Pemigatinib

Pemigatinib

INCB054828

2020/4/17FDA APPROVED, PEMAZYRE

佩米替尼 [Chinese] [INN]

3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,6-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

2H-Pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-8-(4-morpholinylmethyl)-

3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one 

• Originator Incyte Corporation
• Developer Incyte Corporation; Innovent Biologics
• ClassAntineoplastics; Ethers; Fluorobenzenes; Morpholines; Pyridines; Pyrimidinones; Pyrroles; 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 – Myeloproliferative disorders; Lymphoma; Cholangiocarcinoma

• MarketedCholangiocarcinoma
• Phase IIBladder cancer; Lymphoma; Myeloproliferative disorders; Solid tumours; Urogenital cancer
• Phase I/IICancer

• 05 Nov 2020Preregistration for Cholangiocarcinoma (Late-stage disease, Metastatic disease, First line therapy, Inoperable/Unresectable) in Japan (PO) in November 2020
• 05 Nov 2020Incyte Corporation stops enrolment in the FIGHT-205 trial for Bladder cancer due to regulatory feedback
• 26 Oct 2020Preregistration for Cholangiocarcinoma (Second-line therapy or greater, Inoperable/Unresectable, Late-stage disease, Metastatic disease) in Canada (PO)

Pemigatinib, also known as INCB054828, is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. FGFR inhibitor INCB054828 binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells.

Pemigatinib (INN),^[2] sold under the brand name Pemazyre, is a medication for the treatment of adults with previously treated, unresectable locally advanced or metastatic bile duct cancer (cholangiocarcinoma) with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.^[3][4] Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading.^[3]

Pemigatinib belongs to a group of medicines called protein kinase inhibitors.^[5] It works by blocking enzymes known as protein kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs).^[5] FGFRs are found on the surface of cancer cells and are involved in the growth and spread of the cancer cells.^[5] By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer.^[5]

The most common adverse reactions are hyperphosphatemia and hypophosphatemia (electrolyte disorders), alopecia (spot baldness), diarrhea, nail toxicity, fatigue, dysgeusia (taste distortion), nausea, constipation, stomatitis (sore or inflammation inside the mouth), dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin.^[3][4] Ocular (eye) toxicity is also a risk of pemigatinib.^[3][4]

Medical uses

Cholangiocarcinoma is a rare form of cancer that forms in bile ducts, which are slender tubes that carry the digestive fluid bile from the liver to gallbladder and small intestine.^[3] Pemigatinib is indicated for the treatment of adults with bile duct cancer (cholangiocarcinoma) that is locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) or metastatic (when cancer cells spread to other parts of the body) and who have tumors that have a fusion or other rearrangement of a gene called fibroblast growth factor receptor 2 (FGFR2).^[3] It should be used in patients who have been previously treated with chemotherapy and whose cancer has a certain type of abnormality in the FGFR2 gene.^[6]

History

Pemigatinib was approved for use in the United States in April 2020 along with the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.^[3][4][7]

The approval of pemigatinib in the United States was based on the results the FIGHT-202 (NCT02924376) multicenter open-label single-arm trial that enrolled 107 participants with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement who had received prior treatment.^[3][4][6] The trial was conducted at 67 sites in the United States, Europe, and Asia.^[6] During the clinical trial, participants received pemigatinib once a day for 14 consecutive days, followed by 7 days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects.^[3][4][6] To assess how well pemigatinib was working during the trial, participants were scanned every eight weeks.^[3] The trial used established criteria to measure how many participants experienced a complete or partial shrinkage of their tumors during treatment (overall response rate).^[3] The overall response rate was 36% (95% CI: 27%, 45%), with 2.8% of participants having a complete response and 33% having a partial response.^[3] Among the 38 participants who had a response, 24 participants (63%) had a response lasting six months or longer and seven participants (18%) had a response lasting 12 months or longer.^[3][4]

The U.S. Food and Drug Administration (FDA) granted the application for pemigatinib priority review, breakthrough therapy and orphan drug designations.^[3][4][8][9] The FDA granted approval of Pemazyre to Incyte Corporation.^[3]

On 24 August 2018, orphan designation (EU/3/18/2066) was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of biliary tract cancer.^[5] On 17 October 2019, orphan designation EU/3/19/2216 was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.^[10]

PATENT

US 20200281907

 Pemigatinib is described in U.S. Pat. No. 9,611,267, the entirety of which is incorporated herein by reference. Pemigatinib is further described in US Publication Nos.: 2019/0337948 and 2020/0002338, the entireties of which are incorporated herein by reference.

