Patent Application
20240293404
Epidermal Growth Factor Receptor (EGFR) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. When binding to a ligand such as epidermal growth factor (EGF), EGFR is able to form a homodimer on the cell membrane or with other members of the erbB family. The formation of these dimers often causes tyrosine phosphorylation, and can lead to the activation or alteration of various downstream cellular pathways, including cell proliferation, survival, and anti-apoptosis.
Because of this cellular function, disorders in EGFR signaling, including increased expression of EGFR or its ligands and deletions or mutations in the EGFR gene or protein, can activate cell growth or mitigate normal apoptosis mechanisms and pathway, traditional hallmarks of tumor cell growth and proliferation. For example, EFGR mutations or deletions are commonly found in non-small cell lung cancer (NSCLC) tumors.
The two most frequent EGFR alternations found in NSCLC tumors are 1) short in-frame deletions in exon 19 (del19) and 2) L858R, a single missense mutation in exon 21 (Cancer Discovery 2016 6 (6) 601). These two alterations cause ligand-independent EGFR activation and are referred to as primary or activating mutations in EGFR mutant NSCLC (EGFR M+). Clinical experience shows an objective response rate (ORR) of approximately 60-85% in EGFR M+ NSCLC patients treated first line (1L) with EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib and osimertinib (Lancet Oncol. 2010 Vol. 11, 121; Lancet Oncol. 2016 Vol. 17, 577; N. Engl. J. Med. 2017 November 18 Doi:10.1056/NEJMoa1713137; Lancet Oncol. 2011 Vol. 12, 735). These findings show that EGFR mutant NSCLC tumors are dependent on the oncogenic activity of the mutated EGFR and that del19 and L858R are the oncogenic mutation in this disease, which validates these as drug targets and biomarkers for many forms of NSCLC.
However, after an average of 10-12 months of treatment with first generation (erlotinib and gefitinib) and second generation (afatinib) EGFR TKIs, resistance to these small molecule inhibitors has been observed in almost all NSCLC patients (Lancet Oncol. 2010 February; 11(2):121-8; Lancet Oncol. 2016 May; 17(5):577-89; Lancet Oncol. 2011 August; 12(8):735-42). The most common resistance mechanism is the development of a second EGFR mutation, T790M, which occurs in 50% to 70% of patients progressing on lst and 2nd generation EGFR inhibitors. (Blakely et al., Cancer Discov; 2012, 2(10); 872-5; Kobayashi et al., Cancer Res 2005; 65: (16)). This secondary mutation reduces the affinity of the drug with the target, thereby producing drug resistance, and resulting in tumor recurrence or disease progression.
Due to the prevalence of the T790M mutation, a number of companies have attempted to develop new small molecule EGFR inhibitors for treating patients with the drug-resistant mutant. For example, osimertinib (Tagrisso®), a third generation EGFR TKI, has been developed to treat NSCLC patients if the cancer cells are positive for the primary EGFR mutations del19 or L858R with or without the T790M mutation in the gene coding for EGFR. Although the third generation EGFR TKI, osimertinib, has shown efficacy on NSCLC patients, unfortunately, resistance mediated by an exon 20 C797 mutation (often C797S) in EGFR usually develops within approximately 10 months (European Journal of Medicinal Chemistry 2017 Vol. 142: 32-47) and accounts for the majority of osimertinib resistance cases (Cancer Letters 2016 Vol. 385: 51-54). The EGFR del19/L858R T790M C797S cis mutant kinase variant typically emerges in second line (2L) patients following treatment with osimertinib and is often referred to as “triple mutant” EGFR and it can no longer be inhibited by first, second, or third generation EGFR inhibitors.
No approved EGFR TKI can inhibit the triple mutant variant. Therefore, there is a need to develop new EGFR inhibitors, which can inhibit with high selectivity EGFR mutants with the triple mutant, del19/L858R T790M C797S, while at the same time have no or low activity to wild-type EGFR. In addition to treating a mutant form of EGFR for which there is no current therapy, such selective EGFR inhibitors are likely to be more suitable as therapeutic agents, particularly for the treatment of cancer, due to reduction of toxicologies (diarrhea, skin rash) associated with wild-type EGFR inhibition.
PCT Patent Application No. PCT/US20/66629, the entire teachings of which are incorporated herein by reference, discloses inhibitors of “triple mutant” EGFR, which can be used to treat various cancer, such as NSCLC. The structure of one of the inhibitors disclosed in PCT Patent Application No. PCT/US20/66629, referred to herein as “Compound (I)” is shown below:
There is a need to develop new salt forms and/or solid forms of Compound (I) that are suitable to large scale manufacture and commercialization.
The present disclosure is directed to i) novel pharmaceutically acceptable salts of Compound (I) (e.g., 1:0.5 Compound (I) Semi-Succinate, 1:0.5 Compound (I) Semi-Glutarate, 1:1 Compound (I) Fumarate) including the corresponding solid forms; and ii) novel solid forms of the free base of Compound (I) (hereinafter collectively referred to as “Salt or Solid Forms of the Disclosure”).
The designation “1:0.5” is the molar ratio between Compound (I) and the acid (succinic acid or glutaric acid), and the designation “1:1” is the molar ratio between Compound (I) and the acid (fumaric acid).
In one aspect, the present disclosure provides a succinate salt of Compound (I), wherein the molar ratio between Compound (I) and succinic acid is 1:0.5. As noted above, this salt is also referred herein as “1:0.5 Compound (I) Semi-Succinate”.
In another aspect, the present disclosure provides a glutarate salt of Compound (I), wherein the molar ratio between Compound (I) and glutaric acid is 1:0.5. As noted above, this salt is also referred herein as “1:0.5 Compound (I) Semi-Glutarate”.
In another aspect, the present disclosure provides a fumarate salt of Compound (I), wherein the molar ratio between Compound (I) and fumaric acid is 1:1. As noted above, this salt is also referred herein as “1:1 Compound (I) Fumarate”.
In another aspect, the present disclosure provides a first polymorph of the free base of Compound (I). This first polymorph is also referred herein as “Compound (I) Free Base Form A”.
In another aspect, the present disclosure provides a second polymorph of the free base of Compound (I). This second polymorph is also referred herein as “Compound (I) Free Base Form B”.
In another aspect, the present disclosure provides a pharmaceutical composition comprising 1:0.5 Compound (I) Semi-Succinate, 1:0.5 Compound (I) Semi-Glutarate, 1:1 Compound (I) Fumarate, Compound (I) Free Base Form A, or Compound (I) Free Base Form B, and a pharmaceutically acceptable carrier or diluent.
The present disclosure provides a method of treating or ameliorating cancer in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of the salt or free base form disclosed herein or the corresponding pharmaceutical composition. In some aspects, the cancer which is treated or ameliorated is non-small cell lung cancer.
