CN110343090B - Quinazoline derivative salt crystal form, preparation method and application - Google Patents

Quinazoline derivative salt crystal form, preparation method and application Download PDF

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CN110343090B
CN110343090B CN201810423951.8A CN201810423951A CN110343090B CN 110343090 B CN110343090 B CN 110343090B CN 201810423951 A CN201810423951 A CN 201810423951A CN 110343090 B CN110343090 B CN 110343090B
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quinazoline derivative
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钟卫
张金强
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Weishang Shanghai Bio Pharmaceutical Co ltd
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Abstract

The invention discloses a quinazoline derivative salt crystal form, a preparation method and application thereof; the quinazoline derivative is characterized by comprising a hydrochloride crystal form A, a hydrochloride crystal form B, a hydrochloride crystal form D, a hydrochloride crystal form F, a hydrochloride crystal form H, a sulfate crystal form A, a maleate crystal form A, a succinate crystal form A, an adipate crystal form A, a glycolate crystal form A, a malate crystal form A, a fumarate crystal form A, a benzenesulfonate crystal form A, a maleate crystal form B, a benzoate crystal form A, a hippurate crystal form A and an oxalate crystal form A shown in a formula (I). The salt crystal form provided by the invention has good stability, and can be used for treating non-small cell lung cancer brain metastasis, meningeal metastasis and primary cell lung cancerThe application in the medicines of brain cancer or brain glioma and the like, and has better bioavailability, and has important significance for further researching the curative effect of the solid medicines.
Figure DDA0001651016750000011

Description

Quinazoline derivative salt crystal form, preparation method and application
Technical Field
The invention relates to a quinazoline derivative salt form and a crystal form thereof; in particular to a hydrochloride crystal form A, a hydrochloride crystal form B, a hydrochloride crystal form C, a hydrochloride crystal form A, a succinate crystal form A, an adipate crystal form A, a glycolate crystal form A, a malate crystal form A, a fumarate crystal form A, a benzenesulfonate crystal form B, a sulfate crystal form C, a benzoate crystal form A, a hippurate crystal form A and an oxalate crystal form A of (R) -6- [ (3, 3-difluoro-1-methylpiperidine-4-yl) oxy ] -nitrogen- (3-ethynyl-2-fluorophenyl) -7-methoxyquinazoline-4-amine (I), and a preparation method and application thereof.
Background
Biological signaling refers to the transmission of a stimulating or inhibiting signal into a cell, which is transmitted through a series of signals to allow a biological response to occur in the cell. Many signaling pathways and their biological responses have been studied. Different defects that occur in signaling pathways have been found to be responsible for many diseases, including various forms of cancer, metabolic disorders, inflammatory diseases, vascular and neuronal diseases. These defects often occur at the gene level, such as DNA insertions, deletions or translocations, which in some cancers allow uncontrolled proliferation of cells.
Signal transduction is often mediated by certain proteins called kinases. Kinases can be generally classified into protein kinases and lipid kinases, and some kinases exhibit dual specificity. Protein kinases are enzymes that catalyze the phosphorylation of other proteins and/or autophosphorylation, and can be classified based on their effect on substrates, for example: tyrosine kinases refer to the major phosphorylated tyrosine residues (e.g., Kit, EGFR, HER2, VEGFR, PDGFR, SRC, and ABL, etc.), serine/threonine kinases refer to the major phosphorylated serine and/or threonine residues (e.g., mTORC1, mTORC2, ATM, ATR, Akt, etc.), and the bispecific kinases phosphorylate tyrosine, serine, and/or threonine residues of substrates.
Epidermal Growth Factor Receptor (EGFR) belongs to the family of ErbB receptor transmembrane protein tyrosine kinases, including epidermal growth factor receptors EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB 4. Upon binding to Epidermal Growth Factor (EGF) ligand, the induced EGFR receptor forms a homopolymer or heterodimer with another EGFR receptor or another family member, e.g., HER2/ERBB2/NEU, HER3/ERBB3, or HER4/ERBB4, resulting in activation of EGFR tyrosine kinase activity. Activated EGFR then phosphorylates its substrates, resulting in multiple downstream pathways within the cell, including the Pl3K-AKT-mTOR pathway (involved in activation of cell survival), and the RAS-RAF-MEK-ERK pathway (involved in cell proliferation). ErbB receptor signaling and its involvement in tumors, see, e.g., Chong et al nature med.2013; 19(11) 1389-1400); n Engl J Med. (2008) Vol.358,1160-74and Biochemical and Biophysical Research Communications (2004) Vol.319, 1-11.
Brain glioma is the most common primary brain tumor, accounting for 40-50% of brain tumors. About 60% of patients with brain glioma have tumor-associated EGFR mutations. Of these, about 70% of the mutations were exon 2-7 deletions of EGFRV3 (EGFRVIIII). Such mutations increase the kinase activity of EGFR, leading to overactivation of downstream pro-survival signaling pathways. EGFRV3(EGFRVIII) is a deleted gene of exons 2-7 of the epidermal growth factor EGFR and renders the mutant receptor incapable of binding any known ligand. EGFRV3 mutations are expressed in brain cancer, brain glioma, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, head and neck squamous cell carcinoma, lung cancer, lung squamous carcinoma, ovarian cancer, prostate cancer, brain stem tumor, and the like. See Terrance G.Johns et al, FEBS Journal 280(2013) 5350-5370.
Disinhibition of ErbB family signaling promotes proliferation, invasion, metastasis, angiogenesis and tumor cell survival, and has been implicated in a number of human cancers, including lung, head and neck and breastIt is described that the ErbB family therefore represents a reasonable target for the development of anti-cancer drugs, small molecule drugs targeting EGFR or ErbB2, including gefitinib (Iressa)TM) Erlotinib (Tarceva)TM) Afatinib, Tyrasha and lapatinib (TYKERB)TM，TYVERBTM) Clinically approved for non-small cell lung cancer, a particular use for EGFR mutations is Exon19 (Exon 19del) deletion or Exon21L858R (Exon21L858R) mutation. Because EGFRVIII is a deletion gene for exons 2-7 of EGFR and renders mutant receptors incapable of binding any known ligand, unlike Exon19 (Exon 19del) deletions or Exon21L858R (Exon21L858R) mutations, existing EGFR inhibitors do not effectively inhibit EGFRVIII, have much lower biological activity than EGFR exons 19(Exon 19del) deletions or Exon21L858R (Exon21L858R) mutations, and often have 10-fold or even more than 100-fold reduced activity, see, e.g., Paul s. At the same time, the effective dose of these currently approved drugs is much less achieved intracranially due to the presence of the Blood Brain Barrier (BBB). For brain gliomas, radiation therapy and surgery supplemented with chemotherapeutic drugs (tembotproceeding) remain the primary means of treatment, but the therapeutic efficacy is limited, with an overall survival period of about 10 months.
Therefore, it would be particularly useful to develop compositions having high biological activity of EGFRVIII mutations while crossing the blood brain barrier for the treatment or prevention of EGFR-mediated brain gliomas.
It is known that different crystal forms, salt forms and salt forms of the same drug may have significant differences in stability, solubility, bioavailability and the like, thereby affecting the therapeutic effect of the drug. Therefore, the research and development of new salt forms and new crystal forms of the salts of the quinazoline derivatives which are more beneficial to the processing of medicaments and pharmaceutical compositions are very useful for providing more qualitative and quantitative information for the research on the curative effect and safety of solid medicaments, and have important significance.
Disclosure of Invention
The invention aims to solve the problems that the existing EGFR inhibitor can not effectively inhibit EGFR activating mutation EGFRVIII and can effectively pass through a blood brain barrier to reach effective blood concentration in the cranium, and the nature of the free base of the quinazoline derivative (R) -6- [ (3, 3-difluoro-1-methylpiperidine-4-yl) oxy ] -nitrogen- (3-ethynyl-2-fluorophenyl) -7-methoxy quinazoline-4-amine (I) is not beneficial to the use in the drug processing and the drug composition, so that the quinazoline derivative salt crystal form which is more beneficial to the drug processing and the drug composition, the preparation method and the application are provided, and more qualitative and quantitative information is provided for the research on the curative effect and the safety of the solid drug.
The quinazoline derivative provided by the invention has biological activity aiming at EGFRVIII activating mutation, and can effectively pass through a blood brain barrier. The quinazoline derivative is shown as a formula (I):
Figure BDA0001651016730000031
the purpose of the invention is realized by the following technical scheme:
the invention adopts a technical scheme that a novel quinazoline derivative (I) with chirality R is provided.
Preferably, the chiral purity ee is > 90%, more preferably, the chiral purity ee is > 97%.
The invention adopts a technical scheme that a novel quinazoline derivative (I) with chirality R has the biological activity of EGFRVIII activation mutation.
The invention adopts a technical scheme that a novel quinazoline derivative (I) with chirality R has the biological activity of EGFRVIII activating mutation and simultaneously has high capability of passing through a blood brain barrier.
The invention also provides a synthetic method for preparing the quinazoline derivative (I).
The invention adopts a technical scheme that a hydrochloride crystal form A of a quinazoline derivative is provided, and an XRPD pattern of the hydrochloride crystal form A is 2 theta
Main characteristic peaks: 6.5, 13.1,9.4
Minor characteristic peak: 7.3, 18.2, 20.0
Second characteristic peak: 27.5, 26.6, 21.6
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of hydrochloride form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 6.48, 7.31, 9.36, 10.26, 13.12, 14.37, 14.98, 16.06, 16.88, 17.48, 18.25, 20.01, 20.83, 21.55, 22.21, 23.35, 25.47, 26.60, 27.46, 28.29, 29.98, 34.07, 34.89, 36.25, 36.47, 36.87, 37.54, with an error range for the above 2 θ value of ± 0.2.
The invention adopts another technical scheme that a hydrochloride crystal form B of the quinazoline derivative is provided, and the XRPD pattern of the hydrochloride crystal form B is 2 theta
Main characteristic peaks: 6.5, 17.7, 19.8
Minor characteristic peak: 7.3,8.2, 10.5, 13.2
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the hydrochloride form B of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.32, 5.98, 6.54, 7.28, 8.17, 10.52, 13.20, 15.99, 17.74, 18.48, 19.32, 19.84, 22.56, 23.88, 24.36, 24.87, 30.47, 32.92, 33.55, 34.60, 38.06, 38.34, and the error range of the above 2 θ values is ± 0.2.
The invention adopts another technical scheme that a hydrochloride crystal form C of the quinazoline derivative is provided, and the XRPD pattern of the hydrochloride crystal form C is 2 theta
Main characteristic peaks: 7.2, 17.6, 22.0
Minor characteristic peak: 14.0, 13.6, 12.8
Second characteristic peak: 24.6, 26.2, 27.3
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the hydrochloride form C of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 5.66, 7.16, 8.32, 8.86, 9.52, 10.98, 11.63, 12.80, 13.57, 13.96, 14.81, 15.14, 15.49, 16.55, 16.86, 17.61, 22.04, 22.93, 24.55, 26.19, 27.30, 28.49, 34.12, 34.76, 35.65, 36.68, 37.31, 37.80, 38.20, 38.53, with an error range for the above 2 θ values of ± 0.2.
The invention adopts another technical scheme that a hydrochloride crystal form D of the quinazoline derivative is provided, and the XRPD pattern of the hydrochloride crystal form D is 2 theta
Main characteristic peaks: 13.4,7.1, 25.4
Minor characteristic peak: 6.7, 18.0, 19.8
Second characteristic peak: 17.2, 27.3, 24.7
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the hydrochloride form D of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 3.43, 6.72, 7.12, 8.47, 9.32, 12.25, 13.44, 14.07, 15.69, 16.87, 17.22, 17.97, 19.77, 20.73, 22.25, 22.82, 23.64, 24.77, 25.40, 27.28, 28.13, 29.69, 31.01, 33.48, 34.87, 35.42 and 38.08, with a deviation of the above 2 θ values of ± 0.2.
The invention adopts another technical scheme that a hydrochloride crystal form F of the quinazoline derivative is provided, and the XRPD pattern of the hydrochloride crystal form F is 2 theta
Main characteristic peaks: 6.8, 20.5, 13.6
Minor characteristic peak: 14.8, 14.3, 17.9, 11.9
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the hydrochloride form F of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.91, 5.67, 6.51, 6.77, 7.44, 8.58, 9.20, 9.73, 10.40, 10.85, 11.86, 13.58, 14.30, 14.78, 15.57, 15.85, 16.15, 16.41, 16.97, 17.89, 18.96, 19.76, 20.45, 20.79, 21.57, 22.21, 24.17, with a deviation of the above 2 θ values of ± 0.2.
The invention adopts another technical scheme that a hydrochloride crystal form H of the quinazoline derivative is provided, and the XRPD pattern of the hydrochloride crystal form H is 2 theta
Main characteristic peaks: 7.3, 18.0, 14.1
Minor characteristic peak: 6.4, 13.2, 15.8
Second characteristic peak: 16.8, 14.5, 20.3
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the hydrochloride form H of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 5.83, 6.43, 7.26, 8.10, 10.24, 11.93, 13.22, 14.11, 14.45, 14.88, 15.78, 16.80, 17.95, 18.96, 20.25, 21.07, 21.65, 24.16, 24.53, 25.67, 26.37, 27.03, 27.61, with a deviation of the above 2 θ value of ± 0.2.
The invention adopts another technical scheme that a hydrochloride crystal form I of the quinazoline derivative is provided, and the XRPD pattern of the hydrochloride crystal form I is 2 theta
Main characteristic peaks: 18.6,7.4,6.9
Minor characteristic peak: 13.2, 25.1, 12.3
Second characteristic peak: 14.7, 28.1, 14.2
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the hydrochloride form I of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 6.88, 7.42, 8.20, 12.31, 13.20, 13.88, 14.23, 14.66, 15.69, 17.48, 17.90, 18.64, 19.23, 20.24, 20.92, 21.94, 22.88, 23.42, 23.88, 25.12, 25.40, 25.85, 26.64, 28.07, 28.92, 31.19, 33.10, with a deviation of the above 2 θ values of ± 0.2.
The invention also provides a fumarate crystal form A of the quinazoline derivative, and an XRPD pattern of the fumarate crystal form A is 2 theta
Main characteristic peaks: 6.5, 17.8,9.4
Minor characteristic peak: 13.4,7.5, 19.7
Second characteristic peak: 14.6, 18.5
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the present invention provides a quinazoline derivative (I) having an XRPD pattern of form a fumarate salt having derivative peaks at 2 θ of 6.51, 6.74, 7.47, 9.37, 10.82, 13.43, 13.97, 14.61, 17.78, 18.51, 18.80, 19.69, 20.90, 21.36, 21.68, 22.63, 23.76, 24.39, 27.09, 28.73, 29.69, 30.52, 31.07, 35.14, 36.12 and 38.33, with an error range for the above 2 θ values of ± 0.2.
The invention adopts another technical scheme that a succinate crystal form A of a quinazoline derivative is provided, and an XRPD pattern of the succinate crystal form A is 2 theta
Main characteristic peaks: 6.6, 17.8,7.5
Minor characteristic peak: 9.4, 20.3, 18.5
Second characteristic peak: 21.0, 14.5, 19.5
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of form a succinate salt of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 3.92, 4.40, 6.56, 6.74, 7.50, 9.42, 11.92, 12.68, 13.53, 14.50, 14.84, 15.22, 15.68, 16.25, 17.82, 18.55, 19.48, 20.34, 20.99, 22.08, 22.59, 24.14, 24.52, 24.92, 28.07, 30.92 and 36.11, with a deviation of the above 2 θ values of ± 0.2.
The invention adopts another technical scheme that a maleate crystal form A of the quinazoline derivative is provided, and the XRPD pattern of the maleate crystal form A is 2 theta
Main characteristic peaks: 6.3, 18.8, 16.7
Minor characteristic peak: 25.2, 21.2
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the maleate form a of the quinazoline derivative provided by the present invention has derivative peaks at 2 θ of 6.25, 8.44, 8.68, 9.42, 10.41, 14.42, 14.88, 16.65, 17.93, 18.78, 20.58, 21.17, 22.63, 25.16, 31.15, 32.40, 33.66, 34.34, 34.52, 35.82, 36.06, 36.35, 36.91, with a deviation of the above 2 θ value of ± 0.2.
The invention adopts another technical scheme that a glycolate crystal form A of a quinazoline derivative is provided, and an XRPD pattern of the glycolate crystal form A is 2 theta
Main characteristic peaks: 6.6,7.4, 17.9
Minor characteristic peak: 13.3
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the quinazoline derivative provided by the present invention has an XRPD pattern of the glycolate salt form a having derivative peaks at 2 θ ═ 4.53, 5.89, 6.59, 7.35, 10.02, 12.54, 13.26, 15.94, 17.93, 18.67, 19.36, 19.84, 21.06, 24.99, 31.13, 33.48, 34.79, 35.56, 36.17, with a deviation range of the above 2 θ values being ± 0.2.
The invention adopts another technical scheme of providing a sulfate crystal form A of the quinazoline derivative, wherein the XRPD pattern of the sulfate crystal form A is 2 theta
Main characteristic peaks: 7.3, 18.2, 15.0
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the crystalline form a of sulphuric acid of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 7.27, 8.41, 11.88, 14.96, 18.23, 19.68, 20.64, 24.83, 25.82, 27.10, 28.16, 29.79, 30.71, 32.35, 34.12, 35.56, 37.56, 38.37, with the above 2 θ values being within ± 0.2.
The invention adopts another technical scheme that an oxalate crystal form A of a quinazoline derivative is provided, and an XRPD pattern of the oxalate crystal form A is 2 theta
Main characteristic peaks: 6.9, 15.1, 13.7
Minor characteristic peak: 15.4,9.6, 19.0
Second characteristic peak: 20.6, 27.3, 23.4
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the oxalate salt form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 5.43, 6.88, 7.38, 9.56, 13.68, 15.10, 15.43, 16.32, 16.88, 17.68, 18.60, 19.02, 20.58, 21.62, 22.33, 22.70, 23.35, 25.68, 27.29, 27.88, 28.53, 29.37, 31.35, 34.89, 37.11, 37.78, 38.17, 38.36, 39.65, with an error range for the above 2 θ value of ± 0.2.
The invention adopts another technical scheme that a malate crystal form A of a quinazoline derivative is provided, and an XRPD pattern of the malate crystal form A is 2 theta
Main characteristic peaks: 6.5, 18.8, 19.9
Minor characteristic peak: 7.5,8.4,9.2
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
The XRPD pattern of the malate salt form a of the quinazoline derivative (I) provided by the invention has derivative peaks at 2 theta of 5.43, 6.53, 7.49, 8.35, 9.17, 12.10, 13.16, 16.17, 18.77, 19.85, 20.79, 23.14, 23.94, 26.66, 28.25, 29.32, 30.38, 33.24, 33.69, 34.80, 35.97, 36.87 and 37.88, and the error range of the 2 theta value is +/-0.2.