Example 1. Synthesis of Pemigatinib

Step 1: 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

Step 2: 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine

Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 5: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

Step 6: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 7: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (pemigatinib)

PATENT

WO 2019213506

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019213506

PATENT

WO 2019213544

The present disclosure is directed to, inter alia, solid forms, including crystalline forms and amorphous forms, of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)- 1 ,3,4,7 -tetrahydro-2H-pyrrolo [3 ‘,2’ : 5 ,6]pyrido [4,3 -d]pyrimidin-2-one

(Compound 1), and processes and intermediates for preparing the compound. The structure of Compound 1 is shown below.

Compound 1

Compound 1 is described in US Patent No. 9,611,267, the entirety of which is incorporated herein by reference.

Example 1

Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l^, 4,7-tetrahydro-2H-pyrrolo[3^f,2^f:5,6]pyrido[4_r3-d]pyrimidin-2-one (Compound 1) Scheme 1.

Step 1: Synthesis of 4-((4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b ] pyridin-2-yl) methyl) morpholine

To a l-L flask was added 4-chloro-5-(l,3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo [2,3-b] pyridine (50.0 g, 137 mmol) (see, e.g., Example 2) and tetrahydrofuran (THF, 266 g, 300 mL) under N₂. To this mixture at -70 °C was added 2.0 M lithium

diisopropylamide in THF/heptane/ethyl benzene (77.4 g, 95 mL, 190 mmol, 1.4 eq.). The mixture was stirred at -70 °C for 1 h. To the mixture was added /V- formyl morpholine (29.7 g, 258 mmol, 1.9 eq.) in THF (22. 2 g, 25 mL) dropwise. The reaction was done in 30 min after addition. LC/MS showed that the desired product, 4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)- 1 //-pyrrolo [2, 3-61 pyridine-2-carbaldehyde, was formed cleanly. The reaction was quenched with acetic acid (16.4 g, 15.6 mL, 274 mmol, 2.0 eq.) and the dry ice cooling was removed. To the mixture was added morpholine (33.7 g, 33.5 mL, 387 mmol, 2.83 eq.) followed by acetic acid (74.0 g, 70 mL, 1231 mmol, and 9.0 eq.) at 0 °C (internal temperature rose from 0 °C to 18 °C) and stirred overnight. Sodium triacetoxyborohydride (52.50 g, 247.7 mmol, 1.8 eq.) was added and the reaction mixture temperature rose from 20 °C to 32 °C. The mixture was stirred at room temperature for 30 min. HPLC & LC/MS indicated the reaction was complete. Water (100 g, 100 mL) was added followed by 2.0 M sodium carbonate (Na₂C0₃) in water (236 g, 200 mL, 400 mmol, 2.9 eq.) slowly (off gas!). The mixture was stirred for about 30 min. The organic layer was separated and water (250 g, 250 mL) and heptane (308 g, 450 mL) were added. The resulting slurry was stirred for 1 h and the solid was collected by filtration. The wet cake was washed with heptane twice (75.00 mL x 2, 51.3 g x 2) before being dried in oven at 50 °C overnight to give the desired product, 4-((4-chloro-5-( 1 3-dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-2-yl)methyl)morpholine as a light brown solid (52.00 g, 81.8 % yield): LCMS calculated for C21H23CIN2O5S [M+H]⁺: 464.00; Found: 464.0; ftf NMR ^OO MHz, DMSO-de) d 8.48 (s, 1 H), 8.38 (m, 2H), 7.72 (m, 1H), 7.64 (m, 2H), 6.83 (s, 1H), 6.13 (s, 1H), 4.12 (m, 2H), 4.00 (m, 2H), 3.92 (s, 2H), 3.55 (m, 4H), 2.47 (m, 4H).

Step 2: Synthesis of 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b] pyridine-5 -carbaldehyde

To a 2 L reactor with a thermocouple, an addition funnel, and a mechanical stirrer was charged 4-((4-chloro-5 -(1 ,3 -dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo [2,3 -6]pyridin-2-yl)methyl)morpholine (20.00 g, 43.1 mmol) and dichloromethane (265 g, 200 mL) at room temperature. The resulting mixture was stirred at room temperature (internal temperature

