WO2022153157A1 - Forme cristalline de base libre de 2-((4-amino-2-(éthoxyméthyl)-6,7-diméthyl-1 h-imidazo[4,5-c]pyridin-1-yl)méthyl)-2-méthylpropane-1,3-diol - Google Patents

Forme cristalline de base libre de 2-((4-amino-2-(éthoxyméthyl)-6,7-diméthyl-1 h-imidazo[4,5-c]pyridin-1-yl)méthyl)-2-méthylpropane-1,3-diol Download PDF

Info

Publication number
WO2022153157A1
WO2022153157A1 PCT/IB2022/050139 IB2022050139W WO2022153157A1 WO 2022153157 A1 WO2022153157 A1 WO 2022153157A1 IB 2022050139 W IB2022050139 W IB 2022050139W WO 2022153157 A1 WO2022153157 A1 WO 2022153157A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline form
substantially pure
anhydrous crystalline
dimethyl
methyl
Prior art date
Application number
PCT/IB2022/050139
Other languages
English (en)
Inventor
Shane Allen Eisenbeis
Rebecca Barbara WATSON
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO2022153157A1 publication Critical patent/WO2022153157A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to a substantially pure crystalline form of 2-((4-amino-2- (ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol free base, to methods useful for the production and isolation of such crystalline form, to pharmaceutical compositions including them, and to methods of using such crystalline form and compositions in the treatment of abnormal cell growth in mammals, especially humans.
  • TLRs Toll-like receptors
  • PAMPS pathogen-associated molecular patterns
  • TLRs function in the mammalian immune system as front-line sensors of pathogen-associated molecular patterns, detecting the presence of invading pathogens (Takeuchi and Akira 2010 Cell 140:805-820).
  • TLR engagement in sentinel immune cells causes biosynthesis of selected cytokines (e.g., type I interferons), induction of costimulatory molecules, and increased antigen presentation capacity. These are important molecular mechanisms that activate innate and adaptive immune responses.
  • TLR agonists and antagonists of TLRs find use in modulating immune responses.
  • TLR agonists are typically employed to stimulate immune responses, whereas TLR antagonists are typically employed to inhibit immune responses (Gosu et al 2012. Molecules 17:13503-13529).
  • TLR7, TLR8, and TLR9 recognize nucleic acids and their degradation products.
  • the distribution of TLR7, TLR8, and TLR9 is restricted to the endosomal compartments of cells and they are preferentially expressed in cells of the immune system.
  • TLR7 and TLR8 recognize single strand RNA at one ligand binding site and the ribonucleoside degradation products guanosine and uridine, respectively, (as well as small molecule ligands with related structural motifs) at a second ligand binding site (Zhang et al 2016 Immunity 45(4);737-748: Tanji et al 2015 Nat Struct Mol Biol 22: 109-1 15).
  • TLR7 or TLR8 agonists have been identified. Those agonists can be grouped into purine-like molecules, such as 7-thia-8-oxoguanosine (TOG, isatoribine) or the imidazoquinoline-based compounds such as imiquimod. Imiquimod is so far the only approved TLR7 agonist, marketed as a 5% cream (Aldara). It generates approximately 80% 5-year clearance of superficial basal cell carcinomas, which is the most common cancer worldwide, thus demonstrating the importance of TLR7 agonists in cancer immunotherapy. The functional expression of TLR7 appears to be restricted to specific immune cells. Engagement of TLR7 in plasmacytoid dendritic cells leads to the induction of interferon a/p, which plays essential functions in the control of the adaptive immune response (Bao and Liu 2013 Protein Cell 4:40-5).
  • TOG 7-thia-8-oxoguanosine
  • imiquimod imidazoquinoline-based compounds
  • monocytes and monocyte-derived dendritic cells induces a prominent pro-inflammatory cytokine profile, characterized by increased production of tumor necrosis factor-a, interleukin-12, and IL-18 (Eigenbrod et al J Immunol, 2015, 195,1092-1099).
  • TLR7 and TLR8 are highly effective antigen-presenting cells, thereby promoting an effective innate and adaptive immune response.
  • Most antigen presenting cell types express only one of these two receptors, accordingly small molecules with potent agonist activity against both TLR7 and TLR8 receptors are potentially more effective immune adjuvants than TLR7 agonists alone.
  • TLR7/TLR8 small molecule agonist with dual bioactivity could provide further benefit over a more selective TLR7 agonist and would cause innate immune responses in a wider range of antigen presenting cells and other key immune cell types, including plasmacytoid and myeloid dendritic cells, monocytes, and B cells (van Haren et al 2016 J Immunol 197:4413- 4424; Ganapathi et al 2015 Pios One 10(8). e0134640).
  • Such potent dual TLR7/8 agonists may also be effective in stimulating effective anti-tumor responses in cancer (Singh et al 2014 J.
  • TLR7 agonists are potent TLR7 agonists, but also balanced, potent TLR7/8 agonists to expand treatment options for patients for various cancers.
  • These treatment options could be local administrations which would deliver the drug to the tumor directly, whilst limiting systemic side effects.
  • systemically administered TLR7 agonists or TLR7/8 agonists would have the advantage of being able to reach difficult to administer tumors as well as multiple tumors, through the systemic circulation.
  • PF- 07225570 A potent and balanced TLR7/8 dual agonist 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl- 1 /7-imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol (referred to herein as PF- 07225570) has been disclosed in PCT Publication No. WO 2021/009676 A1 , which is hereby incorporated for all purposes.
  • PF-07225570 has the structure: Preparation of PF-07225570 as disclosed in Example 2 of WO 2021/009676 A1 provided a white solid, which was found to be a mixture of crystalline forms that comprises predominantly a crystalline form referred to herein as Form 1 .
  • the percentage of the crystalline Form 1 in the white solid varied between batches. Preparation of a pure and homogeneous crystalline form is critical in the quality control of drug product manufacturing process and drug pharmaceutical compositions. Therefore, there is a need to identify and reproducibly prepare a pure crystalline form for PF-07225570.
