Friday, 28 August 2026

Pariceract

 

Pariceract

CAS 1919820-28-2

MFC20H30N4O2 MW358.5 g/mol

5,7-dimethyl-N-[trans-4-(pentyloxy)cyclohexyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
beta-glucocerebrosidase activator, antiparkinsonian, BIA 28-6156, LTI-291, LIT291, LTI-00291, BIA28-6156, LTI- 91, LIT 291, LTI 00291, Gcase activator 1, V9WUN9UUU8

Pariceract (INNTooltip International Nonproprietary Name; developmental code name BIA 28-6156 or LTI-291) is a β-glucocerebrosidase (GCase) activator or positive allosteric modulator which is under development for the treatment of Parkinson's disease.[1][2][3][4][5] It is taken orally.[1] GCase is a lysosomal enzyme encoded by the gene GBA1.[4][5] Loss-of-function mutations in this gene are thought to promote α-synuclein accumulation and are among the leading genetic risk factors for Parkinson's disease.[4][5][6] As such, activation of GCase might provide a disease-modifying therapy for treatment of Parkinson's disease.[4][5] Pariceract was first described in the scientific literature by 2017.[6] It was originated by Lysosomal Therapeutics and is under development by Lysosomal Therapeutics and Bial.[1][2][3] As of October 2025, it is in phase 2 clinical trials.[1][2][3]

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=F663B00AA9F0AD415A4FD77C12CCF971.wapp1nC?docId=US467040657&_cid=P12-MS418O-86059-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025198486&_cid=P12-MS41BL-88178-1

Example 3 - Preparation of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound of Formula (A))

[00168] Part 1 : Under nitrogen atmosphere, purified water (41.32 L, 2.0 V) and NaOH (5.99 kg, 1.4 eq.) were charged to a reactor at 20 °C; after this, purified water (10.33 L, 0.5 V) was added to wash the walls and the solution was left stirring for 0.5-3 hours until the solid was dissolved; the solution was transferred from the reactor to a clean drum.

[00169] Part 2: Under nitrogen atmosphere, purified water (30.99 L, 1.5 V) and NaCI

(2.27 kg, 0.11 wt.%) were charged to the reactor at 20 °C; after this, purified water (10.33 L, 0.5 V) was charged to wash the walls and the solution was left stirring for 0.5-3 hours until the solid was dissolved; the solution was transferred from the reactor to a clean drum.

[00170] Part 3: Under nitrogen atmosphere, purified water (62 L, 3.0 V) and the compound of Formula (IV) in HCI salt form (27.84 kg, 1.15 eq.), from step 3 of Example 1, were charged to the reactor at 25 °C; after this, purified water (16.5 L, 0.8 V) was charged to wash the walls and then MTBE (165.28 L, 8.0 V) was charged to the reactor and the solution was left stirring for 0.5-1 hour; after this, the solution was cooled down to 5 °C and the NaOH (5.99 kg, 1.4 eq.) aqueous solution (prepared in advance in part 1) was charged in 0.5-2 hours; then, the temperature of the reaction mixture was increased to 25 °C and it was left stirring for 1-3 hours. The agitation was stopped, and the phases were separated. The organic phase was washed two times: the first with 5% NaCI aqueous (41.32 L, 2.0 V) prepared in advance in part 2 and the second with purified water (41.32 L, 2.0 V). Then, the organic phase was concentrated under vacuum until the total volume was 51.65 L - 72.31 L (2.5-3.5 V). MTBE (62 L, 3.0 V) was charged to the reactor and the solution was concentrated under vacuum until the total volume was 51.65 L - 72.31 L (2.5-3.5 V).