was 19.5 °C) to achieve a solution. To the resulting solution was added an aqueous hydrochloric acid solution (0.5 M, 240 g, 200.0 ml, 100 mmol, 2.32 eq.) at room temperature in 7 min. After over 23 h agitations at room temperature, the bilayer reaction mixture turned into a thick colorless suspension. When HPLC showed the reaction was complete, the slurry was cooled to 0-5 °C and aqueous sodium hydroxide solution (1 N, 104 g, 100 mL, 100 mmol, and 2.32 eq.) was added in about 10 min to adjust the pH of the reaction mixture to 10-11. «-Heptane (164 g, 240 mL) was added and the reaction mixture and the mixture were stirred at room temperature for 1 h. The solid was collected by filtration and the wet cake was washed with water (2 x 40 mL), heptane (2 x 40 ml) before being dried in oven at 50 °C under vacuum to afford the desired product, 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-/i |pyridine-5-carbaldehyde as a light brown solid (16.9 g, 93% yield): LCMS calculated for C19H19CIN3O4S [M+H]⁺: 420.00; Found: 420.0; ¾ NMR (400 MHz, DMSO-de) d 10.33 (s, 1H), 8.76 (s, 1 H), 8.42 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 6.98 (s, 1H), 3.96 (m, 2H), 3.564 (m, 4H), 2.51 (m, 4H).

Step 3: Synthesis ofN-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-h] pyridin-5-yl) methyl) -2, 6-difluoro-3,5-dimethoxyaniline

To a 2-L reactor equipped with a thermocouple, a nitrogen inlet and mechanical stirrer were charged AOV-dimethyl formamide (450 mL, 425 g), 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridine-5-carbaldehyde (30.0 g, 71.45 mmol) and 2,6-difluoro-3,5-dimethoxyanihne (14.2 g, 75.0 mmol). To this suspension (internal temperature 20 °C) was added chlorotrimethylsilane (19.4 g, 22. 7 mL, 179 mmol) dropwise in 10 min at room temperature (internal temperature 20-23 °C). The suspension changed into a solution in 5 min after the chlorotrimethylsilane addition. The solution was stirred at room temperature for 1.5 h before cooled to 0-5 °C with ice-bath. Borane-THF complex in THF (1.0 M, 71.4 mL, 71.4 mmol, 64.2 g, 1.0 eq.) was added dropwise via additional funnel over 30 min while maintaining temperature at 0-5 °C. After addition, the mixture was stirred for 4 h. Water (150 g, 150 mL) was added under ice-bath cooling in 20 min, followed by slow addition of ammonium hydroxide solution (28% N¾, 15.3 g, 17 ml, 252 mmol, 3.53 eq.) to pH 9-10 while maintaining the temperature below 10 °C. More water (250 mL, 250 g) was added through the additional funnel. The slurry was stirred for 30 min and the solids were collected by filtration. The wet cake was washed with water (90 g x 2, 90 ml x 2) and heptane (61.6 g x2, 90 ml x 2). The product w as suction dried overnight to give the desired product L^G-((4-chloro-2-(morphohnomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-Z>]pyridin-5-yl)methyl)-2,6- difluoro-3,5-dimethoxyaniline (41.6 g, 96% yield): LCMS calculated for C₂₇H₂₈ClF₂N40₅S[M+H]⁺: 593.10; Found: 593.1 ; ¾ NMR (400 MHz, DMSO-d₆) 5 8.36 (m, 2H), 8.28 (s, 1H), 7.72 (m, 1H), 7.63 (m, 2H), 6.78 (s, 1H), 6.29 (m, 1H), 5.82 (m, 1H), 4.58 (m, 2H), 3.91 (s, 2H), 3.76 (s, 6H), 3.56 (m, 4H), 2.47 (m, 4H).

Step 4: Synthesis of l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-b ] pyridin-5-yl) methyl)-! -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea

To a 2-L, 3-neck round bottom flask fitted with a thermocouple, a nitrogen bubbler inlet, and a magnetic stir were charged /V-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (67.0 g, 113 mmol) and acetonitrile (670 ml, 527 g). The suspension was cooled to 0-5 °C.

To the mixture was charged ethyl isocyanate (17.7 mL, 15.9 g, 224 mmol, 1.98 eq.) over 30 sec. The temperature stayed unchanged at 0.7 °C after the charge. Methanesulfonic acid (16.1 mL, 23.9 g, 248 mmol, 2.2 eq.) was charged dropwise over 35 min while maintaining the temperature below 2 °C. The mixture was warmed to room temperature and stirred overnight. At 24 h after addition showed that the product was 93.7%, unreacted SM was 0.73% and the major impurity (bis-isocyanate adduct) was 1.3%. The mixture was cooled with an ice-bath and quenched with sodium hydroxide (NaOH) solution (1.0M, 235 mL, 244 g, 235 mmol, 2.08 eq.) over 20 min and then saturated aqueous sodium bicarbonate

(NaHCCh) solution (1.07 M, 85 mL, 91 g, 0.091 mol, 0.80 eq.) over 10 min. Water (550 mL, 550 g) was added and the liquid became one phase. The mixture was stirred for 2 h and the solids were collected by filtration, washed with water (165 mL, 165 g) to give l-((4-chloro-2-(morpholinomethyl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo| 2.3-6 |p\ ri din-5 -y l (methy l )- 1 -(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea ( 70.3 g, 93.7% yield).