  • the present invention provides a substantially pure anhydrous crystalline form of 2-((4- amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane- 1 ,3-diol free base (Form 2), pharmaceutical compositions comprising Form 2, and methods of making and using Form 2 for the treatment of cancer.
  • Form 2 has a powder X-ray diffraction (PXRD) pattern comprising peaks values of 8.0, 8.4, and 16.6 °20 ⁇ 0.2 °20.
  • PXRD powder X-ray diffraction
  • Form 2 has at least 95% pure crystalline form. In one preferred aspect, Form 2 has at least 98% pure crystalline form.
  • Form 2 has a PXRD profile that is free of characterization peaks of Form 1 , i.e., free of PXRD peaks of 7.5, 9.3, and 15.7 °20 ⁇ 0.2 °20, with relative intensity over 5%. In one preferred aspect, Form 2 has a PXRD profile that is free of characterization peaks of Form 1 ,
  • the present invention also provides, in part, methods for preparing Form 2, and compositions of the invention, and methods of using the foregoing alone or in combination with additional anticancer therapeutic agents.
  • the invention provides a pharmaceutical composition comprising Form
  • the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.
  • the invention also provides therapeutic methods and uses comprising administering Form 2.
  • the invention provides a method for the treatment of abnormal cell growth, in particular, cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form 2.
  • Form 2 may be administered as single agent or may be administered in combination with other anti-cancer therapeutic agents, including standard of care agents appropriate for the particular form of cancer.
  • This also includes use of Form 2, in the manufacture of a medicament for treating abnormal cell growth, in particular, cancer, in a subject in need thereof.
  • the invention provides Form 2 for use as a medicament, in particular a medicament for the treatment of abnormal cell growth, such as cancer.
  • the invention provides the use of Form 2 for the manufacture of a medicament for the treatment of abnormal cell growth, such as cancer, in a subject.
  • the invention provides a method of preparing the substantially pure anhydrous crystalline Form 2, wherein the method comprises treating 2-(ethoxymethyl)-N,N- bis(4-methoxybenzyl)-6,7-dimethyl-1 -((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 H-imidazo[4,5- c]pyridin-4-amine in a solvent system comprising a solvent with a boiling point of at least 70 °C, with an acid to provide 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1- yl)methyl)-2-methylpropane-1 ,3-diol as a solid, wherein the solid has Form 2 as predominant crystalline form.
  • the method further comprises dissolving the solid having Form 2 as predominant crystalline form in a solvent system comprising a CMO alcohol to form a solution and heating the solution at an elevated temperature; and followed by adding a solvent comprising a C4-10 alkane to the solution to provide the substantially pure anhydrous crystalline Form 2.
  • FIG. 1 shows an illustrative PXRD pattern of Form 2, as prepared in Example 3, carried out on a Bruker D8 Endeavor diffractometer equipped with a copper (Cu) radiation source.
  • FIG. 2 shows a single crystal of Form 2.
  • FIG. 3 shows an illustrative PXRD pattern of PF-07225570, as prepared in Example 2, carried out on a Bruker D8 Endeavor diffractometer equipped with a Cu radiation source.
  • FIG. 4 shows a single crystal of Form 1 mixed with Form 2 as impurity.
  • FIG. 5 shows an illustrative PXRD pattern of the amorphous form of PF-07225570 free base.
  • FIG. 6 provides Raman spectrum of the amorphous form of PF-07225570 free base.
  • the invention concerns Form 2, which is a substantially pure anhydrous, crystalline form of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1- yl)methyl)-2-methylpropane-1 ,3-diol free base.
  • Ci-w alcohol means a straight or branched C1-10 alcohol.
  • C4-10 alkane means a straight or branched C4-10 alkane.
  • the term “predominant” means that in a solid comprising more than one crystalline forms, the crystalline form in the solid with the highest weight percentage is referred as the predominant component.
  • the term “essentially the same” means that variability typical for a particular method is taken into account.
  • the term “essentially the same” means that typical variability in peak position and intensity are taken into account.
  • the peak positions (20) will show some variability, typically as much as ⁇ 0.2°.
  • relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and otherfactors known to those skilled in the art and should be taken as qualitative measures only.
  • a variability may be between ⁇ %.
  • Crystalline as used herein, means having a regularly repeating arrangement of molecules or external face planes. Crystalline forms may differ with respect to thermodynamic stability, physical parameters, x-ray structure and preparation processes.
  • crystalline purity for a specific crystalline form as used herein means the weight percentage of the specific crystalline form in all possible crystalline forms of a solid compound. For example, if a solid compound consists of 90 grams of a crystalline form A and 10 grams of a crystalline form B, the crystalline purity of the crystalline A is 90%.
  • substantially pure as used herein for the crystalline purity of a crystalline compound means the crystalline compound has at least 95% crystalline purity. Preferably, the substantially pure crystalline compound has at least 98% crystalline purity.
  • substantially pure as used herein for the crystalline purity of a crystalline compound means that there is no identified characterization peak of other crystalline forms with a relative intensity over such as 5% in PXRD under the same condition to generate PXRD as disclosed in this invention. In a preferred aspect, there is no identified characterization peak of other crystalline forms with a relative intensity over such as 2% in PXRD under the same condition to generate PXRD as disclosed in this invention.
