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WO2025202991A1 - Forme cristalline de (s)-n-éthyl-3-((9-éthyl-2-(((2r,3s)-2-hydroxypentan-3-yl)amino)-9h-purin-6-yl)amino)-pyrrolidine-1-sulfonamide - Google Patents

Forme cristalline de (s)-n-éthyl-3-((9-éthyl-2-(((2r,3s)-2-hydroxypentan-3-yl)amino)-9h-purin-6-yl)amino)-pyrrolidine-1-sulfonamide

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Publication number
WO2025202991A1
WO2025202991A1 PCT/IB2025/053301 IB2025053301W WO2025202991A1 WO 2025202991 A1 WO2025202991 A1 WO 2025202991A1 IB 2025053301 W IB2025053301 W IB 2025053301W WO 2025202991 A1 WO2025202991 A1 WO 2025202991A1
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WO
WIPO (PCT)
Prior art keywords
crystalline form
amino
cancer
ppm
cthyl
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Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/IB2025/053301
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English (en)
Inventor
Dedong Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
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AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2025202991A1 publication Critical patent/WO2025202991A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates generally to a solid-state form of V-ethyl-3-((9- cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)pyrrolidinc- l - sulfonamide, particularly a crystalline form of (.S')-A'-cthyl-3-((9-cthyl-2-(((2/?,3.S')-2- hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-l -sulfonamide.
  • the present disclosure further relates to pharmaceutical compositions comprising a crystalline form of (.S')-A'-cthyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)- pyrrolidine -1 -sulfonamide; use of a pharmaceutical composition comprising a crystalline form of (.S')-A'-cthyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6- yl)amino)pyrrolidine-l -sulfonamide to treat or prevent cyclin-dependent kinase 2 (CDK2)- mediated conditions; kits comprising a pharmaceutical composition comprising a crystalline form of (.S')- '-cthyl-3-((9-cth
  • Cyclin-dependent kinases including CDK2, are serine/threonine protein kinases involved in cell cycle regulation. CDK2 drives the progression of cells into the S- and M-phases of the cell cycle. Overexpression of CDK2 is associated with abnormal regulation of the cell-cycle and tumor growth in multiple cancer types.
  • the monomeric form of CDK2 is inactive, but is activated when it forms a heterodimeric complex with one of its two regulatory partners, Cyclin A or Cyclin E. Cyclin E binding to CDK2 in the late G1 phase of the cell cycle is required for the transition from the G1 to S phase of the cell cycle. Cyclin A binding to CDK2 is then required to progress through the S phase of the cell cycle.
  • the present disclosure addresses this large unmet need by providing a crystalline form of the CDK2 inhibitor, (S)-A-ethyl-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3- yl)amino)-9//-purin-6-yl)amino)pyrrolidinc- 1 -sulfonamide, that is suitable for use in pharmaceutical compositions and methods for treating CDK2 -mediated conditions such as breast and ovarian cancers.
  • the present disclosure provides a crystalline form of/V-ethyl-3-((9- cthyl-2-(((2/?.3.Sj-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)pyrrolidinc- l - sulfonamide.
  • the present disclosure provides a crystalline form of (S)-A- cthyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)- pyrrolidine- 1 -sulfonamide .
  • the present disclosure provides crystalline Form A of (S)-A- cthyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)- pyrrolidine- 1 -sulfonamide .
  • compositions comprising crystalline Form A of (S)-A-ethyl-3-((9-ethyl-2-(((2J?,35)-2-hydroxypentan-3- yl)amino)-9H-purin-6-yl)amino)pyrrolidine-l -sulfonamide, and one or more pharmaceutically acceptable excipients.
  • the present disclosure provides methods of treating or preventing a cyclin-dependent kinase 2 (CDK2)-mediated condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A of (S)-A-ethyl-3-((9-ethyl-2-(((2J?,3S)-2-hydroxypentan-3- yl)amino)-9H-purin-6-yl)amino)pyrrolidine- 1 -sulfonamide.
  • CDK2 cyclin-dependent kinase 2
  • the present disclosure provides use of a pharmaceutical composition comprising crystalline Form A of (5)-A-ethyl-3-((9-ethyl-2-(((2J?,3S)-2- hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-l -sulfonamide for treating or preventing a cyclin-dependent kinase 2 (CDK2)-mediated condition.
  • CDK2 cyclin-dependent kinase 2
  • FIG. 5-A is a thermal ellipsoid drawing of the crystal structure of crystalline Form A of (.S')-A'-cthyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6- yl)amino)pyrrolidine- 1 -sulfonamide based on single crystal analysis and drawn at a 50% probability level.
  • amorphous form refers to a form of a compound that lacks long range crystalline order.
  • co-administration encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more agents are present.
  • crystalline form is intended to include all crystalline forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), and conformational polymorphs, as well as mixtures thereof, unless a particular crystalline form is referred to.
  • a therapeutically effective amount of a pharmacological agent is an amount that is sufficient to effect beneficial or desired results, including clinical results, and, as such, will depend upon the situation in which it is being administered.
  • a therapeutically effective amount of the agent is an amount of the agent that is sufficient, either alone or in combination with additional therapies, to provide an anti -cancer effect in a subject as compared to the response obtained without administration of the agent.
  • pharmaceutically acceptable is used adjectivally in this specification to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” is intended to include any and all carriers or excipients that are suitable for use in mammals, particularly humans.
  • reflection when used in conjunction with powder X-ray diffraction, refers to the reflection (also known as Bragg-Brentano) sampling mode.
  • preventing is readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the condition and secondary prophylaxis whereby the condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the condition.
  • solvate refers to a crystalline phase of a compound in physical association with one or more molecules of a solvent.
  • the crystalline phase of a compound in physical association with one or more molecules of water is referred to as a “hydrate.”