The present disclosure also provides a method of inhibiting aberrant EGFR activity in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of the salt or free base disclosed herein or the corresponding pharmaceutical composition.
The present disclosure provides a method of inhibiting various mutated forms of EGFR, including EGFR enzymes with amino acid modification selected from the group consisting of L858R, T790M, C797S, and combinations thereof.
The present disclosure is directed to the succinate salt (i.e., 1:0.5 Semi-Succinate salt) of Compound (I), the glutarate salt (i.e., 1:0.5 Semi-Glutarate) of Compound (I), the fumarate salt (i.e., 1:1 Fumarate Salt) of Compound (I), freebase Form A of Compound (I), and freebase Form B of Compound (I).
As used herein, “crystalline” refers to a solid having a crystal structure wherein the individual molecules have a highly homogeneous regular three dimensional configuration.
In some embodiments, for the crystalline forms of Compound (I) salt or free base disclosed herein, at least a particular percentage by weight of the 1:0.5 or 1:1 Compound (I) salt or free base is in a particular crystalline form. Particular weight percentages include 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or a weight percentage of 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-100%, 70-80%, 80-90%, 90-100% by weight of the Compound (I) salt or free base is in a particular crystalline form. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed by the present disclosure.
When the crystalline Compound (I) salt or free base is defined as a specified percentage of one particular crystal form of the Compound (I) salt or free base, the remainder is made up of amorphous form and/or crystal forms other than the one or more particular forms that are specified. Examples of particular crystalline forms include 1:0.5 Compound (I) Semi-Succinate Form C, 1:0.5 Compound (I) Semi-Glutarate Form D, 1:1 Compound (I) Fumarate Form E, Compound (I) Freebase Form A, and Compound (I) Freebase Form B, each of which are characterized by one or more properties as discussed herein.
Compound (I) has 4 chiral centers. Compound (I) in the salts and free base polymorphs disclosed herein is at least 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers, i.e., the ratio of the weight of the stereoisomer over the weight of all the stereoisomers.
The crystalline Compound (I) salts disclosed herein exhibit strong, unique XRPD patterns with sharp peaks corresponding to angular peak positions in 2θ and a flat baseline, indicative of a highly crystalline material (e.g., see
As used herein, an X-ray powder diffractogram is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms are the same±0.2° 2θ. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta (°2θ) referred to herein) generally mean that value reported ±0.2 degrees 2θ of the reported value, an art-recognized variance discussed above.
In some embodiments, the present disclosure provides a succinate salt of Compound (I), represented by the following structural formula:
and wherein the molar ratio between compound (I) and succinic acid is 1:0.5.
In some embodiments, the succinate salt is crystalline.
In some embodiments, 1:0.5 Compound (I) Semi-Succinate is crystalline Form C, characterized by an X-ray powder diffraction pattern which comprises peaks at 4.5°, 9.3°, and 15.3°±0.2 in 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern which comprises at least three peaks chosen from 4.5°, 8.9°, 9.3°, 15.3°, and 17.8°±0.2 in 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern which comprises peaks at 4.5°, 8.9°, 9.3°, 15.3°, and 17.8°±0.2 in 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern which comprises peaks at 4.5°, 8.9°, 9.3°, 13.0°, 15.3°, 16.8°, 17.8°, 18.1°, 18.5°, and 22.3°±0.2 in 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern which comprises peaks at 4.5°, 6.7°, 8.9°, 9.3°, 11.1°, 12.3°, 13.0°, 14.4°, 15.3°, 16.3°, 16.8°, 17.8°, 18.1°, 18.5°, 20.5°, 22.3°, and 26.0°±0.2 in 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern substantially similar to
In some embodiments, Form C is characterized by a differential scanning calorimeter with an onset temperature (i.e., the melting temperature) of 175±2° C. In some embodiments, Form C is characterized by a differential scanning calorimeter with an onset temperature of 176±2° C. In some embodiments, Form C is characterized by a differential scanning calorimeter with a peak temperature of 182±2° C. In some embodiments, Form C is characterized by a differential scanning calorimeter with a peak temperature of 179±2° C.
In some embodiments, Form C is characterized by a thermogravimetric analysis (TGA) substantially similar to
In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of 1:0.5 Compound (I) Semi-Succinate is in crystalline Form C.
In some embodiments, the present disclosure provides a glutarate salt of Compound (I), represented by the following structural formula:
and wherein the molar ratio between compound (I) and glutaric acid is 1:0.5.
In some embodiments, the glutarate salt is crystalline.
In some embodiments, 1:0.5 Compound (I) Semi-Glutarate crystalline Form D, characterized by an X-ray powder diffraction pattern which comprises peaks at 8.8°, 16.10, and 18.3°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern which comprises at least three peaks chosen from 8.8°, 14.8°, 16.1°. 18.3°, and 18.7°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern which comprises peaks at 8.8°, 14.8°, 16.1°. 18.3°, and 18.7°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern which comprises peaks at 7.4°, 8.8°, 12.3°, 14.8°, 16.1°, 18.3°, and 18.7°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern which comprises peaks at 6.6°, 7.4°, 8.8°, 12.3°, 12.9°, 14.8°, 16.1°, 18.3°, 18.7°, 19.2°, 20.0°, and 22.2°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern substantially similar to
In some embodiments, Form D is characterized by a differential scanning calorimeter with an onset temperature of 142±2° C. In some embodiments, Form D is characterized by a differential scanning calorimeter with a peak temperature of 150±2° C. In some embodiments, Form D is characterized by a differential scanning calorimeter with a peak temperature of 148±2° C.
In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) substantially similar to
In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of 1:0.5 Compound (I) Semi-Glutarate is in crystalline Form D.
In some embodiments, the present disclosure provides a fumarate salt of Compound (I), represented by the following structural formula:
and wherein the molar ratio between compound (I) and fumaric acid is 1:1.
In some embodiments, the fumarate salt is crystalline.
In some embodiments, 1:1 Compound (I) Fumarate is in crystalline Form E, characterized by an X-ray powder diffraction pattern which comprises peaks at 6.3°, 8.5°, and 14.5°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern which comprises at least three peaks chosen from 6.3°, 8.5°, 9.0°, 14.5°, 15.7°, and 18.0°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern which comprises peaks at 6.3°, 8.5°, 9.0°, 14.5°, 15.7°, and 18.0°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern which comprises peaks at 6.3°, 8.5°, 9.0°, 12.1°, 14.5°, 15.7°, 18.0°, 19.7°, 20.10, and 21.9°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern which comprises peaks at 6.3°, 8.5°, 9.0°, 12.1°, 14.5°, 15.1°, 15.2°, 15.4°, 15.7°, 18.0°, 18.2°, 18.9°, 19.3°, 19.7°, 20.1°, 20.6°, 20.7°, 21.3°, and 21.9°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern substantially similar to
In some embodiments, Form E is characterized by a differential scanning calorimeter with an onset temperature of 164±3° C. In some embodiments, Form E is characterized by a differential scanning calorimeter with an onset temperature of 165±2° C. In some embodiments, Form E is characterized by a differential scanning calorimeter with an onset temperature of 162±2° C. In some embodiments, Form E is characterized by a differential scanning calorimeter with a peak temperature of 171±2° C.