  • subject refers to a human or animal subject. When the subject is a human, the subject may also be referred to as a “patient”.
  • treat or “treating” a cancer as used herein means to administer a compound of the present invention to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastases or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as "treating” is defined immediately above.
  • the term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.
  • treatment regimen used interchangeably to refer to the dose and timing of administration of each compound of the invention, alone or in combination with another therapeutic agent.
  • Abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous).
  • cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth.
  • Cancer includes primary cancerthat originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a patient with a history of previous cancer of a different type from the second primary cancer.
  • Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas.
  • Cancers of the blood include leukemia, lymphoma and myeloma.
  • cancer includes blastomas and an actinic keratosis.
  • Cancer also includes primary cancer or metastases of a site selected from the group consisting of oral cavity, digestive system, respiratory system, skin, breast, genital system, urinary system, ocular system.
  • Example 2 disclosed in WO 2021/009676 A1 was made and was referred as a white solid. It has been later found that the white solid prepared is not a pure crystalline form although chemically pure. For a pharmaceutical material, a pure and homogeneous crystalline form is critical in the quality control of drug product manufacturing process and drug product compositions. Although extensive effort to prepare pure Form 1 has not been successful, surprisingly, with a unique process, including a unique combination of solvent system, temperature control (See Step 6 for preparing Form 2), the present disclosure provides a substantially pure crystalline form referred as Form 2, which has a powder X-ray diffraction (PXRD) pattern comprising peaks values of 8.0, 8.4, and 16.6 °20 ⁇ 0.2 °20.
  • PXRD powder X-ray diffraction
  • the first factor is the different solvent in the step of converting 2- (ethoxymethyl)-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1 -((2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl)-1 H-imidazo[4,5-c]pyridin-4-amine to 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 H- imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol.
  • Form 1 is the predominant final solid form and it always has another solid form as impurity which cannot be removed.
  • the predominant solid form is the form of Form 2.
  • the invention provides Form 2, which is a substantially pure crystalline form of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1- yl)methyl)-2-methylpropane-1 ,3-diol free base, having the structure:
  • Form 2 is an anhydrous, crystalline solid having a powder X-ray diffraction (PXRD) pattern comprising peaks values of 8.0, 8.4, and 16.6 °20 ⁇ 0.2 °20.
  • PXRD powder X-ray diffraction
  • Form 2 as prepared in this disclosure has at least 95% pure crystalline form. In one preferred aspect, Form 2 has at least 98% pure crystalline form.
  • Form 2 of the present invention has a PXRD profile that is free of characterization peaks of Form 1 , i.e., free of PXRD peaks of 7.5, 9.3, and 15.7 °20 ⁇ 0.2 °20.
  • Another embodiment of Form 2 can be further described as an anhydrous crystalline having at least 99% chemical purity.
  • Another embodiment of Form 2 can be further described as an anhydrous crystalline form having at least 99.6% chemical purity.
  • Another embodiment of the invention provides a pharmaceutical composition comprising Form 2 and a pharmaceutically acceptable carrier or excipient.
  • Another embodiment of the invention provides a method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form 2.
  • Cancers to be treated include squamous cell carcinoma, basal cell carcinomas, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, uterine cancer, bladder cancer, including non-muscular invasive bladder cancer, hepatoma, breast cancer, and head and neck cancer.
  • cancers to be treated include basal cell carcinomas, smallcell lung cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, ovarian cancer, colorectal cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, pancreatic cancer, bladder cancer (non-muscular invasive bladder cancer), hepatoma, breast cancer, and head and neck cancer.
  • Another embodiment of the invention concerns Form 2 for treatment of non-muscular invasive bladder cancer. Another embodiment of the invention concerns Form 2 for use in the treatment of cancer in a subject in need thereof.
  • Another embodiment of the invention concerns Form 2 for use in the treatment of cancer, wherein said treatment comprises the administration of an additional therapeutic agent.
  • the invention provides a method of preparing the substantially pure anhydrous crystalline Form 2, wherein the method comprises treating 2-(ethoxymethyl)-N,N- bis(4-methoxybenzyl)-6,7-dimethyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 H-imidazo[4,5- c]pyridin-4-amine in a solvent system comprising a solvent with a boiling point of at least 70 °C, with an acid to provide 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1- yl)methyl)-2-methylpropane-1 ,3-diol as a solid, wherein the solid has Form 2 as predominant crystalline form.
  • the method further comprises dissolving the solid having Form 2 as predominant crystalline form in a solvent system comprising a Ci-w alcohol to form a solution and heating the solution at an elevated temperature; and followed by adding a solvent comprising a C4-10 alkane to the solution to provide the substantially pure anhydrous crystalline Form 2.
  • the invention provides a method of preparing the substantially pure anhydrous crystalline Form 2, wherein the method comprises a) treating 2-(ethoxymethyl)-
  • Form 2 is prepared by the foregoing methods.
  • EB2 The substantially pure anhydrous crystalline form of EB1 , having a PXRD pattern further comprising a peak value of 21 .6 °2Q ⁇ 0.2 °2Q.