The crude l-((4-chloro-2-(morpholinomethyl)-l -(phenylsulfonyl)- li/-pyrrolo [2, 3-61 pyridin-5-yl) methyl)- 1 -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea (68.5 g, 103 mmol) was added in to acetonitrile (616 mL, 485 g). The mixture was heated 60-65 °C and an amber colored thin suspension was obtained. The solid was filtered off with celite and the celite was washed with acetonitrile (68.5 mL, 53.8 g). To the pale yellow filtrate was added water (685 g, 685 ml) to form a slurry. The slurry was stirred overnight at room temperature and filtered. The solid was added to water (685 mL, 685 g) and stirred at 60 °C for 2 h. The solid was filtered and re-slurred in heptane (685 mL, 469 g) overnight. The product was dried in an oven at 50 °C under vacuum for 48 h to afford l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-difluoro-3.5-

dimethoxyphenyl)-3-ethylurea as a colorless solid (62.2 g, 90.8% yield, 99.9% purity by HPLC area%). KF was 0.028%. Acetonitrile (by ‘H NMR) was about 1.56%, DCM (by ‘H NMR) 2.0%: LCMS calculated for C30H33CIF2N5O6S [M+H]⁺: EM: 664.17; Found: 664.2; ¾ NMR (400 MHz, DMSO-de) d 8.33 (m, 2H), 8.31 (s, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 6.96 (m, 2H), 6.73 (s, 1H), 6.43 (m, 1H), 4.87 (s, 2H), 3.90 (s, 2H), 3.77 (s, 6H), 3.54 (m, 4H),

3.03 (m, 2H), 2.46 (m, 4H), 0.95 (m, 3H).

Step 5: Synthesis of 3-(2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l, 3, 4, 7-tetrahydro-2H-pyrrolo[ 3 2’:5, 6 ]pyrido[ 4, 3-d]pyrimidin-2-one

To a 2000 mL flask equipped with a thermal couple, a nitrogen inlet, and a mechanical stirrer were charged dry l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-1 //-pyrrolo| 2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-dinuoro-3.5-dimetho\yphenyl)-3-ethylurea (30.0 g, 45.2 mmol, KF=0. l l%) and tetrahydrofuran (1200 mL, 1063 g). To this suspension at room temperature was charged 1.0 M lithium hexamethyldisilazide in THF (62.3 mL, 55.5 g, 62.3 mmol, 1.38 eq). The mixture turned into a solution after the base addition. The reaction mixture was stirred for 2 h and HPLC shows the starting material was not detectable. To this mixture was added 1.0 M hydrochloric acid (18.1 mL, -18.1 g. 18.1 mmol, 0.4 eq.). The solution was concentrated to 600 mL and water (1200 mL, 1200 g) was added. Slurry was formed after water addition. The slurry was stirred for 30 min at room temperature and the solid was collected by filtration. The wet cake was washed with water twice (60 mLx2,

60 gx2) and dried at 50 °C overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidin-2-one as a light brown solid (26.58 g, as-is yield 93.7%): THF by ‘H NMR 0.32%, KF 5.26%, adjusted yield was 88.5%: LCMS calculated for C30H32F2N5O6S [M+H]⁺: EM: 628.20; Found: 628.2; ¾ NMR (400 MHz, DMSO-de) d 8.41 (m, 2H), 8.07 (s, 1H), 7.70 (m, 1H), 7.63 (m, 2H), 7.05 (m, 1H), 6.89 (s, 1H), 4.76 (s, 2H), 4.09 (m, 2H), 3.93 (s, 2H), 3.89 (s, 6H), 3.60 (m, 4H), 2.50 (m, 4H), 1.28 (m, 3H).