The invention adopts another technical scheme that a benzene sulfonate crystal form A of a quinazoline derivative is provided, and an XRPD pattern of the crystal form A is 2 theta
Main characteristic peaks: 6.6, 14.0, 15.3
Minor characteristic peak: 7.1,5.5, 19.7
Second characteristic peak: 17.8, 16.9, 21.0
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
The XRPD pattern of the besylate salt form a of the quinazoline derivative provided by the invention has derivative peaks at 2 theta of 5.48, 6.56, 7.08, 7.65, 8.14, 8.48, 9.71, 10.55, 11.14, 11.77, 13.32, 13.95, 15.32, 16.46, 16.89, 17.82, 19.15, 19.70, 20.43, 21.02, 21.98, 22.68, 23.23, 25.26, 26.07, 26.59, 28.63, 29.09, 30.45, 31.12, 32.09, 32.55, 33.66, 35.76, 37.86, 38.67 and 39.11, and the error range of the 2 theta value is +/-0.2.
The invention adopts another technical scheme that a benzene sulfonate crystal form B of a quinazoline derivative is provided, and an XRPD pattern of the crystal form B is 2 theta
Main characteristic peaks: 8.5, 14.5, 23.4
Minor characteristic peak: 18.3, 19.7
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
The XRPD pattern of the besylate salt form B of the quinazoline derivative provided by the invention has derivative peaks at 2 theta of 5.50, 6.32, 7.28, 8.50, 9.74, 10.79, 11.55, 13.22, 14.49, 15.53, 16.26, 16.97, 18.29, 19.71, 21.36, 22.21, 23.44, 24.19, 25.34, 25.87 and 27.16, and the error range of the 2 theta value is plus or minus 0.2.
The invention adopts another technical scheme that a benzene sulfonate crystal form C of the quinazoline derivative is provided, and the XRPD pattern of the crystal form C is 2 theta
Main characteristic peaks: 14.0, 14.7,7.7
Minor characteristic peak: 8.3, 21.2, 19.4,
second characteristic peak: 27.5, 24.7
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the XRPD pattern of the besylate salt form C of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.24, 7.07, 7.68, 8.31, 9.92, 12.55, 14.03, 14.74, 18.72, 19.40, 20.36, 21.19, 24.08, 24.73, 26.14, 27.49, 28.28, 31.68, 33.90, 34.82, 35.06, 35.78, 36.54, 37.57, 37.89, 38.36, 39.0, with a deviation from the above 2 θ values of ± 0.2.
The invention adopts another technical scheme that a benzoate crystal form A of a quinazoline derivative is provided, and an XRPD pattern of the benzoate crystal form A is 2 theta
Main characteristic peaks: 7.3,6.3, 16.8
Minor characteristic peak: 13.5, 18.7, 27.0
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
The quinazoline derivative (I) provided by the invention has an XRPD pattern of a benzoate form A with derivative peaks at 2 theta-4.45, 6.31, 6.65, 7.33, 7.69, 8.01, 11.85, 13.53, 16.02, 16.77, 18.75, 19.95, 21.06, 21.76, 22.56, 23.41, 26.94, 27.44, 27.61, 27.98, 28.55, 29.05, 31.92, 32.29, 32.93, 33.72, 34.61, 35.35, 35.95, 37.08, 38.13 and 39.62, and the error range of the 2 theta values is +/-0.2.
The invention adopts another technical scheme that hippurate crystal form A of the quinazoline derivative is provided, and the XRPD pattern of the crystal form A is 2 theta
Main characteristic peaks: 5.6,6.9, 20.0
Minor characteristic peak: 16.0,7.7, 13.7
Second characteristic peak: 24.3, 26.4
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the present invention provides a quinazoline derivative (I) having an XRPD pattern of hippurate form a having derivative peaks at 2 θ ═ 4.35, 5.59, 6.85, 7.74, 9.17, 9.95, 13.74, 14.73, 15.96, 16.44, 18.10, 18.63, 19.96, 21.38, 24.25, 25.37, 25.72, 26.39, 27.23, 28.56, 30.25, 30.82, 33.31, 34.58, 35.29, 36.39, 37.24, 37.9, with a2 θ value error range of ± 0.2.
The invention adopts another technical scheme that oxalate crystal form A of quinazoline derivative is provided, and XRPD pattern of oxalate crystal form A is 2 theta
Main characteristic peaks: 6.4,9.1, 17.5
Minor characteristic peak: 12.9, 14.5, 26.4
Second characteristic peak: 19.4, 18.3, 15.9
Has a diffraction peak, wherein the error range of the 2 theta value is +/-0.2.
Preferably, the quinazoline derivative (I) provided by the present invention has an XRPD pattern of oxalate form a having derivative peaks at 2 θ ═ 4.11, 6.44, 7.15, 8.75, 9.06, 9.88, 11.26, 11.58, 12.92, 14.52, 15.87, 17.47, 18.29, 19.43, 20.14, 20.49, 23.70, 24.34, 26.36, 26.92, 29.75, 31.72, 32.67, 32.99, 34.21, 34.52, 34.86, 36.36, 36.91, 37.91, 39.03, with a deviation range of the above 2 θ values being ± 0.2.
Preferably, the hydrochloride form a of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 1.
Preferably, the hydrochloride form B of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 2.
Preferably, the crystalline hydrochloride form C of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 10.
Preferably, the crystalline hydrochloride form D of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 11.
Preferably, the crystalline form F hydrochloride of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 9.
Preferably, the hydrochloride form H of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 3.
Preferably, the crystalline hydrochloride form I of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 4.
Preferably, the fumarate salt form a of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 5.
Preferably, the succinate form a of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 6.
Preferably, the crystalline maleate form a of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 7.
Preferably, the crystalline form a of the glycolate salt of the quinazoline derivative according to the present invention has an XRPD pattern substantially as shown in figure 8.
Preferably, the crystalline form a of the sulphate salt of the quinazoline derivative according to the present invention has an XRPD pattern substantially as shown in figure 12.
Preferably, the oxalate form a of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 13.
Preferably, the crystalline form a malate salt of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 14.
Preferably, the besylate salt form a of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 15.
Preferably, the crystalline form B besylate of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 16.
Preferably, the crystalline form C besylate of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 17.
Preferably, the crystalline form a benzoate salt of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 18.
Preferably, the hippurate crystal form a of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 19.
Preferably, the crystalline form I oxalate salt of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in figure 20.
The invention also provides a method for preparing the hydrochloride crystal form A of the quinazoline derivative (I), which comprises the following steps: adding an organic solvent and 0.8-1.2 equivalent of hydrochloric acid into a quinazoline derivative sample shown in a formula (I), stirring at 22-28 ℃, and centrifuging to separate out a lower-layer solid to obtain a crystal form A; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the hydrochloride crystal form B of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative shown in a formula (I) into an organic solvent, adding 0.8-1.2 equivalent of hydrochloric acid into the suspension, stirring at 22-28 ℃, and centrifugally separating out a lower-layer wet-sample solid to obtain a crystal form B; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the hydrochloride crystal form C of the quinazoline derivative (I), which comprises the following steps: adding an organic solvent into a quinazoline derivative sample shown in a formula (I), adding 2-2.5 equivalents of hydrochloric acid, stirring at 22-28 ℃, and centrifuging to separate out a lower-layer wet sample solid to obtain a dihydrochloride crystal form C; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the hydrochloride crystal form D of the quinazoline derivative (I), which comprises the following steps: and heating the hydrochloride crystal form C sample to high temperature, and cooling to 22-28 ℃ to obtain a dihydrochloride crystal form D.
The invention also provides a method for preparing the hydrochloride crystal form F of the quinazoline derivative (I), which comprises the following steps: adding an alcohol and ester organic solvent into a quinazoline derivative hydrochloride crystal form B shown in a formula (I), and performing gas-liquid diffusion at 22-28 ℃ until a solid is separated out to obtain a crystal form F; wherein 10-200 mg of the hydrochloride crystal form B shown in the formula (I) is added into each ml of the organic solvent.
The invention also provides a method for preparing the hydrochloride crystal form H of the quinazoline derivative (I), which comprises the following steps: adding an organic solvent into the hydrochloride crystal form B, filtering, and volatilizing at 22-28 ℃ (open mouth speed) to obtain a crystal form H; wherein 10-200 mg of the hydrochloride crystal form B shown in the formula (I) is added into each ml of the organic solvent.
The invention also provides a method for preparing the hydrochloride crystal form I of the quinazoline derivative (I), which comprises the following steps: and heating the hydrochloride crystal form H sample to a high temperature, and cooling to 22-28 ℃.
The invention also provides a method for preparing the fumarate crystal form A of the quinazoline derivative (I) disclosed by the invention, which comprises the following steps: adding a quinazoline derivative shown as a formula (I) and 0.4-0.6 equivalent of fumaric acid into an organic solvent, stirring at 22-28 ℃, and centrifuging to collect a solid; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the succinate crystal form A of the quinazoline derivative (I) disclosed by the invention, which comprises the following steps: adding an organic solvent into a quinazoline derivative shown in a formula (I) and 0.8-1.2 equivalent of succinic acid, stirring at 22-28 ℃, centrifuging and collecting a solid to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the maleate crystal form A of the quinazoline derivative (I) disclosed by the invention, which comprises the following steps: adding an organic solvent into a quinazoline derivative shown in a formula (I) and maleic acid, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the glycolate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding the quinazoline derivative shown in the formula (I) and 0.8-1.2 equivalent of glycolic acid into an organic solvent, stirring at room temperature, and centrifuging to collect a solid.
The invention also provides a method for preparing the sulfate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of sulfuric acid aqueous solution, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the oxalate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of oxalic acid, stirring at 22-28 ℃, centrifuging, and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the malate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of malic acid, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the benzene sulfonate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzenesulfonic acid, stirring at 22-28 ℃, centrifuging, and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the benzene sulfonate crystal form B of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzenesulfonic acid, stirring at 22-28 ℃, centrifuging, and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the benzene sulfonate crystal form C of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzenesulfonic acid, stirring at 22-28 ℃, centrifuging, and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the benzoate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzoic acid, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing the hippurate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of hippuric acid, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
The invention also provides a method for preparing oxalate crystal form A of the quinazoline derivative (I), which comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of oxalic acid, stirring at 22-28 ℃, centrifuging, and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
In the above method, preferably, the organic solvent is one or more of alcohols, ethers, esters, aliphatic hydrocarbons and aromatic hydrocarbons.
More preferably, the alcohol organic solvent is one or more of methanol, ethanol, isopropanol, n-propanol, isobutanol and n-butanol.
More preferably, the ether organic solvent is diethyl ether, isopropyl ether or methyl tert-butyl ether.
More preferably, the ester organic solvent is ethyl acetate, butyl acetate or isopropyl acetate.
More preferably, the ketone organic solvent is acetone, butanone or 4-methyl-2-pentanone.
More preferably, the aliphatic hydrocarbon organic solvent is n-heptane or acetonitrile.
More preferably, the aromatic hydrocarbon organic solvent is toluene.
Further preferably, in the preparation method of the hydrochloride crystal form a of the quinazoline derivative (I), the organic solvent is methanol.
In the preparation method of the hydrochloride crystal form B of the quinazoline derivative (I), preferably, the organic solvent is acetonitrile, ethyl acetate or tetrahydrofuran/water (15-20/1, v/v).
According to the preparation method of the hydrochloride crystal form C of the quinazoline derivative (I), preferably, the organic solvent is acetone.
The preparation method of the hydrochloride crystal form D of the quinazoline derivative (I) is preferably carried out at the high temperature of 120 ℃ and 160 ℃.
According to the preparation method of the hydrochloride crystal form F of the quinazoline derivative (I), preferably, the alcohol is methanol, and the ester is isopropyl acetate. More preferably, the weight ratio of methanol to ethyl acetate is 1: 1.
In the preparation method of the hydrochloride crystal form H of the quinazoline derivative (I), the organic solvent is preferably ethanol.
The preparation method of the hydrochloride crystal form I of the quinazoline derivative (I) preferably has the high temperature of 120-130 ℃.
According to the preparation method of the fumarate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol, acetone, ethyl acetate or a mixture of the organic solvent and the fumarate crystal form A in a volume ratio of 15-20:1 tetrahydrofuran/water mixture.
In the preparation method of the succinate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol or acetone.
In the preparation method of the maleate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is acetone.
According to the preparation method of the glycolate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol, acetonitrile or ethyl acetate.
According to the preparation method of the sulfate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol, acetonitrile, acetone, ethyl acetate or a mixture of the organic solvent and the sulfate crystal form A in a volume ratio of 15-20:1 tetrahydrofuran/water mixture.
According to the preparation method of the oxalate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol or ethyl acetate.
According to the preparation method of the malate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol, ethyl acetate or a mixture of the organic solvent and the malate crystal form A in a volume ratio of 15-20:1 tetrahydrofuran/water mixture.
In the preparation method of the benzene sulfonate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol.
In the preparation method of the benzene sulfonate crystal form B of the quinazoline derivative (I), preferably, the organic solvent is acetonitrile.
According to the preparation method of the benzene sulfonate crystal form C of the quinazoline derivative (I), the organic solvent is preferably a mixed solvent of tetrahydrofuran and water (the volume ratio is 15-20:1, and more preferably 19: 1).
According to the preparation method of the benzoate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol, acetonitrile, acetone or a mixture of the organic solvent and the benzoate crystal form A in a volume ratio of 15-20:1 tetrahydrofuran/water mixture.
In the preparation method of the hippurate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol.
According to the preparation method of the oxalate crystal form A of the quinazoline derivative (I), preferably, the organic solvent is methanol.
The invention also provides a pharmaceutical composition, which comprises hydrochloride crystal forms A, B, C, D, F, H, I, sulfate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycolate crystal form A, malate crystal form A, fumarate crystal form A, benzenesulfonate crystal forms A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate crystal form A shown in formula (I) or a combination thereof, and pharmaceutically acceptable auxiliary materials or auxiliary components.
Preferably, the auxiliary materials or auxiliary components comprise carriers, excipients, diluents, vehicles and adjuvants.
The invention also provides application of the hydrochloride crystal forms A, B, C, D, F, H, I, sulfate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycolate crystal form A, malate crystal form A, fumarate crystal form A, benzenesulfonate crystal forms A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate crystal form A of the quinazoline derivative shown in the formula (I) or the pharmaceutical composition in preparation of medicines for treating or preventing diseases mediated by epidermal growth factor receptor EGFR protein.
Preferably, the medicament is a medicament for treating or preventing diseases mediated by the epidermal growth factor receptor EGFR protein and caused by activation mutation of EGFRVIII.
The medicine is a medicine for treating or preventing diseases mediated by epidermal growth factor receptor EGFR protein and caused by activating mutation of EGFR Del19 and/or EGFR L858R.
More preferably, the medicament is for preparing a medicament for treating or preventing non-small cell lung cancer brain metastasis, meningeal metastasis, head and neck squamous cell carcinoma, brain stem tumor, primary brain cancer or brain glioma.
The amount of reagents and methods used in the present invention can be adjusted by one of ordinary skill in the art based on his knowledge and experience, including scaling up or down the amounts of starting materials or solvents, and such adjustments are also included in the methods of the present invention.
Compared with the prior art, the invention has the following beneficial effects:
1) the novel R chiral quinazoline derivatives (I) and their pharmaceutical salts of the present invention have unexpected ability to cross the blood brain barrier and can be used as protein kinase inhibitors for drug properties, particularly against medical conditions mediated by certain activated mutant forms of the epidermal growth factor receptor (e.g., epidermal growth receptor EGFR exon 2-7 deletion activating mutants), e.g., gliomas having EGFRVIII mutations, and for the treatment or prevention of disorders associated with aberrant protein kinase activity, e.g., cancer brain metastases, cancer meningeal metastases, and central nervous system diseases, among others.
2) The quinazoline derivative (I) and the pharmaceutical salt thereof have low outflow rate, are not P-glycoprotein efflux enzyme substrates or breast cancer drug-resistant efflux enzyme substrates, and can reduce the drug resistance generated by efflux enzymes.
3) The quinazoline derivative and the pharmaceutical salt thereof have good pharmacokinetics and high biological activity, can reduce the tablet intake burden of patients, and improve the tablet intake compliance of the patients.
4) The quinazoline derivative (I) provided by the invention has hydrochloride crystal forms A, B, C, D, F, H, I, sulfate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycolate crystal form A, malate crystal form A, fumarate crystal form A, benzenesulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate crystal form A with good stability and water solubility, is favorable for being used in pharmaceutical processing and pharmaceutical compositions, can treat cancers mediated by EGFR activating mutation (such as EGFRIII, EGFR del19 or EGFR L858R), such as non-small cell lung cancer brain metastasis, meningeal metastasis, head and neck squamous cell cancer, brain stem tumor, primary brain cancer or brain glioma and the like, and has good bioavailability, meanwhile, qualitative and quantitative information of curative effect and safety is provided, and the method has important significance for further researching the curative effect of the solid medicine.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
figure 1 is an XRPD pattern of hydrochloride form a of a quinazoline derivative of the present invention;
figure 2 is an XRPD pattern of crystalline form B hydrochloride of a quinazoline derivative according to the invention;
figure 3 is an XRPD pattern of hydrochloride form H of a quinazoline derivative of the present invention;
figure 4 is an XRPD pattern of hydrochloride form I of a quinazoline derivative of the present invention;
figure 5 is an XRPD pattern of fumarate salt form a of a quinazoline derivative of the present invention;
figure 6 is an XRPD pattern of succinate form a of the quinazoline derivative of the present invention;
figure 7 is an XRPD pattern of maleate form a of the quinazoline derivative of the present invention;
figure 8 is an XRPD pattern of the glycolate salt form a of the quinazoline derivative of the present invention;
figure 9 is an XRPD pattern of hydrochloride form F of a quinazoline derivative of the present invention;
figure 10 is an XRPD pattern of hydrochloride form C of a quinazoline derivative of the present invention;
figure 11 is an XRPD pattern of crystalline hydrochloride form D of a quinazoline derivative of the present invention;
figure 12 is an XRPD pattern of sulphate form a of a quinazoline derivative according to the invention;
figure 13 is an XRPD pattern of oxalate salt form a of a quinazoline derivative of the invention;
figure 14 is an XRPD pattern of malate form a of the quinazoline derivative of the invention;
figure 15 is an XRPD pattern of besylate form a of a quinazoline derivative of the invention;
figure 16 is an XRPD pattern of besylate form B of a quinazoline derivative of the invention;
figure 17 is an XRPD pattern of besylate form C of a quinazoline derivative of the invention;
figure 18 is an XRPD pattern of benzoate form a of a quinazoline derivative of the present invention;
figure 19 is an XRPD pattern of hippurate form a of the quinazoline derivative of the present invention;
fig. 20 is an XRPD pattern of oxalate form a of the quinazoline derivative of the present invention;
fig. 21 is a schematic representation of the inhibition of EGFRVIII phosphorylation by quinazoline derivatives of the present invention;
FIG. 22 is a schematic diagram showing the study of the pharmacological effects of the quinazoline derivative of the present invention in a subcutaneous model of a humanized brain glioma mouse;
figure 23 is a TGA and DSC profile of a fumarate salt of a quinazoline derivative of the present invention; wherein a is a TGA atlas without obvious weight loss; b is a DSC atlas, the crystal form is stable in the heating process, the crystal form is not transformed, and the melting point is 240 ℃;
FIG. 24 is a schematic diagram showing the mechanism of inhibition of the quinazoline derivatives of the present invention with EGFR.
