Capivasertib

C₂₁H₂₅ClN₆O₂

 428.915

• 1143532-39-1

AZD 5363

4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide

(S)-4-AMINO-N-(1-(4-CHLOROPHENYL)-3-HYDROXYPROPYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE

FDA APPROVED 11/16/2023, To treat breast cancer that meets certain disease criteria, Truqap

Capivasertib, sold under the brand name Truqap, is an anti-cancer medication used for the treatment of breast cancer.^[1][2]

The most common adverse reactions include diarrhea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting, and stomatitis.^[3]

In November 2023, capivasertib was approved in the United States for people with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer when used in combination with fulvestrant.^[3][4][5]

Capivasertib is a novel pyrrolopyrimidine derivative, and an orally available inhibitor of the serine/threonine protein kinase AKT (protein kinase B) with potential antineoplastic activity. Capivasertib binds to and inhibits all AKT isoforms. Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR signaling due to mutations in multiple signaling components. By targeting AKT, the key node in the PIK3/AKT signaling network, this agent may be used as monotherapy or combination therapy for a variety of human cancers.

Medical uses

Capivasertib, used in combination with fulvestrant (Faslodex), is indicated for adults with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within twelve months of completing adjuvant therapy.^[1][3]

History

Efficacy was evaluated in CAPItello-291 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial in 708 participants with locally advanced or metastatic HR-positive, HER2-negative breast cancer, of which 289 participants had tumors with PIK3CA/AKT1/PTEN-alterations.^[3] All participants were required to have progression on aromatase inhibitor-based treatment.^[3] Participants could have received up to two prior lines of endocrine therapy and up to one line of chemotherapy for locally advanced or metastatic disease.^[3]

PATENT

US10654855,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US232562682&_cid=P20-LQKB75-44185-1

EXAMPLE 9: (S)-4-AMINO-N-(1-(4-CHLOROPHENYL)-3-HYDROXYPROPYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE (E9)

(MOL)(CDX)

HCl (4M in Dioxane) (3.00 mL, 12.00 mmol) was added to (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (1.27 g, 2.40 mmol) in dichloromethane (20 mL). The resulting suspension was stirred at 20° C. for 16 hours. The reaction mixture was filtered through a PTFE filter cup and the crude solid was purified by preparative HPLC (Waters XTerra C18 column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% TFA) and MeCN as eluents. Fractions containing the desired compound were purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH 3/MeOH and pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.200 g, 19.4%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.45 (2H, d), 1.86 (1H, d), 1.90-1.93 (1H, m), 2.19 (2H, s), 3.38 (2H, q), 3.51-3.58 (2H, m), 4.35-4.38 (2H, m), 4.53 (1H, t), 4.88 (1H, d), 6.58 (1H, t), 7.16 (1H, t), 7.32-7.38 (4H, m), 8.12 (1H, s), 8.43 (1H, d), 11.63 (1H, s), m/z (ESI+) (M+H)+=429; HPLC tR=1.46 min.

EXAMPLE 9 ALTERNATIVE ROUTE 1: (S)-4-AMINO-N-(1-(4-CHLOROPHENYL)-3-HYDROXYPROPYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE

(MOL)(CDX)

N-Ethyldiisopropylamine (1.676 ml, 9.62 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (1 g, 3.21 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.493 g, 3.21 mmol) in butan-1-ol (15 ml). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO 4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (842 mg) as a white foam. (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide was stirred in ethyl acetate (7 mL) for 18 hours. The solid was collected by filtration, washed with a small amount of ethyl acetate and vacuum oven dried at 55° C. for 18 hours to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.585 g, 42.5%) as a white solid.

m/z (ES+) (M+H)+=429; HPLC tR=1.60 min.

1H NMR (400.13 MHz, DMSO-d 6) δ 1.39-1.47 (2H, m), 1.80-2.02 (4H, m), 2.17 (2H, s), 3.35-3.40 (2H, m), 3.50-3.59 (2H, m), 4.34-4.41 (2H, m), 4.53 (1H, t), 4.88 (1H, d), 6.57 (1H, m), 7.14-7.16 (1H, m), 7.31-7.37 (4H, m), 8.12 (1H, s), 8.42 (1H, d), 11.62 (1H, s)

EXAMPLE 9 ALTERNATIVE ROUTE 2: (S)-4-AMINO-N-(1-(4-CHLOROPHENYL)-3-HYDROXYPROPYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE

(MOL)(CDX)

(S)-3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (2.055 g, 11.07 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (4 g, 11.07 mmol) and DIPEA (5.80 ml, 33.20 mmol) in DMA (40 ml). HATU (4.63 g, 12.18 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO 4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness and triturated with dioxane (40 ml) to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) as a white solid. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) was suspended in dioxane (40.0 ml) and 4M hydrogen chloride in dioxane (7.69 ml, 221.36 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5M NH 3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (1.200 g, 25.3%) as a white solid.

m/z (ES+) (M+H)+=429; HPLC tR=1.67 min.

1H NMR matches previous.

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Clinical data
Trade names	Truqap
Other names	AZD-5363
AHFS/Drugs.com	Truqap
License data	US DailyMed: Capivasertib
Routes of administration	By mouth
Drug class	Threonine kinase inhibitor
ATC code	L01EX27 (WHO)
Legal status
Legal status	US: ℞-only[1]
Identifiers
showIUPAC name
CAS Number	1143532-39-1
PubChem CID	25227436
DrugBank	DB12218
ChemSpider	28189073
UNII	WFR23M21IE
KEGG	D11371
ChEMBL	ChEMBL2325741
PDB ligand	0XZ (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID40150710
ECHA InfoCard	100.208.066
Chemical and physical data
Formula	C21H25ClN6O2
Molar mass	428.92 g·mol−1
3D model (JSmol)	Interactive image
showSMILES
showInChI

References

1. ^ Jump up to:^a b c “Truqap- capivasertib tablet, film coated”. DailyMed. 16 November 2023. Archived from the original on 20 November 2023. Retrieved 20 November 2023.
2. ^ Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, et al. (June 2023). “Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer”. New England Journal of Medicine. 388 (22): 2058–2070. doi:10.1056/NEJMoa2214131. PMID 37256976. S2CID 259002400.
3. ^ Jump up to:^{a b c d e f} “FDA approves capivasertib with fulvestrant for breast cancer”. U.S. Food and Drug Administration. 16 November 2023. Archived from the original on 17 November 2023. Retrieved 17 November 2023.  This article incorporates text from this source, which is in the public domain.
4. ^ “Oncology (Cancer) / Hematologic Malignancies Approval Notifications”. U.S. Food and Drug Administration. 16 November 2023. Archived from the original on 17 November 2023. Retrieved 17 November 2023.
5. ^ “Truqap (capivasertib) plus Faslodex approved in the US for patients with advanced HR-positive breast cancer”. AstraZeneca (Press release). 17 November 2023. Archived from the original on 17 November 2023. Retrieved 17 November 2023.

External links

• Clinical trial number NCT04305496 for “Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer (CAPItello-291)” at ClinicalTrials.gov

///////Capivasertib, Truqap, FDA 2023, APPROVALS 2023, AZD 5363

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