[00171] Part 4: Under nitrogen atmosphere, DMF (92.97 L, 4.5 V), the compound of Formula (VII) (20.66 kg, 1.0 eq.), from step 2 of Example 2, and l,l'-carbonyldiimidazole (21.07 kg, 1.2 eq.) were charged to the reactor at 25 °C; DMF (10.33 L, 0.5 V) was added to wash the walls. The temperature of the reaction mixture was increased to 28 °C, and it was left stirring for 2-5 hours. If necessary, charge additional l,l'-carbonyldiimidazole (1.76 kg, 0.1 eq.) to the reactor at 28 °C and leave it stirring for 2-5 hours. After this, purified water (1.178 kg, 0.6 eq.) was charged to the reactor and it was left stirring for 1-4 hours. Under nitrogen atmosphere, the compound of Formula (IV) Free Base in MTBE solution (27.84 kg ,1.15 eq.), from Part 3, was charged to the reactor in 1-2 hours; MTBE (4.132 L, 0.2 V) was charged to rinse the drum and then it was transferred to the reactor. The solution was left stirring for 16-24 hours and then DMF (20.66 L, 1.0 V) was charged to the reactor. The solution was concentrated under vacuum until the total volume was 123.96 L - 165.28 L (6.0-8.0 V).

[00172] Part 5: The reaction mixture temperature was increased to 40 °C and purified water (41.32 L, 2.0 V) was added dropwise to the reactor in 1-2 hours; the reaction mixture was left stirring for 2-5 hours before cooling down to 20 °C; the slurry was left stirring for 10-15 hours and then purified water (82.64 L, 4.0 V) was added dropwise in 1-3 hours to the reactor; the slurry was left stirring for 3-6 hours. After this, the solid was centrifuged and the cake was washed with DMF:H2O (1: 1, 20.66 L, 1.0 V x 2) two times and then washed with purified water (41.32 L, 2.0 V) one time*. The cake was dried under vacuum at 55 °C for 15-24 hours and 32.35 kg were obtained (83.3% yield and 100% purity by HPLC).

* In one campaign, at this stage the wet cake was dissolved in acetonitrile (25.5 V), the temperature adjusted to 27°C and stirred for 2-6 hours. The solution was filtered via a polish filter (0.22 pirn). The solution was concentrated under vacuum to 5.0 - 7.0 V at a temperature below 35°C. The temperature was adjusted to 20°C and purified water was added (14.0 V) in 2-4 hours. The slurry was stirred for 4-8 hours at 20°C, and afterwards filtered and washed with purified water (4.0 V).

Example 4 - Recrystallisation of 5,7-dimethyl-/V-((l/?,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound of Formula (A))

[00173] Under nitrogen atmosphere, MEK (192 L, 6.0 V) and the compound of Formula (A) from Example 3 in crude (32 kg, 1.0 eq.) were charged to a reactor at 25 °C; MEK (160 L, 5.0 V) was added to wash the walls. The solution was left stirring for 1-3 hours until the solid was dissolved. After this, the solution from the reactor was transferred to a clean drum.

[00174] Under nitrogen atmosphere, the crude compound of Formula (A) in MEK solution was transferred to another reactor via a polish filter. The temperature was set at 17 °C and n-heptane (115.2 kg, 3.6 V) was charged in 2-4 hours. The solution was concentrated under vacuum until the total volume was 320 L - 352 L (10-11 V). In the event that there is no solid precipitation, proceed to the 2nd concentration directly; if there is solid precipitation, take a solid sample for XRPD test, and ensure that the crystal form is polymorph form B; if it is not form B, proceed to the 2nd concentration (and repeat if required). The reactor temperature was kept at 17 °C before cooling down to 0 °C and it was left stirring for 6-12 hours. A solid sample was taken for XRPD test to make sure that the crystal form is form B; if not form B, keep at 0 °C and stir for 6-12 hours; sample solid every 6-10 hours for XRPD until the crystal form is form B. The solid was centrifuged and washed with MEK:n-heptane (1 : 10, 57.6 L, 1.8 V ) and then with n-heptane (57.6 L, 1.8

V). The cake was dried under vacuum at 30 °C for 16-24 hours and 30.67 kg were obtained (95% yield and purity of 100% by HPLC).