Detailed Description
The terms to which the present invention relates are explained as follows:
the terms "ameliorating" and "treating," which are used interchangeably, mean reducing, attenuating, inhibiting, reducing, preventing, or stabilizing the onset or progression of a disease (e.g., a disease or disorder described herein), and refer to a method for obtaining a result that includes a beneficial or desired result, but is not limited to a therapeutic benefit and/or a prophylactic benefit.
"disease" refers to any condition or disorder that impairs or interferes with the normal function of a cell, organ or tissue.
"marker" refers to any change associated with a disease or disorder. For example, any protein or polynucleotide whose expression level or activity is altered in association with a disease or disorder.
As used herein, "including," "comprising," and "having" and similar terms have the meaning ascribed to them in patent law; "consisting essentially of …" or "consisting essentially of has the meaning attributed to them by patent law, and the term is open-ended, allowing the presence of objects other than those cited, provided that the underlying or novel characteristics of the cited are not changed by the presence of objects other than those cited, but does not include prior art embodiments.
As used herein, the terms "antagonist" and "inhibitor" are used interchangeably and refer to a compound or agent that has the ability to inhibit a biological function of a targeted protein or polypeptide, for example, by inhibiting the activity or expression of the protein or polypeptide. Although some of the antagonists herein act with a particular target protein or polypeptide (e.g., bind EGFR), it is expressly included within this definition that a compound inhibits the biological activity of a target protein or polypeptide by interacting with other members of the signaling pathway of other targeted proteins or polypeptides, and also includes inhibiting those biological activities associated with developing, growing, or spreading tumors, or undesirable immune responses exhibited in autoimmune diseases.
The terms "anti-cancer agent," "anti-neoplastic agent," or "chemotherapeutic agent" as used herein refer to any agent useful in the treatment of a neoplastic disorder. One class of anti-cancer agents includes chemotherapeutic agents. "chemotherapy" refers to the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by a variety of methods, including intravenous, oral, subcutaneous, intramuscular, intraperitoneal, intravesical, transdermal, buccal, or inhalation.
The term "cell proliferation" as used herein refers to the phenomenon of an increase in the number of cells as a result of cell division, and also includes cell growth (e.g., an increase in size) that is altered by the morphology of the cells in accordance with a proliferation signal.
The term "co-administration" as used herein refers to the separate use of two or more drugs at the same time, and also includes the use of a composition in which both two or more agents are present at the same time, and also includes the separate administration or administration of two or more drugs and/or metabolites thereof at different times.
The term "effective amount" or "therapeutically effective amount" as used herein means that the amount of a compound or pharmaceutical composition described herein is sufficient to achieve the intended use, including, but not limited to, the treatment of disease. In some embodiments, the amount is detected to be effective for killing or inhibiting cancer cell growth or spread; the size or number of tumors; or the severity level, stage and progression of the cancer. The therapeutically effective amount may vary depending on the intended application, e.g., in vitro or in vivo, the condition and severity of the disease, the age, weight, or mode of administration of the subject, etc. The term also applies to a particular response in which the dose will induce the target cell, e.g., reduce cell migration. The specific dosage will depend, for example, on the particular compound chosen, the species of the subject and their age/existing health or risk of health, the route of administration, the severity of the disease, administration in combination with other agents, the time of administration, the tissue to which it is administered, and the administration device, among other things.
The term "therapeutic effect" as used herein includes a therapeutic benefit and/or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination thereof.
The term "signaling" as used herein is the process during which a stimulatory or inhibitory signal is sent into a cell to elicit an intracellular response, and a "modulator" of a signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins through a particular signal transduction pathway. A "modulator" may increase (agonist) or inhibit (antagonist) the activity of a signaling molecule.
The term "selective inhibition" as used herein refers to the ability of a compound to selectively reduce a signaling activity of interest as compared to off-target signaling activity, by direct interaction or indirect interaction, and the like. For example, a compound selectively inhibits the activity of a mutated EGFR by at least about 2-fold, about 3-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold or more as compared to the activity against wild-type EGFR.
The term "radiation therapy" as used herein refers to exposure of a subject to radiation emitters such as, but not limited to, alpha-particle emitting radionuclides (e.g., actinium and thorium radionuclides), low Linear Energy Transfer (LET) radiation emitters (i.e., beta emitters), converting electron emitters (e.g., strontium-89 and samarium 153-EDTMP), or high energy radiation including, but not limited to, X-rays, gamma rays, and neutrons.
The term "subject" as used herein includes, but is not limited to, humans (i.e., any age group, e.g., male or female (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or advanced adult) of a pediatric subject) and/or other primates (e.g., cynomolgus monkey, rhesus monkey); mammals, including commercially relevant mammals, such as cows, sheep, goats, pigs, horses, cats, and/or dogs; and/or birds, including commercially relevant birds, such as chickens, geese, quails, ducks, and/or turkeys.
The term "in vivo" as used herein refers to an activity occurring within the body of a subject. Also included in vivo are events that occur in rodents, such as rats, mice, guinea pigs, and the like.
The term "in vitro" as used herein refers to an event that occurs in a place other than the body. For example, an in vitro test assay includes any assay that occurs outside the body. In vitro assays include cell assays based on live or dead cells, as well as cell-free assays used in which there are no intact cells.
The term "compound" as used herein is also intended to include salts, prodrugs and prodrug salts of the compounds of the general formulae herein. The term also includes any solvates, hydrates and polymorphs of any of the foregoing. In certain aspects of the invention described in this application, specific references to "prodrug", "prodrug salt", "solvate", "hydrate" or "polymorph" should not be construed as excluding these forms in other aspects of the invention where the term "compound" is used without reference to these other forms.
Salts of the compounds of the invention are formed between an acid and a basic group of the compound, such as an amino functional group. According to another preferred embodiment, the compound is a pharmaceutically acceptable acid addition salt.
Salts of the compounds of the invention are formed between a base and an acidic group of the compound, such as a carboxyl functional group. According to another preferred embodiment, the compound is a pharmaceutically acceptable base addition salt.
As used herein and unless otherwise indicated, the term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. A prodrug may become active only after such a reaction under biological conditions, or may be active in its unreacted form. Examples of prodrugs of the invention include, but are not limited to, analogs or derivatives of compounds of any of the general formulae disclosed herein, as well as biohydrolyzable moieties such as amide and ester analogs.
Prodrug salts are compounds formed between an acid and a basic group of the prodrug, such as an amino functional group, or a base and an acidic group of the prodrug, such as a carboxyl functional group. In one embodiment, the prodrug salt is a pharmaceutically acceptable salt.
Particularly preferred prodrugs and prodrug salts are those that increase the bioavailability of the compounds of the invention when such compounds are used in a mammal or human (e.g., by making the orally administered compound more readily absorbed) or facilitate delivery of the compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species. Preferred prodrugs include derivatives in which a group that increases water solubility or increases active transport through the intestinal membrane is added to the general structure described herein. See, e.g., Design of produgs, edited by H.Bundgaard, (Elsevier,1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K.Widder, et al (Academic Press, 1985); a Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5"Design and Application of Prodrugs", by H.Bundgaard p.113-191 (1991); bundgaard, Advanced Drug Delivery Reviews,8,1-38 (1992); bundgaard, et al, Journal of Pharmaceutical Sciences,77,285 (1988); kakeya, et al, Chem Pharm Bull,32,692 (1984).
The term "pharmaceutically acceptable" as used herein, means a component that is, within the scope of sound medicine, suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a prodrug of the compound.
Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, hydroiodic and phosphoric acid, and organic acids such as trifluoroacetic, citric, maleic, oxalic, picric, acetic, adipic, alginic, aspartic, sulfuric, boric, butyric, valeric, camphoric, camphorsulfonic, diglucolic, dodecylsulfuric, pivalic, formic, heptanoic, fumaric, hydroiodic, benzoic, 2-hydroxy-ethanesulfonic, fumaric, stearic, lactobionic, lauric, nicotinic oleate, lactic acid cinnamate, succinic, mandelic, malic, tartaric, ditartaric, lactic, pyruvic, pectic, methanesulfonic, pamoic, benzenesulfonic, persulfuric, palmitic, glycerophosphoric, 2-naphthalenesulfonic, p-toluenesulfonic acid, Salicylic acid, ascorbic acid, 3-phenylpropionic acid, gluconic acid, glucuronic acid, phosphoric acid, glutamic acid, ethanesulfonic acid, p-bromophenylsulfonic acid, and carbonic acid, and related inorganic and organic acids. Bases commonly used to form pharmaceutically acceptable salts include alkali metal, alkaline earth metal, ammonium, N+(C1-4 alkyl)4Salts, and related inorganic and organic bases. Representative alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, iron, copper, manganese, zinc, aluminum, and the like, as well as salts formed with organic bases including, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium, potassium, sodium, calcium, and magnesium salts. See, e.g., Berge et al J. pharmaceutical Sciences (1977)66: 1-19.
The term "hydrate" as used herein refers to a compound that includes stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces. The term "solvate" as used herein refers to a compound that includes a stoichiometric or non-stoichiometric amount of a solvent that binds by non-covalent intermolecular forces, such as water, dichloromethane, 2-propanol, acetone, methanol, ethanol, or the like. Pharmaceutically acceptable solvates and hydrates are complexes, for example, may include from 1 to about 100, or from 1 to about 10, or from 1 to about 4, about 3, or about 2, solvent or water molecules. It is to be understood that the term "compound" as used herein includes the compounds and solvates, hydrates, and mixtures thereof of the compounds.
The term "polymorph" as used herein refers to a solid crystalline form of a compound or complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., to heat, light, or moisture), density, hygroscopicity, solubility, compressibility, and dissolution rate.
The term "isomer" as used herein is a different compound having the same molecular formula. "stereoisomers" are isomers that differ only in the spatial arrangement of the atoms. The term "isomer" as used herein includes any and all geometric isomers and stereoisomers. For example, "isomers" include cis and trans isomers of geometric double bonds, also known as E-and Z-isomers; the R-and S-enantiomers; diastereomers, (D) isomers and (L) isomers, racemic mixtures thereof, as well as other mixtures thereof, are disclosed herein.
The double bond around the carbon-carbon substituent is designated in either the "Z" or "E" configuration, where the terms "Z" and "E" are used according to the IUPAC standard. Unless otherwise indicated, structurally depicted double bonds include both "E" and "Z" isomers.
Alternative substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" refers to the substituent on the same side of the double bond and "trans" represents the substituent on both sides of the double bond. The arrangement of the surrounding carbocyclic rings of a substituent may also be designated as "cis" or "trans". The term "cis" refers to substituents on the same side of the ring plane and the term "trans" refers to substituents on both sides of the ring plane. The mixture of compounds in which the substituents are on the same and opposite sides of the plane of the two rings is denoted "cis/trans".
The term "enantiomer" as used herein is a pair of stereoisomers that are nonsuperimposable mirror images of each other. A mixture of a pair of enantiomers in any ratio may be referred to as a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "diastereoisomers" refers to compounds having at least two asymmetric atoms, but whose stereoisomers are not mirror images of each other. Absolute stereochemistry was assigned according to the Cahn-lngold-Prelog R-S system. When the compounds are enantiomers, the stereochemistry at each chiral carbon may be designated by R or S. The resolved compounds, whose absolute configuration is unknown, can be assigned (+) or (-), depending on their direction (dextro-or levorotatory) of rotation of plane-polarized light at the wavelength of the sodium D line.
By absolute stereomerically is meant a compound that is (R) -or (S) -at each asymmetric atom, and pharmaceutical compositions and methods include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) -and (S) -can also be prepared using chiral synthetic methods or chiral reagents, or resolved using conventional techniques.
The composition of the term "enantiomeric excess" or "% enantiomeric excess" as used herein can be calculated using the formula shown below. In the examples shown below, the compositions contain 90% of one enantiomer, for example the S enantiomer, and 10% of the other enantiomer, for example the R enantiomer.
The ee value is (90-10)/100 is 80%.
Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%. Some of the compositions described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or about 99% of the S enantiomer. In other words, the composition comprises an enantiomeric excess of the S enantiomer within the R enantiomer. In other embodiments, some compositions described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or about 99% of the R enantiomer. In other words, the composition comprises an enantiomeric excess of the R enantiomer within the S enantiomer. For example, an isomer/enantiomer may, in some embodiments, provide the ee value of the corresponding enantiomer, and may also be referred to as "optically enriched", "enantiomerically pure", and "non-racemic", as used interchangeably herein. These terms refer to the fact that the weight percent of one enantiomer is greater (e.g., greater than 1:1 weight ratio) than the amount of the controlled mixture of the racemic composition in one enantiomer. For example, the S enantiomer may be enantiomerically enriched (by weight) relative to the R enantiomer, such as at least about 75% by weight of the compound having greater than about 50%, and such as at least about 80% by weight. In some embodiments, enrichment of greater than about 80% by weight provides for the preparation of "substantially enantiomerically enriched", "substantially enantiomerically pure", or "substantially non-racemic", meaning a composition whose weight of an enantiomer is at least 85% relative to one of the other enantiomers, such as at least about 90% by weight of the formulation, and further, such as at least about 95% by weight. In certain embodiments, a compound provided herein may consist of at least about 90% by weight of one enantiomer. In other embodiments, the compound may consist of at least about 95%, about 98%, or about 99% by weight of one enantiomer. In some embodiments, the compound is a (S) -and (R) -racemic mixture. In other embodiments, provided herein is a method wherein the individual compounds (S) -of the mixture are predominantly a mixture of the compounds present or (R) -are predominantly a mixture of the compounds present. For example, the mixture of compounds has an (S) -enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In other embodiments, the mixture of compounds has an (S) -enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or higher. In other embodiments, the compound mixture (R) -enantiomeric purity is greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the mixture of compounds has an (R) -enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
In other embodiments, the compound mixture comprises, except for their stereochemical orientation, (S) -or (R) -the same chemical entity. For example, if a compound is disclosed herein having one-ch (R) -unit, and R is not hydrogen, -ch (R) -is in the orientation of each identical chemical entity in (S) -or (R) -stereochemistry. In some embodiments, the (S) -isomer in a mixture of identical chemical entities is present in an (S) -enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or more.
In another embodiment, the mixture of (R) -isomers at the same chemical entity (except for their stereochemical orientation) is at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or higher relative to the (S) -isomer. In some embodiments, the isomer, in a mixture of (R) -identical chemical entities (other than its stereochemical orientation), is present in an (R) -enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
Enantiomers can be separated from the racemic mixture by any method known to those skilled in the art, including chiral High Performance Liquid Chromatography (HPLC), formation and crystallization of chiral salts, or without synthetic separation. See, e.g., Enantiomers, Racemates and solutions (Jacques, Ed., Wiley lnterscience, New York, 1981); wilen et al, Tetrahedron 33:2725 (1977); stereochemistry of Carbon Compounds (E.L.Eliel, Ed., McGraw-Hill, NY, 1962); and Tables of solving Agents and Optical solutions p.268(E.L. EIM, Et al., Univ. of Notre Dame Press, Notre Dame, Ind.1972).
Optical isomers may also be obtained by resolution of the racemic mixture in a conventional manner with an optically active acid or base, for example, by formation of diastereomeric salts. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyl, dibenzoyl, ditoluoyltartaric acid and camphorsulfonic acid. Diastereomeric crystallization followed by separation of the isomers from a mixture of the optically active bases of these salts. Another method, by reacting the disclosed compounds with an activated form of an optically pure acid or an optically pure isocyanate, involves the synthesis of covalent diastereomeric molecules. The enantiomers may be synthesized and separated by conventional methods such as chromatography, distillation, crystallization or sublimation followed by hydrolysis to provide enantiomerically enriched compounds. Optically active compounds can also be obtained by using active raw materials. In some embodiments, these isomers may be in the form of the free acid, free base, ester, or salt.
In certain embodiments, the pharmaceutically acceptable form is a tautomer. The term "tautomer" as used herein is a type of isomer that includes migration and alteration of two or more interconverted compounds from at least one form of a hydrogen atom and a covalent bond (e.g., single bond to double bond, triple bond to single bond, or vice versa). "tautomerism" includes proton or proton transfer tautomerism, which is considered to be a subset of acid-base chemistry. "proton transfer tautomerism" or "proton transfer tautomerism" relates to proton transfer accompanied by a change in bond order. The exact ratio of tautomers depends on several factors including temperature, solvent and pH. Where tautomerism is possible (e.g., in solution), the chemical equilibrium of the tautomer is reached. Tautomerization (i.e., the reaction that provides a tautomeric pair) may be catalyzed by acid or base, or may occur without the action or presence of an external agent. For example, tautomerization includes, but is not limited to, keto-to-enol; amide to imide; lactam to lactam; enamines to imines; and one form of enamine to a different enamine. Specific examples of keto-enol tautomerism are pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol and ketone tautomerism. Specific examples of phenol and ketone tautomers are pyridin-4-phenol and pyridin-4 (1H) -one tautomers.
Unless otherwise indicated, it is also intended that structures described herein include compounds, only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure replaced by deuterium or tritium for one hydrogen, or enriched for carbon 13 or carbon 14 within the scope of this disclosure.
The present disclosure also includes those "isotopically labeled derivatives," which are those pharmaceutically acceptable forms of the same compounds recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H，3H，13C，14C，15N，18O，17O，18F, and36and (4) Cl. Certain isotopically-labeled disclosed compounds (e.g., those labeled with3H and14C) are useful for determining the tissue distribution of compounds and/or substrates. Tritium (i.e. tritium3H) And carbon 14 (i.e.14C) Isotopes can be readily prepared and detected. In addition, the heavy isotopes such as deuterium (i.e.,2h or D) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased half-life in vivo or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting a non-isotopically labeled reagent for an isotopically labeled reagent. In some embodiments, provided herein are compounds that may also contain one or more unnatural isotopic compositions of atoms. All isotopic variations of the compounds as disclosed, whether radioactive or not, are intended to be within the scope of the present disclosure. In some embodiments, radiolabeled compounds may be used to study metabolism and compound tissue distribution to alter metabolic pathways, or rates or other biological functions.
The term "CDCl3"refers to deuterated chloroform.
The term "DMSO-d 6" refers to deuterated dimethyl sulfoxide
The term "LC-MS (ESI)" refers to electrospray ionization liquid chromatography mass spectrometry
The term "alteration" of a protein as used herein is defined as a change from a normal physiological state. Exemplary alterations include mutations, deletions, fusions with other proteins, over-expression, or under-expression.