In some embodiments, Form E is characterized by a thermogravimetric analysis (TGA) substantially similar to
In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of 1:1 Compound (I) Fumarate is in crystalline Form E.
In some embodiments, the present disclosure provides the freebase of Compound (I), represented by the following structural formula:
and wherein the freebase of Compound (I) is in a crystalline Form A.
In some embodiments, Compound (I) Freebase is in a crystalline Form A, characterized by an X-ray powder diffraction pattern which comprises peaks at 9.9°, 12.10, and 14.5°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern which comprises at least three peaks chosen from 9.9°, 12.1°, 14.5°, 15.9°, and 20.1°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern which comprises peaks at 9.9°, 12.1°, 14.5°, 15.9°, and 20.1°±0.2 in 2θ.
In some embodiments, Form A is characterized by an X-ray powder diffraction pattern which comprises peaks at 8.0°, 9.9°, 11.8°, 12.1°, 14.5°, 15.9°, 19.4°, 19.7°, 20.1°, and 20.7°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern which comprises peaks at 6.7°, 8.0°, 9.9°, 11.8°, 12.1°, 14.5°, 15.9°, 18.7°, 19.4°, 19.7°, 20.1°, 20.5°, 20.7°, 22.0°, 22.8°, and 23.8°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern substantially similar to
In some embodiments, Form A is characterized by a differential scanning calorimeter with an onset temperature of 198±2° C. In some embodiments, Form A is characterized by a differential scanning calorimeter with an onset temperature of 197±2° C. In some embodiments, Form A is characterized by a differential scanning calorimeter with a peak temperature of 202±2° C. In some embodiments, Form A is characterized by a differential scanning calorimeter with an onset temperature of 199±2° C. In some embodiments, Form A is characterized by a differential scanning calorimeter with a peak temperature of 203±2° C. In some embodiments, Form A is characterized by a differential scanning calorimeter with an onset temperature of 181±2° C. In some embodiments, Form A is characterized by a differential scanning calorimeter with a peak temperature of 188±2° C.
In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA) substantially similar to
In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) Freebase is in crystalline Form A.
In some embodiments, the present disclosure provides the freebase of Compound (I), represented by the following structural formula:
and wherein the freebase of Compound (I) is in a crystalline Form B.
In some embodiments, Compound (I) Freebase is in crystalline Form B, characterized by an X-ray powder diffraction pattern which comprises peaks at 5.1°, 12.2°, 13.5°, 16.6°, and 20.1°±0.2 in 2θ. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern which comprises peaks at 5.1°, 12.2°, 13.5°, 16.3°, 16.6°, 19.5°, 20.1°, 20.4°, 21.4°, 22.7°, and 25.2°±0.2 in 2θ. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern which comprises peaks at 5.1°, 12.2°, 13.5°, 15.2°, 16.3°, 16.6°, 17.9°, 19.5°, 20.1°, 20.4°, 20.7°, 20.9°, 21.4°, 22.7°, 25.2°, and 26.3°±0.2 in 2θ. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern substantially similar to
In some embodiments, Form B is characterized by a differential scanning calorimeter with an onset temperature of 158±2° C. In some embodiments, Form B is characterized by a differential scanning calorimeter with an onset temperature of 159±2° C. In some embodiments, Form B is characterized by a differential scanning calorimeter with a peak temperature of 165±2° C. In some embodiments, Form B is characterized by a differential scanning calorimeter with a peak temperature of 166±2° C.
In some embodiments, Form B is characterized by a thermogravimetric analysis (TGA) substantially similar to
In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) Freebase is in crystalline Form B.
In some embodiments, the present disclosure provides amorphous form of Compound (I), represented by the following structural formula:
In some embodiments, the amorphous form is characterized by a differential scanning calorimeter with an onset temperature of 106±2° C. In some embodiments, the amorphous form is characterized by a differential scanning calorimeter with an onset temperature of 109±2° C. In some embodiments, the amorphous form is characterized by a differential scanning calorimeter with a peak temperature of 113±2° C. In some embodiments, the amorphous form is characterized by a differential scanning calorimeter with a peak temperature of 114±2° C.
In some embodiments, the amorphous form is characterized by an X-ray powder diffraction pattern substantially similar to
In some embodiments, the amorphous form is characterized by a thermogravimetric analysis (TGA) substantially similar to
In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) Freebase is in the amorphous form.
Pharmaceutical compositions of the disclosure (also referred to herein as the “disclosed pharmaceutical compositions”) comprise a pharmaceutically acceptable carrier or diluent and a Salt or Solid Form of the Disclosure.
Some embodiments of the disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient or a diluent; and a succinate salt of Compound (I), wherein the molar ratio between Compound (I) and succinic acid is 1:0.5. In some embodiments, the succinate salt is crystalline. In some embodiments, the succinate salt of Compound (I) is crystalline Form C.
Some embodiments of the disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient or a diluent; and a glutarate salt of Compound (I), wherein the molar ratio between Compound (I) and glutaric acid is 1:0.5. In some embodiments, the glutarate salt is crystalline. In some embodiments, the glutarate salt of Compound (I) is crystalline Form D.
Some embodiments of the disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient or a diluent; and a fumarate salt of Compound (I), wherein the molar ratio between Compound (I) and fumaric acid is 1:1. In some embodiments, the fumarate salt is crystalline. In some embodiments, the fumarate salt of Compound (I) is crystalline Form E.
Some embodiments of the disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient or a diluent; and Compound (I) free base. In some embodiments, the free base is crystalline. In some embodiments, the free base of Compound (I) is crystalline Form A. In some embodiments, the free base of Compound (I) is crystalline Form B.
“A pharmaceutically acceptable carrier” or “a pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, hydroxymethycellulose, fatty acid esters, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with Salt or Solid Form of the Disclosures or pharmaceutically acceptable salts thereof.
The pharmaceutical compositions of the disclosure optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003—20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
The present disclosure provides a method of inhibiting certain mutant forms of epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject an effective amount of a Salt or Solid Form of the Disclosure or a pharmaceutical composition disclosed herein. Mutant forms of EGFR include for example, EGFR with LRTMCS mutation (the exon 19 deletion (del19) or exon 21 (L858R) substitution mutation, T790M mutation, and C797S mutation). Subjects “in need of inhibiting EGFR” are those having a disease for which a beneficial therapeutic effect can be achieved by inhibiting at least one mutant EGFR, e.g., a slowing in disease progression, alleviation of one or more symptoms associated with the disease or increasing the longevity of the subject in view of the disease.