  • transmission or “transmission mode,” when used in conjunction with powder X-ray diffraction, refers to the transmission (also known as Debye-Scherrer) sampling mode.
  • treating is readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include (1) diminishing the extent or cause of the condition being treated, and/or (2) alleviating or ameliorating one or more symptoms associated with that condition.
  • Treatment of a cancer can include stabilizing (z.e., not worsening), delaying, or slowing the spread or progression of the cancer; prolonging survival as compared to expected survival if not receiving treatment; and/or otherwise ameliorating or palliating the severity of the cancer, in whole or in part.
  • Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (.S)-isomcric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (.S)-isomcr. If that compound has one isomeric form predominant over the other, for example, 80% (.S)-isomcr and 20% (/?)-isomcr. the enantiomeric purity of the compound with respect to the (.S)-isomcric form is 80%.
  • the enantiomeric purity of a compound can be determined in a number of ways, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.
  • an enantiomerically enriched preparation of the (/?)-cnantiomcr means a preparation of the compound having greater than 50% by weight of the (R)- enantiomer relative to the (.S') -enantiomer, such as at least 75% by weight, or such as at least 80% by weight.
  • the enrichment can be significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non- racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight.
  • a “substantially enantiomerically enriched” or a “substantially non- racemic” preparation refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight.
  • the terms “enantiomerically pure” or “substantially enantiomerically pure” refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.
  • a compound that is an active pharmaceutical ingredient in a drug product potentially can exist in different solid-state forms exhibiting different physical properties. These physical property differences can impact the manufacturing and formulation of the drug product.
  • Such physical properties can include, but are not limited to: (1) packing properties such as molar volume, density, and hygroscopicity; (2) thermodynamic properties such as melting temperature, vapor pressure, and solubility; (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions); (4) surface properties such as surface area, wettability, interfacial tension, and shape; (5) mechanical properties such as hardness, tensile strength, compressibility, compactibility, handling, flow and blend; and (6) fdtration properties.
  • solid-state forms of a compound particularly crystalline forms of the compound, that provide an improvement in one or more of these physical properties relative to other solid-state forms of the compound are desirable.
  • the discovery of a new solid-state form of a pharmaceutically useful compound therefore provides a potential opportunity to improve the performance characteristics of the corresponding drug product and related manufacturing process.
  • the present disclosure provides a crystalline form of A-ethyl-S- ⁇ -ethyl ⁇ -
  • the crystalline form possesses one or more of the above-described advantageous properties relative to one or more of the other solid-state forms of the compound.
  • the crystalline form is a crystalline anhydrate.
  • the crystalline form is substantially pure. As used in the present specification, the term "substantially pure" means that the crystalline form of the compound comprises at least about 90 weight % of the desired crystalline form relative to any other solid-state form of the compound.
  • the crystalline form of the compound comprises at least about 95 weight % of the desired crystalline form relative to any other solid-state form of the compound. In another aspect, the crystalline form of the compound comprises at least about 96 weight % of the desired crystalline form relative to any other solid-state form of the compound. In another aspect, the crystalline form of the compound comprises at least about 97 weight % of the desired crystalline form relative to any other solid-state form of the compound relative to any other solid-state form of the compound. In another aspect, the crystalline form of the compound comprises at least about 98 weight % of the desired crystalline form relative to any other solid-state form of the compound. In another aspect, the crystalline form of the compound comprises at least about 99 weight % of the desired crystalline form relative to any other solid-state form of the compound.
  • the present disclosure provides a crystalline form of (S)-A- cthyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)- pyrrolidine -1 -sulfonamide which has the following chemical structure:
  • Form A is further characterized by a solid-state 13 C NMR spectrum that comprises peaks at 161.2 ⁇ 0.2 ppm, 137.6 ⁇ 0.2 ppm, 113.1 ⁇ 0.2 ppm, 72.3 ⁇ 0.2 ppm, and 60.0 ⁇ 0.2 ppm.
  • Form A is further characterized by a solid-state 13 C NMR spectrum that comprises peaks at 161.2 ⁇ 0.2 ppm, 137.6 ⁇ 0.2 ppm, 113.1 ⁇ 0.2 ppm, 72.3 ⁇ 0.2 ppm, and 60.0 ⁇ 0.2 ppm.
  • Form A is further characterized by a solid-state 13 C NMR spectrum that comprises peaks at 161.2 ⁇ 0.2 ppm, 137.6 ⁇ 0.2 ppm, 113.1 ⁇ 0.2 ppm, 72.3 ⁇ 0.2 ppm, and 60.0 ⁇ 0.2 ppm.
  • Form A is characterized by the following: a powder X-ray diffraction pattern that comprises peaks at 8.1 ⁇ 0.2° 20, 13.9 ⁇ 0.2° 20, 16.1 ⁇ 0.2° 20, 16.7 ⁇ 0.2° 20, and 22.6 ⁇ 0.2 °20; a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 122 °C ⁇ 5 °C; and a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 1.0 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ⁇ 0. 1 °C.
  • Form A comprises less than 1 weight % of any other crystalline form of (.S')-A'-cthyl-3-((9-cthyl-2-(((2/?.3.S')-2- hydroxypentan-3-yl)amino)-977-purin-6-yl)amino)pyrrolidine-l -sulfonamide.
  • (.S')-A-Ethyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6- yl)amino)pyrrolidine- 1 -sulfonamide is an inhibitor of cyclin-dependent kinase 2 (CDK2) activity. Overexpression of CDK2 is associated with abnormal regulation of the cell-cycle and tumor growth in multiple cancer types.
  • CDK2 cyclin-dependent kinase 2
  • the present disclosure provides a method for treating or preventing a CDK2-mediated condition in a subject in need thereof by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A.