The compounds of the invention:
in one aspect, the invention provides compounds of formula (I):
Figure BDA0001651016730000261
or a salt thereof; or a prodrug thereof or a salt of a prodrug thereof; or a hydrate, solvate or polymorph thereof.
The synthesis of the novel quinazoline derivative (I) of the chirality R according to the present invention can be easily carried out by a person skilled in ordinary synthetic chemistry. For example, related methods and intermediates disclosed herein. Each of the patents, patent applications, and publications mentioned herein, whether in a traditional journal or available only through the internet, is incorporated by reference in its entirety.
Other ways of synthesizing compound (I) described herein can be readily adapted from the references cited herein. Variations of these procedures and their optimization are within the ability of the ordinarily skilled artisan.
The present invention also provides compositions comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or prodrug of said compound, if applicable; and an acceptable carrier. Preferably, the compositions of the present invention are formulated for pharmaceutical use ("pharmaceutical compositions"), wherein the carrier is a pharmaceutically acceptable carrier. In view of compatibility with the other ingredients of the formulation, and in the case of pharmaceutically acceptable carriers, the carrier must be "acceptable" in an amount that is typically used in medicine without detriment to the recipient thereof.
"pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered at a dosage sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated as disclosed herein. Examples of pharmaceutically acceptable carriers and excipients include, but are not limited to: sugars, such as lactose, sucrose and glucose; starches, for example, potato starch and corn starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, cellulose acetate and ethyl cellulose; gelatin; tragacanth powder; talc; malt; cocoa butter and suppository waxes; oils, for example, peanut oil, safflower oil, cottonseed oil, olive oil, sesame oil, corn oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters, for example, ethyl oleate and ethyl laurate; agar; buffering agents, for example, magnesium hydroxide and aluminum hydroxide; alginic acid; ringer's solution; isotonic saline; ethanol; phosphate buffer; non-toxic compatible lubricants, for example, sodium lauryl sulfate and magnesium stearate; a colorant; a coating agent; a release agent; sweetening, flavoring and perfuming agents; an antioxidant; a preservative; ion exchange; alumina; lecithin; aluminum stearate; self Emulsifying Drug Delivery Systems (SEDDS) such as vitamin E polyethylene glycol 1000 succinate; surfactants for pharmaceutical dosage forms, such as Tweens or other similar polymeric delivery matrices; serum proteins, e.g., human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, for example, protamine sulfate, potassium hydrogen phosphate, disodium hydrogen phosphate, sodium chloride and zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a cellulose-based substance; a polyacrylate; a wax; and polyethylene-polyoxypropylene-block polymers. Cyclodextrins, e.g., alpha, beta, and gamma-cyclodextrins, or chemically modified derivatives, e.g., hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl cyclodextrins, or other solubilized derivatives for enhanced delivery of the compounds described herein.
The pharmaceutical compositions of the invention may be in solid or liquid form for administration, including: oral administration, e.g., drench (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those directed to buccal, sublingual and systemic absorption), hard or soft capsules, pills, syrups, powders, granules, pastes for lingual, intraduodenal routes; parenteral administration, including intravenous, intraarterial, subcutaneous, intramuscular, intraocular, pulmonary, intravascular, intraperitoneal or infusion, e.g., sterile solutions or suspensions, or sustained release formulations; topical application, for example as a cream, ointment, gel, aqueous or oily solution or suspension, or a controlled release patch or spray applied to the skin; intravaginally or intrarectally, e.g. as pessaries, creams, stents or foams; sublingual administration; local delivery through a catheter or stent; intrathecal, or nasal, by insufflation (e.g., as a fine powder) or by inhalation (e.g., as a fine powder or liquid aerosol).
Examples of suitable aqueous and nonaqueous carriers in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in dispersion, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricating agents, and/or antioxidants. The prevention of the action of microorganisms by the compounds described herein can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It can also be in a composition comprising isotonic agents, for example, sugars, sodium chloride and the like. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.
Methods of making these formulations or compositions include the steps of associating a compound described herein and/or with a chemotherapeutic carrier and optionally one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compounds disclosed herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. The preparation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip o.; knoben, James e.; troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; goodman and Gilman, eds., The pharmaceutical Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; n's Pharmaceutical Sciences,20th Edition, Lippincott Williams & Wilkins, 2000, of g by Rem; martindale, the Extra Pharmacopoeia, third-Second Edition (the pharmaceutical Press, London, 1999); these references are incorporated herein by reference in their entirety. The use of excipients is also within the scope of the present disclosure unless any conventional excipient medium is incompatible with the compounds provided herein, e.g., produces any undesirable biological effect or acts deleteriously by interacting with any other component of a pharmaceutically acceptable composition.
In some embodiments, the pharmaceutical composition may provide a concentration of one or more of the disclosed compounds of less than about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.000009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0000.0000%, about 0.0000.7%, about 0.0006%, about 0.7%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% weight/weight, weight/volume, or volume/volume ratio.
In some embodiments, the concentration of one or more compounds as disclosed herein can be greater than about 90% or greater, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%, about 19.50%, about 19.25% about 19%, about 18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%, about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about 14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%, about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about 11.50%, about 11.25%, about 11%, about 10.75%, about 10.25%, about 10.75%, about 9.75%, about 8.75%, about 9.25%, about 8.75%, about 8%, about 8.25%, about 8%, about 8.75%, about 7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%, about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%, about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about 3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.0000.0.0000%, about 0.0000.03%, about 0.0000.06%, about 0.06%, about 0.0000.004%, about 0.06%, about 0.0000.06%, about 0.06%, about 0.0000.004%, about 0.06%, about 0.0000.06%, about 0., or about 0.0001% weight/weight ratio, weight/volume ratio, or volume/volume ratio. In some embodiments, the concentration of one or more compounds disclosed herein may range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10%, weight/weight ratio, or volume/volume ratio. In some embodiments, the concentration of one or more compounds as disclosed herein may range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% weight/weight ratio, weight/volume ratio, or volume/volume ratio.
In some embodiments, the amount of one or more compounds as disclosed herein may be equal to or less than about 10 grams, about 9.5 grams, about 9.0 grams, about 8.5 grams, about 8.0 grams, about 7.5 grams, about 7.0 grams, about 6.5 grams, about 6.0 grams, about 5.5 grams, 5.0 grams, about 4.5 grams, about 4.0 grams, 3.5 grams, about 3.0 grams, about 2.5 grams, about 2.0 grams, about 1.5 grams, about 1.0 gram, about 0.95 grams, about 0.9 grams, about 0.85 grams, about 0.8 grams, about 0.75 grams, about 0.7 grams, about 0.65 grams, about 0.6 grams, about 0.55 grams, about 0.5 grams, about 0.45 grams, about 0.4 grams, about 0.35 grams, about 0.3.008 grams, about 0.65 grams, about 0.6 grams, about 0.06 grams, about 0.05 grams, about 0.06 grams, 0.0008g, about 0.0007 g, about 0.0006 g, about 0.0005g, about 0.0004 g, 0.0003 g, 0.0002 g, or about 0.0001 g. In some embodiments, the amount of one or more compounds disclosed herein can exceed about 0.0001 grams, about 0.0002 grams, 0.0003 grams, about 0.0004 grams, about 0.0005 grams, about 0.0006 grams, about 0.0007 grams, about 0.0008 grams, about 0.0009 grams, about 0.001 grams, 0.0015 grams, about 0.002 grams, 0.0025 grams, about 0.003 grams, about 0.0035 grams. About 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g, 0.009g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045 g, about 0.05g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095 g, about 0.1g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g, about 0.085 g, about 0.9 g, about 0.5g, about 0.75 g, about 0.9 g, about 0.5g, about 0.9 g, about 0.5g, about 0.75 g, about 0.9 g, about 0.5g, about 0.9 g, about 9.5 grams, or about 10 grams.
In some embodiments, the amount of one or more compounds disclosed herein can range from about 0.0001 grams to about 10 grams, from about 0.0005 grams to about 9 grams, from about 0.001 grams to about 0.5 grams, from about 0.001 grams to about 2 grams, from about 0.001 grams to about 8 grams, from about 0.005 grams to about 2 grams, from about 0.005 grams to about 7 grams, from about 0.01 grams to about 6 grams, from about 0.05 grams to about 5 grams, from about 0.1 grams to about 4 grams, from about 0.5 grams to about 4 grams, or from about 1 gram to about 3 grams.
In certain preferred embodiments, pharmaceutical compositions containing a compound as disclosed herein for oral administration, and a pharmaceutical excipient suitable for oral administration. In some embodiments, provided herein are orally administered pharmaceutical compositions: (1) optionally an effective amount of a disclosed compound; (2) an effective amount of one or more second agents; and (3) one or more pharmaceutically acceptable excipients suitable for oral administration. In some embodiments, the pharmaceutical composition further comprises: (4) an effective amount of a third agent.
In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage forms, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient as a powder or granules, or as a liquid, solution aerosol spray or suspension in an aqueous or non-aqueous liquid, an emulsion of an oil in water, or a liquid emulsion of water in an oil. Such dosage forms may be prepared by any pharmaceutical method, but all methods include the step of preparing the composition by uniformly and intimately bringing into association the active ingredient with liquid carriers, liposomes or finely divided solid carriers or both. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and if necessary shaping the product into the desired form. For example, a tablet may be a compressed or molded tablet of optionally one or more ingredients. Tableting may be by compression in a suitable machine of the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents and/or surfactants or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be uncoated, coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein, thereby providing a sustained action over a longer period of time, with a time delay material, such as glyceryl monostearate or glyceryl distearate, being employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
The active ingredient may be intimately associated with a pharmaceutical carrier by conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. In preparing pharmaceutical compositions for oral dosage form, any of the usual pharmaceutical media may be employed as the carrier, e.g., water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and oral liquid preparations (e.g., suspensions, solutions, and elixirs) or aerosols, or the carrier, e.g., starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents may be employed in the case of oral solid preparations, in some embodiments, lactose is not employed. In some embodiments, the compounds may be used in further formulations with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, calcium phosphate, sodium phosphate, calcium sulfate, sodium sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol. For example, in the preparation of solid oral dosage forms, suitable carriers also include powders, capsules and tablets. In some embodiments, the tablets may be coated by standard aqueous or non-aqueous techniques.
Coatings suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural binders and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
Examples of suitable fillers disclosed herein for use in pharmaceutical compositions and dosage forms include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.
Disintegrants can be used in pharmaceutical compositions as provided herein to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant can cause the tablet to disintegrate in the bottle. Too little may be insufficient for disintegration to occur and therefore may alter the rate and extent of release of the active ingredient from the dosage form. Thus, the disintegrant should be in sufficient quantity, neither too little nor too much, to detrimentally alter the release of the active ingredient. The amount of disintegrant depends on the formulation and mode of administration, and can be readily accomplished by one of ordinary skill in the art. About 0.5 to about 15 weight percent of a disintegrant, or about 1 to about 5 weight percent of a disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinised starch, clays, other algins, other celluloses, gums, or mixtures thereof.
Lubricants may be used to form pharmaceutical compositions and dosage forms, including, but not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Lubricants also include, for example, silica gel, a solidifying aerosol, or mixtures thereof. The lubricant may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.
When aqueous suspensions and/or elixirs are used for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, for example, emulsifying and/or suspending agents, diluents, such as water, ethanol, propylene glycol, glycerin and various combinations thereof.
Surfactants that may be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. Suitable hydrophilic surfactants may generally have an HLB value of at least about 10, while suitable lipophilic surfactants may generally have an HLB value of less than about 10. The empirical parameter used to characterize relative hydrophilicity and hydrophobicity is the hydrophilic-lipophilic balance, HLB ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, however, anionic, cationic or zwitterionic compounds, the HLB scale generally not being applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are those having an HLB value equal to or less than about 10. However, the HLB value of surfactants is only a rough guide for general use in industrial, pharmaceutical and cosmetic emulsions.
The hydrophilic surfactant may be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidate salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; derivatives of glycerol esters of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; an alkyl sulfate; a fatty acid salt; docusate sodium; an acyl lactate; tartaric acid esters of mono-and diacetylated mono-and diglycerides; succinylated mono and diglycerides; citric acid esters of mono-and di-glycerides; and mixtures thereof. Ionic surfactants include, but are not limited to, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; an alkyl sulfate; a fatty acid salt; docusate sodium; an acyl lactate; diacetylated tartaric acid esters of mono-and di-glycerides; succinylated mono and diglycerides; citric acid esters of mono-and di-glycerides; and mixtures thereof. Hydrophilic nonionic surfactants include, but are not limited to, alkyl glycosides; an alkyl maltose; an alkyl thioglycoside; lauroyl macrogolglycerides; polyoxyalkylene alkyl ethers, for example, polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, for example, polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, for example, polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid ester; polyglyceryl fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, for example, polyethylene glycol sorbitol fatty acid esters; hydrophilic transesterification products with at least one polyol of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, derivatives thereof, and analogs thereof; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; a hydrophilic transesterification product of a polyethylene glycol sorbitan fatty acid ester and at least one triglyceride, a vegetable oil and a polyol of a hydrogenated vegetable oil. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a saccharide. Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 dilaurate, PEG-12 oleate, and PEG-15 oleate. PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glycerol kowter stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl kowter laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 decyl/caprylic glyceride, PEG-8 decyl/capped evening glyceride, polyglycose per 1-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soyasterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 stearyl ether, PEG-100 tocopheryl succinate, PEG-24 cholesterol, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamers. Suitable lipophilic surfactants include, but are not limited to, for example, fatty alcohols; glycerin fatty acid ester; acetylated glycerin fatty acid ester; lower alcohol fatty acid esters; a propylene glycol fatty acid ester; sorbitol fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterol and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono-and diglycerides.
The pharmaceutical composition may include a solubilizing agent to ensure good solubilization and/or dissolution of the compound and to minimize precipitation of the compound. This may be of particular importance for pharmaceutical compositions intended for non-oral use, e.g. for injectable pharmaceutical compositions. Solubilizers may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion. Examples of suitable solubilizing agents include, but are not limited to, for example, alcohols and polyols, such as, ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, and other cellulose derivatives, cyclodextrins, and cyclodextrin derivatives; ethers of polyethylene glycol having a molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, epsilon-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidine, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters, for example, ethyl propionate, tributyl citrate, triethyl acetylcitrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsilon-caprolactone and their isomers, delta-valerolactone and its isomers, butyrolactone and its isomers; and other known solubilizing agents such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, diethylene glycol monoethyl ether and water. Mixtures of solubilizers may also be used.
The amount of a given solubilizing agent can be limited to a biologically acceptable amount, which can be readily determined by one skilled in the art. The solubilizing agent can be in a weight ratio of about 10%, about 25%, about 50%, about 100%, or up to about 200% by weight, based on the total weight of the drug, as well as other excipients. Small amounts of solubilizers may also be used, if desired, such as about 5%, 2%, 1% or even less. Typically, the solubilizer may be present in about 1% to about 100%, usually about 5% to about 25%, by weight.
The pharmaceutical composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, for example, detackifiers, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, flavoring agents, coloring agents, essential oils, fragrances, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. Preservatives can include, but are not limited to, for example, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. Antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, and sodium sulfite. Chelating agents include, but are not limited to, for example, ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium EDTA, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and triethylenediaminetetraethyl citrate. Antimicrobial preservatives include, but are not limited to, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chloroxylenol, cresol, ethanol, glycerol, hexetidine, imidazolidine urea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, and propylene glycol. Antifungal agents, including, but not limited to, for example, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Preservatives include, but are not limited to, for example, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenols, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol. Acidic preservatives include, but are not limited to, for example, vitamin a, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, for example, tocopherol acetate, cetrimide, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), ethylenediamine, Sodium Lauryl Sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), sodium bisulfate, sodium metabisulfite, potassium sulfite, potassium metabisulfite, methyl paraben. In certain embodiments, the preservative may be an antioxidant. In other embodiments, the preservative may be a chelating agent. In some embodiments, provided herein are pharmaceutical compositions for parenteral administration containing: (1) an effective amount of one of the disclosed compounds; optionally (2) an effective amount of one or more second agents; (3) one or more pharmaceutical excipients suitable for parenteral administration and (4) an effective amount of a third agent.
The pharmaceutical compositions may be administered by injection in the form of aqueous or oily suspensions, or emulsions, sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous physiological saline is also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, benzyl alcohol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, sodium chloride, tragacanth, buffers, and vegetable oils may also be employed. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, or by the use of surfactants in the case of dispersions, to maintain the desired particle size. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. The pharmaceutical compositions may also be injected with a suitable carrier, including saline, dextrose or water, or solubilized with cyclodextrins, cosolvents (e.g., propylene glycol) or micelles (e.g., Tween 80).
Sterile injectable solutions can be prepared by filter sterilization of the compound disclosed herein in the required amount in a suitable solvent with various of the other ingredients enumerated above. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the appropriate other ingredients from those enumerated above. In the preparation of sterile injectable solutions using sterile powders, certain methods of preparation are employed which employ vacuum drying and freeze-drying techniques to produce the active ingredient and any additional sterile-filtered ingredients described above. Sterile injectable preparations may also be prepared by suspending in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol or as a sterile injectable solution. Acceptable carriers and solvents that may be employed include, but are not limited to, for example, water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium, including, but not limited to, for example, synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, find use in the preparation of injectables. The injectable formulations can be sterilized prior to use by, for example, filtration through a bacterial-retaining filter, or by the addition of sterilizing agents incorporated into the sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium. The injectable compositions may contain from about 0.1 to about 5% by weight of a compound disclosed herein.
In some embodiments, provided herein are compounds or pharmaceutical compositions containing one or more pharmaceutical excipients (e.g., transdermal) suitable for topical administration, as disclosed herein. In some embodiments, provided herein are pharmaceutical-containing compositions for topical administration: (1) an effective amount of one of the disclosed compounds; optionally (2) an effective amount of one or more second agents; (3) one or more pharmaceutical excipients suitable for topical administration and (4) an effective amount of a third agent.
The pharmaceutical compositions provided herein may be formulated in solid, semi-solid or liquid form suitable for local or topical administration, such as gels, water-soluble gels, liniments, creams, lotions, suspensions, foams, powders, ointment formulations, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, Dimethylsulfoxide (DMSO) -based solutions. In general, carriers with higher densities are able to provide areas with prolonged exposure to the active ingredient. In contrast, solution formulations may provide more direct contact of selected areas of the active ingredient. For example, ointment formulations may be paraffin or water-miscible. Alternatively, the active ingredient may be formulated as a cream with a cream base of oil in water. The aqueous phase of the cream base may include, for example, at least about 30% by weight of a polyol, such as, for example, propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerin, polyethylene glycol, and mixtures thereof. The pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients which may increase penetration or aid in the delivery of the compound across the stratum corneum permeation barrier of the skin. Examples of such carriers and excipients include, but are not limited to, for example, wetting agents (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium kojie sodium sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.
