Crystalline form of lorlatinib free base

Abstract

This invention relates to the crystalline form (form 7) of the free base of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4-(methiminated bridged)pyrazolo[4,3-h][2,5,11]benzoxazadiazetatetracycline-3-carboxynitrile (lorlatinib). The invention also relates to pharmaceutical compositions comprising form 7 and to methods of treating abnormal cell growth in mammals, such as cancer, using form 7 and such compositions.

Description

[0001] This application is a divisional application of Chinese patent application 201680042321.5, filed on July 27, 2016, entitled "Crystal Form of Lorlatinib Free Base". Technical Field

[0002] This invention relates to a novel crystalline form (form 7) of the free base of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(methimide-bridged)pyrazolo[4,3-h][2,5,11]benzoxazadazetatetracyclo-3-carboxynitrile (lorlatinib), pharmaceutical compositions comprising form 7, and methods of treating abnormal cell growth in mammals using form 7 and such compositions. Background Technology

[0003] As described in WHO Drug Information, Vol. 29, No. 4, p. 541 (2015), the compound represented by formula (I) (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno))pyrazolo[4,3-h][2,5,11]benzoxazadiazetatetramonium-3-carboxynitrile (PF-06463922):

[0004]

[0005] Lorlatinib has been designated by the International Nonproprietary Name (INN). Lorlatinib is a potent macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) receptor tyrosine kinase in both wild-type and resistant mutant forms.

[0006] The preparation of lorlatinib free base as an amorphous solid is disclosed in International Patent Publication No. WO 2013 / 132376 and U.S. Patent No. 8,680,111. The solvated form of lorlatinib free base is disclosed in International Patent Publication No. WO2014 / 207606. The contents of each of the foregoing documents are incorporated herein by reference in their entirety.

[0007] Human cancers encompass a wide variety of diseases, collectively constituting one of the leading causes of death in developed countries worldwide (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). Cancer progression is caused by a complex series of multiple genetic and molecular events, including gene mutations, chromosomal translocations, and karyotype abnormalities (Hanahan & Weinberg, The hallmarks of cancer. Cell 2000; 100: 57-70). Despite the diverse and complex underlying genetic causes of cancer, each cancer type has been observed to exhibit common features and acquired abilities that promote its progression. These acquired abilities include dysregulation of cell growth, the ability to continuously replenish blood vessels (i.e., angiogenesis), and the ability of tumor cells to spread locally and metastasize to secondary organ sites (Hanahan & Weinberg 2000). Therefore, the ability to identify novel therapeutics that inhibit altered molecular targets during cancer progression or that target multiple processes common to cancer progression in various tumors represents a significant unmet need.

[0008] Receptor tyrosine kinases (RTKs) play crucial roles in cellular processes, including cell proliferation, migration, metabolism, differentiation, and survival. RTK activity is tightly controlled in normal cells. Constitutively enhanced RTK activity from point mutations, amplifications, and rearrangements of corresponding genes has been implicated in the development and progression of many types of cancer. (Gschwind et al., The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 2004; 4, 361-370; Krause & Van Etten, Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005; 353: 172-187.)

[0009] Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, belonging to a subfamily within the insulin receptor (IR) superfamily, along with leukocyte tyrosine kinase (LTK). In 1994, ALK was first discovered as a fusion protein with nucleolar protein (NPM) in anaplastic large cell lymphoma (ALCL) cell lines. (Morris et al., Fusion of akinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994; 263: 1281-1284.) NPM-ALK induced by chromosomal translocations is involved in the pathogenesis of human anaplastic large cell lymphoma (ALCL) (Pulford et al., Anaplastic lymphoma kinase proteins ingrowth control and cancer. J. Cell Physiol., 2004; 199: 330-58). The role of constitutively activated aberrant expression of ALK chimeric proteins in the pathogenesis of ALCL has been established (Wan et al., Anaplastic lymphomakinase activity is essential for the proliferation and survival of anaplastic large cell lymphoma cells. Blood, 2006; 107: 1617-1623). Subsequently, other chromosomal rearrangements leading to ALK fusions have been detected in ALCL (50-60%), inflammatory myofibroblastic tumors (27%), and non-small cell lung cancer (NSCLC) (2-7%) (Palmer et al., Anaplastic lymphoma kinase: signaling in development and disease. Biochem. J. 2009; 420: 345-361.).

[0010] The EML4-ALK fusion gene, containing portions of the echinoderm microtubule-associated protein-like 4 (EML4) and ALK genes, was first discovered in archived clinical samples and cell lines of NSCLC. (Soda et al., Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature 2007; 448: 561-566; Rikova et al., Cell 2007; 131: 1190-1203.) When expressed in transgenic mice, the EML4-ALK fusion variant exhibited transformation of NIH-3T3 fibroblasts and induced lung adenocarcinoma, confirming the potent oncogenic activity of the EML4-ALK fusion kinase. (Soda et al., A mouse model for EML4-ALK-positive lung cancer. Proc. Natl. Acad. Sci. USA 2008; 105: 19893–19897.) Oncogenic mutations of ALK have also been reported in familial and sporadic neuroblastoma cases. (Caren et al., High incidence of DNA mutations and geneamplifications of the ALK gene in advanced sporadic neuroblastomatumors. Biochem. J. 2008; 416: 153–159.)

[0011] ROS1 is a proto-oncogene receptor tyrosine kinase belonging to the insulin receptor subfamily and is involved in cell proliferation and differentiation (Nagarajan et al., Proc Natl Acad Sci 1986; 83: 6568-6572). In humans, ROS1 is expressed in epithelial cells of various tissues. Defects in ROS1 expression and / or activation have been found in glioblastoma and tumors of the central nervous system (Charest et al., Genes Chromos. Can. 2003; 37(1): 58-71). Genetic alterations involving ROS1 that lead to aberrant fusion proteins of ROS1 kinases have been described, including FIG-ROS1 deletion translocations in glioblastoma (Charest et al. (2003); Birchmeier et al. Proc Natl Acad Sci 1987; 84: 9270-9274; and FIG-ROS1 deletion translocations in NSCLC (Rimkunas et al., Analysis of Receptor Tyrosine Kinase ROS1-Positive Tumors in Non-Small Cell Lung Cancer: Identification of FIG-ROS1 Fusion, Clin Cancer Res 2012; 18: 4449-4457), SLC34A2-ROS1 translocations in NSCLC (Rikova et al. Cell 2007; 131: 1190-1203), NSCLC (Rikova et al. (2007)), and cholangiocarcinoma (Gu et al. PLoS) CD74-ROS1 translocation in ONE 2011; 6(1): e15640, and a truncated active form of ROS1 known to induce tumor growth in mice (Birchmeier et al. Mol. Cell. Bio. 1986; 6(9): 3109-3115). Other fusions have been reported in tumor samples from lung cancer patients, including TPM3-ROS1, SDC4-ROS1, EZR-ROS1 and LRIG3-ROS1 (Takeuchi et al., RET, ROS1 and ALK fusions in lung cancer, Nature Medicine 2012; 18(3): 378-381).