  • EB3 The substantially pure anhydrous crystalline form of EB1 or EB2, having at least 95% crystalline purity.
  • EB4 The substantially pure anhydrous crystalline form of EB3, having at least 98% crystalline purity.
  • EB5. The substantially pure anhydrous crystalline form of any one of EB1 to EB4, wherein the PXRD pattern is free of peaks with a relative intensity over 5% selected from the group consisting of 7.5, 9.3, and 15.7 °20 ⁇ 0.2 °20.
  • a pharmaceutical composition comprising the substantially pure anhydrous crystalline form of any one of EB1 to EB5, and a pharmaceutically acceptable carrier or excipient.
  • EB8 The method of EB7, wherein the substantially pure anhydrous crystalline form is administered with at least one additional therapeutic agent.
  • EB9 The substantially pure anhydrous crystalline form of any one of EB1 to EB5, for use in the treatment of cancer in a subject in need thereof.
  • EB1 1. The method of EB10, wherein the method further comprises dissolving the solid in a solvent system comprising a C1-10 alcohol to form a solution and heating the solution at an elevated temperature; and followed by adding a solvent comprising a C4-10 alkane to the solution to provide the substantially pure anhydrous crystalline of any one of EB1 to EB5.
  • EB15 The substantially pure anhydrous crystalline form of any one of EB1 to EB5, wherein the substantially pure anhydrous crystalline form is prepared by the method of any of EB10 to EB14.
  • MS mass spectra, MS (m/z), were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI).
  • ESI electrospray ionization
  • APCI atmospheric pressure chemical ionization
  • °C is degrees Celsius
  • CO2 is carbon dioxide
  • DMAC is dimethylacetamide
  • DMSO dimethyl sulphoxide
  • EtOAc is ethyl acetate; g is gram;
  • HCI is hydrochloric acid
  • HPLC high pressure liquid chromatography
  • H 2 O is water
  • Hr or hr is hour
  • LCMS is liquid chromatography mass spectrometry
  • M is molar; mg is milligram; MHz is mega Hertz; min is minutes; mL or ml is milli litre; mmol is millimole; mol is mole;
  • MS m/z is mass spectrum peak
  • NH(PMB)2 is bis(4-methoxybenzyl)amine
  • NMR nuclear magnetic resonance
  • Pd/C is palladium on carbon; pH is power of hydrogen; ppm is parts per million; psi is pounds per square inch;
  • Step 2 Synthesis of N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-3-nitro-N4-((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)pyridine-2,4-diamine
  • Triethylamine (42.3 g, 418 mmol) was added followed by portionwise addition of (2,2,5-trimethyl-1 ,3-dioxan-5-yl)methanamine (72.6 g, 456 mmol) (Prepared from Organic & Biomolecular Chemistry, 14(2), 483-494; 2016). The reaction was stirred at 0 °C for 20min then stirred at 15 °C for 18hrs. The reaction was cooled to 0 °C at which point triethylamine (115 g, 1.14 mol) was added followed by Bis(4-methoxybenzyl)amine (127 g, 494 mmol). The reaction was then stirred at 50°C for 12 hrs.
  • Step 3 Synthesis of N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-N4-((2,2,5-trimethyl-1 ,3-dioxan- 5-yl)methyl)pyridine-2,3,4-triamine
  • Step 4 Synthesis of N-(2-(bis(4-methoxybenzyl)amino)-5,6-dimethyl-4-(((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)amino)pyridin-3-yl)-2-ethoxyacetamide
  • Step 5 Synthesis of 2-(ethoxymethyl)-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1 -((2,2,5- trimethyl-1 ,3-dioxan-5-yl)methyl)-1 H-imidazo[4,5-c]pyridin-4-amine
  • ethanol 3.45 L cooled to 0°C
  • sodium hydroxide 64.4 ml, 15N aqueous
  • Step 6 Synthesis of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 H-imidazo[4,5-c]pyridin-1- yl)methyl)-2-methylpropane-1 ,3-diol (PF-07225570)
  • Step 6A Alternative Step 6 for synthesis of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 H- imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol (PF-07225570)
  • the silica gel was transferred to the top of an 8 inch silica plug conditions with heptane in a 2L filter funnel. The product was then eluted with Heptane/EtOAc (80/20 mix, 3.5L). The product was concentrated to a red solid that was stirred in ethanol (300 mL) for 2hrs. The solids were filtered and washed with ethanol (200 ml) and dried in vacuo to provide title compound as a yellow solid. Yield: 53.4 g, 94.57 mmol, 43.3%. LCMS m/z 564.9 [M+H] + .
  • Step 3(i) Synthesis of N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-N4-((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)pyridine-2,3,4-triamine
  • Step 4(i) Synthesis of N-(2-(bis(4-methoxybenzyl)amino)-5,6-dimethyl-4-(((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)amino)pyridin-3-yl)-2-ethoxyacetamide
  • Step 5(i) Synthesis of 2-(ethoxymethyl)-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1 -((2,2,5- trimethyl-1 ,3-dioxan-5-yl)methyl)-1 H-imidazo[4,5-c]pyridin-4-amine
  • the aqueous was washed with dichloromethane (2 x 400 mL) and combined organics washed with water (1 x 200 mL). The organics were dried over anhydrous sodium sulfate and filtered. The material was then combined with another batch of compound prepared in a similar manner at a similar stage of the synthesis. The combined organics were then concentrated to 15% volume. The solid that formed was filtered and washed with ethanol (250 mL) and then water (1 L). The solids were combined with the filtrate and the liquid and solids decanted away from a red slime that formed at the bottom of the flask. To the decanted heterogenous mixture was added water (1 .3 L) and the mixture stirred for 16 hrs.
  • Step 6(i) Synthesis of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 H-imidazo[4,5-c]pyridin-1- yl)methyl)-2-methylpropane-1 ,3-diol (PF-07225570)
  • the reaction was refluxed for 30 min then cooled to 10 °C. Solids were filtered and washed with water (1 x 300 mL) and tetra hydrofuran (1 x 50 mL). The solids were combined with additional batches prepared under a similar manner to provide 259 g total crude solids. The combined batches were stirred with tetra hydrofuran (350 mL) for 60 min at 45 °C. The reaction was cooled to 15 °C and the solids filtered and washed with tetrahydrofuran (150 mL). The solids were then stirred in tetra hydrofuran (400 mL) for 120 min at 60 °C and then cooled to 20 °C and stirred for 16 hrs.
