Osimertinib D6

货号: B2766964

CAS 编号: 1638281-44-3

分子量: 505.656

InChI 键: DUYJMQONPNNFPI-XERRXZQWSA-N

注意: 仅供研究使用。不适用于人类或兽医用途。

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概述

1. 描述

7. 相似化合物的比较

2. 作用机制

8. 属性

3. 生化分析

9. 合成路线和方法 I

4. 准备方法

10. 合成路线和方法 II

5. 化学反应分析

11. 合成路线和方法 III

6. 科学研究应用

12. 免责声明

描述

Osimertinib D6 is a deuterated form of osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor. It is primarily used in the treatment of non-small cell lung cancer with specific mutations in the epidermal growth factor receptor gene. The deuterated version, this compound, is designed to improve the pharmacokinetic properties of the original compound by replacing certain hydrogen atoms with deuterium.

作用机制

生化分析

Biochemical Properties

Osimertinib D6 interacts with several enzymes and proteins. It is a potent inhibitor of EGFR, specifically targeting the L858R and L858R/T790M mutations . It works by forming a covalent bond with the Cys797 residue located in the ATP-binding site of mutant EGFR . This interaction inhibits the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) in cancer cells .

Cellular Effects

This compound has significant effects on various types of cells and cellular processes. It influences cell function by impacting cell signaling pathways, gene expression, and cellular metabolism . It has been shown to sensitize both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs . It also significantly increases the accumulation of paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of the ABCB1 transporter .

Molecular Mechanism

This compound exerts its effects at the molecular level through several mechanisms. It forms a covalent bond with the Cys797 residue in the ATP-binding site of mutant EGFR, thereby inhibiting the enzyme . This interaction leads to the inhibition of the ABC transporter-mediated MDR in cancer cells . It also stimulates the ATPase activity of the ABCB1 transporter .

Temporal Effects in Laboratory Settings

The effects of this compound change over time in laboratory settings. While specific data on this compound is limited, studies on Osimertinib have shown that resistance to the drug inevitably develops over time . This resistance is a major challenge in the treatment of EGFR-mutated advanced NSCLC .

Metabolic Pathways

This compound is involved in several metabolic pathways. It is mainly metabolized by the CYP3A enzyme in humans . Species differences in Osimertinib metabolism have been identified, and these can be eliminated by genetic modification .

准备方法

Synthetic Routes and Reaction Conditions: The synthesis of Osimertinib D6 involves the incorporation of deuterium atoms into the osimertinib molecule. This can be achieved through various methods, including:

Hydrogen-Deuterium Exchange: This method involves the replacement of hydrogen atoms with deuterium in the presence of a deuterium source, such as deuterium oxide or deuterated solvents.

Deuterated Reagents: Using deuterated reagents in the synthesis process can directly introduce deuterium atoms into the molecule.

Industrial Production Methods: Industrial production of this compound follows similar principles as the laboratory synthesis but on a larger scale. The process involves:

Large-Scale Hydrogen-Deuterium Exchange: Utilizing deuterium oxide or other deuterated solvents in large quantities.

Optimization of Reaction Conditions: Ensuring the reaction conditions are optimized for maximum yield and purity of the deuterated product.

化学反应分析

Types of Reactions: Osimertinib D6 undergoes various chemical reactions, including:

Oxidation: The compound can be oxidized to form various metabolites.

Reduction: Reduction reactions can modify the functional groups within the molecule.

Substitution: Substitution reactions can occur at specific sites within the molecule, leading to the formation of different derivatives.

Common Reagents and Conditions:

Oxidation Reagents: Common oxidation reagents include hydrogen peroxide and potassium permanganate.

Reduction Reagents: Sodium borohydride and lithium aluminum hydride are commonly used for reduction reactions.

Substitution Reagents: Halogenating agents and nucleophiles are used for substitution reactions.

Major Products Formed: The major products formed from these reactions include various metabolites and derivatives of this compound, which can have different pharmacological properties.

科学研究应用

Osimertinib D6 has several scientific research applications, including:

Chemistry: Used as a model compound to study the effects of deuterium substitution on the pharmacokinetics and pharmacodynamics of drugs.

Biology: Investigated for its interactions with biological targets, such as the epidermal growth factor receptor.

Medicine: Used in preclinical and clinical studies to evaluate its efficacy and safety in treating non-small cell lung cancer.

Industry: Employed in the development of new deuterated drugs with improved properties.

相似化合物的比较

Gefitinib: A first-generation epidermal growth factor receptor tyrosine kinase inhibitor.

Erlotinib: Another first-generation epidermal growth factor receptor tyrosine kinase inhibitor.

Afatinib: A second-generation epidermal growth factor receptor tyrosine kinase inhibitor.

Dacomitinib: Another second-generation epidermal growth factor receptor tyrosine kinase inhibitor.