[0012] In 2011, the ALK / ROS1 / c-MET inhibitor crizotinib was approved for the treatment of patients with locally advanced or metastatic NSCLC who were ALK-positive as detected by an FDA-approved test. Crizotinib has also shown efficacy in treating NSCLC with ROS1 translocation (Shaw et al., Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement, presented at the American Society of Clinical Oncology Annual Meeting (Chicago, June 1-5, 2012)). As observed clinically with other tyrosine kinase inhibitors, mutations in ALK and ROS1 that confer resistance to ALK inhibitors have been described (Choi et al., EML4-ALK Mutations in Lung Cancer than Confer Resistance to ALK Inhibitors, N Engl J Med 2010; 363: 1734-1739; Awad et al., Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1, N Engl J Med 2013; 368: 2395-2401).

[0013] Therefore, ALK and ROS1 are attractive molecular targets for cancer therapeutic interventions. There remains a need to identify compounds with novel activity profiles targeting both wild-type and mutant forms of ALK and ROS1.

[0014] This invention provides a novel crystalline form (Form 7) of the free base of lorlatinib, possessing desired properties such as high crystallinity, high purity, low hygroscopicity, and favorable solubility and mechanical properties. In particular, Form 7 provides improved physical stability in pharmaceutical formulations relative to the acetic acid solvate disclosed in International Patent Publication No. WO 2014 / 207606. Such solvated forms can pose challenges for drug development, particularly regarding physical stability. Therefore, the identification of new forms with desired physicochemical properties remains necessary. Summary of the Invention

[0015] In one aspect, the present invention provides a novel crystalline form (form 7) of the lorlatinib free base. Form 7 of the lorlatinib free base is characterized by one or more of the following methods: (1) powder X-ray diffraction (PXRD) (2θ); (2) Raman spectroscopy (cm).-1 (3) 13 C solid-state NMR spectrum (ppm); or (4) 19 F solid-state NMR spectrum (ppm).

[0016] In a first aspect, the present invention provides a lorlatinib free base (form 7), characterized by having:

[0017] (1) Powder X-ray diffraction (PXRD) pattern (2θ) containing: (a) 1, 2, 3, 4, 5 or more peaks selected from Table 1, denoted as °2θ ± 0.2°2θ; (b) 1, 2, 3, 4, 5 or more peaks selected from Table 1, denoted as °2θ ± 0.2°2θ; or (c) peaks substantially similar to... Figure 1 The peak at the same 2θ value shown; or

[0018] (2) Raman spectra, which include: (a) 1, 2, 3, 4, 5 or more of the spectra selected from Table 2 in cm⁻¹ -1 ±2cm -1 The wave number (cm) represents the value. -1 (a) Values; (b) 1, 2, 3, 4, 5 or more selected from Table 2 in cm -1 ±2cm -1 Wavenumber (cm) of the eigenvalues -1 (c) value; or (c) essentially the same as Figure 2 The same wavenumber (cm) shown -1 ) value; or

[0019] (3) 13 C solid-state NMR spectrum (ppm), comprising: (a) 1, 2, 3, 4, 5 or more than 5 resonance (ppm) values ​​selected from Table 3, expressed in ppm ± 0.2 ppm; (b) 1, 2, 3, 4, 5 or more than 5 characteristic values ​​selected from Table 3, expressed in ppm ± 0.2 ppm; or (c) substantially the same as... Figure 3 The same resonance (ppm) value shown; or

[0020] (4) 19 F solid-state NMR spectrum (ppm), comprising: (a) one or two resonance (ppm) values ​​selected from Table 4, expressed in ppm ± 0.2 ppm; or (b) substantially the same as... Figure 4 The same resonance (ppm) value shown;

[0021] Or any combination of 2, 3 or 4 of the aforementioned implementation schemes (1)(a)-(c), (2)(a)-(c), (3)(a)-(c) or (4)(a)-(b), provided that they do not contradict each other.

[0022] In another aspect, the present invention also provides pharmaceutical compositions comprising a lorlatinib free base (form 7) according to any embodiment described herein and a pharmaceutically acceptable carrier or excipient.

[0023] In another aspect, the present invention provides a method for treating abnormal cell growth in mammals, including humans, the method comprising administering a therapeutically effective amount of lorlatinib free base (form 7) to the mammal.

[0024] In another aspect, the present invention provides a method for treating abnormal cell growth in mammals, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising lorlatinib free base (form 7) according to any aspect or embodiment described herein.

[0025] In another aspect, the present invention provides the use of lorlatinib free base (form 7) or a pharmaceutical composition comprising such form 7 according to any aspect or embodiment described herein in a method of treating abnormal cell growth in mammals.

[0026] In another aspect, the present invention provides the use of lorlatinib free base (form 7) according to any aspect or embodiment described herein in the preparation of a medicament for treating abnormal cell growth in mammals.

[0027] In common implementations, abnormal cell growth is cancer. In one implementation, abnormal cell growth is cancer mediated by ALK or ROS1. In some such implementations, abnormal cell growth is cancer mediated by ALK. In other such implementations, abnormal cell growth is cancer mediated by ROS1. In a further implementation, abnormal cell growth is cancer mediated by at least one genetically altered tyrosine kinase, such as genetically altered ALK or genetically altered ROS1 kinase.

[0028] In some such implementations, the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, chordoma, brainstem glioma, or pituitary adenoma, or combinations thereof.

[0029] In other such implementations, the cancer is selected from non-small cell lung cancer (NSCLC), squamous cell carcinoma, hormone-refractory prostate cancer, papillary renal cell carcinoma, colorectal adenocarcinoma, neuroblastoma, anaplastic large cell lymphoma (ALCL), and gastric cancer. In a specific implementation, the cancer is non-small cell lung cancer (NSCLC). In a specific implementation, the cancer is ALK- or ROS1-mediated NSCLC, more specifically, ALK- or ROS1-mediated NSCLC with genetic alterations. Attached Figure Description

[0030] Figure 1 PXRD pattern of lorlatinib free base (form 7).

[0031] Figure 2 FT-Raman spectrum of lorlatinib free base (form 7).

[0032] Figure 3 Carbon CPMAS spectrum of lorlatinib free base (form 7).

[0033] Figure 4 Fluorine MAS spectrum of lorlatinib free base (form 7).

[0034] Figure 5 PXRD pattern of lactose tablets containing lorlatinib free base (form 7).

[0035] Figure 6 PXRD pattern of lorlatinib free base (form 7) in calcium hydrogen phosphate (DCP) tablets.

[0036] Figure 7 FT-Raman spectrum of lactose tablets containing lorlatinib free base (form 7).

[0037] Figure 8 FT-Raman spectra of DCP tablets containing lorlatinib free base (form 7). Detailed Implementation

[0038] The invention can be more readily understood by referring to the following detailed description of embodiments of the invention and the examples included herein. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be further understood that, unless specifically defined herein, the terms used herein should be given their conventional meanings known in the relevant art.

[0039] As used herein, unless otherwise indicated, the singular forms “an,” “a,” and “the” include plural references. For example, “an” substituent includes one or more substituents.

[0040] The term “about” refers to a value that, when considered by a person skilled in the art, falls within the standard error of an accepted mean.

[0041] As used herein, the term "substantially identical" means taking into account the typical variability of a particular method. For example, regarding X-ray diffraction peak positions, the term "substantially identical" means taking into account the typical variability of peak position and intensity. Those skilled in the art will recognize that peak position (2θ) will exhibit some variability, typically up to ±0.2°. Furthermore, those skilled in the art will recognize that relative peak intensities will show variability between devices as well as variability due to crystallinity, preferred orientation, the prepared sample surface, and other factors known to those skilled in the art, and should be used only as a qualitative measure. Similarly, Raman spectral wavenumber (cm²) -1 The value indicates variability, typically up to ±2 cm. 1 ,at the same time 13 C and 19 Solid-state NMR spectra (ppm) show variability, typically up to ±0.2 ppm.

