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WO2025198588A1 - Préparation d'un composé et de formes cristallines de celui-ci - Google Patents

Préparation d'un composé et de formes cristallines de celui-ci

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Publication number
WO2025198588A1
WO2025198588A1 PCT/US2024/020722 US2024020722W WO2025198588A1 WO 2025198588 A1 WO2025198588 A1 WO 2025198588A1 US 2024020722 W US2024020722 W US 2024020722W WO 2025198588 A1 WO2025198588 A1 WO 2025198588A1
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WO
WIPO (PCT)
Prior art keywords
crystalline form
cancer
compound
formula
group
Prior art date
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/US2024/020722
Other languages
English (en)
Inventor
Zhushou Luo
David Sperandio
Xiaoming LIAO
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.)
BridGene Biosciences Inc
Original Assignee
BridGene Biosciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BridGene Biosciences Inc filed Critical BridGene Biosciences Inc
Priority to PCT/US2024/020722 priority Critical patent/WO2025198588A1/fr
Publication of WO2025198588A1 publication Critical patent/WO2025198588A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically provides a preparation method of a therapeutic compound and its crystallized form.
  • TEAD proteins are effectors for oncogenic YAP/TAZ signaling in cancers with deregulated Hippo tumor suppressor pathway signaling.
  • YAP1 Yesl Associated Transcriptional Regulator
  • WWTR1 WW domain-containing Transcription Regulator 1
  • TEAD proteins a transcriptional coactivator paralog to YAP
  • TEAD proteins was demonstrated both in vitro and in vivo. In both cases, the interaction of the proteins leads to increased TEAD transcriptional activity and expression of genes involved in proliferation, survival, angiogenesis, and other hallmarks of cancer.
  • Hippo signaling via MST1/2 and LATS1/2 kinases results in phosphorylation of YAP/TAZ, sequestration in the cytoplasm and proteosomal degradation.
  • MST or LATS stabilizes YAP/TAZ and leads to nuclear translocation, association with TEAD, and activation of TEAD target genes.
  • Genomic amplification of YAP/TAZ, or gene fusions resulting in constitutively active YAP/TAZ are alternative mechanisms of Hippo pathway deregulation.
  • activation of YAP/TAZ signaling has been described as a mechanism of resistance to other targeted cancer therapies, such as inhibitors of EGFR and MEK.
  • inhibitors of TEAD 1, 2, 3 and/or 4 can have great potential in the application of cancer therapy, both as monotherapy in cancers with deregulated Hippo pathway signaling and as combination therapy with other targeted agents.
  • the present application provides a preparation method of compound (R, £)-l-(3-(4- (trifluoromethyl)styryl)pyrrolidin-l-yl)prop-2-en-l-one and its crystalline form.
  • Embodiment 1 A method for preparing a compound of formula I, formula I, wherein comprising the step of reacting a compound of formula 7 with prop-2-enoyl chloride or acrylic anhydride in an organic solvent with a base reagent.
  • Embodiment 2 the method of embodiment 1, wherein reaction conditions for preparing the compound of formula I are:
  • an organic solvent is selected from the group consisting of CH2Q2, THF, 2-Methyl THF, 1,4-di oxane or ACN;
  • a base reagent is selected from the group consisting of NaHCCE, Na2COs, K2CO3, KHCO3, EtsN, iPr2NEt, Pyridine, or N-Methyl morpholine; 3) reaction time: 1 to 24 hours;
  • reaction temperature 0 to 25°C.
  • Embodiment 3 The method of embodiment 1 or 2, wherein the compound of formula 7 is obtained by removing an amino protecting group.
  • Embodiment 4. The method of embodiment 3, wherein the amino protecting group is selected from the group consisting of the group consisting of 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 1 -methyl -1 -(4- biphenyl)ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), and benzyloxycarbonyl (Cbz).
  • Embodiment 5. The method of embodiment 3, wherein the compound of formula 7 is obtained by removing of the amino protecting group and dehydration of the compound of formula 6, formula 6.