  • the present disclosure provides a method for treating a cancer in a subject suffering from or susceptible to the cancer by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A.
  • the cancer is a solid tumor cancer.
  • the cancer is a hematological cancer.
  • the cancer is mediated, in whole or in part, by CDK2.
  • the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer.
  • the solid tumor cancer is breast cancer or ovarian cancer.
  • the cancer is a hematological cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2.
  • the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, colorectal cancer, and skin cancer.
  • the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer.
  • the solid tumor cancer is breast cancer or ovarian cancer.
  • the cancer is breast cancer.
  • the breast cancer is selected from the group consisting of hormone receptor positive (HR+) breast cancer, hormone receptor negative (HR-) breast cancer, and triple negative breast cancer.
  • the breast cancer is HR+ HER2- breast cancer.
  • the breast cancer is a chemotherapy-resistant breast cancer.
  • the breast cancer is a radiotherapy-resistant breast cancer.
  • the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
  • the breast cancer is an advanced or metastatic breast cancer.
  • the subject suffering from breast cancer was previously treated with a CDK4/6 inhibitor.
  • the cancer is ovarian cancer.
  • the ovarian cancer is platinum-sensitive or platinum-resistant ovarian cancer.
  • the ovarian cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
  • the cancer is epithelial ovarian cancer.
  • the ovarian cancer is serous ovarian cancer.
  • the ovarian cancer is high-grade serous ovarian cancer (HGSOC).
  • the ovarian cancer is an advanced or metastatic ovarian cancer.
  • the ovarian cancer is metastatic high-grade serous ovarian cancer (HGSOC).
  • the subject suffering from ovarian cancer was previously treated with a platinum-based chemotherapy.
  • the cancer is lung cancer.
  • the lung cancer is small cell lung cancer (SCLC).
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the non-small cell lung cancer (NSCLC) is squamous cell carcimoma.
  • the non-small cell lung cancer (NSCLC) is adenocarcinoma.
  • the non-small cell lung cancer (NSCLC) is large-cell carcinoma.
  • the present disclosure provides a method for treating or preventing a hematological cancer in a subject suffering from or susceptible to the cancer by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A, wherein the hematological cancer is selected from the group consisting of non-Hodgkin's lymphoma, leukemia, multiple myeloma (MM), and myelodysplastic syndrome (MDS).
  • the hematological cancer is nonHodgkin's lymphoma (NHL).
  • the non-Hodgkin's lymphoma is selected from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma (MCL), and marginal zone lymphoma.
  • the hematological cancer is leukemia.
  • the leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • the hematological cancer is multiple myeloma (MM).
  • the hematological cancer is myelodysplastic syndrome (MDS).
  • a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A is administered as first line therapy.
  • a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A is administered as second line (or later) therapy.
  • the subject to whom a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A is administered exhibits a partial response (PR) in response to such treatment.
  • PR partial response
  • the subject to whom a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A is administered exhibits a complete response (CR) in response to such treatment.
  • the subject to whom a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A is administered exhibits an improved progression free survival (PFS) in response to such treatment.
  • PFS progression free survival
  • the subject to whom a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A is administered exhibits an improved overall survival (OR) in response to such treatment.
  • PR, CR, PFS, and OR can be assessed, for example, in accordance with RECIST (Response Evaluation Criteria in Solid Tumours) guidelines (version 1.1).
  • the subject treated typically will be a human or non-human mammal, particularly a human. Suitable subjects can also include domestic or wild animals; companion animals (including dogs, cats, and the like); livestock (including horses, cows and other ruminants, pigs, poultry, rabbits, and the like); primates (including monkeys such as rhesus monkeys, cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets, tamarins, chimpanzees, macaques, and the like); and rodents (including rats, mice, gerbils, guinea pigs, and the like).
  • companion animals including dogs, cats, and the like
  • livestock including horses, cows and other ruminants, pigs, poultry, rabbits, and the like
  • primates including monkeys such as rhesus monkeys, cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets,
  • the present disclosure provides crystalline Form A for use as a medicament for treating a cancer mediated, in whole or in part, by CDK2.
  • the present disclosure provides for the use of crystalline Form A for the manufacture of medicaments for treating a cancer mediated, in whole or in part, by CDK2.
  • the CDK4/6 inhibitor is palbociclib. In another aspect, the CDK4/6 inhibitor is abemaciclib. In another aspect, the CDK4/6 inhibitor is ribociclib. In another aspect, the CDK4/6 inhibitor is dalpiciclib.
  • the present disclosure provides a combination suitable for use in the treatment of a cancer mediated, in whole or in part, by CDK2, wherein the combination comprises crystalline Form A and endocrine therapy.
  • the cancer is breast cancer.
  • the present disclosure provides a combination suitable for use in the treatment of a cancer mediated, in whole or in part, by CDK2, wherein the combination comprises crystalline Form A and an aromatase inhibitor.
  • the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.
  • the combination further comprises everolimus.
  • the cancer is breast cancer.
  • the present disclosure provides a combination suitable for use in the treatment of a cancer mediated, in whole or in part, by CDK2, wherein the combination comprises crystalline Form A and a selective estrogen receptor degrader (SERD).
  • the SERD is selected from the group consisting of fulvestrant, giredestrant (GDC-9545), amcenestrant (SAR439859), camizestrant (AZD9833), rintodestrant (G1T48), imlunestrant (LY3484356), elacestrant (RAD-1901), taragare strant (D-0502), OP1250 (Olema), LSZ102 (Novartis), ZN-c5 (Zentalis), and SHR9549 (Jiangsu Hengrui Medicine).
  • the SERD is selected from the group consisting of fulvestrant, giredestrant, camizestrant, imlunestrant, and elacestrant; and the CDK4/6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, and dalpiciclib.
