma (bile duct cancer) with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.[1]

PAPER

Journal of Medicinal Chemistry (2011), 54(20), 7066-7083.

https://pubs.acs.org/doi/10.1021/jm2006222

Abstract Image

A novel series of N-aryl-N′-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.

PATENT

US 9067896

PATENT

WO 2020243442

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020243442

 In 2018, it was estimated that 150,350 new patients would be diagnosed with urinary system cancer: 81,190 urinary bladder; 65,340 kidney and renal pelvis; and, 3,820 ureter and other urinary organs. Excluding non-urothelial kidney cancers, approximately 5 to 10% of all urothelial carcinomas are upper tract urothelial carcinomas (UTUC). The incidence of UTUC is 2 to 3 times greater in men than women (Siegel et al, 2018; Roupret et al, 2015).

[0003] In contrast to invasive urinary bladder cancer (UCB), UTUC has a more aggressive clinical course. At the time of diagnosis, 60% of patients with UTUC have invasive cancer compared to 15% to 25% of patients with UCB (Roupret et al, 2015; Margulis et al., 2009). Thirty-six percent have regional disease and 9% distant disease (Raman et al., 2010). A large retrospective review of 1363 patients with UTUC who underwent radical nephroureterectomy (RNU) at 12 centers demonstrated that 28% of the total population had recurrence after RNU (Margulis et al, 2009).

[0004] To reduce the morbidity and mortality in patients with UTUC, neoadjuvant or adjuvant treatment is needed. The POUT study, a large randomized trial in UTUC supports the use of standard-of-care adjuvant cisplatin-based chemotherapy (Birtle et al., 2020). Because many patients with UTUC will have one remaining kidney following RNU and frequently have other significant co-morbid conditions, cisplatin-based therapy is not well tolerated (NCCN Guidelines Version 3, 2018). Renal function before and after RNU greatly limits the number of patients with UTUC who are eligible for platinum-based neoadjuvant or adjuvant therapy. Therefore, targeted therapies are needed for treating UTUC (Lane et al., 2010).

[0005] Despite demonstrated survival benefit for neoadjuvant treatment of invasive UCB, many patients with invasive UCB are unlikely to receive (neo)adjuvant cisplatin-based chemotherapy, due in part to cisplatin ineligibility (Porter et al., 2011). In addition, residual disease following neoadjuvant therapy is associated with a poor prognosis (Grossman et al, 2003). Therefore,

there remains an unmet need for a substantial proportion of patients with invasive UCB who are ineligible or refuse to receive cisplatin-based adjuvant chemotherapy or who have residual disease following neoadjuvant therapy.

 Infigratinib, as depicted in formula (I), is a selective and ATP-competitive pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, also known as 3-(2,6-dichloro-3,5-dimethoxyphenyl)- 1 – { 6- [4-(4-ethyl- 1 -piperazin- 1 -yljphenylamino] -pyrimidinyl-4-yl } – 1 -methylurea. Infigratinib selectively inhibits the kinase activity of FGFR1, FGFR2, FGFR3, and

FGFR4.

PATENT

WO 2011071821

https://patents.google.com/patent/WO2011071821A1/en3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-l-{6-[4-(4-ethyl-piperazin-l-yl)- phenylamino]-pyrimidin-4-yl}-l -methyl-urea (described in USSN 11/570983, filed June 23, 2005, and incorporated by reference in its entirety herein) has the structure of Formula I:

Figure imgf000002_0001

The compound of Formula I is a protein kinase inhibitor and is useful in the treatment of proliferative diseases mediated by protein kinases. In particular, the compound of Formula I inhibits FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret kinases. It is therefore useful in the treatment of cancers including AML, melanocyte neoplasia, breast cancer, colon cancer, lung cancer (especially small-cell lung cancer), cancer of the prostate or Kaposi’s sarcoma.[0003] It is well known that the crystalline form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of the drug’s ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids and in vivo bioavailability. Crystalline forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular crystalline form.Crystalline forms may also include different hydrates or solvates of the same compound. In deciding which form is preferable, the numerous properties of the forms are compared and the preferred form chosen based on the many physical property variables. It is entirely possible that one form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc. are deemed to be critical. In other situations, a different form may be preferred for greater dissolution rate and/or superior bioavailability. It is not yet possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in a therapeutic composition, or which polymorphs will display such desirable properties.Example 2: Manufacture of the Free Base of the Compound of Formula I