Another exemplary formulation used in the disclosed methods uses transdermal administration ("patch"). Such transdermal patches may be used to provide controlled amounts of the pharmaceutical composition, either continuously or discontinuously. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent can be administered to the subject. In the case of microcapsules, the encapsulant may also serve as a film. The use of transdermal patches is well known in the art. See, for example, U.S. Pat. nos. 5,023,252, 4992445 and 5,001, 139.
The pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing a compound of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active components. Such materials include, but are not limited to, for example, polyethylene glycol, beeswax and cocoa butter.
The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and other solubilizing or dispersing agents known in the art.
Particularly advantageous derivatives and prodrugs are those that enhance the bioavailability of the compounds of the invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed), or that enhance delivery of the compound to the parent biological compartment (e.g., the brain or central nervous system) relative to the parent species. Preferred prodrugs include derivatives in which a group that enhances water solubility or active transport through the intestinal membrane is attached to the general structure described herein. See, for example, Alexander et al, Journal of Medicinal Chemistry l988,31, 318-; bundgaard et al, Design of produgs, Elsevier: Amsterdam,1985, 1-92; bundgaard et al, Journal of Medicinal Chemistry l987,30, 451-; bundgaard et al, Textbook of Drug Design and Development, Harwood Academic Publ: Switzerland,1991, 113-191; dictionary of Experimental Pharmacology,1975,28, 86-112.
The application of the subject therapeutic agent may be topical for administration at the target site. Various techniques may be used to provide the subject composition at the target site, such as injection, use of catheters, gels, stents, trocars, propellants, drug-releasing polymers or other devices that provide for internal access.
According to another embodiment, the present invention provides an implantable medical device comprising a compound of the present invention or a composition comprising a compound of the present invention such that the compound is therapeutically active.
According to another embodiment, the present invention provides a method of infusing an implantable drug delivery device comprising the step of contacting the drug delivery device with a compound or composition of the present invention. Implantable drug delivery devices include, but are not limited to, biodegradable polymer capsules or pellets, non-degradable, diffusible polymer capsules and biodegradable polymer sheets.
In another embodiment, the compositions of the present invention further comprise a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent known to have or demonstrating advantageous properties when administered alone or in combination with any of the compounds of the general formulae herein. Drugs that may be usefully combined with these compounds include other kinase inhibitors, and/or other chemotherapeutic agents for treating the diseases and disorders discussed above. Such agents are well described in the art. Preferably, the second therapeutic agent is an agent useful for the treatment or prevention of a disease or condition selected from cancer.
In another embodiment, the invention provides separate dosage forms of the compound of the invention and the second therapeutic agent associated with each other. The term "associated with each other" as used herein means that the individual dosage forms are packaged together or otherwise connected to each other such that the individual dosage forms are intended to be sold or administered together (within less than 24 hours of each other, consecutively or simultaneously).
In the pharmaceutical compositions of the present invention, the compounds of the present invention are present in an effective amount. The term "effective amount" as used herein means an amount sufficient, when administered in a suitable dosing regimen, to reduce or ameliorate the severity, duration or development of the disorder being treated, prevent the progression of the disorder being treated, cause regression of the disorder being treated, or enhance or ameliorate the prophylactic or therapeutic effect of another therapy.
Dose-to-animal and human correlations (in terms of milligrams per square meter of body surface area) are described in Freiich et al, (1966) Cancer chemither Rep 50: 219. The body surface area may be approximately determined based on the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardley, n.y.,1970,537. An effective amount of a compound of the present invention may be from about 0.001-lmg/kg to about 500mg/kg, about 0.01mg/kg to about 50mg/kg, about 0.lmg/kg to about 2.5 mg/kg. The effective dosage may also vary, as recognized by those skilled in the art, depending on the disease being treated, the severity of the disease, the route of administration, the age, sex, and general health of the patient, excipient usage, the possibility of co-use with other therapeutic methods (e.g., the use of other agents), and the judgment of the treating physician.
For pharmaceutical compositions comprising a second therapeutic agent, the effective amount of the second therapeutic agent is between about 20% and 100% of the dose typically utilized in a monotherapy regimen utilizing only that agent. Preferably, the effective amount is between about 70% and 100% of the normal monotherapeutic dose. Normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al, Pharmacotherapy Handbook, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Tarascon Publishing, Loma Linda, Calif. (2000), which references are incorporated herein by reference in their entirety.
It is contemplated that certain second therapeutic agents mentioned herein will act synergistically with the compounds of the present invention. When it does occur, it will allow for an effective dose of the second therapeutic agent and/or compound of the invention that is less than that required in monotherapy. This has the advantage that: minimizing toxic side effects of the second therapeutic agent or the compound of the invention, improving efficacy, improving ease of administration or use, and/or reducing the overall cost of the compound preparation or formulation.
The treatment method comprises the following steps:
according to another embodiment, the invention provides a method of treating a subject suffering from or susceptible to a disease or disorder or symptoms thereof (e.g., those described herein), comprising the step of administering to the subject an effective amount of a compound or composition of the invention. These diseases are well known in the art and are also disclosed herein.
The methods of treatment involve the treatment of disorders mediated by protein kinases such as EGFR.
In another aspect, the present invention provides a method of treating a disease in a subject comprising administering to the subject a composition comprising a compound of any of the formulae herein.
In certain embodiments, the disease is mediated by EGFR kinase.
In another embodiment, the disease is cancer or a proliferative disease.
In another embodiment, the compounds of formula (I), and pharmaceutically acceptable salts, as inhibitors against activating mutants of EGFR exon 2-7 deletions, are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by the activity of EGFRVIII mutants, such as cancer. This type of cancer, or a pharmaceutically acceptable salt thereof, that may be treated using a compound of formula (I), includes, but is not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, Acute Myelogenous Leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain cancer, membranous adenocarcinoma, skin cancer or head and neck squamous cell carcinoma.
In another embodiment, the compounds of formula (I), and pharmaceutically acceptable salts, as inhibitors against EGFR Exon21L858R mutant and Exon19 deletion activating mutant are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by the activity of EGFR mutants, such as cancer diseases. This type of cancer, or a pharmaceutically acceptable salt thereof, that may be treated using a compound of formula (I), includes, but is not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, Acute Myelogenous Leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain cancer, membranous adenocarcinoma, skin cancer or head and neck squamous cell carcinoma.
In another embodiment, the disease is brain glioma.
In another embodiment, the disease is non-small cell lung cancer (NSCLC) with brain metastases.
In another embodiment, the disease is a central nervous system disease.
In one embodiment, the methods of the invention are used to treat a subject suffering from or susceptible to a disease or condition. Such diseases, disorders or symptoms thereof include, for example, those modulated by protein kinases (e.g., EGFR protein kinase). The disease or disease symptom can be, for example, cancer or a proliferative disease or disorder. The disease or disease symptom may be ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, Acute Myelogenous Leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain cancer, membranous adenocarcinoma, skin cancer, or head and neck squamous cell carcinoma. The methods delineated herein include those in which the subject is identified as being in need of the specifically recited treatment. Identifying a subject in need of such treatment can be within the judgment of the subject or a health care professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
In another embodiment, the compounds herein (and compositions thereof) can be used to treat subjects having a disease or disorder and who have been treated and developed resistance with other therapeutic agents (e.g., anti-cancer agents, neurological agents, psychiatric agents, cardiovascular agents, anti-obesity or diabetes agents). In one aspect, the methods herein include those wherein a subject who is resistant to treatment (or identified as having developed resistance to gefitinib, erlotinib treatment) is administered a compound of the general formula herein (or a composition thereof). In other aspects, the subject is therefore responsive to such treatment, whereby the disorder is modulated or ameliorated, relative to prior treatment with a compound of the general formula herein.
In another embodiment, the invention provides a method of modulating the activity of a protein kinase (e.g., a protease-tyrosine kinase, kinases listed herein) in a cell comprising contacting the cell with one or more compounds of any of the formulae herein.
The anti-cancer treatments described above may be administered with the compounds of the invention as monotherapy or together with the compounds of the invention using conventional surgery or radiotherapy or chemotherapy or immunotherapy. Such chemotherapy may be administered concurrently, simultaneously, sequentially or separately with the compounds of the invention, and may include, but is not limited to, one or more of the following classes of antineoplastic agents: for example, antiproliferative/antineoplastic agents, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas), antimetabolites (e.g., gemcitabineAnd antifolates such as, for example, 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, dactinomycin and mithramycin); antimitotic agents (e.g. vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxanes such as taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (e.g., etoposide and teniposide, amsacrine, topotecan, and camptothecin); cell growth inhibitors such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and idoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide acetate and cyclopropan acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin, progestins (e.g., megestrol acetate, aromatase inhibitors (e.g., such as anastrozole, letrozole, vorozole and exemestane) and inhibitors of 5 α reductase such as finasteride), anti-invasiveness agents (e.g., inhibitors of the c-Src kinase family, such as secatinib, dasatinib and bosutinib, and metalloprotease inhibitors such as marimastat, inhibitors of the prourokinase plasminogen activator receptor function or inhibitors of the antibody heparinase, e inhibitors of growth factor, e.g., such inhibitors include growth factor antibodies and growth factor receptor antibodies For example, the anti-erbB 2 antibody trastuzumab [ herceptinTM]anti-EGFR antibody panitumumab, anti-ErbB antibody cetuximab (erbitux, C225) and antibodies to any of the growth factors or growth factor receptors disclosed by Stem et al. Such inhibitors also include tyrosine kinase inhibitors, for example epidermal growth factor family inhibitors (e.g., tyrosine kinase inhibitors of the EGFR family of tyrosine inhibitors such as gefitinib, erlotinib, camerana and taggeris, erbB2, e.g., lapatinib, lenatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; platelet derived factorInhibitors of the long factor family, such as imatinib and/or nilotinib; inhibitors of serine/threonine kinases (e.g. RAS/RAF signal inhibitors such as farnesyl transferase inhibitors, e.g. sorafenib, tipifami and lonafami, cell signal inhibitors via MEK and/or AKT kinases, c-kit inhibitors, abl fusion kinase inhibitors, PI3 kinase inhibitors, PLT3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors, aurora kinase inhibitors and cyclin-dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors), anti-angiogenic agents, e.g. those inhibiting the effect of vascular endothelial growth factors, e.g. the anti-vascular endothelial growth factor antibody bevacizumab (avastin's) andTM) And for example VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib, pazopanib and cediranib, compounds that work by other mechanisms (e.g., tricarboxyaminoquinoline, functional inhibitors of integrin α V3 and angiogenesis inhibitors); antisense (nucleic acid) therapy gene therapy, e.g., those listed above, such as ISIS 2503, antisense (nucleic acid) therapy against the ras gene; gene therapy approaches, including, for example, approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2 (e.g., Olaparib, Niraparib, Rucaparib, Talazoparib), GDEPT (gene-directed enzyme prodrug therapy), such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes and those approaches to enhance the patient's tolerance to chemotherapy or radiation therapy such as multidrug resistance gene therapy approaches, including, for example, approaches to increase the immunogenicity of patient's tumor cells, such as immunogenicity transfected with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage stimulating factor, to reduce T cell anergy, approaches to employ transfected immune cells such as cytokine-transfected dendritic cells, approaches to cytokine-transfected tumor cell lines, approaches to employ anti-idiotypic antibodies, to reduce the function of immunosuppressive cells, such as regulatory T cells, myeloid derived suppressor cells or IDO, TDO, and cancer vaccines using proteins or peptides derived from tumor associated antigens such as NY-ES0-1, MAGE-3, WTI or HER 2/neu. Or as a basis in cancer treatment protocols in generalAny other agent administered with the agent or adjuvant (e.g., an antiemetic, an anti-anemia agent, etc.).
The term "co-administered" as used herein means that the second therapeutic agent can be administered with the compound of the invention, either as part of a single dosage form (e.g., a composition of the invention comprising the compound of the invention and the second therapeutic agent as described above) or as a separate, multiple dosage form. Alternatively, additional agents may be administered prior to, or sequentially to, or after administration of the compounds of the invention. In such combination therapy, the compound of the invention and the second therapeutic agent are administered by conventional methods. Administration of a composition of the invention comprising a compound of the invention and a second therapeutic agent to a subject does not preclude separate administration of the same therapeutic agent, any other second therapeutic agent, or any compound of the invention to the subject at other times during the course of treatment. Wherein the continuous or separate administration, or delayed administration of the second component should not lose the advantage of the effect resulting from the use of the combination.
Effective amounts of the second therapeutic agent are well known to those skilled in the art, see, e.g., Wells et al, Pharmacotherapy Handbook, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical textbooks. However, it is within the ability of one skilled in the art to determine the optimal effective amount range for the second therapeutic agent.
In one embodiment of the invention, when a second therapeutic agent is administered to a subject, the effective amount of a compound of the invention is lower than its effective amount without the administration of the second therapeutic agent. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount without administration of the compound of the present invention. In this way, the undesirable side effects associated with high doses of either agent can be minimized. Potential advantages will be apparent to those skilled in the art (including, but not limited to, for example, improved dosing regimens and/or reduced drug costs).
In a further aspect, the present invention provides the use of a compound of any of the formulae herein, alone or in combination with one or more second therapeutic agents described herein, in the manufacture of a medicament, as a single composition or as a separate dosage form, for the treatment or prevention of a disease, disorder or condition enumerated herein, in a subject. Another aspect of the invention is the use of a compound of the general formula herein to treat or prevent a disease, disorder or condition described herein in a subject.
In other aspects, the methods herein include those further comprising monitoring the subject's response to the administration of the treatment. Such monitoring may include periodic sampling of the subject's tissue, body fluids, cerebrospinal fluids, samples, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of a treatment regimen. In other methods, the subject is pre-screened or identified as in need of such treatment by assessing the suitability of the relevant marker or indicator for such treatment.
In one embodiment, the invention provides a method of monitoring the progress of a treatment. The method includes the step of determining the level of a diagnostic marker (marker) (e.g., any target or cell type delineated herein modulated by a compound herein) or a diagnostic measurement (e.g., screening, assay) in a subject suffering from or susceptible to a disorder described herein or a symptom thereof, wherein the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptom thereof. The level of the marker determined in the method can be compared to known levels of the marker in healthy normal controls or other diseased patients to establish the disease condition of the subject. In a preferred embodiment, a second level of the marker in the subject is measured at a time point later than the determination of the first level, and the two levels are compared to monitor the course of the disease or the efficacy of the therapy. In certain preferred embodiments, the level of the marker prior to treatment in the subject is determined prior to the start of treatment according to the invention; the pre-treatment level of such a marker can be compared to the level of the marker in the subject after initiation of treatment to determine the efficacy of the treatment.
In certain method embodiments, the level of the marker or marker activity in the subject is determined at least once. Comparison of the marker level with another measurement of the marker level, e.g., obtained earlier or later from the same patient, another patient, or a normal subject, can be used to determine whether the therapy according to the invention has the desired effect, and thereby allow the dosage level to be adjusted as appropriate. Determination of marker levels can be performed using any suitable sampling/expression assay known in the art or described herein. Preferably, a tissue or liquid sample is first removed from the subject. Examples of suitable samples include blood, urine, cerebrospinal fluid, tissue, mouth or cheek cells, and hair samples containing roots. Other suitable samples are known to those skilled in the art. The determination of protein levels, ctDNA, cfDNA and/or mRNA levels (e.g., marker levels) in a sample can be performed using any suitable technique known in the art, including, but not limited to, enzyme immunoassays, ELISA, radiolabeling assay techniques, blotting/chemiluminescence methods, real-time PCR, electrochemical signaling, and the like.
The invention also provides a kit for treating a disease, disorder, or symptom thereof, including those described herein. These kits comprise: 1) including compounds of any of the formulae herein or salts thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate or polymorph thereof, wherein the pharmaceutical composition is in a container; and 2) instructions describing a method of using the pharmaceutical composition to treat a disease, disorder, or symptom thereof, including those described herein. The container may be any container or other sealed or sealable device capable of holding the pharmaceutical composition. Examples include bottles, divided or multi-chamber reservoir bottles, wherein each partition or compartment comprises a single dose of the composition; a divided foil package, wherein each partition comprises a single dose of the composition; or a dispenser that dispenses a single dose of the composition. The container may be of any conventional shape or form known in the art, made of a pharmaceutically acceptable material, such as a paper or cardboard box, a glass or plastic bottle or can, a resealable bag (e.g., to contain a "refill" of tablets for placement into a different container), or a blister pack with individual doses for extrusion from the pack according to a treatment schedule. The container employed may depend on the exact dosage form involved, for example, a conventional cardboard box will not typically be used to contain a liquid suspension. It is possible that more than one container may be used together in a single package to market a single dosage form. For example, the tablets may be contained in bottles, which are then contained in boxes. Preferably, the container is a blister pack.
The kit may additionally include information and/or instructions for a physician, pharmacist, or subject. These memory aids include numbers printed on each compartment or section containing the medicament that correspond to the number of days of the regimen that the specified tablet or capsule should be ingested, or the number of days of the week printed on each compartment or section, or a card containing the same type of information.
In the uses described herein having an EGFRV3 activating mutation, the quinazoline derivative (I) of the present invention has an enantiomeric purity of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or greater.
The compounds delineated herein can be evaluated for their biological activity using protocols known in the art, including, for example, those delineated herein. Certain compounds herein demonstrate unexpectedly superior attributes (e.g., metabolic stability, high selectivity, low efflux rate, high permeability, non-P glycoprotein efflux substrates, etc.) making them excellent candidates for potential therapeutic agents.
All references cited herein, whether in electronic, printed, computer-readable storage media or other form, are expressly incorporated by reference in their entirety, including, but not limited to, abstracts, articles, journals, publications, texts, treatises, technical data sheets, internet web sites, databases, patents, patent applications, and patent publications.
The present invention will be described in detail with reference to examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that it would be apparent to those skilled in the art that several modifications and improvements can be made without departing from the inventive concept. All falling within the scope of the present invention.
EXAMPLE 1 preparation of quinazoline derivative (I)
1.1 Synthesis of intermediates 5-fluoro-4-methoxy-2-nitrobenzonitrile A6 and 1-bromo-5-fluoro-4- (deuterated methoxy) -2-nitrobenzene C1
The synthetic route is as follows:
Figure BDA0001651016730000451
the method comprises the following steps: a solution of ethyl chloroformate (1.4 g, 12.6mmol) in dichloromethane (3 mL) was added dropwise at 0 deg.C to a solution of A1(2.0 g, 10.5mmol) and triethylamine (1.3 g, 12.6mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 0 ℃ for 1 hour and allowed to reach room temperature. The reaction mixture was then washed twice with water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give product a2(2.7 g, 100% yield) as a colorless oil.