In some embodiments, the disclosure provides a method of treating a disease/condition/or cancer associated with or modulated by mutant EGFR, wherein the inhibition of the mutant EGFR is of therapeutic benefit, including but not limited to the treatment of cancer in a subject in need thereof. The method comprises administering to the subject an effective amount of a Salt or Solid Form of the Disclosure or pharmaceutical composition disclosed herein.
In another embodiment, the disclosure provides a method of treating a subject with cancer, comprising administering to the subject an effective amount of a Salt or Solid Form of the Disclosure or a pharmaceutical composition disclosed herein. Cancers to be treated according to the disclosed methods include lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancers, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, including metastasis (in particular brain metastasis) of all cancers listed. Typically, the cancer is characterized by at one or more EGFR mutations described herein. In a specific embodiment, the cancer has progressed on or after EGFR tyrosine kinase inhibitor (TKI) Therapy. In a specific embodiment, the disease has progressed on or after first line osimertinib.
In a specific embodiment, the cancer to be treated is lung cancer. In a more specific embodiment, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology and NSCLC with non-squamous histology. In another embodiment, the lung cancer is NSCLC adenocarcinoma. In another specific embodiment, the lung cancer (or non-small cell lung cancer) has metastasized to the brain.
In another embodiment, the disease/condition/or cancer associated with or modulated by mutant EGFR that is characterized by an EGFR genotype selected from genotypes 1-17 according the Table below (del18=Exon 18 deletion, specifically, e.g., delE709_T710 insD; del19=Exon 19 deletion, specifically, e.g., delE746_A750 (most common), delE746_S752insV, del747_A750insP, delL747_P753insS, and delS752_I759; ex20ins-Exon 20 insertion, specifically, e.g., D761-E762insX, A763-Y764insX, Y764-V765insX, V765-M766insX, A767-S768insX, 5768-D769insX, V769-D770insX, N771-P772insX, P772-H773insX, H773-V774insX, and V774-C775insX):
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 C797S.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 C797X (C797G or C797N).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M C797S.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M (C797G or C797N).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 L792X (L792F, L792H or L792Y).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M L792X (L792F, L792H, or L792Y).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 G796R (G796S).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 L792R (L792V or L792P).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 L718Q (L718V).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M G796R (G796S).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M L792R (L792V or L792P).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M L718Q (L718V).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R C797S.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R C797X (797G or C797N). In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M C797S.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M C797X (797G or C797N).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R L792X (L792F, L792H or L792Y).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R L790M L792X (L792F, L792H or L792Y).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R G796R (G796S).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R L792R (L792V or L792P).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R L718Q (L718V).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M G796R (G796S).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M L792R (L792V or L792P).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M L718Q (L718V). In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del18.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719R, G719D, or G719V).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR E709X (E709K, E709H, or E709A).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR ex20ins.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR ex20ins L718Q.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR ex20ins T790M.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR ex20ins C797S.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR S76811.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR T790M.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR T790M C797S/G L792X (L792F, L792H, L792R, or L792Y).
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by an EGFR genotype selected from genotypes 1-17.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to osimertinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to afatinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to dacomitinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to gefitinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to erlotinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to osimertinib and afatinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to osimertinib and dacomitinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to osimertinib and gefitinib.
In another embodiment, the disease/condition/or cancer (e.g., NSCLC) being treated with a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR mutations that confer resistance to osimertinib and erlotinib.
Another embodiment is the treatment a subject with metastatic NSCLC with tumors harboring activating Exon 19 Deletion or L858R EGFR mutations as well as a resistance mutation disclosed herein as detected by an approved molecular testing methodology. Another embodiment is a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, used in combination with a 1st or 3rd generation TKI indicated for the treatment of subject with metastatic NSCLC with tumors harboring T790M and C797S mutations as detected by an approved test, and whose disease has progressed on or after at least 2 prior EGFR TKI therapies.
Another embodiment is a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, for the treatment of subjects with metastatic NSCLC whose disease with on-target EGFR resistance has progressed on or after any EGFR TKI. In a specific embodiment, the Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is used in combination with a 1st or 3rd generation TKI indicated for the treatment of subject with metastatic NSCLC.
Another embodiment is a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, for the treatment of subjects with metastatic EGFR C797S mutation-positive NSCLC as detected by an approved molecular test, whose disease has progressed on or after first-line osimertinib. In a specific embodiment, the Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, is used in combination with a 1st or 3rd generation TKI indicated for the treatment of subject with metastatic NSCLC.
In a particular embodiment, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.
A person of ordinary skill in the art can readily determine the certain EGFR alterations a subject possesses in a cell, cancer, gene, or gene product, e.g., whether a subject has one or more of the mutations or deletions described herein using a detection method selected from those known in the art such as hybridization-based methods, amplification-based methods, microarray analysis, flow cytometry analysis, DNA sequencing, next-generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot, and Southern blot.
To detect one or more EGFR deletions and/or mutations, a primary tumor sample, circulating tumor DNA (ctDNA), circulating tumor cells (CTC), and/or circulating exosomes may be collected from a subject. The samples are processed, the nucleic acids are isolated using techniques known in the art, then the nucleic acids are sequenced using methods known in the art. Sequences are then mapped to individual exons, and measures of transcriptional expression (such as RPKM, or reads per kilobase per million reads mapped), are quantified. Raw sequences and exon array data are available from sources such as TCGA, ICGC, and the NCBI Gene Expression Omnibus (GEO). For a given sample, individual exon coordinates are annotated with gene identifier information, and exons belonging to kinase domains are flagged. The exon levels are then z-score normalized across all tumors samples.
The Salts and Solid Forms of the Disclosure, or pharmaceutical compositions disclosed herein, may be used for treating to a subject who has become refractory to treatment with one or more other EGFR inhibitors. “Refractory” means that the subject's cancer previously responded to drugs but later responds poorly or not at all. In some embodiments, the subject has become refractory to one or more first generation EGFR inhibitors such as erlotinib, gefitinib, icotinib or lapatinib. In some embodiments, the subject has been become refractory to treatment with one or more second generation EGFR inhibitors such as afatinib, dacomitinib, poziotinib, or neratinib. In some embodiments the subject has become refractory to treatment with one or more first generation inhibitors and one or more second generation inhibitors. In some embodiments, the subject has become refractory to treatment with one or more third generation inhibitors such as osimertinib, nazartinib, or avitinib. In one embodiment, the subject has become refractory to treatment with one or more first generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more second generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more first generation inhibitors, and one or more third generation EGFR inhibitors.
