Derivatives of an egfr inhibitor and uses thereof

Abstract

The present application provides a kind of compound EGFR inhibitor derivative of formula (I) and its preparation method and application.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and in particular relates to a derivative of an EGFR inhibitor of formula (I) and its preparation method and application. Background Technology

[0002] EGFR (Epidermal Growth Factor Receptor) is the most common driver gene in NSCLC (Non-Small Cell Lung Cancer), with EGFR gene mutations present in 30% to 50% of Asian NSCLC patients.

[0003] CN105601573A discloses a compound of formula (I), which is a third-generation EGFR TKI (Tyrosine Kinase Inhibitor); CN110372607A discloses a pharmaceutically acceptable salt of compound (I); CN110446701A discloses a formulation of compound (I).

[0004]

[0005] Formulations of compounds of formula (I) were developed for the treatment of T790M blast cancer that had progressed after prior EGFR-TKI therapy. + Or primary T790M + Clinical studies related to locally advanced or metastatic NSCLC, including a pivotal study that enrolled 301 participants, showed significant clinical benefit. The objective response rate (ORR) assessed by independent imaging (IRC) was 68.8%; the median progression-free survival (PFS) assessed by IRC was 11.0 months; patients with brain metastases also showed significant benefit, with an ORR of 64.6% assessed by IRC in participants with baseline brain metastases. The clinical study summary was published in the journal *Journal of Thoracic Oncology* (Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790 Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study). Summary of the Invention

[0006] This invention discloses derivatives of EGFR inhibitors of formula (I), such as compounds of formula (II), oxidative impurities, double bond auto-addition related impurities, metabolites, etc.

[0007] In a first aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof;

[0008]

[0009] Among them, R 1 Selected from H, or C 1-4 Alkyl group. Preferably, the R 1 Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. Preferably, the R... 1 H is preferred. The R is... 1 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0010] In one embodiment of the present invention, the compound of formula (II) is a compound of formula (IIa); that is, R 1 =Methyl. During the synthesis of compound (I), the product compound (I) reacts with R. 1 -OH (methanol) undergoes an addition reaction, possibly producing a compound of formula (IIa).

[0011]

[0012] In one embodiment of the present invention, the compound of formula (II) is a compound of formula (IIb); that is, R 1 =H. The intermediate state of compound (I) during its synthesis may be hydrolyzed under alkaline conditions, or the compound (I) may be degraded in water (especially in alkaline solutions), which may give rise to compound (IIb).

[0013]

[0014] A second aspect of the invention provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof, said compound (II) or a pharmaceutically acceptable salt thereof as a reference in drug research and manufacturing processes; said drug contains a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] One embodiment of the present invention provides the use of a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, said compound of formula (IIa) or a pharmaceutically acceptable salt thereof as a reference in drug research and manufacturing processes; said drug contains a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] One embodiment of the present invention provides the use of a compound of formula (IIb) or a pharmaceutically acceptable salt thereof, said compound of formula (IIb) or a pharmaceutically acceptable salt thereof as a reference in drug research and manufacturing processes; said drug contains a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] In one embodiment of the present invention, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof contains not less than 95% by mass of a compound of formula (I) or a pharmaceutically acceptable salt thereof, not more than 1% by mass of a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, and not more than 1% by mass of a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

[0019] Preferably, it contains not less than 98% by mass of a compound of formula (I) or a pharmaceutically acceptable salt thereof, not more than 0.5% by mass of a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, and not more than 0.5% by mass of a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

[0020] More preferably, it contains not less than 99% by mass of a compound of formula (I) or a pharmaceutically acceptable salt thereof, not more than 0.3% by mass of a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, and not more than 0.3% by mass of a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment of the present invention, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof contains not less than 95% by mass of a compound of formula (I) or a pharmaceutically acceptable salt thereof, not more than 1% by mass of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and not more than 1% by mass of a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

[0022] Preferably, it contains not less than 98% by mass of a compound of formula (I) or a pharmaceutically acceptable salt thereof, not more than 0.5% by mass of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and not more than 0.5% by mass of a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

[0023] More preferably, it contains not less than 99% by mass of a compound of formula (I) or a pharmaceutically acceptable salt thereof, not more than 0.3% by mass of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and not more than 0.3% by mass of a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

[0024] Among them, R in compound (II) 1 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0025] In one embodiment of the present invention, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof has a mass ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the compound of formula (IIa) or a pharmaceutically acceptable salt thereof of not less than 100:1, preferably not less than 200:1, and more preferably not less than 300:1.