Step two fuming nitric acid (0.73 mL, 15.5mmol) was added dropwise at 10 deg.C to a solution of A2(2.7 g, 10.3mmol) in concentrated sulfuric acid (4.6 mL). After 1 hour, the reaction mixture was poured into ice/water and extracted twice with ethyl acetate. The combined organic layers were washed with water, sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo to give a residue which was purified on a silica gel column (n-hexane/ethyl acetate-20/1) to afford product A3 as a yellow oil (3.0 g, 94.6% yield).
Step three to a solution of a3(3.0 g, 9.8mmol) in methanol (17 ml) was added sodium bicarbonate (1.6 g, 19.6 mmol). The reaction mixture was stirred at 60 ℃ for 3 hours. Methanol was evaporated under vacuum. Water (15 ml) was added to the residue and the aqueous layer was acidified to pH 5 by addition of a solution of 5 mol hydrogen chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated in vacuo to give product a4(2.3 g, 100% yield) as a yellow solid.
Step four to a solution of a4(2.31 g, 9.8mmol) in nitrogen, nitrogen-dimethylformamide (18.5 ml) was added potassium carbonate (2.7 g, 19.6mmol) and methyl iodide (1.22 ml, 19.6 mmol). The reaction mixture was stirred at 60 ℃ for 3 hours. The resulting mixture was separated between water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give product a5(2.35 g, 97% yield) as a yellow solid.
Step five, after stirring in a solution of a mixture of A5(5.17 g, 20.7mmol) and zinc cyanide (1.46 g, 12.4mmol) in nitrogen, nitrogen-dimethylacetamide (104 mL) and venting air with nitrogen, the palladium catalyst, Pd, was added2(dba)3(1.90 g, 2.07mmol), and the ligand, 2-dicyclohexylphosphino-2' - (nitrogen, nitrogen-dimethylamine) -biphenyl (815 mg, 2.07mmol), and the reaction mixture was stirred at 110 ℃ for 5 hours. It was then cooled to room temperature, diluted into ethyl acetate and filtered through celite. The organic solution was washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by a silica gel column (ethyl acetate/n-hexane: 1:50 to 1: 10) to give product a6(3.47 g, 85.7% yield) as a pale yellow solid.1HNMR:(400MHz,DMSO-d6)δppm:8.28(d,J＝10.7Hz,1H),8.13(d,J＝7.5Hz,1H),4.08(s,1H).LC-MS:(ESI)m/z＝197(M+H)+。
1.2 Synthesis of intermediates tert-butyl 3, 3-difluoro-4-hydroxypiperidine-1-carboxylate B8 and 3, 3-difluoro-1-methylpiperidin-4-ol C2
The synthetic route is as follows:
Figure BDA0001651016730000461
the method comprises the following steps: to a solution of benzotriazole (47 g, 394.5mmol) in methanol (300 ml) was added B1(81.7 g, 394.5mmol) and 37% formaldehyde (37.9 ml, 512.9mmol), and the resulting mixture was stirred at room temperature for 16 h. The mixture was removed under vacuum and the residue was poured into water (500 ml), extracted with ethyl acetate (500 ml × 3), dried over sodium sulfate, filtered and concentrated to give product B2 as a yellow oil (132 g, 98.8% yield).
Step two: to a solution of zinc dust (56 g, 862mmol) in tetrahydrofuran (500 ml) was added trimethylsilyl chloride (49 g, 452mmol) at room temperature. The resulting suspension was stirred at room temperature for 15 minutes, then ethyl difluorobromoacetate (96 g, 474mmol) was added dropwise and the mixture was stirred for 15 minutes. A solution of B2(146 g, 431mmol) in tetrahydrofuran (500 mL) was then added at room temperature and stirred overnight. The mixture was poured into a saturated aqueous solution of sodium bicarbonate (2.5 l), extracted with ethyl acetate (500 ml), filtered over celite, separated, the organic phase was dried over sodium sulfate, filtered and concentrated to give a residue which was purified on a silica gel column (ethyl acetate/n-hexane: 1/50 to 1/20) to give product B3 as a yellow oil (90 g, 60.8% yield).
Step three: to a solution of diisopropylamine (63.0 g, 629mmol) in tetrahydrofuran (500 ml) was added dropwise a solution of n-butyllithium (2.5M hexane, 231.5 ml, 576mmol) at-70 ℃ and the resulting mixture was warmed to-10 ℃ for 30 minutes. The system was then cooled to-70 ℃ and a solution of B3(90 g, 262mmol) in tetrahydrofuran (500 l) was added dropwise. Stirred for 30 minutes and gradually warmed to room temperature and stirred for an additional 1 hour. The mixture was poured into saturated aqueous ammonium chloride (500 ml), extracted with ethyl acetate (500 l × 3), the organic phase was dried over sodium sulfate, filtered and concentrated to give product B4 as a yellow oil (90.7 g). The crude product was used in the next step without purification.
Step four: b4(90 g, 302mmol) was added to 6 mol aqueous hydrochloric acid (900 ml) and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was slowly poured into 8 mol sodium hydroxide (1 l), extracted three times with ethyl acetate (1 l), the organic phase was concentrated to 4-5 l, n-hexane (600 ml) was added, the mixture was stirred for 1 hour and filtered to give product B5(34 g, two-step yield 46.5%) as a white solid.
Step five: to a solution of B5(34 g, 139mmol) in methanol (730 mL) was added sodium borohydride (7.9 g, 209mmol) portionwise at 0-5 deg.C. After stirring the mixture at 0-5 ℃ for a further 15 min, aqueous sodium bicarbonate (0.1 mol, 54 ml) was added and the mixture was stirred for 5 min, the mixture was dried over sodium sulfate, concentrated and purified by silica gel column (ethyl acetate/n-hexane: 1/20 to 1/10) to give product B6(30 g, 97.1% yield) as a colorless oil.
Step six: to a solution of B6(30 g, 134mmol) in ethanol (600 mL) was added the catalyst palladium hydroxide/activated carbon (10%, 3.0 g), and the mixture was stirred under a hydrogen balloon for 4 hours. The mixture was filtered and concentrated to give product B7 as a white solid (15.8 g, 85.8% yield). 1HNMR (400MHz, DMSO-d6) delta ppm 5.43(d, J ═ 5.1Hz,1H),3.71(m, 1H), 2.98(m,1H), 2.84-2.57 (m,2H),2.23(s,1H), 1.85-1.64 (m,1H), 1.60-1.34 (m, 1H). LC-MS (ESI) M/z 138.0(M + H)+
Step seven: to a solution of B7(500 mg, 3.6mmol) in 88% formic acid (941 mg, 18.0mmol) was added at room temperature
Figure BDA0001651016730000482
Was added to the reaction solution (584 mg, 7.2 mmol). The solution was stirred at 78 degrees celsius for 30 minutes. The mixture is washed with aqueous sodium hydroxide solution to adjust the pH
Figure BDA0001651016730000483
The mixture was extracted with ethyl acetate (30 ml × 3). The organic phase was dried over sodium sulfate and concentrated to give product B8 as a white solid (340 mg, 62.5% yield).1H NMR(400MHz,DMSO-d6)δ5.48(d,J＝5.4Hz,1H),3.79–3.48(m,1H),2.74(dd,J＝22.1,12.2Hz,1H),2.46–2.34(m,1H),2.20(s,4H),1.90–1.69(m,1H),1.69–1.47(m,1H)。LC-MS:(ESI)m/z＝152[M+H]+。
Synthesis of intermediate (Z) -Nitrogen' - { 2-cyano-4- [ (3, 3-difluoro-1-methylpiperidin-4-yl) oxy ] -5-methoxyphenyl } -Nitrogen, Nitrogen-2-Methylcarboxamidine A9
The synthetic route is as follows:
Figure BDA0001651016730000481
the method comprises the following steps: to a solution of sodium hydride (4.85 g, 102mmol) in nitrogen, nitrogen-dimethylacetamide (10 ml) was added dropwise a solution of a6(10 g, 51mmol) and B8(7.71 g, 51mmol) in nitrogen, nitrogen-dimethylacetamide (30 ml) at 50 degrees c under nitrogen protection. Stir at 0 ℃ for 1 hour. The mixture was poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by silica gel column (ethyl acetate/n-hexane ═ 1:3 to 1: 1) to give product a7(12 g, 71% yield) as a yellow solid.1HNMR:(400MHz,CDCl3-d6)δppm:7.85(s,1H),7.39(s,1H),4.56(td,J＝9.7,4.9Hz,1H),4.06(s,3H),2.96–2.86(m,1H),2.79(dd,J＝19.9,12.3Hz,1H),2.57(dd,J＝29.0,23.4Hz,2H),2.43(s,3H),2.18(dd,J＝8.1,3.9Hz,2H).LC-MS:(ESI)m/z＝328(M+H)+
Step two: to a solution of A7(5 g, 15.28mmol) in acetic acid (250 mL) was added zinc powder (9.93 g, 152.8 mmol). The mixture was stirred at 30-40 ℃ for 0.5 h. The reaction solution was poured into ethyl acetate (200mL) and water (400mL) and sodium bicarbonate was added to adjust the pH to 7. The mixture was filtered and the filtrate was concentrated in vacuo to give product A8 as a yellow oil (4.4 g, 88.0% yield) which was used directly in the next step. LC-MS (ESI) 298(M + H) M/z+
Step three: a mixture of A8(4.4 g, 14.8mmol) and nitrogen, nitrogen-dimethylformamide dimethyl acetal (8.8 g, 74mmol) in toluene (50 mL) was stirred at 100 deg.C under nitrogen for 20 h. The mixture was concentrated in vacuo to give a residue which was purified on a silica gel column (dichloromethane/methanol 100:1) to give product a9(3.4 g, 63%) as a yellow oil.1HNMR:(400MHz,DMSO)δppm:7.58(s,1H),7.17(s,1H),6.47(s,1H),4.20(tt,J＝10.1,5.1Hz,1H),3.88(s,3H),3.08(s,6H),2.90(ddd,J＝18.4,11.8,4.4Hz,1H),2.69(dt,J＝30.2,9.6Hz,2H),2.46(dd,J＝15.2,8.9Hz,1H),2.39(s,3H),2.08(s,2H).LC-MS:(ESI)m/z＝353(M+H)+。
1.4 Synthesis of quinazoline derivative (I)
The synthetic route is as follows:
Figure BDA0001651016730000491
the method comprises the following steps: a mixture of A9(3.4 g, 9.65mmol) and 2-fluoro-3- ((trimethylsilanyl) ethynyl) aniline (4 g, 19.3mmol) in acetic acid (90 mL) was stirred at 80 deg.C under nitrogen for 16 h. After cooling, it was treated with a saturated solution of sodium bicarbonate to pH 8 and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified on a silica gel column (dichloromethane/methanol 100:1) to give product a10 as a white solid (2.4 g, 48% yield). LC-MS (ESI) M/z 515(M + H)+
Step two: TBAF (1M in tetrahydrofuran, 1.94 ml, 1.94mmol) was added to a solution of A10(1 g, 1.94mmol) in tetrahydrofuran (10 ml) and stirred at room temperature for 0.5 h. Concentrated in vacuo and purified on a silica gel column (dichloromethane/methanol 200: 1 to 100:1) to give product a11(800 mg, 93% yield) as a yellow solid.1HNMR:(400MHz,CDCl3-d6)δppm:8.74(s,1H),8.63(td,J＝8.0,1.7Hz,1H),7.42(s,1H),7.35(d,J＝8.5Hz,2H),7.28–7.18(m,2H),4.50(dd,J＝9.5,4.9Hz,1H),4.05(s,3H),3.38(s,1H),3.07–2.91(m,1H),2.88–2.69(m,2H),2.56(s,1H),2.45(s,3H),2.30–2.13(m,2H)。LC-MS:(ESI)m/z＝443(M+H)+
Step three: racemic mixture A11(1.03 g) was subjected to high performance liquid chiral separation column OJ-H (4.6X 100X 5um) and chromatographed using methanol (0.2% methanolic ammonia) to give enantiomerically pure (R)/(-) free base compound (I) (480 mg, ee%>99％,LC-MS:(ESI)m/z＝443(M+H)+)。
The method is a hydrate, has hygroscopicity, and has crystal form conversion during heating. Solid formulations are difficult to formulate under pharmaceutical processing conditions due to moisture absorption and thermal instability. Therefore, there is a need for further preparation of preferred salt forms and crystal forms of salts of quinazoline derivatives having superior physicochemical properties, which can be advantageously used in pharmaceutical processing and pharmaceutical compositions.
Example 2 preparation of hydrochloride form A of quinazoline derivative (I) according to the invention
About 20 mg of a quinazoline derivative represented by the formula (I) (i.e., (R) -6- [ (3, 3-difluoro-1-methylpiperidin-4-yl) oxy ] -n- (3-ethynyl-2-fluorophenyl) -7-methoxyquinazolin-4-amine (I)) was weighed into a 1.5ml vial, 0.6 ml of methanol and 46. mu.l of hydrochloric acid (1mol/L) were added, and after stirring at room temperature for about two days, a lower wet-like solid was separated by centrifugation. The solid was hydrochloride form a by XRPD detection.
Example 3 preparation of hydrochloride form B of quinazoline derivative (I) according to the invention
About 160 mg of a sample of the quinazoline derivative of the formula (I) was weighed, 5ml of tetrahydrofuran/water (19/1, v/v) was added, 0.37 ml of hydrochloric acid (1mol/L) was added to the suspension, the mixture was stirred at room temperature for about two days, and the lower layer of a wet-like solid was separated by centrifugation. The solid was hydrochloride form B by XRPD detection.
Example 4 preparation of hydrochloride form H of quinazoline derivative (I) according to the invention
About 10mg of the hydrochloride form B sample was weighed into a 3ml vial, 2 ml of ethanol was added, filtered and rapidly evaporated open at room temperature. XRPD detection shows that the obtained solid is hydrochloride crystal form H.
Example 5 preparation of hydrochloride form I of quinazoline derivative (I) according to the invention
About 10mg of hydrochloride form H sample was weighed, heated to 125 ℃ by DSC Q2000 and then cooled to room temperature to obtain hydrochloride form I.
Example 6 preparation of fumarate salt form A of quinazoline derivative (I) of the present invention
About 160 mg of the quinazoline derivative represented by the formula (I) and 45 mg of fumaric acid were weighed into a 20 ml glass bottle, 5ml of methanol was added thereto, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was fumarate form a as detected by XRPD.
Example 7 preparation of succinate form A of quinazoline derivative (I) according to the invention
About 160 mg of the quinazoline derivative represented by the formula (I) and 43 mg of succinic acid were weighed into a 20 ml glass bottle, 5ml of acetone was added thereto, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was succinate form a as detected by XRPD.
Example 8 preparation of maleate form A of the quinazoline derivative (I) according to the invention
About 10mg of the quinazoline derivative represented by the formula (I) and 2.6 mg of maleic acid were weighed into a 1.5ml glass bottle, 0.3ml of acetone was added thereto, stirred at room temperature for about two days, and centrifuged to collect a solid. The solid was maleate form a as detected by XRPD.
Example 9 preparation of the glycolate salt of the quinazoline derivative (I) of the invention in crystalline form A
About 150 mg of the quinazoline derivative represented by the formula (I) and 27 mg of glycolic acid were weighed into a 1.5ml glass bottle, 5ml of ethyl acetate was added, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was identified as glycolate form a by XRPD.
EXAMPLE 10 preparation of hydrochloride form F of quinazoline derivative (I) according to the invention
About 5mg of the hydrochloride salt sample was weighed into a 3ml glass vial and dissolved by adding 0.1 ml of methanol. The resulting clear solution was placed in a 20 ml glass bottle containing 5ml isopropyl acetate and allowed to gas-liquid diffuse at room temperature until a solid precipitated. The obtained solid was hydrochloride form F by XRPD detection.
Example 11 preparation of hydrochloride form C of quinazoline derivative (I) according to the invention
About 10mg of a sample of the quinazoline derivative of the formula (I) is weighed, 0.3ml of acetonitrile is added, 46. mu.l of hydrochloric acid (1mol/L) is added to the suspension, and after stirring at room temperature for about two days, the lower wet-like solid is separated by centrifugation. And XRPD detection shows that the compound is identified as dihydrochloride crystal form C.
Example 12 preparation of hydrochloride form D of quinazoline derivative (I) according to the invention
About 2 mg of the hydrochloride form C sample was weighed, heated to 140 degrees using DSC Q2000 and cooled to room temperature to give dihydrochloride form D.
Example 13 preparation of the sulphate salt form A of the quinazoline derivative (I) according to the invention
About 10mg of a sample of the quinazoline derivative of the formula (I) was weighed into a 1.5ml glass bottle, 0.3ml of methanol and 23. mu.l of an aqueous solution of sulfuric acid (1mol/L) were added, stirred at room temperature for about two days, and the solid was collected by centrifugation. The solid was found to be sulfate form a by XRPD detection.
Example 14 preparation of the oxalate salt form A of a quinazoline derivative (I) according to the invention
About 10mg of the quinazoline derivative represented by the formula (I) and 3.7 mg of adipic acid were weighed into a 1.5ml glass bottle, 0.3ml of methanol was added thereto, stirred at room temperature for about two days, and centrifuged to collect a solid. The solid is adipate crystal form A (containing a small amount of unreacted and complete adipic acid, and the characteristic peaks are 21.6 and 25.7) through XRPD detection.
Example 15 preparation of malate form a of quinazoline derivative (I) of the present invention
About 10mg of the quinazoline derivative represented by the formula (I) and 2.9 mg of malic acid were weighed into a 1.5ml glass bottle, 0.3ml of methanol was added thereto, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was malate form a by XRPD detection.
EXAMPLE 16 preparation of besylate form A of quinazoline derivative (I) according to the invention
About 10mg of the quinazoline derivative represented by the formula (I) and 3.7 mg of benzenesulfonic acid were weighed into a 1.5ml glass bottle, 0.3ml of methanol was added, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was crystalline form a besylate salt as detected by XRPD.
Example 17 preparation of besylate form B of quinazoline derivative (I) of the invention
About 10mg of the quinazoline derivative represented by the formula (I) and 3.5 mg of benzenesulfonic acid were weighed into a 1.5ml glass bottle, 0.3ml of acetonitrile was added, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was crystalline form B besylate as detected by XRPD.
EXAMPLE 18 preparation of besylate form C of quinazoline derivative (I) of the invention
About 10mg of a quinazoline derivative represented by the formula (I) and 3.9 mg of benzenesulfonic acid were weighed into a 1.5ml glass bottle, 0.3ml of a mixed solvent of tetrahydrofuran and water (19:1, v/v) was added, stirred at room temperature for about two days, and centrifuged to collect a solid. The solid was crystalline form C besylate as detected by XRPD.
Example 19 preparation of benzoate form A of quinazoline derivative (I) of the present invention
About 10mg of the quinazoline derivative represented by the formula (I) and 3.0 mg of benzoic acid were weighed into a 1.5ml glass bottle, 0.3ml of methanol was added thereto, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was crystalline benzoate form a as detected by XRPD.