  • Embodiment 6 The method of embodiment 5, wherein reaction conditions for preparing the compound of formula 7 are:
  • a solvent is selected from the group consisting of 2-Me-THF or 1,4-dioxane; 2) reaction time: 1 to 10 hours;
  • reaction temperature 80 to 100 °C;
  • Embodiment 7 The method of embodiment 5, wherein the compound of formula 6 is obtained by reducing the compound of formula 5, formula 5.
  • Embodiment 8. The method of embodiment 7, wherein reaction conditions for preparing the compound of formula 6 are:
  • a solvent is selected from the group consisting of MeOH, EtOH or THF;
  • a reducing agent is selected from the group consisting of NaBEU, NaB(CN)H3 or DIBAL-H; 3) equivalents of reducing reagents: 0.3 to 1.2eq.
  • Embodiment 9 The method of embodiment 7, wherein the compound of formula 5 is obtained by reacting the compound of formula 3 with the lithium reagent generated from n-BuLi and the compound of formula 4,
  • X in the compound of formula 4 is Br or I; and a reaction solvent is selected from the group consisting of THF, 2-Me-THF, diethyl ether and 1,4-di oxane.
  • Embodiment 10 The method of embodiment 9, wherein the compound of formula 3 is obtained by reacting the compound of formula 1 with the compound of formula 2, wherein reaction conditions are:
  • a solvent is selected from the group consisting of THF, 2-Me-THF, 1,4-dioxane, DMF or CH2CI2; 2) reaction temperature: 0 to 25°C;
  • a coupling reagent is select from CDI, HATU, HBTU/HOBT, or EDCI; 5) a base is selected from the group consisting of EtsN, iPr2NEt or N-methyl morpholine;
  • Embodiment 11 A crystalline form of a compound represented by formula I: formula I, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 29 angles ( ⁇ 0.2°) 20.4°, 21.1°, and 21.7°.
  • Embodiment 12 The crystalline form of embodiment 11, wherein the crystalline form is further characterized by X-ray powder diffraction peaks at 29 angle ( ⁇ 9.2°) 15.2° and 23.9°.
  • Embodiment 13 The crystalline form of embodiment 12, wherein the crystalline form is further characterized by X-ray powder diffraction peaks at 29 angle ( ⁇ 9.2°) 13.6°, 14.9°, 16.5° and 17.9°.
  • Embodiment 14 The crystalline form of any one of embodiments 11-13, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1.
  • Embodiment 15 The crystalline form of any one of embodiments 11-14, wherein the crystalline form is at least 69% a single crystalline form, at least 79% a single crystalline form, at least 89% a single crystalline form, at least 99% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight.
  • Embodiment 16 The crystalline form of any one of embodiments 11-15, wherein the crystalline form has a chemical purity of at least 69%, at least 79%, at least 89%, at least 99%, at least 95%, or at least 99% by weight.
  • Embodiment 17 The crystalline form of any one of embodiments 11-16, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 87 ⁇ 2°C, preferably about 86.9-88.6°C.
  • Embodiment 18 The compound crystalline form of embodiment 17, wherein the crystalline form is characterized by the DSC curve substantially similar to FIG. 2.
  • Embodiment 19 The crystalline form of any one of embodiments 11-18, wherein the crystalline form is an anhydrate.
  • Embodiment 20 A crystalline form of a compound represented by formula I: formula I, wherein the crystalline form characterized by X-ray powder diffraction peaks at 29 angle ( ⁇ 0.2°) 17.3° and 18.3°.
  • Embodiment 21 The crystalline form of embodiment 20, wherein the crystalline form further characterized by X-ray powder diffraction peaks at 29 angle ( ⁇ 0.2°) 20.4°, 21.1° and 21.7°.
  • Embodiment 22 The crystalline form of embodiment 20 or embodiment 21, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to the curve in FIG. 3.