[0042] The term "crystallization" as used in this article refers to molecules or outer surface planes that have a regular repeating arrangement. Crystallization forms can vary in terms of thermodynamic stability, physical parameters, X-ray structure, and preparation process.

[0043] The term "amorphous" refers to a disordered solid state.

[0044] As used herein, the term "solvent" refers to a solvent, such as water, acetic acid, methanol, or mixtures thereof, that has stoichiometric or non-stoichiometric amounts of solvents, such as water, acetic acid, methanol, etc., bound together by non-covalent intermolecular forces on a surface, in a crystal lattice, or on a surface and in a crystal lattice. The term "hydrate" can be specifically used to describe solvates containing water.

[0045] The term "anhydrous" as used in this article refers to a crystalline form containing less than about 1% (w / w) of adsorbed water, as determined by standard methods such as Karl-Fisher analysis.

[0046] The invention described herein may be suitably practiced in the absence of any one or more elements not specifically disclosed herein. Thus, for example, in each case herein, any one of the terms “comprising,” “substantially consisting of,” and “consisting of” may be replaced by any of the other two terms.

[0047] In one aspect, the present invention provides a lorlatinib free base (form 7). As disclosed herein, form 7 is a crystalline form of anhydrous, non-solventized lorlatinib free base having physical stability, manufacturability, and mechanical properties favorable for use in pharmaceutical formulations. The methods described herein provide a lorlatinib free base (form 7) that is substantially pure and free of substitute forms, including the previously disclosed solvated forms.

[0048] As described in this article, Form 7 was obtained through PXRD, Raman spectroscopy, and... 13 C and 19 Solid-state NMR spectroscopy can be used to characterize this crystalline form. Further characterization can be achieved using other techniques such as Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or differential thermal analysis (DTA).

[0049] In some embodiments of each aspect of the invention, the lorlatinib free base (form 7) is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments of each aspect of the invention, the lorlatinib free base (form 7) is characterized by its Raman spectrum. In other embodiments of each aspect of the invention, the lorlatinib free base (form 7) is characterized by its... 13 Characterized by C20 solid-state NMR spectroscopy. In other embodiments of each aspect of the invention, the lorlatinib free base (form 7) is derived from its... 19 Solid-state NMR spectroscopy characterization.

[0050] In a further embodiment, the lorlatinib free base (form 7) is characterized by a combination of two, three, or four of these methods. Exemplary combinations comprising two or more of the following are provided herein: powder X-ray diffraction (PXRD) pattern (2θ); Raman spectral wave value (cm²). -1 ); 13 C solid-state NMR spectrum (ppm); or 19 F solid-state NMR spectrum (ppm). It should be understood that other combinations of two, three, or four techniques can be used to uniquely characterize the lorlatinib free base (form 7) disclosed herein.

[0051] In one embodiment, the lorlatinib free base (form 7) has a PXRD pattern containing one or more peaks selected from the following 2θ values: 9.6, 10.1, 14.3, 16.2, and 17.3°2θ ± 0.2°2θ. In another embodiment, the lorlatinib free base (form 7) has a PXRD pattern containing two or more peaks selected from the following 2θ values: 9.6, 10.1, 14.3, 16.2, and 17.3°2θ ± 0.2°2θ. In yet another embodiment, the lorlatinib free base (form 7) has a PXRD pattern containing three or more peaks selected from the following 2θ values: 9.6, 10.1, 14.3, 16.2, and 17.3°2θ ± 0.2°2θ.

[0052] In another embodiment, form 7 has a PXRD pattern containing peaks at the following 2θ values: 9.6, 10.1, and 16.2°2θ ± 0.2°2θ. In some such embodiments, form 7 further has a PXRD pattern containing peaks at the following 2θ value: 17.3°2θ ± 0.2°2θ. In other such embodiments, form 7 further has a PXRD pattern containing peaks at the following 2θ value: 14.3°2θ ± 0.2°2θ.

[0053] In another embodiment, the free base of lorlatinib (form 7) has a PXRD pattern containing a peak at the following 2θ value: 9.6°2θ ± 0.2°2θ. In another embodiment, form 7 has a PXRD pattern containing a peak at the following 2θ value: 10.1°2θ ± 0.2°2θ. In another embodiment, form 7 has a PXRD pattern containing a peak at the following 2θ value: 16.2°2θ ± 0.2°2θ. In another embodiment, form 7 has a PXRD pattern containing a peak at the following 2θ value: 17.3°2θ ± 0.2°2θ. In another embodiment, form 7 has a PXRD pattern containing peaks at the following 2θ values: 9.6 and 10.1°2θ ± 0.2°2θ.

[0054] In another embodiment, the free lorlatinib base (form 7) has a PXRD pattern containing peaks at the following 2θ values: 9.6, 10.1, 16.2, and 17.3°2θ ± 0.2°2θ. In yet another embodiment, the free lorlatinib base (form 7) has a PXRD pattern containing peaks at the following 2θ values: 9.6, 10.1, 14.3, and 16.2°2θ ± 0.2°2θ. In still another embodiment, the free lorlatinib base (form 7) has a PXRD pattern containing peaks at the following 2θ values: 9.6, 10.1, 14.3, 16.2, and 17.3°2θ ± 0.2°2θ. In some such embodiments, the PXRD pattern further includes one or more additional peaks selected from the peaks in Table 1 at the 2θ values.

[0055] In a specific implementation, the free base of lorlatinib (form 7) has a PXRD pattern comprising: (a) 1, 2, 3, 4, 5, or more than 5 peaks selected from those in Table 1, expressed as °2θ ± 0.2°2θ; (b) 1, 2, 3, 4, 5, or more than 5 peaks selected from those in Table 1, expressed as °2θ ± 0.2°2θ; or (c) peaks substantially similar to those in Table 1. Figure 1 The peak at the same 2θ value shown.

[0056] In one embodiment, the lorlatinib free base (form 7) has a Raman spectrum containing one or more wavenumbers (cm²) selected from the following -1 Values: 774, 1553, 1619, 2229, and 2240 cm -1 ±2cm -1 In another embodiment, the lorlatinib free base (form 7) has a Raman spectrum containing two or more wavenumbers (cm²) selected from the following -1 Values: 774, 1553, 1619, 2229, and 2240 cm -1 ±2cm -1 In another embodiment, the lorlatinib free base (form 7) has a Raman spectrum containing three or more wavenumbers (cm²) selected from the following: -1 Values: 774, 1553, 1619, 2229, and 2240 cm -1 ±2cm -1 .

[0057] In another embodiment, the lorlatinib free base (form 7) has a Raman spectrum, said Raman spectrum comprising wavenumbers (cm²). -1 Values: 2229 and 2240 cm -1 ±2cm -1 In another embodiment, the lorlatinib free base (form 7) has a Raman spectrum, said Raman spectrum comprising wavenumbers (cm²).-1 Value: 2229cm -1 ±2cm -1 In another embodiment, form 7 has a Raman spectrum, which includes wavenumbers (cm²). -1 Value: 2240cm -1 ±2cm -1 In some such embodiments, form 7 has a Raman spectrum, which further includes a wavenumber (cm²). -1 Value: 1619cm -1 ±2cm -1 In other such embodiments, form 7 has a Raman spectrum, which further includes a wavenumber (cm²). -1 Value: 1553cm -1 ±2cm -1 In other such embodiments, form 7 has a Raman spectrum, which further includes a wavenumber (cm²). -1 Value: 774cm -1 ±2cm -1 .