Example 20 preparation of hippurate form A of quinazoline derivative (I) according to the invention
About 10mg of the quinazoline derivative represented by the formula (I) and 4.2 mg of hippuric acid were weighed into a 1.5ml glass bottle, 0.3ml of methanol was added thereto, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid is hippurate crystal form A detected by XRPD.
Example 21 preparation of oxalate form A of the quinazoline derivative (I) of the present invention
About 10mg of the quinazoline derivative represented by the formula (I) and 2.0 mg of oxalic acid were weighed into a 1.5ml glass bottle, 0.3ml of methanol was added thereto, and the mixture was stirred at room temperature for about two days, and then centrifuged to collect a solid. The solid was oxalate form a as detected by XRPD.
Example 22 characterization of the crystalline forms of the salts of quinazoline derivatives (I) according to the invention by XRPD patterns
XRPD instrument information is as follows:
XRPD patterns were collected on a Bruker X-ray powder diffraction analyzer with XRPD parameters as shown in table 1.
TABLE 1 XRPD test parameters
Figure BDA0001651016730000531
The hydrochloride form a of the quinazoline derivative (I) prepared according to the method described in this example has an XRPD (X-ray powder diffraction) pattern as shown in figure 1 and is characterized in the following table 2:
TABLE 2
Figure BDA0001651016730000532
Figure BDA0001651016730000541
The hydrochloride form B of the quinazoline derivative (I) prepared in accordance with the procedures described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in figure 2 and is characterized in particular by the following table 3:
TABLE 3
Figure BDA0001651016730000551
The hydrochloride form H of the quinazoline derivative (I) prepared in accordance with the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in figure 3 and is characterized in particular by the following table 4:
TABLE 4
Figure BDA0001651016730000552
Figure BDA0001651016730000561
The hydrochloride form I of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in figure 4and is characterized in particular by the following table 5:
TABLE 5
Figure BDA0001651016730000562
Figure BDA0001651016730000571
Crystalline fumarate salt form a of quinazoline derivative (I) prepared according to the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 5 and as characterized in particular in table 6 below:
TABLE 6
Figure BDA0001651016730000581
Figure BDA0001651016730000591
Crystalline form a succinate salt of quinazoline derivative (I) prepared according to the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 6, and as characterized in the following table 7:
TABLE 7
Figure BDA0001651016730000592
Figure BDA0001651016730000601
Crystalline maleate form a of quinazoline derivative (I) prepared in accordance with the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 7 and as characterized in particular in table 8 below:
TABLE 8
Figure BDA0001651016730000602
Figure BDA0001651016730000611
The quinazoline derivative (I) prepared according to the method described in the examples has a crystalline form A as a glycolate, and an XRPD (X-ray powder diffraction) pattern as shown in figure 8, and is characterized in the following table 9:
TABLE 9
Figure BDA0001651016730000612
Figure BDA0001651016730000621
Crystalline hydrochloride form F of quinazoline derivative (I) prepared in accordance with the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 9 and as characterized in particular in table 10 below:
watch 10
Figure BDA0001651016730000622
Figure BDA0001651016730000631
The hydrochloride form C of the quinazoline derivative (I) prepared in accordance with the procedures described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in figure 10 and is characterized in particular by the following table 11:
TABLE 11
Figure BDA0001651016730000632
Figure BDA0001651016730000641
Crystalline hydrochloride form D of quinazoline derivative (I) prepared according to the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 11 and as characterized in particular in table 12 below:
TABLE 12
Figure BDA0001651016730000642
Figure BDA0001651016730000651
The sulphate form a of quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in figure 12 and is characterised in particular by the following table 13:
watch 13
Figure BDA0001651016730000652
Figure BDA0001651016730000661
An oxalate salt form a of a quinazoline derivative (I) prepared in accordance with the procedures set forth in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 13 and characterized in particular by the following table 14:
TABLE 14
Figure BDA0001651016730000662
Figure BDA0001651016730000671
The quinazoline derivative (I) prepared according to the method described in the examples had the malate form A with an XRPD (X-ray powder diffraction) pattern as shown in figure 14 and is characterized in the following Table 15:
watch 15
Figure BDA0001651016730000672
Figure BDA0001651016730000681
Crystalline form a besylate salt of quinazoline derivative (I) prepared according to the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 15 and as characterized in the following table 16:
TABLE 16
Figure BDA0001651016730000682
Figure BDA0001651016730000691
Crystalline form B besylate salt of quinazoline derivative (I) prepared according to the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 16 and as characterized in the following table 17:
TABLE 17
Figure BDA0001651016730000701
Crystalline form C besylate salt of quinazoline derivative (I) prepared according to the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 17 and as characterized in the following table 18:
watch 18
Figure BDA0001651016730000702
Figure BDA0001651016730000711
The quinazoline derivative (I) prepared according to the method described in the examples has the benzoate form A with an XRPD (X-ray powder diffraction) pattern as shown in figure 18 and is characterized in the following table 19:
watch 19
Figure BDA0001651016730000721
Figure BDA0001651016730000731
An XRPD (X-ray powder diffraction) pattern of the hippurate form a of quinazoline derivative (I) prepared according to the process described in the examples is shown in figure 19 and is characterized in particular by the following table 20:
watch 20
Figure BDA0001651016730000732
Figure BDA0001651016730000741
Crystalline form a of the oxalate salt of quinazoline derivative (I) prepared in accordance with the procedures described in the examples having an XRPD (X-ray powder diffraction) pattern as shown in figure 20 and as characterized in particular in table 21 below:
TABLE 21
Figure BDA0001651016730000742
Figure BDA0001651016730000751
d is the interplanar spacing of two adjacent faces in the crystal lattice, in angstroms, and I% is the intensity.
As can be seen from fig. 1, the XRPD pattern of the hydrochloride form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 6.48, 7.31, 9.36, 10.26, 13.12, 14.37, 14.98, 16.06, 16.88, 17.48, 18.25, 20.01, 20.83, 21.55, 22.21, 23.35, 25.47, 26.60, 27.46, 28.29, 29.98, 34.07, 34.89, 36.25, 36.47, 36.87, and 37.54, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 2, the XRPD pattern of the hydrochloride form B of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.32, 5.98, 6.54, 7.28, 8.17, 10.52, 13.20, 15.99, 17.74, 18.48, 19.32, 19.84, 22.56, 23.88, 24.36, 24.87, 30.47, 32.92, 33.55, 34.60, 38.06, 38.34, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 3, the XRPD pattern of the hydrochloride form H of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 5.83, 6.43, 7.26, 8.10, 10.24, 11.93, 13.22, 14.11, 14.45, 14.88, 15.78, 16.80, 17.95, 18.96, 20.25, 21.07, 21.65, 24.16, 24.53, 25.67, 26.37, 27.03, and 27.61, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 4, the XRPD pattern of the hydrochloride form I of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 6.88, 7.42, 8.20, 12.31, 13.20, 13.88, 14.23, 14.66, 15.69, 17.48, 17.90, 18.64, 19.23, 20.24, 20.92, 21.94, 22.88, 23.42, 23.88, 25.12, 25.40, 25.85, 26.64, 28.07, 28.92, 31.19, and 33.10, and the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 5, the XRPD pattern of the fumarate salt form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 6.51, 6.74, 7.47, 9.37, 10.82, 13.43, 13.97, 14.61, 17.78, 18.51, 18.80, 19.69, 20.90, 21.36, 21.68, 22.63, 23.76, 24.39, 27.09, 28.73, 29.69, 30.52, 31.07, 35.14, 36.12 and 38.33, and the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 6, the XRPD pattern of the succinate salt form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 3.92, 4.40, 6.56, 6.74, 7.50, 9.42, 11.92, 12.68, 13.53, 14.50, 14.84, 15.22, 15.68, 16.25, 17.82, 18.55, 19.48, 20.34, 20.99, 22.08, 22.59, 24.14, 24.52, 24.92, 28.07, 30.92, and 36.11, and the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 7, the XRPD pattern of the maleate form a of the quinazoline derivative provided by the present invention has derivative peaks at 2 θ ═ 6.25, 8.44, 8.68, 9.42, 10.41, 14.42, 14.88, 16.65, 17.93, 18.78, 20.58, 21.17, 22.63, 25.16, 31.15, 32.40, 33.66, 34.34, 34.52, 35.82, 36.06, 36.35, and 36.91, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 8, the XRPD pattern of the glycolate form a of the quinazoline derivative provided by the present invention has derivative peaks at 2 θ ═ 4.53, 5.89, 6.59, 7.35, 10.02, 12.54, 13.26, 15.94, 17.93, 18.67, 19.36, 19.84, 21.06, 24.99, 31.13, 33.48, 34.79, 35.56, and 36.17, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 9, the XRPD pattern of the hydrochloride form F of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.91, 5.67, 6.51, 6.77, 7.44, 8.58, 9.20, 9.73, 10.40, 10.85, 11.86, 13.58, 14.30, 14.78, 15.57, 15.85, 16.15, 16.41, 16.97, 17.89, 18.96, 19.76, 20.45, 20.79, 21.57, 22.21, and 24.17, where the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 10, the XRPD pattern of the hydrochloride form C of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 5.66, 7.16, 8.32, 8.86, 9.52, 10.98, 11.63, 12.80, 13.57, 13.96, 14.81, 15.14, 15.49, 16.55, 16.86, 17.61, 22.04, 22.93, 24.55, 26.19, 27.30, 28.49, 34.12, 34.76, 35.65, 36.68, 37.31, 37.80, 38.20, and 38.53, and the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 11, the XRPD pattern of the hydrochloride form D of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 3.43, 6.72, 7.12, 8.47, 9.32, 12.25, 13.44, 14.07, 15.69, 16.87, 17.22, 17.97, 19.77, 20.73, 22.25, 22.82, 23.64, 24.77, 25.40, 27.28, 28.13, 29.69, 31.01, 33.48, 34.87, 35.42, and 38.08, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 12, the XRPD pattern of the sulfuric acid form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 7.27, 8.41, 11.88, 14.96, 18.23, 19.68, 20.64, 24.83, 25.82, 27.10, 28.16, 29.79, 30.71, 32.35, 34.12, 35.56, 37.56, and 38.37, and the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 13, the XRPD pattern of the oxalate salt form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 5.43, 6.88, 7.38, 9.56, 13.68, 15.10, 15.43, 16.32, 16.88, 17.68, 18.60, 19.02, 20.58, 21.62, 22.33, 22.70, 23.35, 25.68, 27.29, 27.88, 28.53, 29.37, 31.35, 34.89, 37.11, 37.78, 38.17, 38.36, and 39.65, where the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 14, the XRPD pattern of the malate salt form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ of 5.43, 6.53, 7.49, 8.35, 9.17, 12.10, 13.16, 16.17, 18.77, 19.85, 20.79, 23.14, 23.94, 26.66, 28.25, 29.32, 30.38, 33.24, 33.69, 34.80, 35.97, 36.87 and 37.88, and the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 15, the XRPD pattern of besylate salt form a of the quinazoline derivative provided by the present invention has derivative peaks at 2 θ ═ 5.48, 6.56, 7.08, 7.65, 8.14, 8.48, 9.71, 10.55, 11.14, 11.77, 13.32, 13.95, 15.32, 16.46, 16.89, 17.82, 19.15, 19.70, 20.43, 21.02, 21.98, 22.68, 23.23, 25.26, 26.07, 26.59, 28.63, 29.09, 30.45, 31.12, 32.09, 32.55, 33.66, 35.76, 37.86, 38.67, and 39.11, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 16, the XRPD pattern of besylate salt form B of the quinazoline derivative provided by the present invention has derivative peaks at 2 θ ═ 5.50, 6.32, 7.28, 8.50, 9.74, 10.79, 11.55, 13.22, 14.49, 15.53, 16.26, 16.97, 18.29, 19.71, 21.36, 22.21, 23.44, 24.19, 25.34, 25.87, and 27.16, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 17, the XRPD pattern of besylate salt form C of quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.24, 7.07, 7.68, 8.31, 9.92, 12.55, 14.03, 14.74, 18.72, 19.40, 20.36, 21.19, 24.08, 24.73, 26.14, 27.49, 28.28, 31.68, 33.90, 34.82, 35.06, 35.78, 36.54, 37.57, 37.89, 38.36, and 39.0, and the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 18, the XRPD pattern of the benzoate form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.45, 6.31, 6.65, 7.33, 7.69, 8.01, 11.85, 13.53, 16.02, 16.77, 18.75, 19.95, 21.06, 21.76, 22.56, 23.41, 26.94, 27.44, 27.61, 27.98, 28.55, 29.05, 31.92, 32.29, 32.93, 33.72, 34.61, 35.35, 35.95, 37.08, 38.13, and 39.62, and the error range of the above 2 θ value is ± 0.2.
As can be seen from fig. 19, the XRPD pattern of the hippurate crystal form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.35, 5.59, 6.85, 7.74, 9.17, 9.95, 13.74, 14.73, 15.96, 16.44, 18.10, 18.63, 19.96, 21.38, 24.25, 25.37, 25.72, 26.39, 27.23, 28.56, 30.25, 30.82, 33.31, 34.58, 35.29, 36.39, 37.24, and 37.9, where the error range of the above 2 θ values is ± 0.2.
As can be seen from fig. 20, the XRPD pattern of oxalate form a of the quinazoline derivative (I) provided by the present invention has derivative peaks at 2 θ ═ 4.11, 6.44, 7.15, 8.75, 9.06, 9.88, 11.26, 11.58, 12.92, 14.52, 15.87, 17.47, 18.29, 19.43, 20.14, 20.49, 23.70, 24.34, 26.36, 26.92, 29.75, 31.72, 32.67, 32.99, 34.21, 34.52, 34.86, 36.36, 36.91, 37.91, 39.03, and the error range of the above 2 θ values is ± 0.2.
The error range for the 2 theta values may also be ± 0.2 as tested it will be understood by those skilled in the art that these diffraction peaks do not represent an exhaustive list of diffraction peaks shown by the hydrochloride form a, B, C, D, F, H, I, the sulfate form a, the maleate form a, the succinate form a, the adipate form a, the glycolate form a, the malate form a, the fumarate form a, the benzenesulfonate form a, B, C, the benzoate form a, the hippurate form a and the oxalate form a of the quinazoline derivative (I). The 2 θ values of the X-ray powder diffraction pattern are those that may vary slightly with machine and sample preparation variations and batch-to-batch variations, and the values quoted are not considered absolute values. It should also be understood that the absolute intensity of the peak may also vary with orientation effects, and thus, the intensities shown herein are exemplary and not used for absolute comparisons.
EXAMPLE 23 biological Activity of quinazoline derivatives (I)
Cell viability assays for tumor cells and brain gliomas with EGFR activating mutation (Exon 19 deletion Exon19 Del) protein using CellTiter-glo (CTG) assay; approximately 5000 cells were plated in each blank 96-well plate, and after 16 hours, the scaled-down compounds were added and allowed to equilibrate at room temperature for 30 minutes 72 hours after drug addition. Add 100. mu.l CellTiter-Glo reagent to each well and mix well on an orbital shaker for 2 minutes to induce cell lysis. The plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal. The luminescence signal was recorded on a TECAN Infinite M1000Pro instrument.
TABLE 22 inhibition of growth (IC) of non-small cell lung carcinoma PC-9 tumor cells and glioma tumor cells5oIs nM)
Figure BDA0001651016730000791
As can be seen from table 22, the quinazoline derivative (I) of the configuration R according to the present invention has an unexpected EGFRVIII mutation activity > 100-fold higher than the enantiomer activity. Has similar biological activity with EGFR Del19 activating mutation.
As shown in fig. 21, in a western blot (western blot) experiment, the phosphorylation of EGFRV3 was inhibited by quinazoline derivative (I), which showed that quinazoline derivative (I) has good biological activity and is specific for cancers mediated by EGFRV3 phosphorylation.
Example 24 blood brain Barrier crossing Rate of quinazoline derivative (I)
To determine whether the quinazoline derivative (I) is capable of crossing the Blood Brain Barrier (BBB), rats are administered a test compound. At 4 hours after dosing, rats were killed, blood and brain tissue were collected and assayed for test compound concentration. Brain penetration is defined as the ratio of the concentration of a compound in brain tissue to the concentration in plasma. The rate of crossing the blood-brain barrier is the ratio of the free concentration of the drug in brain tissue to the free concentration of the drug in plasma. P-glycoprotein is a blood brain barrier efflux protein that discharges P-glycoprotein substrate outside of the brain. The breast cancer drug-resistant protein is blood brain barrier efflux protein, and is excreted out of the cranium.
TABLE 23 ability to cross blood brain barrier of quinazoline derivatives (I)
Figure BDA0001651016730000792
Figure BDA0001651016730000801
The compounds (I) of the present invention have a ratio of compound free concentration in brain tissue to free concentration in plasma of more than 50% in a cross-blood-brain-barrier-rate assay, and are not P-glycoprotein substrates or efflux substrates of breast cancer resistant proteins, and are able to cross the blood-brain-barrier, and therefore they have the potential to reach effective blood levels intracranial, for the treatment of brain gliomas or the treatment and prevention of cancer brain metastases, meningeal metastases, brain cancers and other central nervous diseases, and reduce the risk of dose-limiting toxicity outside the cranium.
Example 25 quinazoline derivative (I) on brain tumors with the EGFRV3 mutation Primary tumors in murine subcutaneous patients Efficacy of tumor-transplanted animal models of tissues
The primary tumor tissue (brain tumor) of the patient is inoculated into the subcutaneous tissue of the mouse, and the administration is started after the tumor grows to about 150 cubic millimeters, and the treatment is carried out for three weeks.
In the experiment of efficacy of brain tumor with EGFRV3 mutation in tumor transplantation animal model of primary tumor tissue of subcutaneous mouse patient, the first group was a control group without any drug. The second group of quinazoline derivatives (I) were administered as a single dose at 3 mg/kg orally, twice daily, the third group of quinazoline derivatives (I) were administered as a single dose at 10 mg/kg orally, twice daily, and the fourth group of quinazoline derivatives (I) were administered as a single dose at 20 mg/kg orally, twice daily. As shown in fig. 22, the drug groups (second, third, and fourth groups) all showed good inhibition of tumor growth and statistically significant drug efficacy compared to the first group (control group), showing dose-dependent drug efficacy in animal models, and the fourth group showed good drug efficacy with reduced tumor. And has statistically significant pharmacodynamic differences. RNA sequencing of tumors showed mutations in EGFRV3, showing that quinazoline derivative (I) has good biological activity and potency against the EGFRV3 mutation.
Example 26 equilibrium solubility of quinazoline derivatives (I) and their salt forms in Water
The experimental method comprises the following steps: about 10mg of solid sample (free base and each salt form and crystal form) was weighed, 1.5mL of water was added, 0.3mL of turbid solution was taken out after equilibration for 24 hours at room temperature, and the lower solid and the supernatant were separated by centrifugation. The supernatant was filtered through a 0.45 μm (PTFE) frit and the concentration of free base was measured separately.