PAT

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References

References

  1.  "LTI 291". AdisInsight. Springer Nature Switzerland AG. 15 October 2025. Retrieved 19 February 2026.
  2.  "Delving into the Latest Updates on Pariceract with Synapse". Synapse. 8 May 2025. Retrieved 19 February 2026.
  3.  "Pariceract Drug Profile". Ozmosi. 1 January 1900. Retrieved 19 February 2026.
  4.  den Heijer JM, Kruithof AC, Moerland M, Walker M, Dudgeon L, Justman C, et al. (July 2023). "A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator". Movement Disorders. 38 (7): 1197–1208. doi:10.1002/mds.29346. hdl:1887/3722043. PMID 37195859.
  5.  den Heijer JM, Kruithof AC, van Amerongen G, de Kam ML, Thijssen E, Grievink HW, et al. (September 2021). "A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator". British Journal of Clinical Pharmacology. 87 (9): 3561–3573. doi:10.1111/bcp.14772. PMC 8451761. PMID 33576113.
  6.  Ellis JM, Fell MJ (September 2017). "Current approaches to the treatment of Parkinson's Disease". Bioorganic & Medicinal Chemistry Letters. 27 (18): 4247–4255. doi:10.1016/j.bmcl.2017.07.075. PMID 28869077. Increased degradation of a-synuclein is another potential mechanism explored in the clinic. Currently, the leading candidates for this approach center on modulating the activity of the Glucocerebrosidase (GBA) pathway. Mutations in GBA are the leading genetic risk factor for sporadic PD and reductions in GBA activity are thought to lead to an accumulation of a-synuclein. Lysosomal Therapeutics is currently developing a brain penetrant, small molecule enhancer of GBA activity called LTI-291 (structure not reported) which is expected to enter Phase 1 testing in 2017.

External links

Clinical data
Other namesBIA 28-6156; LTI-291; LIT291; LTI-00291
Routes of
administration		Oral[1]
Drug classβ-Glucocerebrosidase (GCase) activator or positive allosteric modulator
Identifiers
IUPAC name
CAS Number1919820-28-2
PubChem CID121327414
ChemSpider68028144
UNIIV9WUN9UUU8
Chemical and physical data
FormulaC20H30N4O2
Molar mass358.486 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

////////pariceract, ANAX LABS, beta-glucocerebrosidase activator, antiparkinsonian, BIA 28-6156, LTI-291, LIT291, LTI-00291, BIA28-6156, LTI- 91, LIT 291, LTI 00291, Gcase activator 1, V9WUN9UUU8

#pariceract, #ANAX LABS, #beta-glucocerebrosidase activator, #antiparkinsonian, #BIA 28-6156, #LTI-291, #LIT291, #LTI-00291, #BIA28-6156, #LTI- 91, #LIT 291, #LTI 00291, #Gcase activator 1, #V9WUN9UUU8

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Pasodacigib

 

Pasodacigib

Cas 2648721-77-9

MFC24H23FN4O3 mw 434.5 g/mol

3-Quinolinecarboxamide, 6-fluoro-1,2-dihydro-1-methyl-4-[4-(5-methyl-2-benzoxazolyl)-1-piperidinyl]-2-oxo-

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide
diacylglycerol kinase inhibitor, antineoplastic, BAY 2862789, BAY-2862789, XM6U88YE6H

Pasodacigib (also known by its developmental code BAY 2862789 or BAY-2862789) is an investigational small-molecule drug developed by Bayer AG. It functions as a potent and selective diacylglycerol kinase alpha (DGKα) inhibitor designed for cancer immunotherapy.

🧪 Mechanism of Action

  • Targeting DGKα: Diacylglycerol kinase alpha (DGKα) is an enzyme that converts diacylglycerol (DAG) into phosphatidic acid (PA) within cells.
  • T-Cell Reactivation: In the tumor microenvironment, overactive DGKα metabolises DAG, which depletes the signaling required for T-cell activation. By blocking this enzyme, pasodacigib aims to restore DAG levels, reactivating the patient's own T-cells to mount a clinically beneficial anti-tumor immune response.