[0058] In another embodiment, form 7 has a Raman spectrum, the Raman spectrum comprising wavenumbers (cm²). -1 Values ​​1619, 2229, and 2240 cm -1 ±2cm -1 In another embodiment, form 7 has a Raman spectrum, which includes wavenumbers (cm²). -1 Values: 1553, 2229, and 2240 cm -1 ±2cm -1 In yet another embodiment, form 7 has a Raman spectrum, the Raman spectrum comprising wavenumbers (cm²). -1 Values: 774, 2229, and 2240 cm -1 ±2em -1 In other embodiments, form 7 has a Raman spectrum, the Raman spectrum comprising wavenumbers (cm²). -1 Values: 774, 1619, 2229, and 2240 cm -1 ±2cm -1 In another embodiment, form 7 has a Raman spectrum, which includes wavenumbers (cm²). -1 Values: 774, 1553, 2229, and 2240 cm -1 ±2cm -1 In yet another embodiment, form 7 has a Raman spectrum, the Raman spectrum comprising wavenumbers (cm²). -1 Values: 774, 1553, 1619, 2229, and 2240 cm-1 ±2cm -1 .

[0059] In the specific implementation scheme, the lorlatinib free base (form 7) has a Raman spectrum comprising: (a) 1, 2, 3, 4, 5 or more of 5 selected from Table 2 in cm⁻¹ -1 ±2cm -1 The wave number (cm) represents the value. -1 (a) Values; (b) 1, 2, 3, 4, 5 or more selected from Table 2 in cm -1 ±2cm -1 Wavenumber (cm) of the eigenvalues -1 (c) value; or (c) essentially the same as Figure 2 The same wavenumber (cm) shown -1 )value.

[0060] In one implementation, the lorlatinib free base (form 7) has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains one or more resonance (ppm) values ​​selected from the following: 25.8, 39.1, 112.3, 117.7, and 142.1 ppm ± 0.2 ppm. In another embodiment, the lorlatinib free base (form 7) has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains two or more resonance (ppm) values ​​selected from the following: 25.8, 39.1, 112.3, 117.7, and 142.1 ppm ± 0.2 ppm. In another embodiment, the lorlatinib free base (form 7) has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains three or more resonance (ppm) values ​​selected from the following: 25.8, 39.1, 112.3, 117.7 and 142.1 ppm ± 0.2 ppm.

[0061] In some implementations, the free base of lorlatinib (form 7) has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains a resonance (ppm) value of 142.1 ppm ± 0.2 ppm. In another embodiment, form 7 has... 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains a resonance (ppm) value of 39.1 ppm ± 0.2 ppm. In another embodiment, form 7 has... 13 C solid-state NMR spectrum, the 13The solid-state NMR spectrum contains resonance (ppm) values ​​of 39.1 and 142.1 ppm ± 0.2 ppm. In some such embodiments, form 7 has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum further includes a resonance (ppm) value of 112.3 ppm ± 0.2 ppm. In other such embodiments, form 7 has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum further includes a resonance (ppm) value of 25.8 ppm ± 0.2 ppm. In other such embodiments, form 7 has 13 C solid-state NMR spectrum, the 13 The C solid-state NMR spectrum further includes a resonance (ppm) value: 117.7ppm ± 0.2ppm.

[0062] In another implementation, form 7 has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains resonance (ppm) values ​​of 39.1, 112.3, and 142.1 ppm ± 0.2 ppm. In another embodiment, form 7 has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains resonance (ppm) values ​​of 25.8, 39.1, and 142.1 ppm ± 0.2 ppm. In another embodiment, form 7 has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains resonance (ppm) values ​​of 39.1, 117.7, and 142.1 ppm ± 0.2 ppm. In another embodiment, form 7 has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains resonance (ppm) values ​​of 25.8, 39.1, 112.3, 117.7 and 142.1 ppm ± 0.2 ppm.

[0063] In the specific implementation plan, the free base of lorlatinib (form 7) has... 13 C solid-state NMR spectrum (ppm), comprising: (a) 1, 2, 3, 4, 5 or more than 5 resonance (ppm) values ​​selected from Table 3, expressed in ppm ± 0.2 ppm; (b) 1, 2, 3, 4, 5 or more than 5 characteristic values ​​selected from Table 3, expressed in ppm ± 0.2 ppm; or (c) substantially the same as... Figure 3 The same resonance (ppm) value is shown.

[0064] In one implementation, the lorlatinib free base (form 7) has19 F solid-state NMR spectrum, the 19 The F solid-state NMR spectrum contains one or more resonance (ppm) values ​​selected from the following: -108.2 and -115.2 ppm ± 0.2 ppm.

[0065] In another embodiment, the free base of lorlatinib (form 7) has 19 F solid-state NMR spectrum, the 19 The F solid-state NMR spectrum contains resonance (ppm) values ​​of -115.2 ppm ± 0.2 ppm. In another embodiment, form 7 has 19 F solid-state NMR spectrum (ppm), including resonance (ppm) values: -108.2ppm ± 0.2ppm. In another embodiment, the lorlatinib free base (form 7) has 19 F solid-state NMR spectrum, the 19 The solid-state NMR spectrum contains resonance (ppm) values ​​of -108.2 and -115.2 ppm ± 0.2 ppm.

[0066] In another implementation, form 7 has 19 F solid-state NMR spectrum (ppm), which includes: (4) 19 F solid-state NMR spectrum (ppm), comprising: (a) one or two resonance (ppm) values ​​selected from Table 4, expressed in ppm ± 0.2 ppm; or (b) substantially the same as... Figure 4 The same resonance (ppm) value is shown.

[0067] In other embodiments, the free base of lorlatinib (form 7) is characterized by a combination of two, three, or four of the above embodiments that do not contradict each other. Exemplary embodiments of form 7 that can be used to uniquely characterize the free base of lorlatinib are provided below.

[0068] In one embodiment, the lorlatinib free base (form 7) has a powder X-ray diffraction pattern containing peaks at the following 2θ values: 9.6, 10.1, and 16.2°2θ ± 0.2°2θ.

[0069] In another embodiment, the lorlatinib free base (form 7) has a powder X-ray diffraction pattern containing peaks at the following 2θ values: 9.6, 10.1, 16.2 and 17.3°2θ ± 0.2°2θ.

[0070] In another embodiment, the lorlatinib free base (form 7) has a powder X-ray diffraction pattern containing peaks at the following 2θ values: 9.6, 10.1, 16.2, 14.3, and 17.3°2θ ± 0.2°2θ.

[0071] In another embodiment, the lorlatinib free base (form 7) has: (a) a powder X-ray diffraction pattern containing peaks at the following 2θ values: 9.6, 10.1, 16.2°2θ ± 0.2°2θ; and (b) a Raman spectrum containing wavenumbers (cm⁻¹). 1 Values: 2229 and 2240 cm -1 ±2cm -1 .

[0072] In yet another embodiment, the lorlatinib free base (form 7) has: (a) a powder X-ray diffraction pattern containing peaks at the following 2θ values: 9.6, 10.1, and 16.2°2θ ± 0.2°2θ; and (b) 13 The solid-state NMR spectrum of 1200 ppm contains resonance (ppm) values ​​of 39.1 and 142.1 ppm ± 0.2 ppm.