TABLE 23
Figure BDA0001651016730000802
Figure BDA0001651016730000811
As can be seen from table 23, each salt form of the quinazoline derivative (I) of the present invention has good equilibrium solubility in water, and preferably, the equilibrium solubility of the hydrochloride form a, B, H, I and the fumarate form a of the quinazoline derivative (I) of the present invention in water is more than 500 ug/mL. This is very advantageous for the absorption of the drug.
Example 27 stability test
The salt form and the crystal form of the quinazoline derivative (I) with the week physicochemical stability are stored for a week at 25 ℃/60% RH and 40 ℃/75% RH, and the physicochemical property is stable. The TGA patterns in the heating process show that the crystal forms in the examples 2-21 have no obvious change, and particularly, the DSC pattern shows that the fumarate crystal form A shows good stability. As shown in fig. 23, fumarate form a did not significantly lose weight during heating, with a melting point of about 240 degrees celsius. Such properties are advantageous for manufacturing and processing into tablets.
Example 28 quinazoline derivatives (I) according to the present invention have good bioavailability
In the rat pharmacokinetic study, one group of rats (three rats) was intravenously injected with 1-2 mg/kg, the second group of rats (three rats) was orally administered with 2-40 mg/kg, and blood was taken at 7 time points (0.25, 0.5, 1, 2,4, 8, 16 hours) to measure the concentration of the quinazoline derivative (I) in the blood, and the peak area and half-life were calculated. Bioavailability was calculated as: (oral peak area of drug/oral dose)/(peak area of drug for intravenous injection/intravenous dose) x 100%. The quinazoline derivative (I) has good bioavailability of more than 35% in all salt forms and crystal forms.
Preferably: hydrochloride form B, H, I (bioavailability > 60%) and fumarate form a (bioavailability 80%);
more preferably: fumarate salt form a (bioavailability 80%, half-life 7.4 hours).
Example 29The mechanism of action of the quinazoline derivative (I) of the present invention
In the experiment of the action mechanism of the quinazoline derivative (I) for inhibiting the EGFR, a 384-well plate with 6 to 0.0125nM concentrations and 0 concentration diluted from 0.4nM in an equal proportion (2 times) is added with a solution of EGFR enzyme in PolyE4Y1, after incubation for 15 minutes and addition of 7 concentrations of ATP diluted from 600uM in an equal proportion (2 times) for reaction for 60 minutes, ADP-Glo reagent and detection reagent are added for measuring RLU signals for forty minutes. As shown in fig. 24, the quinazoline derivative (I) according to the present invention showed an unexpected mechanism of non-ATP competitive action. The advantage of the action mechanism is obvious, and the quinazoline derivative (I) provided by the invention has the characteristics of high activity, high selectivity, small side effect and drug resistance.
In conclusion, the quinazoline derivative (I) has 6-substituted (3, 3-difluoro-1-methylpiperidin-4-yl) oxy with chirality of R, and has the advantages of high activity, high selectivity, high blood brain barrier crossing rate, non-efflux substrate, inhibition property of non-ATP competitive mechanism, obvious drug effect on non-small cell lung cancer and brain glioma, and high bioavailability. It is emphasized that the quinazoline derivatives (I) according to the present invention have unexpectedly high biological activity, high selectivity and high blood-brain barrier crossing rate for both non-small cell lung cancer (those mediated by certain EGFR activating forms, particularly EGFR Del19 and/or EGFR L858R activating mutations) and brain glia (those mediated by certain EGFR activating forms, particularly EGFR viii activating mutations). In particular, the quinazoline derivative (I) with chirality R has high activity and selectivity brought by the non-competitive inhibition characteristic, and particularly has high activity on brain glioma.
The solubility of the hydrochloride crystal form A, the hydrochloride crystal form B, the sulfate crystal form A, the maleate crystal form A, the succinate crystal form A, the adipate crystal form A, the glycolate crystal form A, the malate crystal form A, the fumarate crystal form A, the benzenesulfonate crystal form A, the maleate crystal form B, the benzoate crystal form A, the hippurate crystal form A and the oxalate crystal form A in water is higher than that of the quinazoline derivative shown in the formula (I), so that the quinazoline derivative has better solubility, does not undergo crystal form transformation in the heating process, and has good stability.
The hydrochloride crystal forms A, B, C, D, F, H and I, the sulfate crystal form A, the maleate crystal form A, the succinate crystal form A, the adipate crystal form A, the glycolate crystal form A, the malate crystal form A, the fumarate crystal form A, the benzenesulfonate crystal forms A, B and C, the benzoate crystal form A, the hippurate crystal form A and the oxalate crystal form A of the quinazoline derivative have unexpected excellent physicochemical properties and are favorable for being used in pharmaceutical processing and pharmaceutical compositions. The method can be applied to the medicines for treating non-small cell lung cancer brain metastasis, meningeal metastasis, head and neck squamous cell carcinoma, brain stem tumor, primary brain cancer or brain glioma and the like, and simultaneously provides qualitative and quantitative information of curative effect and safety, thereby having important significance for further researching the curative effect and safety of the solid medicines.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims (41)

1. A crystal form of hydrochloride of a quinazoline derivative shown as a formula (I), wherein the crystal form is a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form F, a crystal form H or a crystal form I;
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wherein the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 6.48, 7.31, 9.36, 13.12, 14.37, 17.48, 18.25, 20.01, 21.55, 23.35, 26.60, 27.46;
the XRPD pattern of form B has characteristic peaks at the following 2 Θ: 5.98, 6.54, 7.28, 8.17, 10.52, 13.20, 17.74, 18.48, 19.84, 23.88;
the form C is a dihydrochloride form having an XRPD pattern with characteristic peaks at the following 2 Θ: 7.16, 9.52, 12.80, 13.57, 13.96, 17.61, 22.04, 22.93, 24.55, 26.19, 27.30, 28.49;
the form D is a dihydrochloride form, and an XRPD pattern of the form D has characteristic peaks at the following 2 theta positions: 6.72, 7.12, 13.44, 14.07, 16.87, 17.22, 17.97, 22.25, 24.77, 25.40, 27.28, 28.13;
the XRPD pattern of form F has characteristic peaks at the following 2 Θ: 6.51, 6.77, 13.58, 14.30, 14.78, 15.85, 17.89, 19.76, 20.45, 20.79;
the XRPD pattern of form H has characteristic peaks at the following 2 Θ: 6.43, 7.26, 13.22, 14.11, 14.45, 17.95, 18.96, 20.25, 24.16, 25.67, 26.37, 27.61;
the XRPD pattern of form I has characteristic peaks at the following 2 Θ: 6.88, 7.42, 12.31, 13.20, 14.23, 14.66, 18.64, 25.12, 25.40, 25.85, 26.64, 28.07;
wherein the error range of the 2 theta value is +/-0.2.
2. The crystalline form of claim 1, wherein the form a has an XRPD pattern substantially as depicted in figure 1;
form B has an XRPD pattern substantially as shown in figure 2;
form C has an XRPD pattern substantially as shown in figure 10;
form D has an XRPD pattern substantially as shown in figure 11;
said form F having an XRPD pattern substantially as shown in figure 9;
form H has an XRPD pattern substantially as shown in figure 3;
the form I has an XRPD pattern substantially as shown in figure 4.
3. A process for the preparation of the crystalline form according to claim 1 or 2,
the preparation method of the crystal form A comprises the following steps: adding an organic solvent and 0.8-1.2 equivalent of hydrochloric acid into a quinazoline derivative shown in a formula (I) and stirring at 22-28 ℃, and centrifugally separating out a lower-layer solid to obtain a crystal form A; wherein 10-200 mg of quinazoline derivatives shown in formula (I) are added into each ml of organic solvent; the organic solvent is methanol;
the preparation method of the crystal form B comprises the following steps: adding a quinazoline derivative shown in a formula (I) into an organic solvent, adding 0.8-1.2 equivalent of hydrochloric acid into the suspension, stirring at 22-28 ℃, and centrifugally separating out a lower-layer wet-sample solid to obtain a crystal form B; wherein 10-200 mg of quinazoline derivatives shown in formula (I) are added into each ml of organic solvent; the organic solvent is acetonitrile, ethyl acetate or tetrahydrofuran/water solution with the volume ratio of 15-20: 1;
the preparation method of the crystal form C comprises the following steps: adding a quinazoline derivative shown in a formula (I) into an organic solvent, adding 2-2.5 equivalents of hydrochloric acid, stirring at 22-28 ℃, and centrifugally separating out a lower-layer wet sample solid to obtain a dihydrochloride crystal form C; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent; the organic solvent is acetone;
the preparation method of the crystal form D comprises the following steps: heating a quinazoline derivative hydrochloride crystal form C sample shown in a formula (I) to 120-160 ℃, and cooling to 22-28 ℃ to obtain a dihydrochloride crystal form D;
the preparation method of the crystal form F comprises the following steps: adding a quinazoline derivative hydrochloride crystal form B shown in a formula (I) into an alcohol organic solvent and an ester organic solvent, and performing gas-liquid diffusion at the temperature of 22-28 ℃ until a solid is separated out to obtain a crystal form F; wherein 10-200 mg of hydrochloride crystal form B shown in the formula (I) is added into each ml of organic solvent; the alcohol organic solvent is methanol, and the ester organic solvent is isopropyl acetate;
the preparation method of the crystal form H comprises the following steps: adding an organic solvent into a quinazoline derivative hydrochloride crystal form B shown in a formula (I), filtering, and volatilizing at 22-28 ℃ to obtain a crystal form H; wherein 10-200 mg of hydrochloride crystal form B shown in the formula (I) is added into each ml of organic solvent; the organic solvent is ethanol;
the preparation method of the crystal form I comprises the following steps: heating a quinazoline derivative hydrochloride crystal form H sample shown in the step (I) to 120-130 ℃, and then cooling to 22-28 ℃.
4. A crystalline form of a fumarate salt of a quinazoline derivative represented by formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 6.51, 6.74, 7.47, 9.37, 13.43, 14.61, 17.78, 18.51, 19.69, 21.36, 22.63; wherein the error range of the 2 theta value is +/-0.2.
5. The crystalline form of claim 4, wherein the form A has an XRPD pattern substantially as shown in figure 5.
6. A method of preparing the crystalline form of claim 4 or 5, comprising: adding a quinazoline derivative shown in a formula (I) and 0.4-0.6 equivalent weight of fumaric acid into an organic solvent, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
7. A crystalline form of succinate salt of a quinazoline derivative represented by formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 6.56, 6.74, 7.50, 9.42, 12.68, 14.50, 14.84, 15.22, 17.82, 18.55, 20.34, 20.99; wherein the error range of the 2 theta value is +/-0.2.
8. The crystalline form of claim 7, wherein the form A has an XRPD pattern substantially as shown in figure 6.
9. A method of preparing the crystalline form of claim 7 or 8, comprising: adding an organic solvent into a quinazoline derivative shown in a formula (I) and 0.8-1.2 equivalent of succinic acid, stirring at 22-28 ℃, centrifuging and collecting a solid to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
10. A crystalline form of the maleate salt of a quinazoline derivative represented by formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 6.25, 8.44, 8.68, 14.42, 14.88, 16.65, 17.93, 18.78, 21.17, 22.63; wherein the error range of the 2 theta value is +/-0.2.
11. The crystalline form of claim 10, wherein the form a has an XRPD pattern substantially as shown in figure 7.
12. A method of preparing the crystalline form of claim 10 or 11, comprising: adding a quinazoline derivative shown in a formula (I) and 0.8-1.2 equivalent of maleic acid into an organic solvent, stirring at 22-28 ℃, centrifuging and collecting a solid to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
13. A crystalline form of the glycolate salt of a quinazoline derivative represented by the formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 5.89, 6.59, 7.35, 12.54, 13.26, 15.94, 17.93, 18.67, 19.84, 21.06, 24.99; wherein the error range of the 2 theta value is +/-0.2.
14. The crystalline form of claim 13, wherein the form a has an XRPD pattern substantially as depicted in figure 8.
15. A method of preparing the crystalline form of claim 13 or 14, comprising: adding an organic solvent into a quinazoline derivative shown in a formula (I) and 0.8-1.2 equivalent of glycolic acid, stirring at 22-28 ℃, centrifuging and collecting a solid to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
16. A crystalline form of a sulfate salt of a quinazoline derivative represented by formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 7.27, 8.41, 11.88, 14.96, 18.23, 19.68, 20.64, 24.83, 25.82, 27.10, 28.16, 29.79; wherein the error range of the 2 theta value is +/-0.2.
17. The crystalline form of claim 16, wherein the form a has an XRPD pattern substantially as shown in figure 12.
18. A method of preparing the crystalline form of claim 16 or 17, comprising: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of sulfuric acid aqueous solution, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
19. A crystal form of an oxalate salt of a quinazoline derivative represented by the formula (I), wherein the crystal form is a crystal form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 6.88, 9.56, 13.68, 15.10, 15.43, 19.02, 20.58, 21.62, 23.35, 25.68, 27.29, 27.88; wherein the error range of the 2 theta value is +/-0.2.
20. The crystalline form of claim 19, wherein the form a has an XRPD pattern substantially as shown in figure 13.
21. A method of preparing the crystalline form of claim 19 or 20, comprising: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of oxalic acid, stirring at 22-28 ℃, centrifuging, and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
22. A crystalline form of the malate salt of a quinazoline derivative represented by the formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ:5.43, 6.53, 7.49, 8.35, 9.17, 12.10, 18.77, 19.85, 20.79, 23.94, 26.66, 28.25, 29.32; wherein the error range of the 2 theta value is +/-0.2.
23. The crystalline form of claim 22, wherein the form a has an XRPD pattern substantially as shown in figure 14.
24. A method of preparing the crystalline form of claim 22 or 23, comprising: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of malic acid, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
25. A crystal form of a benzenesulfonate salt of a quinazoline derivative represented by the formula (I), wherein the crystal form is crystal form a, crystal form B or crystal form C;
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wherein the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 5.48, 6.56, 7.08, 13.95, 15.32, 16.89, 17.82, 19.70, 21.02, 23.23, 26.07, 26.59;
the XRPD pattern of form B has characteristic peaks at the following 2 Θ: 5.50, 6.32, 7.28, 8.50, 9.74, 13.22, 14.49, 15.53, 18.29, 19.71, 23.44, 27.16;
the XRPD pattern of form C has characteristic peaks at the following 2 Θ: 7.07, 7.68, 8.31, 14.03, 14.74, 18.72, 19.40, 21.19, 24.08, 24.73, 27.49;
wherein the error range of the 2 theta value is +/-0.2.
26. The crystalline form of claim 25, wherein the form a has an XRPD pattern substantially as shown in figure 15;
form B has an XRPD pattern substantially as shown in figure 16;
the form C has an XRPD pattern substantially as shown in figure 17.
27. A process for preparing the crystalline form of claim 25 or 26, wherein the process for preparing form a comprises: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzenesulfonic acid, stirring at 22-28 ℃, centrifuging and collecting a solid to obtain the crystal form A; wherein 10-200 mg of quinazoline derivatives shown in formula (I) are added into each ml of organic solvent; the organic solvent is methanol;
the preparation method of the crystal form B comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzenesulfonic acid, stirring at 22-28 ℃, centrifuging and collecting a solid to obtain the crystal form B; wherein 10-200 mg of quinazoline derivatives shown in formula (I) are added into each ml of organic solvent; the organic solvent is acetonitrile;
the preparation method of the crystal form C comprises the following steps: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzenesulfonic acid, stirring at 22-28 ℃, centrifuging, and collecting a solid to obtain the crystal form C; wherein 10-200 mg of quinazoline derivatives shown in formula (I) are added into each ml of organic solvent; the organic solvent is a mixed solvent of tetrahydrofuran and water in a volume ratio of 15-20: 1.
28. A crystalline form of a benzoate salt of a quinazoline derivative represented by formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 6.31, 6.65, 7.33, 11.85, 13.53, 16.77, 18.75, 19.95, 21.76, 23.41, 27.98, 29.05; wherein the error range of the 2 theta value is +/-0.2.
29. The crystalline form of claim 28, wherein the form a has an XRPD pattern substantially as shown in figure 18.
30. A method of preparing the crystalline form of claim 28 or 29, comprising: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of benzoic acid, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
31. A crystalline form of hippurate of a quinazoline derivative represented by the formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 5.59, 6.85, 7.74, 13.74, 14.73, 15.96, 18.10, 19.96, 21.38, 26.39, 27.23, 28.56; wherein the error range of the 2 theta value is +/-0.2.
32. The crystalline form of claim 31, wherein the form a has an XRPD pattern substantially as shown in figure 19.
33. A method of preparing the crystalline form of claim 31 or 32, comprising: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of hippuric acid, stirring at 22-28 ℃, centrifuging and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
34. A crystalline form of an oxalate salt of a quinazoline derivative represented by the formula (I), wherein the crystalline form is form a;
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the XRPD pattern of form a has characteristic peaks at the following 2 Θ: 6.44, 9.06, 12.92, 14.52, 15.87, 17.47, 18.29, 19.43, 26.36, 26.92; wherein the error range of the 2 theta value is +/-0.2.
35. The crystalline form of claim 34, wherein the form a has an XRPD pattern substantially as shown in figure 20.
36. A method of preparing the crystalline form of claim 34 or 35, comprising: adding a quinazoline derivative sample shown in a formula (I) into an organic solvent and 0.8-1.2 equivalent of oxalic acid, stirring at 22-28 ℃, centrifuging, and collecting solids to obtain the crystal form; wherein 10-200 mg of quinazoline derivative shown in formula (I) is added into each ml of organic solvent.
37. The method according to any one of claims 6, 9, 12, 15, 18, 21, 24, 30 and 33, wherein the organic solvent is one or more of alcohols, ethers, esters, aliphatic hydrocarbons and aromatic hydrocarbon organic solvents.
38. A pharmaceutical composition comprising the crystalline form of any one of claims 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 or a combination thereof, and a pharmaceutically acceptable adjuvant or auxiliary ingredient.
39. Use of the crystalline form of any one of claims 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 or the pharmaceutical composition of claim 37 in the manufacture of a medicament for treating or preventing a disease mediated by the epidermal growth factor receptor, EGFR, protein; the medicine is used for treating or preventing diseases mediated by an Epidermal Growth Factor Receptor (EGFR) protein and caused by activation mutation of EGFRVIII.
40. The use according to claim 39, wherein the medicament is a medicament for the treatment or prevention of a disease mediated by the epidermal growth factor receptor EGFR protein and resulting from EGFR Del19 and/or EGFR L858R activating mutations.
41. The use of claim 39 or 40, wherein the medicament is a medicament for treating or preventing non-small cell lung cancer brain metastases, meningeal metastases, squamous cell carcinoma of the head and neck, squamous cell carcinoma, brain stem tumor, primary brain cancer or brain glioma.
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