📋 Key Details & Chemical Properties

  • Developer: Bayer AG
  • CAS Registry Number: 2648721-77-9
  • Molecular Formula: C₂₄H₂₃FN₄O₃
  • Molecular Weight: 434.46 g/mol
  • Research Status: It is an investigational drug that has entered clinical trial assessment (such as the Bayer-led study NCT05858164) to evaluate its safety and efficacy in treating advanced malignancies.

⚠️ Important Medical Disclaimer

Pasodacigib is strictly an investigational compound undergoing clinical development and laboratory research. It is not approved by the FDA or any other global regulatory authority for prescription, public medical use, or patient purchase.

If you are looking into this molecule for scientific research or a clinical study, please let me know if you need specific details regarding its chemical structure, information on related DGK inhibitors, or updates on active oncology clinical trials

Pat

US11998539,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US400268899&_cid=P22-MS6W4B-66581-1

Example 298

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

      
      68 mg 6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile (160 μmol, example 217), 9 mg palladium(II)acetate (40 μmol) and 142 mg acetaldoxime (2.4 mmol) were stirred in 1.5 mL ethanol for 5 h at 80° C. The reaction mixture was diluted with water, extracted with ethyl acetate two times, the combined organic layers were filtered through a waterresistant filter and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 41.4 mg of the title compound (100% purity, 60% yield).
       1H NMR (400 MHz, DMSO-d 6) δ ppm 2.02-2.15 (m, 2H) 2.17-2.26 (m, 2H) 2.44 (s, 3H) 3.13-3.25 (m, 3H) 3.35-3.43 (m, 2H) 3.59 (s, 3H) 7.18 (d, 1H) 7.47-7.63 (m, 6H) 7.73 (br s, 1H).
      LC-MS (Method 2): R t=1.17 min; MS (ESIpos): m/z=435.4 [M+H] +

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021105117&_cid=P22-MS6W2Y-65422-1

Intermediate 101

6-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1 H)-dione

To a solution of 5.00 g 6-fluoro-2H-3,1-benzoxazine-2,4(1 H)-dione (26.8 mmol, CAS 321-69-7) and 9.3 ml. N,N-diisopropylethylamine (54 mmol) in 40 ml. dimethylformamide was added 5.1 ml. iodomethane (80 mmol) at rt and the mixture was stirred overnight. The reaction mixture was diluted with 1000 ml. water and the resulting solid was collected by filtration, the filter cake was washed with water and dried in vacuum to give 4.93 g of the title compound (99 % purity, 93 % yield).

1H NMR (400 MHz, DMSO-cfe) d ppm 3.47 (s, 3H), 7.40-7.61 (m, 1 H), 7.69-7.93 (m, 2H).Intermediate 102

6-fluoro-4-hydroxy-1-methyl-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile

4.85 g 6-fluoro-1 -methyl-2H-3,1 -benzoxazine-2,4(1 H)-dione (intermediate 101 , 24.6 mmol,) was solubilised in 50 ml. tetrahydrofurane, 34 ml. triethylamine (250 mmol) and then 15.1 ml. ethyl cyanoacetate (133 mmol) were added carefully and the suspension was stirred 72 h at 900. The reaction mixture was cooled down to rt, concentrated under reduced pressure, the residue was diluted with water and ethyl acetate (1 :1) and the mixture was adjusted to pH = 1 with hydrogen chloride solution (2 M in water). The resulting solid was filtered and the filter cake was washed with less water and ethyl acetate to give 4.40 g of the title compound (100 % purity, 82 % yield).

1H NMR (400 MHz, DMSO-cfe) d ppm 3.34 (br s, 3H), 7.01 -7.44 (m, 2H), 7.51 -7.70 (m, 1 H).

Intermediate 103

4-chloro-6-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

A mixture of 4.40 g 6-fluoro-4-hydroxy-1-methyl-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile (intermediate 102, 20.0 mmol) and 19 ml. phosphoric trichloride (200 mmol) was stirred overnight at 900. The reaction mixture was cooled down to rt, diluted with hexane and the resulting solid was filtered. The filter cake was carefully added to a half saturated solution of sodium bicarbonate, the resulting suspension was filtered, the solid was washed with water, ethyl acetate and then with ethanol and dried in vacuum to give 4.17 g of the title compound (100 % purity, 88 % yield).