  • the SERD is selected from the group consisting of fulvestrant and camizestrant; and the CDK4/6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, and ribociclib.
  • the SERD is camizestrant; and the CDK4/6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, and ribociclib.
  • the cancer is breast cancer.
  • the present disclosure provides a combination suitable for use in the treatment of a cancer mediated, in whole or in part, by CDK2, wherein the combination comprises crystalline Form A and a PROTAC estrogen receptor degrader (PROTAC ER Degrader).
  • the PROTAC ER Degrader is vepdegestrant.
  • the cancer is breast cancer.
  • the present disclosure provides a combination suitable for use in the treatment of a cancer mediated, in whole or in part, by CDK2, wherein the combination comprises crystalline Form A and a selective estrogen receptor modulator (SERM).
  • SERM is selected from the group consisting of anordrin, apeledoxifene, broparestrol, clomifene, cyclofenil, lasofoxifene, ormeloxifene, ospemifene, raloxifene, tamoxifen, and toremifene.
  • the SERM is tamoxifen.
  • the SERM is toremifene.
  • the present disclosure provides a combination suitable for use in the treatment of a cancer mediated, in whole or in part, by CDK2, wherein the combination comprises crystalline Form A and radiotherapy.
  • the present disclosure provides a combination suitable for use in the treatment of a cancer mediated, in whole or in part, by CDK2, wherein the combination comprises crystalline Form A and chemotherapy.
  • the present disclosure provides a combination suitable for use in the treatment of breast cancer, wherein the combination comprises crystalline Form A and chemotherapy.
  • chemotherapy comprises administration of a combination of cyclophosphamide and doxorubicin ("AC").
  • chemotherapy comprises administration of a combination of cyclophosphamide, doxorubicin, and a taxane such as paclitaxel or docetaxel ("CAT").
  • chemotherapy comprises administration of a combination of cyclophosphamide, methotrexate, and fluorouracil (or "CMF").
  • chemotherapy comprises administration of a combination of carboplatin and either paclitaxel or docetaxel.
  • chemotherapy comprises administration of topotecan.
  • chemotherapy comprises administration a combination of bleomycin, etoposide, and cisplatin (BEP).
  • chemotherapy comprises administration of vincristine, dactinomycin, and cyclophosphamide (VAC).
  • chemotherapy comprises administration of combination of paclitaxel, gemcitabine, and oxaliplatin.
  • excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fdlers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing.
  • the compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • the total daily dose will necessarily be varied depending upon the subject treated, the route of administration, any therapies being co-administered, and the severity of the illness being treated, and may include single or multiple doses. Specific dosages can be adjusted, for example, depending upon the condition being treated; the age, body weight, general health condition, sex, and diet of the subject; administration routes; dose intervals; excretion rate; and other drugs being co-administered to the subject.
  • An ordinarily skilled physician provided with the disclosure of the present specification will be able to determine appropriate dosages and regimens for administration of the therapeutic agent to the subject, and to adjust such dosages and regimens as necessary during the course of treatment, in accordance with methods well-known in the therapeutic arts.
  • the crystalline form of the present disclosure typically will be administered to a warm-blooded animal at a unit dose within the range 2.5 to 5000 mg/m 2 body area of the animal, or approximately 0.05 mg/kg to 100 mg/kg, and this normally provides a therapeutically effective dose.
  • compositions for use in therapy comprising crystalline Form A and at least one pharmaceutically acceptable excipient.
  • the present disclosure provides pharmaceutical compositions for use in the treatment of an CDK2 -mediated condition, comprising crystalline Form A and at least one pharmaceutically acceptable excipient.
  • the CDK2-mediated condition is a solid tumor cancer.
  • the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, colorectal cancer, and skin cancer.
  • the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer.
  • the solid tumor cancer is breast cancer or ovarian cancer.
  • the CDK2 -mediated condition is breast cancer.
  • the CDK2 -mediated condition is ovarian cancer.
  • the CDK2-mediated condition is endometrial cancer.
  • the CDK2 -mediated condition is lung cancer.
  • the present disclosure provides a pharmaceutical composition comprising crystalline Form A, and one or more pharmaceutically acceptable excipients.
  • the composition comprises at least 90 weight % of Form A relative to any other crystalline forms of the compound.
  • the composition comprises at least 95 weight % of Form A relative to any other crystalline forms of the compound.
  • the composition comprises at least 96 weight % of Form A relative to any other crystalline forms of the compound.
  • the composition comprises at least 97 weight % of Form A relative to any other crystalline forms of the compound.
  • the composition comprises at least 98 weight % of Form A relative to any other crystalline forms of the compound.
  • the composition comprises at least 99 weight % of Form A relative to any other crystalline forms of the compound.
  • the composition comprises Form A substantially free of any other crystalline forms of the compound.
  • kits comprising a unit dosage form comprising crystalline Form A contained within a packaging material and a label or package insert which indicates that the unit dosage form can be used for treating one or more of the previously described conditions.
  • the kit comprises a unit dosage form comprising crystalline Form A contained within a packaging material and a label or package insert which indicates that the pharmaceutical composition can be used for treating a CDK2-mediated condition.
  • the CDK2 -mediated condition is a solid tumor cancer.
  • the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, colorectal cancer, and skin cancer.
  • the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer.
  • the solid tumor cancer is breast cancer or ovarian cancer.
  • the CDK2 -mediated condition is breast cancer.
  • the CDK2 -mediated condition is ovarian cancer.
  • the CDK2 -mediated condition is endometrial cancer.
  • the CDK2-mediated condition is lung cancer.