  • the solids were collected and stirred with water (650 mL, HPLC grade) at reflux for 7 hrs. Water (200 mL, HPLC grade) was added and the mixture stirred at 60 °C for 48 hrs. The reaction was cooled to 20 °C, the solids collected and washed with water (500 ml, HPLC grade), and then the solids were then refluxed in water (1 L, HPLC grade) for 16 hrs. Water was added (200 mL, HPLC grade) and reflux was continued for an additional 16hrs. Water was added (100 mL, HPLC grade) and reflux was continued for an additional 60hrs. The mixture was cooled to 15 °C and solids collected and washed with water (150 mL, HPLC grade).
  • HPLC @210nM 99.62% The chemical purity was determined using a Waters Acquity UPLC/PDA/TQD instrument. The chromatographic conditions were as follows: Mobile phase A: 10 mM of ammonium bicarbonate in water. Mobile phase B: acetonitrile. Flow rate: 0.5 ml/min. Column: Acquity UPLC BEH C8 1.7 urn, 2.1 mm x 100 mm. Column temperature: 45C.
  • the gradient started at A:B 95%:5% and was linearly increased to 100% B within 8.30 min and held at 100% B for 0.5 min, before it was returned back to the initial gradient of A:B 95%:5% at 8.80 min and was equilibrated at A:B 95%:5% for 1 .5 min.
  • PDA 200 nm to 400 nm with resolution 1 .2 nm and sampling rate 10 points/sec. The raw data was acquired and processed with Waters Empower 3 software. PDA 210 nm relative peak areas % were obtained with Apex Detection and Integration algorism. The chemical purity % was reported as the relative peak area % of Example 2, with a value of 99.62%.
  • qNMR 99.0 (wt/wt)% qNMR potency factor (weight percentage) was determined as follows: 6.63 mg of Example 3 was weighed into a pre-tared vial. To this vial, 884.47 mg of an internal standard (Cambridge Isotope Laboratories Inc, Dimethyl Sulfoxide-d6 (D, 99.9%)+0.05% V/V TMS+20 mM Maleic Acid, lot # PR-25603. Potency 0.976) was added. After thorough mixing, the resulting solution was transferred to an NMR tube and the qNMR raw data was acquired using an Oxford AS500 NMR system with the following acquisition parameters: Acquisition Time: 8.1789 sec. Frequency: 500 MHz. Nucleus: 1 H.
  • Pulse Sequence zg30. SW: 8012.82 Hz. Original Points Count: 65536.
  • the raw data was processed with ACD/Labs 2017 software and the potency factor of Example 2 was calculated using a qNMR potency calculation micro.
  • the potency factor value is 99.0 (wt/wt)%.
  • Step 2 Synthesis of Intermediate (B): 2-Chloro-5,6-dimethyl-3-nitro-A/-((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)pyridine-4-amine.
  • Step 3 Synthesis of Intermediate (C): A/ 2 ,A/ 2 -bis(4-methoxybenzyl)-5,6-dimethyl-3-nitro-A/ 4 - ((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-pyridin-2,4-diamine
  • Step 4 Synthesis of Intermediate (D): 2-(ethoxymethyl)-A/,A/-bis(4-methoxybenzyl)-6,7-dimethyl- 1 -((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 /7-imidazo[4,5-c]pyridin-4-amine
  • Intermediate (D) 2-(ethoxymethyl)-A/,A/-bis(4-methoxybenzyl)-6,7-dimethyl- 1 -((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 /7-imidazo[4,5-c]pyridin-4-amine
  • the reaction was then stirred at 90 °C for 40hrs.
  • the reaction was cooled to 22 °C and isopropanol (55 ml) was added.
  • the reaction was heated to 70 °C, until all solids dissolved. At this point, the reaction was cooled to 22 °C at a ramp rate of 0.1 °C/min.
  • the solids were filtered, washed with isopropanol (33 ml) and dried under vacuum to provide Intermediate (D) as a white solid. Yield. 9.70 g, 16.1 mmol, 90.9%.
  • Step 5 Synthesis of Intermediate (E): 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 H- imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol
  • Step 6 Preparation of pure Form 2 of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7- imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol (PF-07225570)
  • Intermediate (E) (1.75 g, 5.43 mmol) in 1 -butanol (10.5 ml) was heated to 60 °C and stirred for 18hrs. At 60 °C, n-heptane (7 ml) was added over 1 hr, and then stirred for 2hrs. The reaction was then cooled to 22 °C over 4hrs.
  • Powder X-ray diffraction data were collected on Bruker D8 Endeavor diffractometer equipped with a Cu radiation source.
  • the divergence slit was set at 11 mm constant illumination.
  • the sample rotation was set to 15 rpm.
  • Diffracted radiation was detected by a LYNXEYE detector, with the position sensitive detector (PSD) opening set at 3.998 degrees.
  • the X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively.
  • Data was collected in the theta-theta goniometer at the Cu wavelength from 2.0 to 55.0 degrees 2-theta using a step size of 0.019 degrees and a time per step of 0.20 seconds.
  • the sample was prepared by placing the powder in Si low background cavity holder.
  • the sample powder was pressed by a glass slide to ensure that a proper sample height was achieved.
  • Data were collected using Bruker DIFFRAC software and analysis was performed by DIFFRAC EVA software.
  • the PXRD patterns collected were imported into Bruker DIFFRAC EVA software.
  • the minor error associated with this measurement can occur because of a variety of factors including: (a) sample preparation (e.g., sample height), (b) instrument, (c) calibration, (d) operator (including those errors present when determining the peak locations), and (e) the nature of the material (e.g. preferred orientation and transparency errors). Therefore, peaks are considered to have an associated error of ⁇ 0.2° 2-theta. Peaks existing as shoulders, on a higher intensity adjacent peak, have also been removed from the peak list. While the shoulders may be > 0.2° 2-theta from the position of the adjacent peak, they are not considered as discernible from the adjacent peak. To obtain the absolute peak positions, the powder pattern should be aligned against a reference. This was done using the simulated powder pattern from the crystal structure of this solid form solved at room temperature.
  • the PXRD profile of Form 2 is provided in FIG. 1 .
  • Table 1 provides a list of peaks having relative intensity greater than 5% for Form 2.