1H NMR (400 MHz, DMSO-cfe) d ppm 3.67 (s, 3H); 7.58 - 8.09 (m, 3H).

Example 217

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)pipendin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

80 mg 4-chloro-6-fluoro-1-methyl-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile (338 pmol, intermediate 103) was suspended in 2.5 ml. 2-propanol, 180 mI_ N,N-diisopropylethylamine (1.0 mmol) and 87.7 mg 5-methyl-2-(piperidin-4-yl)-1 ,3-benzoxazole (406 pmol, CAS 199292-77-8) were added and the mixture was stirred for 2 h at 900. The reaction mixture was cooled down to rt and the suspension was diluted with water and stirred for 15 min. The solid was filtered off and washed with water and ethanol to give 127 mg of the title compound (98 % purity, 88 % yield).

1H NMR (400 MHz, DMSO-cfe) d ppm 2.07 - 2.19 (m, 2 H) 2.27 - 2.35 (m, 2 H) 2.44 (s, 3 H) 3.43 (tt, 1 H) 3.55 - 3.64 (m, 5 H) 3.81 (br d, 2 H) 7.18 (dd, 1 H) 7.53 (d, 1 H) 7.54 - 7.61 (m, 2 H) 7.61 - 7.70 (m, 2 H).

LC-MS (Method 2): R, = 1.32 min; MS (ESIpos): m/z = 417.4 [M+H]+

Example 298

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)pipendin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

68 mg 6-fluoro-1 -methyl-4-[4-(5-methyl-1 ,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile (160 pmol, example 217), 9 mg palladium(ll)acetate (40 pmol) and 142 mg acetaldoxime (2.4 mmol) were stirred in 1 .5 ml. ethanol for 5 h at 80TT The reaction mixture was diluted with water, extracted with ethyl acetate two times, the combined organic layers were filtered through a waterresistant filter and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5pm 100x30mm, mobile phase: acetonitrile / water (0.2 vol. % ammonia 32 %)-gradient) to give 41 .4 mg of the title compound (100 % purity, 60 % yield).

1H NMR (400 MHz, DMSO-cfe) d ppm 2.02 - 2.15 (m, 2 H) 2.17 - 2.26 (m, 2 H) 2.44 (s, 3 H) 3.13 - 3.25 (m, 3 H) 3.35 - 3.43 (m, 2 H) 3.59 (s, 3 H) 7.18 (d, 1 H) 7.47 - 7.63 (m, 6 H) 7.73 (br s, 1 H).

LC-MS (Method 2): R, = 1 .17 min; MS (ESIpos): m/z = 435.4 [M+H]

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References

/////////pasodacigib, anax labs, diacylglycerol kinase inhibitor, antineoplastic, BAY 2862789, BAY-2862789, XM6U88YE6H

#pasodacigib, #anax labs, #diacylglycerol kinase inhibitor,#antineoplastic, #BAY 2862789, #BAY-2862789, #XM6U88YE6H

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Thursday, 27 August 2026

Perzebertinib, Bizrolertinib

 

Perzebertinib, Bizrolertinib

CAS 2414056-31-6

MFC27H26F2N8O3 MW548.5 g/mol

5-[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]oxy-6-methoxy-N-[3-methyl-4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)phenyl]quinazolin-4-amine

5-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]oxy}-6-methoxy-N-{3-methyl-4-[([1,2,4]triazolo[1,5-c]pyrimidin-7-yl)oxy]phenyl}quinazolin4-amine
epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, ZN-A-1041, ZN 1041, RG 6596, Bizrolertinib, UN8TM5120C

Perzebertinib (also known as bizrolertinib or by developmental codes ZN-A-1041, ZN-1041, and RG6596) is an orally active, potent, and highly selective HER2 (ERBB2) tyrosine kinase inhibitor (TKI) designed to treat advanced solid tumors, primarily HER2-positive breast cancer.