Figure imgf000022_0001

IA. N- [4-(4-ethyl-piperazin- 1 -yl)-phenyl] -N’ -methyl-pyrimidine-4,6-diamine[0077] A mixture of 4-(4-ethylpiperazin-l-yl)-aniline (1 g, 4.88 mmol), (6-chloro- pyrimidin-4-yl)-methyl-amine (1.81 g, 12.68 mmol, 1.3 eq.), and 4N HC1 in dioxane (15 ml) is heated in a sealed tube to 150°C for 5h. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR= 1.10 min (gradient J); TLC: Rf = 0.21 (DCM/MeOH, 93:7).B. 4-(4-Ethylpiperazin- 1 -yl)-aniline[0078] A suspension of l-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred for 7 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [MH]+; TLC: Rf = 0.15 (DCM/MeOH + 1 % NH3aq, 9:l).C. 1 -Ethyl-4-(4-nitro-phenyl)-piperazine[0079] A mixture of l-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to 80°C for 15h. After cooling to RT, the reaction mixture is diluted with water and DCM/MeOH, 9:1. The aqueous layer is separated and extracted with DCM/MeOH, 9:1. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography(DCM MeOH + 1 % NH3aq, 9:1) affords 6.2 g of the title compound as a yellow solid: ESI- MS: 236.0 [MH]+; tR= 2.35 min (purity: 100%, gradient J); TLC: Rf = 0.50 (DCM/MeOH + 1 % NH3aq, 9:1).D. (6-chloro-pyrimidin-4-yl)-methyl-amine[0080] This material was prepared by a modified procedure published in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of commercially available 4,6- dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol (40.1 ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperature does not rise above 50°C. After completion of the addition the reaction mixture was stirred for lh at room temperature. Then, water (50 ml) is added and the suspension formed is chilled in an ice bath to 5°C. The precipitated product is filtered off, washed with cold isopropanol/water 2:1 (45 ml) and water. The collected material is vacuum dried over night at 45°C to afford the title compound as colorless powder: tR = 3.57 min (purity: >99%, gradient A), ESI-MS: 144.3 / 146.2 [MH]+.E. (3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-l-{6-[4-(4-ethyl-piperazin-l-yl)-phenylamino]- pyrimidin-4-yl} – 1 -methyl-urea)[0081] The title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl- isocyanate (1.25 eq.) to a solution of N-[4-(4-ethyl-piperazin-l-yl)-phenyl]-N’-methyl- pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) in toluene and stirring the reaction mixture for 1.5h at reflux. Purification of the crude product by silica gel column chromatography (DCM MeOH + 1 % NH3aq, 95:5) affords the title compound as a white solid: ESI-MS: 560.0 / 561.9 [MHf; tR= 3.54 min (purity: 100%, gradient J); TLC: Rf = 0.28 (DCM/MeOH + 1 % NH3aq, 95:5). Analysis: C26H3iN703Cl2, calc. C 55.72% H 5.57% N 17.49% O 8.56% CI 12.65%; found C 55.96% H 5.84% N 17.17% O 8.46% CI 12.57%. The title compound was characterized by XRPD, thermal and other methods as described below. Example 3: Manufacture of the Monophosphoric Acid Salt Form A of the Compound of Formula I.[0082] To a round bottom flask was added 3-(2,6-dichloro-3,5-dimethoxyphenyl)-l-{6-[4- (4-ethylpiperazin-l-yl)phenylamino]-pyrimidine-4-yl}-l -methyl-urea (134 g, 240 mmol) and IPA (2000 ml). The suspension was stirred and heated to 50°C and a solution of phosphoric acid (73.5 g, 750 mmol) in water (2000 ml) added to it portions. The mixture was stirred at 60°C for 30 min. and filtered through a polypropylene pad. The pad was washed with warm IP A/water (1:1, 200 ml) and the filtrates were combined. To this clear solution, IPA (6000 ml) was added and the mixture was stirred under reflux for 20 min, cooled slowly to room temperature (25° C), and stirred for 24 hours. The white salt product was collected by filtration, washed with IPA (2 χ 500 ml) and dried in the oven at 60° C under reduced pressure for two days to provide the phosphate salt (form A) 110 g. Yield 70%. Purity >98% by HPLC. Analysis: C26H34 707C12P, calc. C 47.42% H 5.20% N 14.89% O 17.01% CI 10.77% P 4.70%; found C 47.40% H 5.11% N 14.71% O 17.18% CI 10.73% P 4.87%. The title compound was characterized by XRPD, thermal and other methods as described below.

References

  1. Jump up to:a b c d “Infigratinib prescribing information” (PDF). U.S. Food and Drug Administration. May 2021.
  2. Jump up to:a b c “BridgeBio Pharma’s Affiliate QED Therapeutics and Partner Helsinn Group Announce FDA Approval of Truseltiq (infigratinib) for Patients with Cholangiocarcinoma” (Press release). BridgeBio Pharma. 28 May 2021. Retrieved 28 May 2021 – via GlobeNewswire.
  3. ^ Botrus G, Raman P, Oliver T, Bekaii-Saab T (April 2021). “Infigratinib (BGJ398): an investigational agent for the treatment of FGFR-altered intrahepatic cholangiocarcinoma”. Expert Opinion on Investigational Drugs30 (4): 309–316. doi:10.1080/13543784.2021.1864320PMID 33307867.
  4. ^ “Infigratinib Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 11 September 2019. Retrieved 30 May 2021.

External links

EfficacyAntineoplastic, Angiogenesis inhibitor
  DiseaseCholangiocarcinoma (FGFR2 fusion or other rearrangement)
Clinical data
Trade namesTruseltiq
Other namesBGJ-398
License dataUS DailyMedInfigratinib
Routes of
administration
By mouth
Drug classTyrosine kinase inhibitor
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number872511-34-7
PubChem CID53235510
DrugBankDB11886
ChemSpider26333103
UNIIA4055ME1VK
KEGGD11589
CompTox Dashboard (EPA)DTXSID70236238 
Chemical and physical data
FormulaC26H31Cl2N7O3
Molar mass560.48 g·mol−1
3D model (JSmol)Interactive image
hideSMILESCCN1CCN(CC1)C2=CC=C(C=C2)NC3=CC(=NC=N3)N(C)C(=O)NC4=C(C(=CC(=C4Cl)OC)OC)Cl
hideInChIInChI=1S/C26H31Cl2N7O3/c1-5-34-10-12-35(13-11-34)18-8-6-17(7-9-18)31-21-15-22(30-16-29-21)33(2)26(36)32-25-23(27)19(37-3)14-20(38-4)24(25)28/h6-9,14-16H,5,10-13H2,1-4H3,(H,32,36)(H,29,30,31)Key:QADPYRIHXKWUSV-UHFFFAOYSA-N

////////Infigratinib phosphate, FDA 2021 APPROVALS 2021,  Truseltiq, インフィグラチニブリン酸塩 , Orphan Drug,  Cholangiocarcinoma, BGJ 398, BGJ-398, BGJ398, NVP-BGJ398, WHO 10032

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DR ANTHONY CRASTO

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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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