Step 6: Synthesis of 3-( 2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-1,3, 4, 7 -tetrahydro-2H-pyrrolo [ 3 ‘, 2 5, 6 ]pyrido[ 4, 3-dJpyrimidin-2-one

To a stirring suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2i/-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (10.0 g, 15.93 mmol) in l,4-dioxane (100 ml, 103 g) in a 500 mL flask equipped with a nitrogen inlet, a condenser, a thermocouple and a heating mantle was added 1 M aqueous sodium hydroxide (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75 °C for 18 h. LCMS showed the reaction was complete. Water (100 mL, 100 g) was added to give a thick suspension. This slurry was stirred at room temperature for 1 h and filtered. The cake was washed with water (3 x 10 mL, 3 x 10 g) and heptane (2 x 10 mL, 2 x 6.84 g). The cake was dried overnight by pulling a vacuum through the filter cake and then dried in an oven at 50 °C under vacuum overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5, 6]pyrido[4,3-d]pyrimidin-2-one (6.8 g, 87.6% yield): LCMS calculated for C24H28F2N5O4 [M+H]⁺: 488.20; Found: 488.2.

PATENT

US 20130338134

https://patents.google.com/patent/US20130338134A1/en

• [0831]
  

Step 1: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

• [0832]
  
• [0833]
  To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (Example 49, Step 3: 900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). The resulting mixture was stirred at 0° C. for 30 min then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h at which time LC-MS showed the reaction completed to the desired product. The reaction was quenched with saturated NH₄Cl solution and diluted with water. The white precipitate was collected via filtration then washed with water and hexanes, dried to afford the desired product (1.2 g, 98%) as a white solid which was used in the next step without further purification. LC-MS calculated for C₂₅H₂₃F₂N₄O₅S [M+H]⁺ m/z: 529.1; found: 529.1.

Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

• [0834]
  
• [0835]
  To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was added freshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 30 min then quenched with water and extracted with EtOAc. The organic extracts were combined then washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography eluted with 0 to 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). LC-MS calculated for C₂₆H₂₃F₂N₄O₆S (M+H)⁺ m/z: 557.1; found: 556.9.

Step 3: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

• [0836]
  
• [0837]
  To a solution 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred at room temperature overnight then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 h at which time LC-MS showed the reaction went to completion to the desired product. The reaction was quenched with saturated NaHCO₃ then extracted with ethyl acetate (EtOAc). The organic extracts were combined then washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography eluted with 0 to 40% EtOAc in DCM to give the desired product as a yellow solid (1.85 g, 95%). LC-MS calculated for C₃₀H₃₂F₂N₅O₆S (M+H)⁺ m/z: 628.2; found: 628.0.

Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

• [0838]
  To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₄H₂₈F₂N₅O₄ (M+H)⁺ m/z: 488.2; found: 488.0. ¹H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).

PATENTS

References

1. ^ “Pemigatinib (Pemazyre) Use During Pregnancy”. Drugs.com. 11 August 2020. Retrieved 24 September 2020.
2. ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80”. WHO Drug Information. 32 (3): 479. hdl:10665/330907.
3. ^ Jump up to:^{a b c d e f g h i j k l m n o} “FDA Approves First Targeted Treatment for Patients with Cholangiocarcinoma, a Cancer of Bile Ducts”. U.S. Food and Drug Administration (FDA) (Press release). 17 April 2020. Retrieved 17 April 2020.  This article incorporates text from this source, which is in the public domain.
4. ^ Jump up to:^{a b c d e f g h} “FDA grants accelerated approval to pemigatinib for cholangiocarcinoma”. U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 20 April 2020.  This article incorporates text from this source, which is in the public domain.
5. ^ Jump up to:^{a b c d e} “EU/3/18/2066”. European Medicines Agency (EMA). 19 December 2018. Retrieved 20 April 2020.  This article incorporates text from this source, which is in the public domain.
6. ^ Jump up to:^a b c d “Drug Trials Snapshot: Pemazyre”. U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 5 May 2020.  This article incorporates text from this source, which is in the public domain.
7. ^ “Pemazyre: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 21 April 2020.
8. ^ “Pemigatinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
9. ^ “Pemigatinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
10. ^ “EU/3/19/2216”. European Medicines Agency (EMA). 23 January 2020. Retrieved 19 April 2020.  This article incorporates text from this source, which is in the public domain.

Further reading

• Roskoski R (January 2020). “The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder”. Pharmacol. Res. 151: 104567. doi:10.1016/j.phrs.2019.104567. PMID 31770593.

External links

• “Pemigatinib”. Drug Information Portal. U.S. National Library of Medicine.
• “Pemigatinib”. National Cancer Institute.
• Clinical trial number NCT02924376 for “Efficacy and Safety of Pemigatinib in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Who Failed Previous Therapy – (FIGHT-202)” at ClinicalTrials.gov

/////////Pemigatinib, 佩米替尼 , PEMAZYRE, FDA 2020, 2020 APPROVALS, INCB054828, INCB 054828, Orphan Drug Status, Myeloproliferative disorders, Lymphoma,  Cholangiocarcinoma, INCYTE

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