Mechanism of Action

Perzebertinib functions as a selective, irreversible inhibitor of the HER2 tyrosine kinase. It blocks the ATP-binding site of the receptor to stop autophosphorylation. This action shuts down downstream signaling via the PI3K/AKT and MAPK pathways, successfully suppressing the growth, survival, and migration of tumor cells overexpressing HER2.

Key Clinical Advantages

  • Blood-Brain Barrier (BBB) Penetration: The drug is designed to cross the blood-brain barrier effectively. This makes it highly valuable for treating brain metastases, a common and aggressive complication in advanced HER2-positive breast cancers.
  • EGFR Sparing: Unlike older pan-EGFR/HER2 inhibitors, perzebertinib is engineered to spare wild-type EGFR. Sparing EGFR helps minimise common on-target side effects like severe skin rash and diarrhea.
  • Efflux Resistance: It is not a substrate for P-gp or BCRP efflux pumps, allowing it to maintain high concentrations within central nervous system (CNS) tissues.

Development and Clinical Status

Initially discovered and developed by Suzhou Zanrong Pharmaceutical Technology (Zion Pharma), the asset is being co-developed in partnership with Roche and Genentech.

The drug has progressed through Phase 1 clinical studies evaluating its safety and pharmacokinetics in advanced solid tumors, moving forward into Phase 2/3 evaluations for HER2-positive advanced or locally advanced metastatic breast cancer. It is frequently evaluated as a monotherapy or in combination regimens alongside established therapies like capecitabine, trastuzumab, or pertuzumab

PAT

US11723908, Example 37, EG 77

https://patentscope.wipo.int/search/en/detail.jsf?docId=US344952565&_cid=P10-MS9QYW-06569-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=34DD4AB27E9264643AB08F2936B38B1B.wapp1nA?docId=EP476958262&_cid=P10-MS9QXM-05913-1

 International Patent Publication No. WO 2020/057511 A1, which is incorporated herein by reference in its entirety, discloses quinazoline compounds that inhibit type I receptor tyrosine kinases, demonstrate good brain penetration in animals, and possess favorable toxicity profiles (for example a decreased activity against hERG), and thus particularly useful in the treatment of type I receptor tyrosine kinases mediated diseases or conditions, in particular ErbB2-associated disease or conditions, including cancer (e.g., metastatic cancer, such as brain metastases). A specific compound, which is identified as (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine (also referred to as compound (I) herein),

PAT

WO2020057511

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020057511&_cid=P10-MS9R3W-09545-1

Example 32

[0681]

(S) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine

Step 5: (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine and

[0696]

(S) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine

[0697]

[0698]

To a solution of 4-chloro-5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazoline (410 mg, 1.19 mmol) in Propan-2-ol (60 mL) was added TsOH. H 2O (68 mg, 0.36 mmol) and 4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylaniline (259 mg, 1.07 mmol) . The resulting mixture was stirred at 100℃ under Ar 2protection and concentrated. The residue was dissolved in H 2O (100 mL) , basified with aq. NaHCO 3to pH =7-8, extracted with DCM: MeOH = 20: 1 (100 mLx3) . The combined organic layers were dried over anhydrous Na 2SO 4, filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH=30/1) to give product (300 mg, 46%yield) as white solid. The racemic material was subsequently separated by chiral SFC to give two isomers:

[0699]

(R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine (Peak 1, retention time 6.241 min, ee: >99%) (100 mg, 67%) as a white solid. MS (ESI) m/z: 549.2 (M+H) +. 1H NMR (400 MHz, CDCl 3) δ 10.04 (s, 1H) , 9.20 (s, 1H) , 8.61 (s, 1H) , 8.33 (s, 1H) , 7.88 (d, J = 2.0 Hz, 1H) , 7.79-7.76 (m, 1H) 7.69 (d, J = 9.2 Hz, 1H) , 7.53 (d, J = 9.2 Hz, 1H) , 7.11 (d, J = 8.8 Hz, 1H) , 6.90 (s, 1H) , 4.84-4.79 (m, 1H) , 4.03 (s, 3H) , 3.22-3.21 (m, 1H) , 2.93 (d, J = 7.2 Hz, 1H) , 2.38 (s, 3H) , 2.41-2.34 (m, 1H) , 2.34-2.27 (m, 1H) , 2.19 (s, 3H) , 2.16-2.10 (m, 2H) .