  • the kit comprises: (a) a first unit dosage form comprising a crystalline form of the present disclosure; (b) a second unit dosage form comprising a pharmacological agent selected from the group consisting of CDK4/6 inhibitors, aromatase inhibitors, selective estrogen receptor degraders, PROTAC estrogen receptor degraders, selective estrogen receptor modulators, anti-HER2 agents, poly ADP ribose polymerase inhibitors, and Protein kinase B inhibitors; (c) a container means for containing said first and second dosage forms; and (d) a label or package insert which indicates that the first unit dosage form and second unit dosage form can be used for treating a CDK2-mediated condition.
  • a pharmacological agent selected from the group consisting of CDK4/6 inhibitors, aromatase inhibitors, selective estrogen receptor degraders, PROTAC estrogen receptor degraders, selective estrogen receptor modulators, anti-HER2 agents, poly ADP ribose polymerase inhibitors, and Protein kinase B inhibitors
  • the kit comprises: (a) a first unit dosage form comprising crystalline Form A; (b) a second unit dosage form comprising a CDK4/6 inhibitor; (c) a container means for containing said first and second dosage forms; and (d) a label or package insert which indicates that the first unit dosage form and second unit dosage form can be used for treating a CDK2 -mediated condition.
  • the second unit dosage form comprises a CDK4/6 inhibitor selected from the group consisting of palbociclib, abemaciclib, ribociclib, and dalpiciclib.
  • the CDK2 -mediated condition is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer.
  • the CDK2 -mediated condition is breast cancer or ovarian cancer.
  • the kit comprises: (a) a first unit dosage form comprising crystalline Form A; (b) a second unit dosage form comprising a CDK4/6 inhibitor; (c) a third unit dosage form comprising a selective estrogen receptor degrader (SERD); (d) a container means for containing said first and second dosage forms; and (e) a label or package insert which indicates that the first unit dosage form and second unit dosage form can be used for treating a CDK2 -mediated condition.
  • SESD selective estrogen receptor degrader
  • the second unit dosage form comprises a CDK4/6 inhibitor selected from the group consisting of palbociclib, abemaciclib, ribociclib, and dalpiciclib; and the third unit dosage form comprises camizestrant (AZD9833).
  • the CDK2 -mediated condition is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer. In another aspect, the CDK2 -mediated condition is breast cancer or ovarian cancer.
  • Embodiment 1 A crystalline form of A'-cthyl-3-((9-cthyl-2-(((2/?.3.S')-2- hydroxypentan-3 -yl)amino)-9H-purin-6-yl)amino)pyrrolidine- 1 -sulfonamide .
  • Embodiment 2 A crystalline form of (.S')-A'-cthyl-3-((9-cthyl-2-(((2/?.3.S')-2- hydroxypentan-3 -yl)amino)-9H-purin-6-yl)amino)pyrrolidine- 1 -sulfonamide .
  • Embodiment 3 The crystalline form of Embodiment 2 characterized by a powder X-ray diffraction pattern comprising at least one peak selected from the group consisting of 8.1 ⁇ 0.2° 20, 13.9 ⁇ 0.2° 20, 16.1 ⁇ 0.2° 20, 16.7 ⁇ 0.2° 20, and 22.6 ⁇ 0.2 °20.
  • Embodiment 4 The crystalline form of Embodiment 2 characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from the group consisting of 8.1 ⁇ 0.2° 20, 13.9 ⁇ 0.2° 20, 16.1 ⁇ 0.2° 20, 16.7 ⁇ 0.2° 20, and 22.6 ⁇ 0.2 °20.
  • Embodiment 5 The crystalline form of Embodiment 2 characterized by a powder X-ray diffraction pattern comprising peaks at 8.1 ⁇ 0.2° 20, 13.9 ⁇ 0.2° 20, 16.1 ⁇ 0.2° 20, 16.7 ⁇ 0.2° 20, and 22.6 ⁇ 0.2 °20.
  • Embodiment 6 The crystalline form of Embodiment 5 characterized by a powder X-ray diffraction pattern further comprising at least one peak selected from the group consisting of 17.7 ⁇ 0.2° 20, 20.2 ⁇ 0.2° 20, 21.3 ⁇ 0.2° 20, 25.9 ⁇ 0.2° 20, and 29.2 ⁇ 0.2 °20.
  • Embodiment 7 The crystalline form of Embodiment 5, wherein the powder X- ray diffraction pattern further comprises peaks at 17.7 ⁇ 0.2° 20, 20.2 ⁇ 0.2° 20, 21.3 ⁇ 0.2° 20, 25.9 ⁇ 0.2° 20, and 29.2 ⁇ 0.2 °20.
  • Embodiment 8 The crystalline form of any of Embodiments 3 to 7, wherein the powder X-ray diffraction is carried out using Cu radiation.
  • Embodiment 9 The crystalline form of any of Embodiments 3 to 8, wherein the powder X-ray diffraction is carried out using a Bruker D8 Advantage diffractometer operating in reflection geometry, a tube voltage of 45 kV, and filament emission of 40 mA.
  • Embodiment 10 The crystalline form of Embodiment 3, wherein the powder X- ray diffraction pattern is substantially the same as the powder X-ray diffraction pattern of FIG. 5-B.
  • Embodiment 11 The crystalline form of any of Embodiments 3 to 10 further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 122 °C ⁇ 5 °C.
  • Embodiment 12 The crystalline form of any of Embodiments 3 to 10 further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 122 °C ⁇ 2 °C.
  • Embodiment 13 The crystalline form of any of Embodiments 3 to 10 further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 128 °C ⁇ 5 °C.
  • Embodiment 14 The crystalline form of any of Embodiments 3 to 10 further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 128 °C ⁇ 2 °C.
  • Embodiment 15 The crystalline form of any of Embodiments 3 to 10 further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 122 °C ⁇ 5 °C and a peak at about 128 °C ⁇ 5 °C.