[0073] In another embodiment, the lorlatinib free base (form 7) has a Raman spectrum, said Raman spectrum comprising wavenumbers (cm²). -1 Values: 2229 and 2240 cm -1 ±2cm -1 .

[0074] In another embodiment, the lorlatinib free base (form 7) has a Raman spectrum, said Raman spectrum comprising wavenumbers (cm²). -1 Values: 1619, 2229, and 2240 cm -1 ±2cm -1 .

[0075] In yet another embodiment, the lorlatinib free base (form 7) has a Raman spectrum, said Raman spectrum comprising wavenumbers (cm²). -1 Values: 1553, 1619, 2229, and 2240 cm -1 ±2cm -1 .

[0076] In yet another embodiment, the lorlatinib free base (form 7) has a Raman spectrum, said Raman spectrum comprising wavenumbers (cm²). -1 Values: 774, 1553, 1619, 2229, and 2240 cm -1 ±2cm -1 .

[0077] In another embodiment, the lorlatinib free base (form 7) has: (a) a Raman spectrum containing wavenumbers (cm²) -1 Values: 2229 and 2240 cm -1 ±2cm -1 ; and (b) 13The solid-state NMR spectrum of 1200 ppm contains resonance (ppm) values ​​of 39.1 and 142.1 ppm ± 0.2 ppm.

[0078] In another embodiment, the lorlatinib free base (form 7) has: (a) a Raman spectrum containing wavenumbers (cm²) -1 Values: 2240 and 2229 cm -1 ±2cm -1 ; and (b) 19 F solid-state NMR spectrum, including resonance (ppm) values: -115.2 and -108.2ppm ± 0.2ppm.

[0079] In another embodiment, the free base of lorlatinib (form 7) has 19 F solid-state NMR spectrum, the 19 The solid-state NMR spectrum contains resonance (ppm) values ​​of -115.2ppm ± 0.2ppm.

[0080] In other embodiments, the free base of lorlatinib (form 7) has 19 F solid-state NMR spectrum, the 19 The solid-state NMR spectrum includes resonance (ppm) values ​​of -115.2 and -108.2 ppm ± 0.2 ppm.

[0081] In another embodiment, the free base of lorlatinib (form 7) has 13 C solid-state NMR spectrum, the 13 The C solid-state NMR spectrum includes resonance (ppm) values ​​of 39.1 and 142.1 ppm ± 0.2 ppm.

[0082] In another embodiment, the free base of lorlatinib (form 7) has 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectrum contains resonance (ppm) values ​​of 39.1, 112.3, and 142.1 ppm ± 0.2 ppm.

[0083] In yet another implementation, the free base of lorlatinib (form 7) has... 13 C solid-state NMR spectrum, the 13 The solid-state NMR spectra of 1000 ppm include resonance (ppm) values ​​of 25.8, 39.1, 112.3 and 142.1 ppm ± 0.2 ppm.

[0084] In another embodiment, the free base of lorlatinib (form 7) has 13 C solid-state NMR spectrum, the 13The solid-state NMR spectrum contains resonance (ppm) values ​​of 25.8, 39.1, 112.3, 117.7 and 142.1 ppm ± 0.2 ppm.

[0085] In another aspect, the present invention provides a pharmaceutical composition comprising a lorlatinib free base (form 7) characterized according to any embodiment described herein and a pharmaceutically acceptable carrier or excipient.

[0086] In another aspect, the present invention provides a method for treating abnormal cell growth in mammals, preferably humans, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of the present invention to the mammal.

[0087] As used herein, the term "therapeutic effective amount" refers to the amount of a compound applied that will alleviate, to some extent, one or more symptoms of the treated condition. In the treatment of cancer, a therapeutic effective amount refers to an amount that has the following effects: (1) reducing tumor size, (2) inhibiting (i.e., slowing, preferably stopping) tumor metastasis, (3) inhibiting (i.e., slowing, preferably stopping) tumor growth or tumor invasiveness to some extent, and / or (4) alleviating (or preferably eliminating) one or more cancer-related signs or symptoms to some extent.

[0088] As used herein, “mammal” refers to a human or animal object. In some preferred embodiments, the mammal is a human.

[0089] Unless otherwise specified, the term "treating" as used herein means reversing, alleviating, inhibiting progression, or preventing a condition or condition to which such terms apply, or one or more symptoms of such a condition or condition. Unless otherwise specified, the term "treatment" as used herein refers to the therapeutic act that is defined as "treating" immediately preceding it. The term "treating" also includes adjunctive and neoadjunctive therapies for the subject.

[0090] Unless otherwise stated, "abnormal cell growth" as used herein refers to cell growth that does not depend on normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous). In a common implementation of the methods provided herein, abnormal cell growth is cancer.

[0091] As used herein, “cancer” means any malignant and / or invasive growth or tumor caused by abnormal cell growth. The term “cancer” includes, but is not limited to, primary cancer originating in a specific part of the body, metastatic cancer that has spread from its site of origin to other parts of the body, recurrence from the original primary cancer after remission, and a second primary cancer (a new primary cancer in a person with a history of a previous cancer of a different type than the latter).

[0092] In some embodiments, abnormal cell growth is cancer mediated by anaplastic lymphoma kinase (ALK). In some such embodiments, the ALK is genetically altered. In other embodiments, abnormal cell growth is cancer mediated by ROS1 kinase. In some such embodiments, the ROS1 kinase is genetically altered. In common embodiments, abnormal cell growth is cancer, particularly NSCLC. In some such embodiments, NSCLC is mediated by either ALK or ROS1. In specific embodiments, the cancer is NSCLC mediated by either genetically altered ALK or genetically altered ROS1.

[0093] The pharmaceutical compositions of the present invention may be, for example, in forms suitable for oral administration (as tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions), parenteral injection (as sterile solutions, suspensions, or emulsions), topical application (as ointments or creams), or rectal administration (as suppositories). The pharmaceutical compositions may be in unit-dose form suitable for precise single-dose administration. The pharmaceutical compositions will comprise conventional pharmaceutical carriers or excipients and the compound according to the present invention as the active ingredient. Furthermore, they may include other medical or pharmaceutical reagents, carriers, adjuvants, etc.

[0094] Exemplary parenteral formulations include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solution. Such formulations may be appropriately buffered if desired.

[0095] Suitable drug carriers include inert diluents or fillers, water, and various organic solvents. If desired, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, etc. Thus, for oral administration, tablets containing various excipients (such as citric acid) can be used with various disintegrants (such as starch, alginate, and certain complex silicates) and binders (such as sucrose, gelatin, and gum arabic). Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are frequently used for tableting purposes. Similar types of solid compositions can also be used in soft and hard-filled gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycol. When an aqueous suspension or elixir is required for oral administration, the active compound therein can be combined with various sweeteners or flavoring agents, coloring agents or dyes, and, if desired, emulsifiers or suspending agents and diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0096] Methods for preparing various pharmaceutical compositions containing specific amounts of the active compound are known or obvious to those skilled in the art. For example, see... Remington's Pharmaceutical Sciences , Mack Publishing Company, Easter, Pa., 15th ed. (1975).

[0097] Example

[0098] The examples and formulations provided below further illustrate and demonstrate specific aspects and embodiments of the invention. It should be understood that the scope of the invention is not limited to the scope of the following examples.