  • Characteristic PXRD peaks for Form 2 are 8.0, 8.4, and 16.6 °2-Theta ⁇ 0.2 °2-Theta. Characteristic PXRD peaks for Form 2 can also include 21 .6, providing 8.0, 8.4, 16.6, and 21 .6 °2- Theta ⁇ 0.2 °2-Theta.
  • An embodiment of the present invention includes an anhydrous crystalline form of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1-yl)methyl)-2- methylpropane-1 ,3-diol free base, having a powder X-ray diffraction (PXRD) pattern comprising peaks values of 8.0, 8.4, and 16.6 °20 ⁇ 0.2 °2Q.
  • PXRD powder X-ray diffraction
  • Another embodiment of the present invention includes the anhydrous crystalline form having a PXRD pattern comprising peaks values of 8.0, 8.4, and 16.6 °20 ⁇ 0.2 °2Q, and further comprising a peak value of 21 .6 °20 ⁇ 0.2 °20.
  • a single crystal of Form 2 was obtained as presented in FIG. 2. The single crystal was grown by slow evaporation from methanol at room temperature. The single crystal data shows that the crystalline solid is anhydrous.
  • Example 2 Powder X-Ray Diffraction of PF-07225570 as prepared in Example 2 (Predominantly Form 1 with Form 2 as crystalline impurity): The PXRD profile of PF-07225570 prepared in Example 2 (with Form 1 as predominant crystalline form and with some Form 2 as crystalline impurity) is provided in FIG. 3. Table 2 provides a list of peaks having relative intensity greater than 5% for Form 1 . The impurity peaks of Form 2 are indicated by an asterisk (*) Table 2: PXRD peak list for PF-07225570 as prepared in Example 2, with Form 1 as predominant crystalline form and with Form 2 as an impurity of Form 1. Table shows only peaks with relative intensity > 5%.
  • Form 2 peaks are indicated by an asterisk (*)
  • Simulated powder pattern of Form 1 was obtained from single crystal structure. Single crystal was grown from acetonitrile. Single crystal data indicates that the material analysed is anhydrous (FIG. 4).
  • a simulated powder pattern from the single crystal structure was obtained via a calculation using Reflex/Powder Diffraction Toolbox in Materials Studio 2018 software package. The simulated pattern from the crystal structure is consistent with the experimentally obtained powder pattern for Form 1 except for several peaks of Form 2 indicated in the Table 2 with an asterisk (*).
  • Characteristic PXRD peaks for Form 1 comprises 7.5, 9.3, and 15.7 °20 ⁇ 0.2 °20. Characteristic PXRD peaks for Form 1 can also include 9.7, providing 7.5, 9.3, 9.7, and 15.7 °20 ⁇ 0.2 °20. Characteristic PXRD peaks for Form 1 can also include 18.5 °20 ⁇ 0.2 °20, providing
  • the peak 16.6 °20 ⁇ 0.2 °20 has a relative intensity of 26.6%.
  • no characteristic peak of Form 1 shows in the PXRD peak profile for Form 2. Therefore, the present disclosure provides a pure or substantially pure crystalline form of 2-((4-amino-2- (ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol free base, which can provide better quality control of drug product manufacturing process and drug product compositions.
  • the amorphous form of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7-imidazo[4,5- c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol free base was manufactured by cryo-milling. Approximately 430mg Form 2 was loaded into a 5mL steel milling jar with a 7mm steel milling ball, which was then sealed and submerged in liquid nitrogen for 5 minutes. The milling jar was then removed from the liquid nitrogen and placed on a Retsch MM400 ball mill, where the sample was milled for 10 minutes at 30Hz, before being returned to the liquid nitrogen. This process was repeated 4 times, such that the total milling time was 40 minutes.
  • the PXRD profile collected for the obtained powder provided in FIG. 5 is typical for amorphous material.
  • Raman spectra for amorphous form of 2-((4-amino-2-(ethoxymethyl)-6,7-dimethyl-1 /7- imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylpropane-1 ,3-diol free base were collected using a RAM II FT-Raman module attached to a Vertex 70 spectrometer (Bruker Optik GmbH). The instrument is equipped with a 1064 nm solid-state (Nd:YAG) laser and a liquid nitrogen cooled germanium detector. Prior to data acquisition, instrument performance and calibration verifications were conducted using a white light source, and polystyrene and naphthalene references.
  • Samples were prepared and analysed in truncated NMR tubes.
  • a sample rotator (Ventacon, UK) was used during measurement to maximise the volume of material exposed to the laser during data collection.
  • the backscattered Raman signal from the sample was optimized and data were collected at a spectral resolution of 2 cm -1 using a laser power of 750 mW.
  • a Blackmann-Harris 4-term apodization function was applied to minimise spectral aberrations. Spectra were generated between 3500 and 50 cm -1 with the number of scans adjusted accordingly to ensure adequate signal to noise.
  • Spectra were normalised by to the intensity of the most intense peak to 2.00. Peaks were then identified using the automatic peak picking function in the OPUS v8.2 software (BrukerOptik GmbH) with the sensitivity set to 2%. Peak positions and relative peak intensities were extracted and tabulated. The variability in the peak positions with this experimental configuration is within ⁇ 2 cm' 1 , unless otherwise stated in Table 3.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un 2-((4-amino-2-(éthoxyméthyl)-6,7-diméthyl-1H-imidazo[4,5-c]pyridin-1-yl)méthyl)-2-méthylpropane-1,3-diol cristallin sensiblement pur, des compositions pharmaceutiques comprenant ladite forme cristalline sensiblement pure, des procédés de préparation et d'utilisation de ladite forme cristalline sensiblement pure, et des compositions pour le traitement d'une croissance cellulaire anormale, comprenant le cancer, chez un sujet.
PCT/IB2022/050139 2021-01-13 2022-01-10 Forme cristalline de base libre de 2-((4-amino-2-(éthoxyméthyl)-6,7-diméthyl-1 h-imidazo[4,5-c]pyridin-1-yl)méthyl)-2-méthylpropane-1,3-diol WO2022153157A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202163136844P 2021-01-13 2021-01-13
US63/136,844 2021-01-13
US202163284047P 2021-11-30 2021-11-30
US63/284,047 2021-11-30