  • Embodiment 16 The crystalline form of any of Embodiments 3 to 10 further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 122 °C ⁇ 2 °C and a peak at about 128 °C ⁇ 2 °C.
  • Embodiment 17 The crystalline form of any of Embodiments 11 to 16, wherein the differential scanning calorimetry is conducted on a TA Instruments Differential Scanning Calorimeter, model Q2000, with a sample placed in an aluminum pan and heated under nitrogen at a rate of 10 °C/minute to a temperature of 300 °C.
  • Embodiment 18 The crystalline form of Embodiment 11, wherein the differential scanning calorimetry curve is substantially the same as the differential scanning calorimetry curve of FIG. 6.
  • Embodiment 19 The crystalline form of any of Embodiments 3 to 18 further characterized by a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 1.0 weight % from about 25 °C to about 100 °C.
  • Embodiment 21 The crystalline form of Embodiment 19, wherein the weight loss is less than about 0.1 weight %.
  • Embodiment 22 The crystalline form of Embodiment 19, wherein the thermogravimetric analysis thermogram is substantially the same as the thermogravimetric analysis thermogram of FIG. 7.
  • Embodiment 23 The crystalline form of any of Embodiments 3 to 22 further characterized by a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 1.0 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ⁇ 0.1 °C.
  • Embodiment 24 The crystalline form of Embodiment 23, wherein the reversible moisture uptake is less than about 0.7 weight %.
  • Embodiment 25 The crystalline form of Embodiment 23, wherein the reversible moisture uptake is less than about 0.4 weight %.
  • Embodiment 26 The crystalline form of Embodiment 23, wherein the gravimetric vapor sorption plot is substantially the same as the gravimetric vapor sorption plot of FIG. 8.
  • Embodiment 28 The crystalline form of any of Embodiments 3 to 10, wherein the crystalline form is further characterized by the following: a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 122 °C ⁇ 5 °C; and a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 1.0 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ⁇ 0.1 °C.
  • Embodiment 29 The crystalline form of any of Embodiments 3 to 10, wherein the crystalline form is further characterized by the following: a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 1.0 weight % from about 25 °C to about 100 °C; and a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 1.0 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ⁇ 0. 1 °C.
  • a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 1.0 weight % from about 25 °C to about 100 °C
  • a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 1.0 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ⁇ 0. 1 °C.
  • Embodiment 30 The crystalline form of any of Embodiments 3 to 10, wherein the crystalline form is further characterized by the following: a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 122 °C ⁇ 5 °C; a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 1.0 weight % from about 25 °C to about 100 °C; and a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 1.0 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ⁇ 0.1 °C.
  • Embodiment 31 The crystalline form of any of Embodiments 3 to 30 further characterized by a solid-state 13 C NMR spectrum comprising one, two, three, or four peaks selected from the group consisting of 161.2 ⁇ 0.2 ppm, 137.6 ⁇ 0.2 ppm, 113.1 ⁇ 0.2 ppm, 72.3 ⁇ 0.2 ppm, and 60.0 ⁇ 0.2 ppm.
  • Embodiment 32 The crystalline form of any of Embodiments 3 to 30 further characterized by a solid-state 13 C NMR spectrum comprising peaks at 161.2 ⁇ 0.2 ppm, 137.6 ⁇ 0.2 ppm, 113.1 ⁇ 0.2 ppm, 72.3 ⁇ 0.2 ppm, and 60.0 ⁇ 0.2 ppm.
  • Embodiment 34 The crystalline form of Embodiment 31, wherein the solid-state 13 C NMR spectrum is substantially the same as the solid-state 13 C NMR spectrum of FIG.
  • Embodiment 35 The crystalline form of any of Embodiments 28 to 34, wherein the crystalline form is a crystalline anhydrate.
  • Embodiment 36 The crystalline form of any of Embodiments 3 to 35, wherein the crystalline form comprises less than 5 weight % of any other crystalline form of (S)- V- cthyl-3-((9-cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)- pyrrolidine- 1 -sulfonamide .
  • Embodiment 37 The crystalline form of any of Embodiments 3 to 35, wherein the crystalline form is substantially free of any other crystalline form of (.S')- '-cthyl-3-((9- cthyl-2-(((2/?.3.S')-2-hydroxypcntan-3-yl)amino)-9//-purin-6-yl)amino)-pyrrolidinc- l - sulfonamide.
  • Embodiment 38 A pharmaceutical composition comprising a crystalline form of any of Embodiments 1 to 37, and one or more pharmaceutically acceptable excipients.
  • Embodiment 39 A method of treating or preventing a CDK2 -mediated condition in a subject suffering from or susceptible to the CDK2 -mediated condition, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of any of Embodiments 1 to 37.
  • Embodiment 41 The method of Embodiment 39, wherein the CDK2 -mediated condition is breast cancer.
  • Embodiment 42 The method of Embodiment 39, wherein the CDK2 -mediated condition is ovarian cancer.
  • Embodiment 43 The use of a crystalline form of any of Embodiments 1 to 37 for the manufacture of a medicament for treating or preventing a CDK2 -mediated condition
  • Embodiment 44 A kit comprising a unit dosage form comprising a crystalline form of any of Embodiments 1 to 37 contained within a packaging material, and a label or package insert which indicates that the unit dosage form can be used for treating a CDK2- mediated condition.
  • lodoethane (5.15 ml, 63.75 mmol) was added to a stirred suspension of 6-chloro- 2-fluoro-9H-purine (Intermediate 1, 10 g, 57.96 mmol) and potassium carbonate (10.01 g, 72.44 mmol) in dimethyl sulfoxide (DMSO, 52.8 mL) at 23°C.
  • DMSO dimethyl sulfoxide
  • the resulting suspension was stirred at 23 °C for 20 hours (h).