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Petadeferitrin

 

Petadeferitrin

CAS911714-45-9

MFC16H21NO6S MW355.4 g/mol

(4S)-2-[2-hydroxy-4-[2-(2-methoxyethoxy)ethoxy]phenyl]-4-methyl-5H-1,3-thiazole-4-carboxylic acid

(4S)-2-{2-hydroxy-4-[2-(2-methoxyethoxy)ethoxy]phenyl}-4-methyl4,5-dihydro-1,3-thiazole-4-carboxylic acid
iron chelating agent, SP 420, WBX54NZ436

Petadeferitrin is an orally bioavailable iron-chelating agent and derivative of desferrithiocin, with iron chelating and protective activities in diseases of iron overload. Upon oral administration, petadeferitrin targets, binds to and chelates free iron. This induces the excretion of iron, prevents iron accumulation and prevents cellular and/or tissue damage associated with iron overload.

Petadeferitrin (formerly known as SP-420) is an investigational, orally bioavailable, small-molecule iron chelator being developed by Pharmacosmos (and its subsidiary Abfero Pharmaceuticals) to treat patients with transfusion-dependent iron overload. The drug works by binding to excess free iron in the body and forming complexes that are primarily excreted through bile and feces.

Key Characteristics & Mechanisms

  • Drug Class: It is a tridentate iron chelator and a derivative of desferrithiocin.
  • Enhanced Efficiency: In preclinical studies, it demonstrated a higher iron clearance efficiency (ICE value of 26.7) compared to desferrithiocin.
  • Brain-Penetrant: It is uniquely characterized as a brain-penetrant agent, which could expand its potential protective use in specific diseases associated with iron accumulation.

Clinical Development Status

  • Investigational Status: The drug remains investigational and has not yet been approved for commercial use anywhere in the world.
  • Target Diseases: Clinical evaluation focuses on individuals who suffer from iron overload due to frequent blood transfusions, such as patients with β-thalassemia and sickle cell disease.
  • Ongoing Studies: Pharmacosmos is actively evaluating the drug in Phase II clinical trials (such as ClinicalTrials.gov ID NCT05693909) to assess its safety, tolerability, and dosing advantages over existing options. Early human data suggests it may offer effective clearance with less frequent dosing compared to some currently approved alternatives.
  • A Trial Testing SP-420 in Subjects With Transfusion-dependent β-thalassemia or Low-risk Myelodysplastic SyndromesCTID:NCT05693909Phase:Phase 2Status:RecruitingDate:2025-09-24
  • Safety of SP-420 in the Treatment of Transfusional Iron OverloadCTID:NCT04741542Phase:Phase 1Status:TerminatedDate:2024-12-27
  • SP-420 in Subjects With Transfusion-dependent Beta-Thalassemia or Other Rare AnemiasCTID:NCT03801889Phase:Phase 2Status:WithdrawnDate:2020-10-05
  • Safety and Pharmacokinetic Study of Escalating Doses of SP-420, an Iron Chelator, in Patients With β-ThalassemiaCTID:NCT02274233Phase:Phase 1Status:TerminatedDate:2015-09-29

An open-label, dose-escalation, dose-finding, and proof-of-concept trial of SP-420 in subjects with transfusion-dependent β-thalassemiaEudraCT:2022-002395-36

Phase:Phase 2, Status:Trial now transitioned, Date:2022-12-16

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US42268401&_cid=P21-MSCM3W-69668-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006107626&_cid=P21-MSCM3W-69668-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43268075&_cid=P21-MSCM3W-69668-1

PAT

Desferrithiocin polyether analoguesPublication Number:

US-2017217912-A1Priority Date:

2005-04-04

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/////////petadeferitrin, ANAX LABS, iron chelating agent, SP 420, WBX54NZ436

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