The Salt or Solid Form of the Disclosure, or pharmaceutical compositions disclosed herein can be used in combination with one or more additional pharmacologically active substances. For example, the disclosure includes methods of treating a condition/disease/or cancer comprising administering to a subject in need thereof a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, in combination with an EGFR (or EGFR mutant) inhibitor, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST 2818), almonertinib (HS10296), BBT-176, BI-4020, CH7233163, gilitertinib, JND-3229, lazertinib, nazartinib (EGF 816), PCC-0208027, rezivertinib (BPI-7711), TQB3804, zorifertinib (AZ-3759), or DZD9008; an EGFR antibody such as cetuximab, panitumumab, necitumumab, HLX07, JMT101; or a bispecific EGFR and MET antibody (e.g., amivantamab ((JNJ-61186372, JNJ-372)). For the treatment of cancer e.g., NSCLC using a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, in combination with a first line therapy, for example a first, second, or third generation EGFR inhibitor (i.e., as an initial treatment before the cancer has become refractory) may forestall or delay the cancer from becoming refractory. Typically, the cancer is characterized by one of the EGFR genotypes described herein.
Alternatively, a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, can be administered in combination with other anti-cancer agents that are not EGFR inhibitors e.g., in combination with MEK, including mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib, glumetinib, tepotinib) and MET antibodies (emibetuzumab, telisotuzumab vedotin (ABBV 339)); mitotic kinase inhibitors (CDK4/6 inhibitors such as palbociclib, ribociclib, abemacicilb, GIT38); anti-angiogenic agents e.g., bevacizumab, nintedanib; apoptosis inducers such as Bcl-2 inhibitors e.g, venetoclax, obatoclax, navitoclax, palcitoclax (APG-1252), and Mcl-1 inhibitors e.g., AZD-5991, AMG-176, S-64315; mTOR inhibitors e.g, rapamycin, temsirolimus, everolimus, ridoforolimus; RET inhibitors, like pralsetinib and selpercatinib, and PI3K inhibitors dactolisib (BEZ235), pictilisib (GDC-0941), LY294002, idelalisib (CAL-101); JAK inhibitors (e.g., AZD4205, itacitinib), Aurora A inhibitors (e.g., alisertib); BCR/ABL and/or Src family tyrosine kinase inhibitors (e.g., dasatinib); VEGF inhibitors (e.g., MP0250; ramucirumab); multi-kinase protein inhibitors (e.g., anlotinib, midostaurin); PARP inhibitors (e.g., niraparib); platinum therapies (e.g., cisplatin (CDDP), carboplatin (CBDCA), or nedaplatin (CDGP)); PD-L1 inhibitors (e.g., durvalumab (MEDI 4736)); HER2/neu receptor inhibitors (e.g., trastuzumab); anti-HER2 or anti-HER3 antibody-drug conjugates (e.g., patritumab deruxtecan (U3-1402), trastuzumab emtansine); or immunogene therapy (e.g., oncoprex).
A “subject” is a human in need of treatment.
The precise amount of the Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the cancer, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti-cancer agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a Salt or Solid Form of the Disclosure being used by following, for example, dosages reported in the literature and recommended in the Physician's Desk Reference (57th Ed., 2003).
“Treating” or “treatment” refers to obtaining a desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or substantially reducing the extent of the disease, condition or cancer; ameliorating or improving a clinical symptom or indicator associated with the disease, condition or cancer; delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or cancer; or decreasing the likelihood of recurrence of the disease, condition or cancer.
The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day; and in another alternatively from 10 mg to 1 gram per day).
The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
In addition, a Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, can be co-administered with other therapeutic agents. As used herein, the terms “co-administration”, “administered in combination with”, and their grammatical equivalents, are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. In some embodiments the Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, will be co-administered with other agents. These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present. Thus, in some embodiments, the Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are admixed in the composition.
The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years. However, a person of ordinary skill in the art would immediately recognize appropriate and/or equivalent doses looking at dosages of approved compositions for treating a disease using the disclosed EGFR inhibitors for guidance.
The Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The Salt or Solid Form of the Disclosure, or a pharmaceutical composition disclosed herein, may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred embodiments, the pharmaceutical composition is formulated for intravenous administration.
Typically, for oral therapeutic administration, a Salt or Solid Form of the Disclosure may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
Typically for parenteral administration, solutions of a Salt or Solid Form of the Disclosure be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Typically, for injectable use, sterile aqueous solutions or dispersion of, and sterile powders of, a Salt or Solid Form of the Disclosure for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate.
The following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure.
DSC was performed using a Mettler Toledo DSC3+. The sample (1-5 mg) was weighed directly in a 40 μL hermetic aluminum pan with pin-hole and analyzed according to the parameters below:
DVS was performed using a DVS Intrinsic 1. The sample (5-25 mg) was loaded into a sample pan, suspended from a microbalance and exposed to a humidified stream of nitrogen gas. The sample was held for a minimum of 5 min at each level and only progressed to the next humidity level if there was <0.002% change in weight between measurements (interval: 60 s) or 60 min had elapsed. The following program was used:
HPLC was conducted using an Agilent 1220 Infinity LC. Flow rate range was 0.2-5.0 mL/min, operating pressure range was 0-600 bar, temperature range was 5° C. above ambient to 60° C., and wavelength range was 190-600 nm. The HPLC method is shown below:
The liquid chromatography-mass spectrometry (LC-MS) data were obtained with an Agilent model-1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization fitted with an Agilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0×50 mm dimensions) reverse-phase column at 22.4° C. The mobile phase consisted of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 4 minutes was utilized. The flow rate was constant at 1 mL/min.
Proton NMR (1H NMR) was performed on a Bruker Avance 300 MHz spectrometer. Solids were dissolved in 0.75 mL deuterated solvent in a 4 mL vial, transferred to an NMR tube (Wilmad 5 mm thin wall 8″ 200 MHz, 506-PP-8) and analyzed according to the following parameters:
1H
pH was measured using a Mettler Toledo FP20 bench meter equipped with a Mettler Toledo InLab Micro pH electrode. The electrode had a ceramic junction and membrane resistance of <600 MQ. The internal reference electrolyte solution used was KCl and the operating range was 0-14 pH units and 0-80° C.
TGA and DSC were performed on the same sample simultaneously using a Mettler Toledo TGA/DSC3+. Protective and purge gas was nitrogen at flowrate 20-30 mL/min and 50-100 mL/min respectively. The desired amount of sample (5-10 mg) was weighed directly in ahermetic aluminum pan with pin-hole and analyzed according to the parameters below:
XRPD was performed using a Bruker D8 Advance equipped with LYNXEYE detector in reflection mode (i.e. Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters for XRPD methods used are listed below:
Compound (I) in freebase (301 mg) was weighed in a 20 mL vial, to which 1.3 eq of succinic acid (83.4 mg) and a stir bar were added. 15 volumes of EtOAc (4.51 mL) were added at 45° C. and left to stir for one hour. Solids were bright yellow and were filtered and washed with 2×2 vol. of EtOAc. Solids were dried in a vacuum oven at 50° C. overnight. The XRPD pattern indicated excess succinic acid was present. Solids were then re-slurried in 5 vol.