  • the reaction was diluted with water, adjusted to pH 7-8 with glacial acetic acid and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • the powder X-ray diffraction (PXRD) pattern is determined by mounting a sample on a zero-background holder, single silicon crystal, and spreading out the sample into a thin layer.
  • the PXRD is recorded with a Theta-Theta Bruker D8 Advantage (wavelength of X-rays 1.5418 A nickel-fdtered Cu radiation, Voltage 45 kV, filament emission 40 mA).
  • Variable divergence and anti-scatter slits and incident and diffracted seller slit 0.04° are used. The samples are rotated during measurement.
  • Samples are scanned from 5 to 4O°20 using a 0.013° step width and a 115.770 s count time together with a PIXcellD detector (active length 3.35°20).
  • the PXRD patterns are obtained in Bragg-Brentano geometry.
  • a PXRD pattern may be obtained which has one or more measurement errors depending on measurement conditions, such as equipment or machine used (Jenkins, R & Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction Procedures).
  • the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios that may affect analysis of samples.
  • Amorphous (.S)- '-cthyl-3-((9-cthyl-2-(((2/?.3.S)-2-hydroxypcntan-3-yl)amino)- 9H-purin-6-yl)amino)pyrrolidine-l -sulfonamide 100 mg was suspended in methyl tertbutyl ether (2.0 mL) at room temperature.
  • Form A seeds (2 mg to 3 mg) were added. After five minutes, the amorphous material became a gel while the Form A seeds remained in solid form. After 15 minutes, the gel started to solidify and formed a solid cluster after one hour.
  • the solid cluster was broken up by spatula and the resulting slurry was stirred at room temperature for one day.
  • the methyl tert-butyl ether was evaporated from the slurry and a white solid was obtained.
  • PXRD analysis showed that the isolated material was crystalline Form A.
  • Thermal analysis showed that the isolated material was anhydrous and had a melting point of 119°C.
  • Form A can be obtained by evaporating the ethyl acetate from the slurry without the need to add the heptane to the slurry first.
  • Characterization of Form A was carried out using various techniques including single crystal analysis, PXRD (FIG. 5-B), differential scanning calorimetry (DSC) (FIG. 6), thermogravimetic analysis (TGA) (FIG. 7), gravimetric vapor sorption (GVS) (FIG. 8), and 13 C solid-state NMR (FIG. 9).
  • a single crystal analysis was conducted for Form A.
  • Single clear colorless needle-shaped crystals of Form A were obtained from slow evaporation of an ethyl acetate solution of (.S)-A'-cthyl-3-((9-cthyl-2-(((2/?.3.S)-2-hydroxypcntan-3-yl)amino)-9//-purin-6- yl)amino)-pyrrolidine-l-sulfonamide.
  • a suitable crystal was selected and mounted on a Hampton loop in perfluoroether oil.
  • X-ray diffraction data was collected at 100 K using Cryostream 800 (Oxford Cryosystem, UK) in rn-scan mode with XtaLab Synergy-S (Rigaku, Japan) equipped with Cu Ka micro focus source (50 kV, 0.01 mA) and Hypix-Arc 100 detector.
  • the diffraction pattern was initially indexed and the total number of runs and images was based on the strategy calculation from the program CrysAlisPro 1.171.42.46a (Rigaku, Japan).
  • Data reduction, scaling and absorption corrections were performed using CrysAlisPro 1.171.42.46a (Rigaku, Japan).
  • the integrated and scaled data were corrected using numerical absorption correction based on gaussian integration over a multifaceted crystal model and empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.
  • FIG. 5-B shows a representative PXRD pattern for Form A measured using reflection geometry.
  • the PXRD pattern of FIG. 5-B confirms that Form A is crystalline.
  • Table 1-B below lists selected peaks identified in the PXRD pattern of FIG. 5-B.
  • Form A shows characteristic peaks at 8.1 ⁇ 0.2° 20, 13.9 ⁇ 0.2° 20, 16.1 ⁇ 0.2° 20, 16.7 ⁇ 0.2° 20, and 22.6 ⁇ 0.2 °20.
  • Form A shows further characteristic peaks at 17.7 ⁇ 0.2° 20, 20.2 ⁇ 0.2° 20, 21.3 ⁇ 0.2° 20, 25.9 ⁇ 0.2° 20, and 29.2 ⁇ 0.2 °20.
  • FIG. 6 shows a representative differential scanning calorimetry (DSC) thermogram for Form A. Exothermic events are plotted in the upward direction.
  • the melting endotherm shown in FIG. 6 has an onset temperature of about 122°C and a heat enthalpy of approximately 105 J/g for the melting endotherm.
  • the DSC values obtained can vary by as much as ⁇ 5°C depending upon the instrument used, how samples are prepared, and differences between batches.
  • FIG. 7 shows a representative thermogravimetic analysis (TGA) thermogram for Form A.
  • TGA thermogravimetic analysis
  • FIG. 8 shows a representative gravimetric vapor sorption (GVS) plot for Form A.
  • Form A exhibited a reversible moisture uptake of about 0.3 weight % between 0% relative humidity and 80% relative humidity at 25 °C ⁇ 0.1 °C.
  • the desorption curve indicates that Form A lost moisture at a similar rate to the moisture gained during sorption, with limited hysteresis. No form change was observed by PXRD after the GVS experiment.
  • Section 5.11 of European Pharmacopoeia 6.0 provides the following hygroscopicity classification according to specified analytical method:
  • Form A was analyzed by 13 C solid-state NMR.
  • MCF-7 and OVCAR3 cells in RPMI supplemented with 10% Fetal bovine serum were seeded into 384-well plates (Greiner, Kremsmunster, Austria; 781091), 30 pL/well, using a WellMate.