  • Embodiment 23 A method to form the crystalline form according to any one of embodiments 11-22, the crystalline form is formed by evaporation or evaporation crystallization, wherein the solvent used in any one of Embodiments 11-19 is selected from the group consisting of tetrahydrofuran (THF), acetonitrile (ACN), methyl tert-butyl ether (MTBE), the solvent used in any one of Embodiments 29-22 is selected from the group consisting of acetone, ethyl acetate (EA), methyl ethyl ketone(MEK) and ethanol.
  • THF tetrahydrofuran
  • ACN acetonitrile
  • MTBE methyl tert-butyl ether
  • the solvent used in any one of Embodiments 29-22 is selected from the group consisting of acetone, ethyl acetate (EA), methyl ethyl ketone(MEK) and ethanol.
  • Embodiment 24 A pharmaceutical composition, comprising a pharmaceutically effective amount of the crystalline form according to any one of embodiments 11-22 and a pharmaceutically acceptable carrier.
  • Embodiment 25 A method of treating cancer in a subject in need thereof, comprising administering to the subj ect a therapeutically effective amount of the compound crystalline form of any one of embodiments 11-22 or the pharmaceutical composition of embodiment 24; or the compound crystalline form of any one of embodiments 11-22 or the pharmaceutical composition of embodiment 24, for use as a medicament for treating cancer in a subject in need thereof; or use of the compound crystalline form of any one of embodiments 11-22 or the pharmaceutical composition of embodiment 24 in the manufacture of a medicament for treating cancer in a subject in need thereof.
  • Embodiment 26 The method or use of embodiment 25, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), glioblastoma, gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, leukemia, non-Hodgkin’s lymphoma, prostate cancer, rectal cancer, malignant melanomas, alimentary/gastrointestinal tract cancer, liver cancer, skin cancer, lymphoma, malignant pleural mesothelioma (MPM), kidney cancer, muscle cancer, bone cancer, brain cancer, eye or ocular cancer, rectal cancer, colorectal cancer, cervical cancer, oral cancer, benign and malignant tumors, stomach cancer, corpus uteri, testicular cancer, renal cancer, throat cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma
  • Embodiment 27 A method of inhibiting TEAD1, 2, 3, and/or 4 in a subject or in a sample, comprising administering to the subject a therapeutically effective amount of the compound crystalline form of any one of embodiments 11-22 or the pharmaceutical composition of embodiment 24, or the compound crystalline form of any one of embodiments 11-22 or the pharmaceutical composition of embodiment 24, for use as a medicament for inhibiting TEAD1, 2, 3, and/or 4 in a subject or in a sample; or use of the compound crystalline form of any one of embodiments 11-22 or the pharmaceutical composition of embodiment 24 in the manufacture of a medicament for inhibiting TEAD1, 2, 3, and/or 4 in a subject or in a sample, preferably, TEAD1 and 3 are inhibited selectively over TEAD2 and 4.
  • Embodiment 28 A compound represented by the formula of compound 6 or 7, formula 7.
  • references to “the method” includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure.
  • the term “about” will be understood by persons of ordinary skill in the art. Whether the term “about” is used explicitly or not, every quantity given herein refers to the actual given value, and it is also meant to refer to the approximation to such given value that would be reasonably inferred based on the ordinary skill in the art. Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se.
  • crystalline refers to a solid form of Compound I, wherein there exists long- range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern. If the XRPD shows sharp intensity peaks in the XRPD then the compound is crystalline.
  • a solid form of Compound I that is “crystalline” is a solid that is completely crystalline or partially crystalline, and encompasses solids that are at least 80% crystalline, 85% crystalline, 90% crystalline, 95% crystalline, and 99% crystalline, by weight. Crystalline solids are ordered arrangements of molecules that possess distinguishable crystal lattice or unit cell, and consequently have definable long range ordering.
  • substantially crystalline refers to a solid form of Compound I that is at least 80% crystalline.
  • substantially crystalline refers to a solid form that is at least 90% crystalline.
  • chemical purity refers to extent to which the disclosed form is free from materials having different chemical structures.
  • Chemical purity of the compound in the disclosed crystal forms means the weight of the compound divided by the sum of the weight of the compound plus materials/impurities having different chemical structures multiplied by 100%, i.e., percent by weight.