[0099] General Method 1. Powder X-ray Diffraction (PXRD)

[0100] Figure 1 The PXRD data in this document is collected according to the following general scheme.

[0101] Instrumentation and Methods: PXRD patterns were acquired on a Bruker-AXS Ltd. A D4 powder X-ray diffractometer equipped with an automatic sample changer, θ-θ goniometer, automatic beam divergence slit, and PSD Vantec-1 detector was used. The X-ray tube voltage and ampere were set to 40 kV and 40 mA, respectively. The diffractometer was calibrated and checked using corundum reference material on the day of data acquisition. Data were acquired at Cu wavelengths using 0.018-degree steps and 11.3-hour scan times from 2.0 to 65.0 degrees 2θ. Sample powder was prepared by placing the powder in a slightly greased, low-background support. The sample powder was pressed onto a glass slide to ensure adequate sample height and rotated during acquisition. Data were acquired using Bruker DIFFRAC software and analyzed using DIFFRAC EVA software (version 3.1).

[0102] Import the acquired PXRD patterns into Bruker DIFFRAC EVA software. Before selecting peak positions, verify that the measured PXRD pattern of the active pharmaceutical ingredient (API) form 7 matches the simulation from single-crystal data. Figure 1 To. Use Bruker software for peak search. Carefully check the peak selection to ensure all peaks are captured and all peak positions are accurately assigned.

[0103] Peak selection method:

[0104] Peak selection was performed using the peak search algorithm in EVA software (version 3.1). Initial peak assignment was performed using a threshold of 1 and a width value of 0.27 (maximum 0.55, minimum 0.02). The automatically assigned output was visually inspected to ensure validity, and manual adjustments were made as necessary. Peak intensity was normalized relative to the highest intensity peak equal to 100%. Peaks with a relative intensity ≥2% were typically selected. A typical error of ±0.2°²-θ in the peak location was applied to the data. Small errors associated with this measurement can occur as a result of various factors including: (a) sample preparation (e.g., sample height), (b) instrumentation, (c) calibration, (d) operator error (including those errors present when determining peak locations), and (e) material properties (e.g., preferred orientation and transparency errors). Therefore, peaks were considered to have a typical associated error of ±0.2°²-θ. When two peaks in the list were considered to overlap (±0.2°²-θ), the lower-intensity peak was removed from the list. Peaks existing as shoulders adjacent to higher-intensity peaks were also removed from the peak list.

[0105] Ideally, the powder pattern should be consistent with a reference. This can be a simulated powder pattern from a crystal structure of the same form or an internal standard such as silica. The PXRD pattern of the API of form 7 used to generate the peaks listed in Table 1 is consistent with the simulated pattern from a single crystal structure.

[0106] General Method 2. Raman Spectroscopy

[0107] Figure 2 The Raman spectral data in the sample were acquired according to the following general scheme.

[0108] Instrumentation and Methods:

[0109] Raman spectra were acquired using the RAM II FT Raman module connected to a Vertex 70 FTIR spectrometer (Bruker, UK). This instrument is equipped with a 1064 nm Nd:YAG laser and a liquid nitrogen-cooled germanium detector. Instrument performance and calibration were performed using a white light source and polystyrene and naphthalene references prior to data acquisition.

[0110] Samples were analyzed in a truncated NMR tube (5 mm diameter) that was rotated during spectral acquisition. The Raman signal from the backscattered image of the sample in the rotator was optimized, and the following parameters were used to acquire the spectrum from each sample:

[0111]

[0112] In this experimental setup, the peak position variability was ±2 cm. -1 Within.

[0113] Peak selection method

[0114] Before peak selection, the intensity scale of the Stokes scattered Raman signal was normalized to 1.00. Then, the peak positions were identified using the peak selection function in GRAMS / AIv.9.1 software (Thermo Fisher Scientific), with a threshold set to 0.007.

[0115] Peaks with relative intensities of 1.00–0.75, 0.74–0.30, and below 0.29 were labeled as strong, medium, and weak, respectively.

[0116] Since FT-Raman and dispersive Raman are similar techniques, the peak positions of the FT-Raman spectra reported in this paper are expected to be consistent with those observed using dispersive Raman measurements (assuming proper instrument calibration).

[0117] General Method 3. Solid-State NMR (ssNR) Spectroscopy:

[0118] Figure 3 and 4 The carbon CPMAS and fluorine MAS ssNMR data were acquired according to the following general scheme.

[0119] Instrumentation and Method: Solid-state NMR (ssNMR) analysis was performed at ambient temperature and pressure using a Bruker-BioSpinAvance III 500 MHz instrument. 1The ss NMR spectra were acquired using a Bruker-BioSpin CPMAS probe in a H-frequency NMR spectrometer. The filled rotor was magic-angle oriented and rotated at 14.5 kHz. Carbon ss NMR spectra were acquired using a proton-decoupled cross-polarized magic-angle rotation experiment. A phase-modulated proton decoupling field of 80–90 kHz was applied during acquisition. The cross-polarized contact time was set to 2 ms, and the recirculation delay was set to 5 seconds. The number of scans was adjusted to obtain a sufficient signal-to-noise ratio. Crystalline adamantane was used as an external standard (with its high magnetic field resonance set to 29.5 ppm (determined by pure TMS)) as a reference carbon spectrum. Fluorine ss NMR spectra were acquired using a proton-decoupled direct-polarized magic-angle rotation experiment. A phase-modulated proton decoupling field of 80–90 kHz was applied during acquisition. The recirculation delay was set to 60 seconds. The number of scans was adjusted to obtain a sufficient signal-to-noise ratio. The reference fluorine chemical shift scale was used in direct polarization experiments conducted on an external standard of 50 / 50 volume / volume trifluoroacetic acid and water (with its resonance set to -76.54 ppm).

[0120] Peak selection method:

[0121] Automatic peak selection was performed using Bruker-BioSpin TopSpin version 3.2 software. Typically, a 5% relative intensity threshold was used for initial peak selection. The output of the automatic peak selection was visually inspected to ensure effectiveness, and manual adjustments were made as necessary.

[0122] Although specific details are reported in this article 13 C and 19 F solid-state NMR peaks, but due to differences in instrumentation, sample, and sample preparation, there is indeed a range of these peaks. This inherent variation in peak values ​​is standard practice in the field of solid-state NMR. 13 C and 19 The typical variability of the F chemical shift x-axis value for crystalline solids is on the order of addition or subtraction of 0.2 ppm. The solid-state NMR peak heights reported in this paper are relative intensities. Solid-state NMR intensities can vary depending on the actual experimental parameter settings and the thermal history of the sample.

[0123] Example 1

[0124] (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(trimethylamino-1,2-di ... The free base of methylbridged pyrazolo[4,3-h][2,5,11]benzoxazodiazetatetradecanoic-3-carboxynitrile (lorlatinib) Laboratory-scale preparation of Formula 7

[0125] Lorlatinib free base form 7 was prepared by using the acetic acid solvate (form 3) of lorlatinib as described in International Patent Publication No. WO 2014 / 207606 via the methanol solvate hydrate form (form 2) of lorlatinib intermediate.