  • the MCF7 and OVCAR3 cells were seeded at 800 and 1200 cells/well, respectively.
  • Test compounds were added to the wells using an Echo 555 liquid handler and the plates were placed in incubator maintained at 37°C and 5% CO2 and incubated for two days. On Day 2, an EdU assay was performed following the manufacturer’s protocol (Thermo Fisher, Cl 0351). The cells were read on an Acumen eX3 instrument.
  • the IC50 values of test compounds were determined in Genedata by assessing the ratio of signal intensity at 488nm to the area of signal at 405 nm.
  • OVCAR3 cells were seeded at 60,000 cells per well in 24 well plates, 4 wells per sample, in RPMI with 10% Fetal bovine serum. Test compounds were diluted in 96 well plates in dimethyl sulfoxide (DMSO) and then added to the wells containing the cells. The 24 well plates were placed in an incubator maintained at 37°C and 5% CO2 and incubated for 20 to 24 hours. The next day an EdU assay was performed following the manufacturer’s protocol (Thermo Fisher, C10425 EdU Alexa Fluor 488). Antibody staining was carried out using PE Mouse Anti-Cleaved PARP (BD Biosciences Catalog No. 552933) and 4’,6- diamidino-2-phenylindole (DAPI). Cells were then analyzed by flow cytometry.
  • DMSO dimethyl sulfoxide
  • Example 1 induced Gl/S cell cycle arrest, inhibited pRB phosphorylation, and inhibited cell proliferation.
  • Treatment of the OVCAR3 cells with the compound of Example 1 at concentrations of 0.03, 0.1, 0.3, 1, and 3 pM increased the population of cells in the GO and G1 phases.
  • OVCAR3 cells were seeded at 60K cells per well in 24 well plates in RPMI with 10% Fetal bovine serum. Test compounds were diluted in 96 well plates in DMSO and then added to the cells. The treated cells were placed in an incubator maintained at 37°C and 5% CO2 and incubated for 20 to 24 hours. On Day 2, the cells were rinsed once with phosphate buffer saline (PBS) and scraped to 1% SDS lysing buffer. The protein lysate was quantified using a PierceTM BCA Protein Assay Kit (Thermo Fisher 23225).
  • the membranes were incubated into secondary antibody (CST Anti-rabbit IgG, HRP -linked Antibody #7074) in blocking buffer at room temperature for one hour. After washing three times in PBST, the signals were developed using SuperSignalTM West Dura Extended Duration Substrate (Thermo Fisher 3707) and imaged in chemiluminescence imager.
  • Example 1 The compound of Example 1 was similarly analyzed by Western blot to assess modulation of pSer2 of RNAPII, a CDK9 phosphosubstrate. No modulation of pSer2 of RNAPII was observed for the compound indicating that it was not impacting CDK9 activity.
  • Cells were plated in 384 well plates (Perkin-Elmer 6057300) in RPMI-1640 / 10% FBS / lx L-Glu at 500 cells per well in 30uL and incubated with test compound at 37°C and 5% CO2 for 7 days. Cells were then stained using the CyQuant Direct Cell Proliferation Assay Kit (Thermo Cat#C7026) in accordance with the kit protocol. The stained cells were imaged using an Operetta high content imager to generate cell counts and IC50 values were calculated relative to DMSO controls.
  • IC50 values for the compound of Example 1 are reported in Table 4. The compound inhibited cellular proliferation in the CCNE-1 amplified OVCAR3 cells more potently than in the non-amplified SKOV3 cell line. TABLE 4

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Abstract

L'invention concerne une forme cristalline de N-éthyl-3-((9-éthyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9 H-purin-6-yl)amino)-pyrrolidine-1-sulfonamide; des compositions pharmaceutiques correspondantes; des utilisations pour traiter ou prévenir des affections médiées par la kinase 2 dépendante de la cycline (CDK2); des kits; et des procédés de préparation. (I)
PCT/IB2025/053301 2024-03-29 2025-03-28 Forme cristalline de (s)-n-éthyl-3-((9-éthyl-2-(((2r,3s)-2-hydroxypentan-3-yl)amino)-9h-purin-6-yl)amino)-pyrrolidine-1-sulfonamide Pending WO2025202991A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024127350A1 (fr) * 2022-12-16 2024-06-20 Astrazeneca Ab Purines 2,6,9-trisubstituées

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024127350A1 (fr) * 2022-12-16 2024-06-20 Astrazeneca Ab Purines 2,6,9-trisubstituées

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Title
BUNN, C.W.: "Chemical Crystallography", 1948, CLARENDON PRESS
DOLOMANOV, O.V., BOURHIS, J., GILDEA. R.J., HOWARD, J.A.K., PUSCHMANN, H. J., APPL. CRYST., vol. 42, 2009, pages 339 - 431
ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
ELIELWILEN: "Stereochemistry of Organic Compounds", 1994, WILEY-INTERSCIENCE
FLACK, H.DBERNARDINELLI, G, ACTA CRYST., vol. A55, 1999, pages 908 - 915
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JENKINS, RSNYDER, R.L: "Introduction to X-Ray Powder Diffractometry", 1996, JOHN WILEY & SONS
KITAIGORODSKY, A.I: "Handbook of Pharmaceutical Excipients", 1973, PHARMACEUTICAL PRESS
KLUG, H. PALEXANDER, L. E., X-RAY DIFFRACTION PROCEDURES, 1974
LIANG HANZHI ET AL: "Structure-Based Design of 2-Aminopurine Derivatives as CDK2 Inhibitors for Triple-Negative Breast Cancer", FRONTIERS IN PHARMACOLOGY, vol. 13, 1 May 2022 (2022-05-01), CH, pages 864342 - 864342, XP093294289, ISSN: 1663-9812, DOI: 10.3389/fphar.2022.864342 *
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