(1.36 mL) of IPA for 1 hour and were then filtered and washed with 2×2 vol of IPA. Solids were dried in a vacuum oven at 50° C. overnight. Purity by HPLC was 99.50 area %. The solid obtained was further characterized by XRPD using the Regular Scan Method (see
The combined DSC and TGA thermogram showed a total mass loss of 0.85 wt. % and an endotherm onset at 176.3° C. (
DVS was completed and showed a mass change of 7.1 wt. % between 2 and 95% relative humidity at 25° C. After the standard 60 minutes at 95% RH, the compound had not reached equilibrium and thus this interval was held for a total of 240 minutes. After this time the compound still had not reached equilibrium, and experiment was continued as described in the DVS analysis conditions above.
Compound (I) in freebase (401 mg) was weighed in a 20 mL vial, to which 1.1 eq of glutaric acid (104.6 mg) and a stir bar were added. 15 volumes of EtOAc were added at 45° C. After one hour, the temperature was decreased to RT, and the thin yellow slurry was left to stir overnight. The following morning, the slurry was noticeably thicker and a more vibrant yellow in color. The slurry was filtered, washed with 2×2 volumes of EtOAc, and dried under active vacuum (−30 in Hg) for 5 h at 50° C. Purity by HPLC was 99.45 area % and stoichiometry was calculated to be 1:0.53 Compound (I) Semi-Glutarate based on 1H NMR. The solid obtained was further characterized by XRPD using the Regular Scan Method (see
The combined DSC and TGA thermogram showed essentially no mass loss and an endotherm onset at 142.5° C. (
Compound (I) in freebase (409.5 mg) was weighed in a 20 mL vial, to which 1.1 eq of fumaric acid (96.6 mg) and a stir bar were added. 15 volumes of EtOAc were added at 45° C. After one hour, the temperature was decreased to RT, and the slurry remained pastel-yellow and thin after stirring overnight. TFE was added (100 μL) to aid in the dissolution of the solids at 45° C. The solvent was evaporated with stirring at 45° C. and 5 mL of TFE was added to achieve full dissolution of the solids. The solvent was once again evaporated with active stirring overnight, and the vial was placed under active vacuum at 50° C. for 3 h. Once dry, 15 vol. of EtOAc was added to the solids at 45° C. The bright-yellow slurry was stirred at 45° C. for one hour, then at RT. The slurry was filtered, washed with 2×2 volumes of EtOAc, and dried under active vacuum (−30 in Hg) for 5 h at 50° C. Purity by HPLC was 99.31 area % and the stoichiometry was calculated to be 1:0.95 Compound (I) Fumarate based on 1H NMR. The solid obtained was further characterized by XRPD using the Regular Scan Method (see
The combined DSC and TGA thermogram showed a total mass loss of 0.3 wt. % and an endotherm onset at 162.2° C. (
(2R,3S)-1-benzhydryl-2-methylazetidin-3-ol (Pharmablock, 20 g, 78.9 mmol) was dissolved in 300 mL DCM and TEA (9.55 g, 94.6 mmol) was added and the reaction mixture cooled in an ice bath. Mesyl chloride (9.93 g, 86.7 mmol) was added dropwise and allowed to stir, warming slowly to rt and stirred overnight. The mixture was diluted with DCM and washed with water and the organic phase dried over sodium sulfate, filtered and evaporated to give 26 g (98%) of the title compound as a viscous yellow oil.
Analytical Data: LC-MS: (ES, m/z)=332 [M+1].
(2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (26 g, 78.4 mmol) and methyl 2-(methylsulfonyl)acetate (15.3 g, 101 mmol) were dissolved in 260 mL DMF and then NaH (3.75 g of 60% dispersion in mineral oil, 6.63 mmol) was added and stirred for −15 minutes, until hydrogen evolution had ceased. The reaction mixture was heated to 80° C. overnight. The reaction was cooled and then diluted with −200 mL water and extracted with EtOAc and combined organics washed with water, brine and dried over sodium sulfate, filtered and evaporated to give the crude product. The residue was purified by chromatography (0 to 7% MeOH/DCM). Pure fractions combined and evaporated to give 24 g (80%) of the title compound as a pale-yellow foam.
(S)-methyl-2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (24 g, 61.9 mmol) was dissolved in 240 mL DMA and lithium chloride (20.9 g, 495 mmol) was added and the flask put into a preheated block that was kept at 150° C. LC/MS indicated the starting material was consumed after 1.5 h. Cooled to room temperature and dilute with water, extracted with EtOAc and the combined organics washed with water, brine and dried over sodium sulfate. Filtered and evaporated to give the crude product and further purified by chromatography (0 to 5% MeOH/DCM). Pure fractions were combined and evaporated to give 19 g (93%) of the title compound as a pale-yellow foam.
Analytical Data: LC-MS: (ES, m/z)=330 [M+1].
To a solution of (2R,3S)-1-(diphenylmethyl)-3-(methanesulfonylmethyl)-2-methylazetidine (1 9 g, 57.3 mmol) in MeOH (270 mL) was added TFA (9 mL) and Pd(OH)2 (5.7 g), the reaction was stirred overnight at rt under H2 atmosphere. The reaction mixture was filtered and evaporated to give the crude title compound (17 g) as a light-brown oil.
Analytical Data: LC-MS: (ES, m/z)=164 [M+1].
Sodium hydride (218.90 mg, 9.122 mmol, 4 equiv.) was added to tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.280 mmol, 1 equiv.) in THF (10 mL) at 0° C. After stirring for 20 min, methyl iodide (1294.73 mg, 9.122 mmol, 4 equiv.) was added. The resulting solution was stirred for additional 1 h at 0° C. The reaction was then quenched by addition of 10 mL of water. The solids were filtered out. The resulting solution was extracted with EtOAc and concentrated under vacuum. This resulted in 500 mg (94.1%) of the title compound as light-yellow oil.
Analytical Data: LC-MS: (ES, m/z)=178 [M+1-56].
The solution of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate (500 mg, 2.143 mmol, 1 equiv.) in TFA/DCM ( 3/10 mL) was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum to afford 500 mg (crude) of the title compound as a solid.