[0126] Lorlatinib acetate solvate (form 3) (5 g, 10.72 mmol) was slurried in methanol (10 mL / g, 1235.9 mmol) at room temperature in an Easymax flask with magnetic stirring, followed by the addition of triethylamine (1.2 equivalents, 12.86 mmol) over 10 minutes. The resulting solution was heated to 60 °C, and water (12.5 mL / g, 3469.3 mmol) was added over 10 minutes while maintaining the temperature at 60 °C. Crystallization was initiated by scraping the inside of the glass container to form a rapidly precipitated suspension, which was then ground to keep the system fluid. The suspension was then cooled to 25 °C for 1 hour, followed by cooling to 5 °C and granulation for 4 hours. The white slurry was filtered and washed with 1 mL / g chilled water / methanol (1:1), and then vacuum dried overnight at 50 °C to provide lorlatinib methanol solvate hydrate form 2.

[0127] Form 7 was then prepared by re-slurrying of lorlatinib in methanol solvate hydrate form 2 in heptane. 100 mg of lorlatinib form 2 was weighed into a 4-dextrose vial, and 3 mL of heptane was added. The mixture was slurryed on a drum mixer at room temperature for 2 hours. The form conversion was confirmed by PXRD, showing a complete change in form 7 to the free base of lorlatinib.

[0128] Example 2

[0129] (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(trimethylamino-1,2-di ... The free base of methylbridged pyrazolo[4,3-h][2,5,11]benzoxazodiazetatetradecanoic-3-carboxynitrile (lorlatinib) Alternative preparation of Formula 7

[0130]

[0131] To a 100 mL Easymax reactor equipped with a top-mounted stirrer, add 7 g (10 mmol) of bis-Boc protected macrocyclic 1 (prepared as described in Example 4 of International Patent Publication No. WO 2014 / 207606) and methanol (28 mL; 4 mL / g PF-06668559). Heat the slurry to 60 °C and treat with 6 N hydrochloric acid (9 mL, 54 mmol) for 3 hours. Once the reaction is complete, cool the mixture to 40 °C and treat with 1 N sodium hydroxide (39 mL, 39 mmol) to partially neutralize the mixture. Treat the mixture with 2-methyltetrahydrofuran (53 mL) and then neutralize to pH 7 with 1 N sodium hydroxide (13.5 mL, 13.5 mmol). Treat the mixture with sodium chloride (10.1 g, 173 mmol) and heat to 60 °C. Remove the aqueous layer at the bottom using a separatory funnel. Wash the organic phase with water (50 mL) at 60 °C. Remove the washings using a separatory funnel. The organic layer was filtered cleanly into a 125 mL reactor equipped with a top stirrer and distillation head. An additional 70 mL of 2-methyltetrahydrofuran was added to the organic mixture, and the mixture was concentrated to approximately 30 mL by atmospheric distillation. The solution was then treated with 12 mL of 2-methyltetrahydrofuran and adjusted to 60 °C.

[0132] The solution was treated with n-heptane (10.5 mL), followed by the addition of seed crystals of form 7 of lorlatinib free base (45 mg, 0.11 mmol). After aging the slurry for 1 hour, n-heptane (73.5 mL) was added over 2 hours at 60 °C. The resulting slurry was maintained at 60 °C for 1 hour, then cooled to 20 °C for 1 hour and granulated for 16 hours. The slurry was filtered, and the product filter cake was washed with n-heptane (12 mL). The solid was dried in an oven at 60 °C for 12 hours to give form 7 of PF-0463922 free base (8.24 mmol, 3.36 g) as a white solid, with a yield of 82% and a purity >98%.

[0133] Characterization of lorlatinib free base (form 7)

[0134] PXRD data

[0135] Figure 1 This table displays the PXRD data for the free base of lorlatinib (Form 7) acquired according to General Method 1. Table 1 provides a list of PXRD peaks at diffraction angles of 2-θ° (°2θ) ± 0.2°2θ and their relative intensities. Characteristic PXRD peaks distinguishing Form 7 are indicated by asterisks (*).

[0136] Table 1: List of PXRD peaks for Form 7 (2-θ°)

[0137]

[0138] FT-Raman Data

[0139] Figure 2 The FT-Raman spectra of the free base of lorlatinib (form 7), acquired according to General Method 2, are shown in Table 2. The spectra are expressed in cm⁻¹. -1 ±2cm -1 Provides FT-Raman Peak (cm) -1 List and qualitative intensity of ) Distinguishing characteristic FT-Raman peaks (cm) of form 7. -1 Use an asterisk (*) to indicate the peak intensity. The normalized peak intensities are as follows: W = weak; M = moderate; S = strong.

[0140] Table 2: List of FT Raman peaks of Form 7 (cm) -1 )

[0141]

[0142]

[0143] ssNMR data

[0144] Figure 3 The carbon CPMAS spectra of the free base of lorlatinib (form 7) acquired according to General Method 3 are shown. Chemical shifts are expressed in parts per million (ppm) with reference to an external sample of solid-phase adamantane at 29.5 ppm. SSNMR spectra of form 7 are provided in ppm ± 0.2 ppm in Table 3. 13 List of C chemical shifts (ppm). Characteristic ssNMR for distinguishing form 7. 13 C chemical shift (ppm) is indicated by an asterisk (*).

[0145] Table 3: ssNMR of Form 7 13 C chemical shift (ppm)

[0146]

[0147]

[0148] Figure 4 The fluorine MAS (ss NMR) spectrum of the free base of lorlatinib (form 7) acquired according to General Method 3 is shown. Chemical shifts are expressed in parts per million (ppm) with reference to an external sample of trifluoroacetic acid (50% V / V (in H2O)) at -76.54 ppm.

[0149] Table 4 provides the ssNMR of Form 7 in ppm ± 0.2 ppm. 19 F chemical shift (ppm). Characteristic ssNMR distinguishing form 719 Chemical shift (ppm) is indicated by an asterisk (*).

[0150] Table 4: ssNMR of Form 7 19 F chemical shift (ppm)

[0151]

[0152] Example 3

[0153] Representative drug formulations of lorlatinib free base (form 7)

[0154] Immediate-release (IR) tablets containing lorlatinib free base (form 7) can be prepared using conventional excipients commonly used in tablet formulations.

[0155] Tablets typically contain 1%–30% lorlatinib (w / w). Microcrystalline cellulose, anhydrous calcium hydrogen phosphate (DCP), and lactose monohydrate can be used as tablet fillers, and sodium starch glycolate can be used as a disintegrant. Magnesium stearate can be used as a lubricant.

[0156] Table 5 provides typical IR tablet formulations (DCP tablets) containing anhydrous dicalcium phosphate (DCP) as a tablet filler.

[0157] Table 5. Typical composition of IR tablets using anhydrous calcium dicalcium phosphate (DCP) as a tablet filler

[0158] composition%

[0159]

[0160] Table 6 provides typical IR tablet formulations (lactose tablets) containing lactose as a tablet filler in form 7.

[0161] Table 6. Typical composition of IR tablets using lactose as a tablet filler

[0162] composition%

[0163]

[0164] Lorlatinib free base (form 7) IR tablets can be manufactured using a dry granulation process prior to compression. In this process, the crystalline material is mixed with excipients falling within the aforementioned range in a specific proportion, and the mixture is dried and granulated using a roller press. As part of this process, the granules are crushed. The granules are then mixed with any remaining excipients (e.g., magnesium stearate) prior to compression.