[0026] In one embodiment of the present invention, in the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the mass ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the compound of formula (II) or a pharmaceutically acceptable salt thereof is not less than 100:1, preferably not less than 200:1, and more preferably not less than 300:1; wherein, in the compound of formula (II), R 1 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0027] In one embodiment of the present invention, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof has a mass ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the compound of formula (IIb) or a pharmaceutically acceptable salt thereof of not less than 100:1, preferably not less than 200:1, and more preferably not less than 300:1.

[0028] In this invention, the terms "containing" or "including (comprising)" can be open-ended, semi-closed, or closed-ended. In other words, the terms also include "consisting substantially of" or "consisting of".

[0029] In this invention, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0030] In this invention, the term "pharmaceutically acceptable salt" refers to a salt of a compound prepared by reacting a compound having specific substituents with a relatively non-toxic acid or base. Pharmaceutically acceptable salts can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods.

[0031] The derivatives of the compound of formula (I) disclosed in this invention, such as the compound of formula (II), oxidative impurities, impurities related to double bond auto-addition, metabolites, etc., can be applied to the quality control of the compound of formula (I) and in vivo and in vitro pharmacological and efficacy studies; thereby ensuring the safety, efficacy and quality control of the compound of formula (I) and its drug preparations in medical applications. Attached Figure Description

[0032] Figure 1 The ¹H NMR spectrum of the compound of formula (IIa) obtained in Example 1;

[0033] Figure 2 The ¹H NMR spectrum of the compound of formula (IIb) obtained in Example 2 is shown. Detailed Implementation

[0034] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0035] Example 1: N-(5-((5-chloro-4-(naphth-2-ylamino)pyrimidin-2-yl)amino)-2-((2-dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-3-methoxypropionamide (Compound of Formula IIa)

[0036] Compound (I) was refluxed in methanol, followed by liquid-phase separation to obtain compound (IIa); purity 94.23%. The molecular ion peak (M+H) of the obtained compound (IIa) was detected by mass spectrometry. + The m / z is 578.2659, consistent with the molecular weight. The HNMR (solvent deuterated DMSO) spectrum is as follows... Figure 1 As shown.

[0037] Example 2: N-(5-((5-chloro-4-(naphth-2-ylamino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-3-hydroxypropionamide (Compound of Formula IIb)

[0038] Compound (I) was stirred overnight in a mixture of hydrogen peroxide and acetone, dissolved, and then subjected to liquid-phase separation to obtain compound (IIb); purity: 99.15%. The molecular ion peak (M+H) of the prepared compound (IIb) was detected by mass spectrometry. + The m / z value is 564.2454, which is consistent with the molecular weight. The HNMR (solvent deuterated DMSO) spectrum is as follows... Figure 2 As shown.

[0039] Example 3: Detection of related substances in formulations of compound (I)

[0040] Referring to CN110446701A, seven batches of tablets containing compound (I) were prepared. Related substances were detected using high-performance liquid chromatography (HPLC) as described in General Chapter 0512 of Part IV of the Chinese Pharmacopoeia (2020 edition).

[0041] The content of compound (IIa) in each batch of tablets is approximately 0.039% to 0.093% (compared to the content of compound (I) in the tablet itself).

[0042] No compound of formula (IIb) was detected in any batch of tablets; accelerated stability testing of selected batches for 6 months also showed no detection of compound of formula (IIb); long-term stability testing of selected batches for 36 months also showed no detection of compound of formula (IIb).

[0043] One oxidizing impurity of compound (I) was detected in some batches of tablets; multiple oxidizing impurities of compound (I) were detected in some batches of tablets.

[0044] In addition, various impurities related to double bond autoaddition in the compound of formula (I) in the tablets were also tested, and the sum of impurities related to double bond autoaddition in each batch did not exceed 0.1%.

[0045] Metabolites of compound (I) in Example 4

[0046] The possible metabolites of compound (I) in various hepatocyte incubation systems (human, canine, monkey, rat, and mouse) were identified using UPLC / Q-TOF MS. The main metabolites detected were N-demethylated metabolites, N-dealkylated metabolites, glutathione-bound metabolites, and cysteine-bound metabolites.

[0047] The possible metabolites in plasma, urine, feces, and bile samples from rats after a single oral administration of 9 mg / kg of compound (I) were identified using UPLC-UV / Q-TOF MS. The results showed that N-dealkyl and demethylated metabolites, N-demethylated metabolites, cysteine-bound metabolites, sulfite-bound metabolites, cysteylglycine-bound metabolites, glutathione-bound metabolites, and N-dealkylated metabolites were detectable.

[0048] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing description of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Compound of formula (IIa), (IIa)。 2. The use of the compound of claim 1 as a reference standard in the research and manufacturing process of a drug; the drug contains a compound of formula (I) or a pharmaceutically acceptable salt thereof. （I）。

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