Publications (1)

Publication Number Publication Date
WO2022153157A1 true WO2022153157A1 (fr) 2022-07-21

Family

ID=79686928

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/050139 WO2022153157A1 (fr) 2021-01-13 2022-01-10 Forme cristalline de base libre de 2-((4-amino-2-(éthoxyméthyl)-6,7-diméthyl-1 h-imidazo[4,5-c]pyridin-1-yl)méthyl)-2-méthylpropane-1,3-diol

Country Status (1)

Country Link
WO (1) WO2022153157A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015023958A1 (fr) * 2013-08-15 2015-02-19 The University Of Kansas Agonistes de récepteurs de type toll
US20150299194A1 (en) * 2014-04-22 2015-10-22 Hoffmann-La Roche Inc. 4-amino-imidazoquinoline compounds
WO2021009676A1 (fr) 2019-07-17 2021-01-21 Pfizer Inc. Dérivés d'imidazo [4,5-c] pyridine en tant qu'agonistes du récepteur de type toll

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015023958A1 (fr) * 2013-08-15 2015-02-19 The University Of Kansas Agonistes de récepteurs de type toll
US20150299194A1 (en) * 2014-04-22 2015-10-22 Hoffmann-La Roche Inc. 4-amino-imidazoquinoline compounds
WO2021009676A1 (fr) 2019-07-17 2021-01-21 Pfizer Inc. Dérivés d'imidazo [4,5-c] pyridine en tant qu'agonistes du récepteur de type toll