[0165] Figure 5 and 6PXRD patterns of the prototype lactose tablets and DCP tablets containing 10% w / w lorlatinib free base (form 7) are shown, respectively. Figure 7 and 8 The FT-Raman spectra of the prototype lactose tablets and DCP tablets containing 10% w / w lorlatinib free base (form 7) are shown, respectively.

[0166] Example 4

[0167] Thermodynamic stability of lorlatinib free base (form 7)

[0168] The thermodynamic stability of anhydrous lorlatinib free base (form 7) was evaluated using a slurry experiment under specific water activity and temperature conditions. The suspension of form 7 was equilibrated for two weeks in different solvent systems at three different temperatures (5°C, room temperature, and 40°C) and water activities ranging from 0.25 to 1.00. After two weeks, the equilibrated solids were separated, and the solid form was evaluated by PXRD.

[0169] The results summarized in Table 7 show that the anhydrous form of 7API can form a solvated form in several solvent systems and a hydrate in pure water, but does not transform into different anhydrous solid states under the explored conditions.

[0170] Table 7. Slurry output information for anhydrous lorlatinib form 7. Forms 5, 13, 16, and 20 are solvated forms of the free base of lorlatinib, and form 18 is a hydrate.

[0171] solvent Water activity 5℃ RT 40℃ nBuOH 0 Form 7 Form 20 Form 7 iProAc 0 Form 7 Form 7 Form 7 MiBK 0 Form 7 Form 7 Form 7 TBME 0 Form 7 Form 7 Form 7 Toluene 0 Form 7 Form 7 Form 7 IPA 0.25 Form 16 Form 7 Form 7 IPA 0.50 Form 13 Form 13 Form 5 IPA 0.70 Form 13 Form 13 Form 5 IPA 0.90 Form 13 Form 13 Form 13 water 1.00 Form 7 + Form 18 Form 18 Form 7

[0172] Example 5

[0173] Anhydrous lorlatinib free base (form 7) and solid-state physical stability of the pharmaceutical product

[0174] The physical stability of the anhydrous lorlatinib free base (form 7) API was investigated over extended periods at elevated relative humidity (%RH) and over shorter periods under accelerated stability conditions. Form 7 did not undergo any physical changes after 12 months of storage at ambient temperature and humidity levels of 75%RH and 90%RH, and after 1 week of storage at 70°C / 75%RH and 80°C / 75%RH. The results are shown in Table 8.

[0175] Table 8. Long-term stability of Form 7 API

[0176] condition time solid form 75% RH, ambient temperature 12 months Form 7 90% RH, ambient temperature 12 months Form 7 70℃ / 75%RH 1 week Form 7 80℃ / 40%RH 1 week Form 7 .

[0177] The representative pharmaceutical formulation of Form 7 exhibits superior physical stability relative to the acetic acid solvate of the free base of lorlatinib disclosed in WO 2014 / 207606.

[0178] The physical stability of lorlatinib form 7 and the acetate solvate in the pharmaceutical product was investigated under various conditions using FT-Raman and solid-state NMR spectroscopy. The results are summarized in Table 9.

[0179] Table 9. Physical stability of Form 7 pharmaceutical products compared to acetic acid solvates (comparing the amount of physical impurities)

[0180] condition time Lorlatinib Acetic Acid Solvate Lorlatinib free base form 7 70℃ / 75%RH l week Impurities > 50% No changes were detected. 50℃ / 75%RH 2 weeks >10% impurities <50% No changes were detected. 70℃ / 40%RH 2 weeks Impurities > 50% No changes were detected. 70℃ / 10%RH 3 weeks Impurities > 50% No changes were detected. 25℃ / 60%RH 12 months >10% impurities <50% No changes were detected. 30℃ / 65%RH 12 months >10% impurities <50% No changes were detected. .

[0181] Table 10. Summary of physical stability studies of lorlatinib in its free base form 7 in several pharmaceutical formulations.

[0182]

[0183] Example 6

[0184] Representative tablet formulations

[0185] Immediately released film-coated tablets in 25 mg, 50 mg, and 100 mg immediate doses were prepared using a dry granulation manufacturing process. The composition of the tablets is provided in Table 11.

[0186] Table 11. Composition of three different intensities of IR tablets

[0187] *Removed during processing. Does not appear in the final product.

[0188]

[0189]

[0190] Example 7

[0191] Chemical stability of representative tablet formulations

[0192] For the 25 mg tablets prepared according to Example 6, chemical stability data were generated after 12 months at 25°C / 60%RH and 30°C / 75%RH, and after 6 months at 40°C / 75%RH. Three major degradation products (amide, formaldehyde dimer, and oxidative photodegradation products) were monitored to assess the chemical stability of the test formulation. Chemical stability data for these chemical impurities are provided in Table 12.

[0193] Table 12. Summary of chemical stability data for 25 mg IR film-coated tablets of lorlatinib form 7

[0194]

[0195] **

[0196] Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in detail with reference to one or more specific embodiments, those skilled in the art will recognize that changes may be made to the embodiments specifically disclosed herein, and that such changes and modifications are within the scope and spirit of the invention.

Claims

1. (10 R )-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2 H -8,4-(methionine-bridged)pyrazolo[4,3- h [2,5,11]The crystalline form of the free base of benzoxazadiazonium triazocyclo-3-carboxynitrile (lorlatinib) has powder X-ray diffraction (PXRD) patterns containing peaks at the following 2θ values: 9.6, 10.1, 14.3, 16.2 and 17.3°2θ ± 0.2°2θ.

2. The crystalline form of claim 1 having a Raman spectrum comprising wave number (cm -1 ) values: 2229 and 2240 cm -1 ± 2 cm -1 -1.

3. The crystalline form of claim 1 having 13 C solid state NMR spectrum comprising resonance (ppm) values: 39.1 and 142.1 ppm ± 0.2 ppm. 13 C solid state NMR spectrum comprising resonance (ppm) values: 39.1 and 142.1 ppm ± 0.2 ppm.

4. The crystalline form of claim 1, having 19 F solid-state NMR spectrum, the 19 The F solid-state NMR spectrum includes resonance (ppm) values ​​of -108.2 and -115.2 ppm ± 0.2 ppm.

5. The crystalline form of claim 2, wherein the Raman spectrum further comprises wavenumbers (cm²). -1 Value: 1619 cm -1 ±2 cm -1 1553 cm -1 ± 2 cm -1 and 774 cm -1 ± 2 cm -1 .

6. The crystalline form of claim 5, having 13 C solid-state NMR spectrum, the 13 The C solid-state NMR spectrum includes resonance (ppm) values ​​of 39.1 and 142.1 ppm ± 0.2 ppm.

7. The crystalline form of claim 5, having 19 F solid-state NMR spectrum, the 19 The F solid-state NMR spectrum includes resonance (ppm) values ​​of -108.2 and -115.2 ppm ± 0.2 ppm.

8. The crystalline form of claim 3, wherein... 13 The C solid-state NMR spectra further include resonance (ppm) values: 112.3 ppm ± 0.2 ppm, 25.8 ppm ± 0.2 ppm, and 117.7 ppm ± 0.2 ppm.

9. A pharmaceutical composition comprising the crystalline form of the lorlatinib free base according to any one of claims 1-8 and a pharmaceutically acceptable carrier or excipient.

10. Use of the crystalline form of lorlatinib free base according to any one of claims 1-8 in the preparation of a medicament for treating cancers in mammals, wherein the cancer is mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1).

11. The use of claim 10, wherein the cancer is non-small cell lung cancer (NSCLC).

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