The mixture of (3S,4R)-3-fluoro-4-methoxypiperidine(3 g, 22.528 mmol, 1 equiv.), 2-chloropyrimidin-4-amine (2.33 g, 0.018 mmol, 0.8 equiv.) and TEA (6.84 g, 0.068 mmol, 3 equiv.) in IPA (3 mL) was stirred for 12 h at 100° C. The solvent was removed under vacuum and residue was purified by FLASH (5% MeOH in DCM) to give 3.3 g (66%) of the title compound as a light-yellow solid.
Analytical Data: LC-MS: (ES, m/z)=227 [M+1]. 1H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J=5.6 Hz), 6.39 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.83 (d, 1H, J=49.3 Hz), 4.60-4.49 (m, 1H), 4.29 (d, 1H, J=13.3 Hz), 3.55-3.42 (m, 1H), 3.28 (d, 1H, J=13.3 Hz), 3.20-3.04 (m, 1H), 1.76-1.48 (m, 2H)
Trifluoromethanesulfonyl trifluoromethanesulfonate (45.7 g, 162 mmol) was added dropwise to 8-bromo-3-chloroisoquinolin-5-ol (14 g, 54.1 mmol) and TEA (21.8 g, 216 mmol) in DCM (400 mL) at −60° C. The resulting mixture was warmed to room temperature naturally and stirred at rt for 1 h. The mixture was concentrated under vacuum. The residue was purified by a silica gel column with PE:EA=5:1 to afford 18 g (85%) the title compound as a white solid.
Analytical Data: LC-MS: (ES, m/z)=392 [M+1]; 1H NMR (400 MHz, DMSO-d6) δ 9.46 (d, 1H, J=0.8 Hz), 8.20 (d, 1H, J=8.3 Hz), 8.02 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=0.7 Hz).
The mixture of K2CO3 (6 g, 43.5 mmol), 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (17 g, 43.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.30 g, 43.5 mmol) and Pd(dppf)Cl2·CH2·Cl2 (2.83 g, 3.48 mmol) in dioxane/H2O (200/20 mL) was stirred for 3 h at 45° C. The mixture was diluted with 500 mL of EA and washed with brine 200 mL*2. The organic layer was dried with Na2SO4 and concentrated under vacuum. The residue was purified by a silica gel column with PE:EtOAc=20:1 to afford 8.0 g (67%) the title compound as an off-white solid.
Analytical Data: LC-MS: (ES, m/z)=282 [M+1].
PtO2 (1.7 g 7.04 mmol) and 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (7.1 g, 25.1 mmol) in EA (300 mL) were stirred under an atmosphere of H2 balloon at rt and stirred for 1 h. The solid was filtered out. The mother solvent was concentrated under vacuum. The crude product was purified by a silica gel column with PE:EtOAc=10:1 to get 6.7 g (93%) the title compound as a brown solid.
Analytical Data: LC-MS: (ES, m/z)=284 [M+1].
To a solution of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (9 g, 31.6 mmol) in 1,4-dioxane (130 mL) was added (2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (5.15 g, 31.6 mmol), Cs2CO3 (20.6 g, 63.2 mmol) and Xantphos Pd G4 (1.51 g, 1.58 mmol) under nitrogen. The mixture was stirred at 100° C. for 3 h under nitrogen. The reaction mixture was cooled to rt and diluted with 300 mL of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-60% EtOAc in PE) to give 7.2 g (62.6%) of 3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline as yellow solid.
To a solution of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (18.50 mg, 0.082 mmol, 1 equiv.), 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (30 mg, 0.082 mmol, 1 equiv.) and Cs2CO3 (53.3 mg, 0.164 mmol, 2 equiv.) in 1,4-Dioxane (0.82 ml) was added BrettPhos Precatalyst (Gen IV) (3.76 mg, 4.09 μmol, 0.05 equiv.) under N2, the mixture was stirred at 90° C. for 16 h. The mixture was filtered and concentrated in vacuo. The crude mixture was purified by reverse phase chromatography (0 to 60% acetonitrile/water containing 0.1% TFA). Pure fractions were combined and neutralized with saturated sodium bicarbonate solution and then extracted with 10% MeOH/DCM (5 mL×3). Combined organic phases dried over sodium sulfate, filtered and evaporated to give 17.4 mg of the title compound (38%) as a yellow solid.
XRPD diffractogram of the obtained product demonstrated that the solid was a crystalline material which was denoted as Form A. It was later determined that the obtained product contains XPhos related impurities which show peaks at 2θ of ˜8.34 and ˜9.54 in the XRPD.
Approximately 20-25 mg of the amorphous Compound (I) (see Example 6) were placed in 2 mL vials with 5 mm stir bars. The respective solvent was added to the vials by mixing with a stirring rate of 300 rpm at RT and the clear solutions/slurries were stirred at RT. In most cases, the solids dissolved completely into clear solutions and were stirred continuously without adding additional solids. Thin or very thick slurries were observed from the clear solutions in 2 min to 1 h. The slurries were sampled on day 0 (as soon as the slurries were observed), day 1, day 4, and day 5. The observations were recorded and are summarized below in Table 4.
Approximately 10-20 mg of the amorphous Compound (I) were weighed into 2 mL vials and the vials were placed in 20 mL scintillation vials containing 2 mL of the respective diffusing solvent. The 20 mL scintillation vials were sealed with caps and parafilm. The observations were made immediately after exposure of the amorphous solid into vapor diffusion and the are summarized in Table 5. In most of the cases, the fluffy amorphous solids were observed to shrink into a dark-yellow thin layer at the bottom of the vial.
Approximately 25-35 mg of the amorphous Compound (I) was dissolved in the solvent mostly at RT. Twice the amount of antisolvent was taken in a separate vial, to which the solution was added as one transfer with rapid stirring. For example, if solids dissolved in 0.5 mL of solvent, then the solution was added to 1.0 mL of antisolvent as one transfer with vigorous stirring. Once solids were formed, the slurries were filtered, and the recovered solids were analyzed by XRPD. The results of antisolvent crystallizations in reverse additions are shown in Table 6.
Only in MEK/n-heptane, a medium-thin slurry formed in 15 min after the solution was added to the antisolvent by vigorous stirring. The slurry was filtered and the solid recovered was analyzed by XRPD. A hazy solution formed in tetrahydrofuran (THF)/EtOH 2 h after adding solution to the antisolvent with continued stirring (˜600 rpm). The hazy solution turned to a thin slurry, which was filtered under reduced pressure and the solid was analyzed by XRPD. Also, hazy solutions formed in THF/isopropyl acetate (IPAc) and THF/toluene, 3 h after adding solution to antisolvent with continued stirring at RT. For other solvents, the clear solutions were transferred to a chiller block at −5° C. with continued stirring for one week. The clear solutions remained clear, and the vials were transferred to the freezer at −20° C. A small amount of crystalline solids or precipitate were observed.
