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

International/Other BrandsTruseltiq (BridgeBio Pharma, Inc.)

• 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 FGFR1, FGFR2, FGFR3).^[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

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/en

Example 2: Manufacture of the Free Base of the Compound of Formula I

I

A. 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]⁺; t_R= 1.10 min (gradient J); TLC: R_f = 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: R_f = 0.15 (DCM/MeOH + 1 % NH₃ ^aq, 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 % NH₃ ^aq, 9:1) affords 6.2 g of the title compound as a yellow solid: ESI- MS: 236.0 [MH]⁺; t_R= 2.35 min (purity: 100%, gradient J); TLC: R_f = 0.50 (DCM/MeOH + 1 % NH₃ ^aq, 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 % NH₃ ^aq, 95:5) affords the title compound as a white solid: ESI-MS: 560.0 / 561.9 [MHf; t_R= 3.54 min (purity: 100%, gradient J); TLC: R_f = 0.28 (DCM/MeOH + 1 % NH₃ ^aq, 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

External links

• “Infigratinib”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT02150967 for “A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma” at ClinicalTrials.gov

nfigratinib

Clinical data
Trade names	Truseltiq
Other names	BGJ-398
License data	US DailyMed: Infigratinib
Routes of administration	By mouth
Drug class	Tyrosine kinase inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only [1]
Identifiers
CAS Number	872511-34-7
PubChem CID	53235510
DrugBank	DB11886
ChemSpider	26333103
UNII	A4055ME1VK
KEGG	D11589
CompTox Dashboard (EPA)	DTXSID70236238
Chemical and physical data
Formula	C26H31Cl2N7O3
Molar mass	560.48 g·mol−1
3D model (JSmol)	Interactive image
hide SMILES CCN1CCN(CC1)C2=CC=C(C=C2)NC3=CC(=NC=N3)N(C)C(=O)NC4=C(C(=CC(=C4Cl)OC)OC)Cl
hide InChI InChI=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