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
BAOLIU, PROTEIN CELL, vol. 4, 2013, pages 40 - 5
DOWLING, IMMUNOHORIZONS, vol. 2, no. 6, 2018, pages 185 - 197
EIGENBROD ET AL., J IMMUNOL, vol. 195, 2015, pages 1092 - 1099
GANAPATHI ET AL., PLOS ONE, vol. 10, no. 8, 2015, pages e0134640
GOSU ET AL., MOLECULES, vol. 17, 2012, pages 13503 - 13529
NOUR BOU KARROUM ET AL: "Novel and Selective TLR7 Antagonists among the Imidazo[1,2- a ]pyrazines, Imidazo[1,5- a ]quinoxalines, and Pyrazolo[1,5- a ]quinoxalines Series", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 15, 8 July 2019 (2019-07-08), US, pages 7015 - 7031, XP055723486, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b00411 *
ORG. LETT., vol. 5, no. 25, 2003, pages 4779 - 4782
ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 14, no. 2, 2016, pages 483 - 494
PATIL ET AL., MINI REV MED CHEM, vol. 16, 2016, pages 309 - 322
SABADO ET AL., CANCER IMMUNOL RES, vol. 3, 2015, pages 278 - 287
SINGH ET AL., J. IMMUNOL, vol. 193, 2014, pages 4722 - 4731
SPINETTI ET AL., ONCOIMMUNOL, vol. 5, no. 11, 2016, pages e1230578
TAKEUCHIAKIRA, CELL, vol. 140, 2010, pages 805 - 820
TANJI ET AL., NAT STRUCT MOL BIOL, vol. 22, 2015, pages 109 - 115
THEODORA W GREENEPETER G M WUTS: "Greene's Protective Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS
VAN HAREN ET AL., J IMMUNOL, vol. 197, 2016, pages 4413 - 4424
ZHANG ET AL., IMMUNITY, vol. 45, no. 4, 2016, pages 737 - 748

Similar Documents

Publication Publication Date Title
EP4144732A1 (fr) Composé de benzothiazolyle biaryle, son procédé de préparation et son utilisation
JP7137733B2 (ja) ｔｏｌｌ様受容体アゴニストとしてのイミダゾ［４，５－Ｃ］ピリジン誘導体
EP0418099A2 (fr) Analogue de la 10,11-méthylènedioxy-20(RS)camptothécine et de la 10,11-méthylènedioxy-20(S)-camptothécine
CN110167941B (zh) 取代的稠合杂芳基化合物作为激酶抑制剂及其应用
EP2100894A1 (fr) Pyridopyrimidinones utilisés comme inhibiteurs de la kinase de type Plk1 (polo-like kinase)
CN112778337A (zh) 作为ret激酶抑制剂的3、6二氮杂双环[ 3.1.1 ]庚烷衍生物
CN113527299B (zh) 一类含氮稠环类化合物、制备方法和用途
CN116867788A (zh) 4-氨基喹唑啉化合物
EP3807274B1 (fr) 4-substitué pyrrolo[2,3-b] pyridine en tant que modulateurs erbb utiles pour le traitement du cancer
WO2022153157A1 (fr) Forme cristalline de base libre de 2-((4-amino-2-(éthoxyméthyl)-6,7-diméthyl-1 h-imidazo[4,5-c]pyridin-1-yl)méthyl)-2-méthylpropane-1,3-diol
JP5313895B2 (ja) 抗腫瘍活性を有するカンプトテシン誘導体
CN116143806A (zh) 一类含氮杂环类化合物、制备方法和用途
WO2022143576A1 (fr) Composé pyrazoloquinazoline, son procédé de préparation et son utilisation
KR102629854B1 (ko) 단백질 키나제 저해제로서 유용한 피리도퀴나졸린 유도체
CN114364677B (en) Imidazo [4,5-C ] pyridine derivatives as TOLL-like receptor agonists
RU2785124C1 (ru) Производные имидазо[4,5-с]пиридина в качестве агонистов toll-подобного рецептора
CA3068357C (fr) Nouveau sel de n-(2,6-diethylphenyl)-8-{4-[4-(dimethylamino)piperidine-1-yl]-2-methoxyphenyl} amino)-1-methyle-4,5-dihydro-1h-pyrazolo[4,3-h]quinazoline-3-carboxamide, preparation et formulation le comportant
WO2022121967A1 (fr) Inhibiteur de la tyrosine kinase de l'egfr et ses utilisations
OA20485A (en) IMIDAZO[4,5-C]pyridine derivatives as tolllike receptor agonsits
CN115772156A (zh) 用作hpk1激酶抑制剂的化合物及其制备方法和应用
CN116143805A (zh) 一类含氮杂环联芳基类化合物、制备方法和用途
EP4293029A1 (fr) Composé azahétéroaryle, son procédé de préparation et son application
CN117800976A (zh) 一类含氮杂环类化合物、制备方法和用途
CN117003770A (zh) 一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用
EA042196B1 (ru) Способ получения модуляторов соматостатина

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22700203

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22700203

Country of ref document: EP

Kind code of ref document: A1