Approximately 22-35 mg of the amorphous Compound (I) was taken in either 2 mL or 4 mL vials, depending upon the solvent required to dissolve the solid. The solvent was added to the solids and the thin/medium slurries were stirred at 30° C. with stir bars (5 mm for 2 mL vials and 10 mm thin bars for 4 mL vials) for up to 1 h to obtain a clear solution. Twice the volume of solvent was used as antisolvent. For example, if solids dissolved in 0.5 mL solvent, then 1.0 mL of the antisolvent was used for the direct addition. The antisolvent was added in four equal portions dropwise to the vigorously stirring solution over an hour.
In the cases of MEK, 1,4-dioxane, and THF, thin slurries formed on adding the solvent to the solids, which remained even after stirring for 1 h at 30° C. However, the thin slurries were dissolved into clear solution by heating the vials at 40° C. for less than 5 min. The vials were then transferred to RT and the antisolvent was added. In the case of 2-methyltetrahydrofuran (2-MeTHF): dimethyl sulfoxide (DMSO) (9:1 vol.), the solids dissolved in 7 vol of the solvent. Thehazy solutions/very thin slurries were continuously stirred at RT for 2 days and medium to thick slurries were observed in most of the cases. The summary of the experiments is given Table 7.
Approximately 25-35 mg of the amorphous Compound (I) was weighed into 2 mL vial. The solvents and 5 mm stir bars were added to vial and stirred at 50° C. at a stirring rate of 450 rpm. The thin slurry/hazy solutions were heated to 60° C. to obtain clear solutions if required. The clear solutions were transferred to an ice-water bath near 0° C. without mixing. Care was taken to ensure no visible crust was present prior to cooling of the samples. In general, no slurries or solids were observed in fast-cooling crystallization upon transferring solutions to the ice-water bath. However, in some cases hazy solutions were observed after allowing the solutions to stir at RT on stir plate inside the ice-water bath for up to 1 h and solids obtained after being transferred to the freezer at −20° C. The summary of the fast-cooling crystallization is given in Table 8.
Approximately 25-35 mg of the amorphous Compound (I) was weighed into 2 mL vials. The solvents and 5 mm stir bars were added to vial and stirred at 50° C. at a stirring rate of 450 rpm. In all the cases, thin slurries were formed at −50° C. due to the concentration of the solids in the solvents. Hence, the vials were heated up to 67° C. to obtain clear solutions. Care was taken to ensure no visible crust was present prior to cooling of the samples. The clear solutions at 67 RC were then cooled to RT with the cooling rate of 5° C./h. This was achieved by reducing the temperature of hotplate by 2.5° C. every 30 min. The summary of the slow-cooling crystallization is given in Table 9.
Approximately 25-35 mg of the amorphous Compound (I) was weighed into 2 mL vials. The solvents and 5 mm stir bars were added to the vial and stirred at 50° C. at a stirring rate of 450 rpm. The thin slurry/hazy solutions were heated to 60° C. to obtain clear solutions, if required. The clear solutions were transferred to a freezer at −20° C. and crystallization process was observed periodically. Care was taken to ensure no visible crust was present prior to cooling of the samples. The summary of the experiments is given in Table 10.
Approximately 25-35 mg of the amorphous Compound (I) was weighed in 2 mL or 4 mL vials depending on the amount of solvent required to completely dissolve the solids into clear solutions. The solvents were added to the vials by mixing with 5 mm (for 2 mL vials) or 10 mm (for 4 mL vials) stir bars on the stir plate at RT at a stirring rate of 300 rpm. Once the solids were dissolved completely into clear solutions, the vials were capped or sealed, and the caps were pinned with high gauge syringe needles to allow solvents to slowly evaporate from the vials. The solutions continued to stir during the slow evaporation. The summary of the experiments is given in Table 11.
Approximately 25-35 mg of the amorphous Compound (I) was weighed in 4 mL vials and the solvents were added by mixing with 10 mm stir bars. The microscope slides were placed on preheated hotplate at −115° C. The clear solutions were added dropwise using glass pipette on the hot microscope slides. The solutions were evaporated instantly while dropping on the slides and overall, the solutions turned to fluffy solids in less than 2 min. The solids were recovered by scrapping the slides by spatula and used for analysis. The summary of the flash evaporation experiments is given in Table 12.
Slow evaporation in the presence of crystallographic template was carried out with clear solutions obtained in the presence of the templates. A ground mixture of various minerals (fluorite, garnet, pyrite, apophyllite, dolomite, corundum, tourmaline, topaz, celestite, staurolite, diopside, and amazonite) were used as crystallographic templates for this purpose. The solutions with the templates were allowed to evaporate with the sealed caps, pinned with high gauge syringe needles to allow solvents to evaporate from the vials by mixing the solutions. The summary of the slow evaporation with and crystallography template are given in Table 13.
The obtained Compound (I) Form A was characterized by XRPD using the High Resolution Scan Method (see
The combined DSC and TGA thermogram showed a total mass loss of 0.7 wt. % and endotherm onsets at 170.53° C. and 196.81° C. (
Form B of Compound (I) (351.2 mg) was made via reverse antisolvent addition with DMAc/water as described above for Form A. The thick light-yellow slurry was filtered and washed with 1×2.0 vol. of water and left on the filter paper for 5 min with active suction from the aspirator. The sample was then placed in the oven at 50° C. under active vacuum for 15 min and then left on the benchtop overnight to dry. After drying, The solid obtained was further characterized by XRPD using the High-Resolution Scan Method (see
The combined DSC and TGA thermogram showed a total mass loss of 0.1 wt. % and an endotherm onset at 158.7° C. (
DVS was completed and showed a mass change of 2.1 wt. % between 2 and 95% relative humidity at 25° C.
Approximately 263 mg of the Compound (I) was weighed into a 20 mL scintillation vial and 10 mm stir bar was added. To the vial was added 8 mL of ACN:water (8:2 vol.) by mixing at RT and a medium-thin slurry was formed. The slurry was stirred at −55° C. for 10 min and it turned to a thin slurry. Additional solvent (2 mL) was added and the thin slurry continued to stir for another 10 min at −55° C. A very thin slurry remaining after 10 min was syringe filtered using 45 m filter into another clean 20 mL scintillation vial. The clear yellow solution was freeze-dried by placing the vial in liquid nitrogen for 2-3 min. The vial with fully frozen solid was lyophilized overnight. The solid recovered after overnight lyophilization was fluffy and amorphous in nature. The solid obtained was further characterized by XRPD using the Regular Scan Method (see
The combined DSC and TGA thermogram showed onset endotherms at 30.7° C. and 108.7° C. (
This application claims priority to U.S. Provisional Application No. 63/214,089, filed on Jun. 23, 2021. The entire contents of the aforementioned application are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/034550 | 6/22/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63214089 | Jun 2021 | US |