Comparison: Osimertinib D6 is unique among these compounds due to its third-generation status and its ability to target the T790M resistance mutation. This makes it particularly effective in patients who have developed resistance to first- and second-generation inhibitors. Additionally, the deuterium substitution in this compound can enhance its pharmacokinetic properties, potentially leading to improved efficacy and reduced side effects.

属性

IUPAC Name	N-[2-[2-[bis(trideuteriomethyl)amino]ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide	Source
Details	Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI	InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)/i2D3,3D3	Source
Details	Computed by InChI 1.0.6 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI Key	DUYJMQONPNNFPI-XERRXZQWSA-N	Source
Details	Computed by InChI 1.0.6 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Canonical SMILES	CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC	Source
Details	Computed by OEChem 2.3.0 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Isomeric SMILES	[2H]C([2H])([2H])N(CCN(C)C1=CC(=C(C=C1NC(=O)C=C)NC2=NC=CC(=N2)C3=CN(C4=CC=CC=C43)C)OC)C([2H])([2H])[2H]	Source
Details	Computed by OEChem 2.3.0 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Formula	C28H33N7O2	Source
Details	Computed by PubChem 2.1 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Weight	505.6 g/mol	Source
Details	Computed by PubChem 2.1 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Synthesis routes and methods I

Procedure details

A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 mL, 0.42 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL) and washed with sat.NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (75 mg, 39%) as a cream solid after trituration with diethyl ether; 1H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s); m/z: ES+ MH+ 500.42.

Name

acryloyl chloride

Quantity

34.5 mg

Type

reactant

Reaction Step One

Name

N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine

Quantity

170 mg

Type

reactant

Reaction Step One

Name

Intermediate 100

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

DIPEA

Quantity

0.073 mL

Type

reactant

Reaction Step One

Name

CH2Cl2

Quantity

1 mL

Type

solvent

Reaction Step One

Name

CH2Cl2

Quantity

5 mL

Type

solvent

Reaction Step One

Name

CH2Cl2

Quantity

25 mL

Type

solvent

Reaction Step Two

Name

title compound

Yield

39%

Details

Synthesis routes and methods II

Procedure details

To a stirred solution of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at 0° C. was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65° C. for 10 h. The mixture was then cooled to r.t. and CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 mL) and dried at 50° C. for 12 h to give the title compound (7.0 g, 94%) as a solid form identified herein as polymorphic Form D. 1H NMR: 2.69 (3H, s) 2.83 (6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (1H, d) 6.28 (1H, d) 6.67 (1H, dd) 7.05-7.23 (2H, m) 7.29 (1H, t) 7.43 (1H, d) 7.56 (1H, d) 8.21 (2H, s) 8.81 (1H, s) 9.47 (1H, s) 9.52 (1H, s) ES+ MH+ 500.26.

Name

N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine

Quantity

10 g

Type

reactant

Reaction Step One

Name

Intermediate 100

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

3-chloropropanoyl chloride

Quantity

3.28 g

Type

reactant

Reaction Step One

Name

THF

Quantity

95 mL

Type

solvent

Reaction Step One

Name

water

Quantity

9.5 mL

Type

solvent

Reaction Step One

Name

NaOH

Quantity

3.48 g

Type

reactant

Reaction Step Two

Name

CH3OH

Quantity

40 mL

Type

reactant

Reaction Step Three

Name

water

Quantity

70 mL

Type

solvent

Reaction Step Three

Name

title compound

Yield

94%

Details

Synthesis routes and methods III

Procedure details

To a stirred solution of 3-chloro-N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide (Intermediate 174, 31.5 g, 58.76 mmol) in acetonitrile (310 mL) was added triethylamine (17.84 g, 176.28 mmol) at r.t. The resulting mixture was heated to 80° C. for 6 h then cooled to r.t. Water (130 mL) was then added and the mixture stirred for 12 h. The mixture was then filtered, washed with a mixture of water and acetonitrile (160 mL, 1:1) and dried at 50° C. for overnight to give the title compound (19.2 g, 94%) as a solid form identified herein as polymorphic form D. 1H NMR: 2.69 (3H, s), 2.83 (6H, d), 3.35 (4H, s), 3.84 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.28 (1H, d), 6.67 (1H, dd), 7.05-7.23 (2H, m), 7.29 (1H, t), 7.43 (1H, d), 7.56 (1H, d), 8.21 (2H, s), 8.81 (1H, s), 9.47 (1H, s), 9.52 (1H, s), m/z: ES+ MH+ 500.26.

Name

3-chloro-N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide

Quantity

31.5 g

Type

reactant

Reaction Step One

Name

Intermediate 174

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

triethylamine

Quantity

17.84 g

Type

reactant

Reaction Step One

Name

acetonitrile

Quantity

310 mL

Type

solvent

Reaction Step One

Name

Water

Quantity

130 mL

Type

reactant

Reaction Step Two

Name

title compound

Yield

94%

Details

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