  • the compound in the disclosed crystalline forms has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.
  • hydrate refers to a crystalline Compound I where a stoichiometric or non- stoichiometric amount of water is incorporated into the crystal structure.
  • a hydrate is a solvate wherein the solvent incorporated into the crystal structure is water.
  • anhydrous when used with respect to a compound means substantially no solvent incorporated into the crystal structure, e.g., less than 0.1% by weight as determined by Karl Fisher analysis.
  • a compound that is anhydrous is referred to herein as an “anhydrate”.
  • amorphous means a solid that is present in a non-crystalline state or form.
  • Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering.
  • Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
  • (trifluoromethyl)styryl)pyrrolidin-l-yl)prop-2-en-l-one is present as a single crystal or a plurality of crystals, in which each crystal has the same crystalline form (z.e., crystalline form I or II).
  • crystal form is defined as a specified percentage of one particular single crystalline form of the compound, the remainder is made up of amorphous form and/or crystalline forms other than the one or more particular forms that are specified.
  • the crystalline form is at least 60% a single crystalline form, at least 70% a single crystalline form, at least 80% a single crystalline form, at least 90% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal forms present plus the weight of amorphous form present multiplied by 100%.
  • the 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation. Therefore, unless otherwise defined, the XRPD patterns and/or the 2-theta peak values recited herein are not to be construed as absolute and can vary by ⁇ 0.2 degrees.
  • the 2-theta values provided herein were obtained using Cu, k- Alpha radiation.
  • Temperature values e.g., for DSC peak temperatures and DSC onset temperatures herein may vary slightly from one instrument to another and also depending on variations in sample preparation, the rate of temperature increases over the course of the experiment, batch to batch variation of the material, and other environmental factors. Therefore, unless otherwise defined, temperature values recited herein are not to be construed as absolute and can vary by ⁇ 5 degrees.
  • “Substantially the same XRPD pattern” or “an X- ray powder diffraction pattern substantially similar to” a defined figure means that for comparison purposes, at least 90% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in 2-theta peak positions from those shown is allowed, such as ⁇ 0.2 degrees. It should be understood that when the expression “characterized by X-ray powder diffraction peaks at 29 angles ( ⁇ 0.2°)” followed by a list of 2-theta peak positions that the ⁇ 0.2 degrees applies to each and every one of the peak positions listed.
  • treatment is used interchangeably herein with the term “therapeutic method” and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions, disease or disorder, and 2) and prophylactic/ preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disease or disorder as well as those who may ultimately acquire the disorder (i.e. , those needing preventive measures).
  • Treating” or “treatment” of any condition or disorder refers, in some or any embodiments, to ameliorating a condition or disorder that exists in a subject, including prophylactically.
  • “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject.
  • “treating” or “treatment” includes modulating the condition or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • “treating” or “treatment” includes delaying the onset of the condition or disorder.
  • “treating” or “treatment” includes the reduction or elimination of either the condition (e.g.
  • “treating” or “treatment” includes administering a compound described herein prophylactically.
  • “Treating” or “treatment” of a disease includes: (1) inhibiting the disease, i.e. , arresting (i.e. , stabilizing) or reducing the development of the disease or its clinical symptoms; or (2) relieving the disease, i.e. , causing regression of the disease or its clinical symptoms.
  • subject refers to any individual or patient to which the subject methods are performed. Generally, the subject is human, although as will be appreciated by those in the art, the subject may be an animal.
  • terapéuticaally effective amount refers to the amount of a subject compound or composition that will elicit the biological or medical response in a tissue, system, animal, individual, or human that is being sought by administering said compound.
  • pharmaceutical compositions comprising compound crystalline forms disclosed herein.
  • pharmaceutically acceptable carrier refers to a non-toxic carrier that may be administered to a patient, together with a compound of this disclosure, and which does not destroy the pharmacological activity thereof.
  • the compound crystalline forms of this disclosure may be employed in a conventional manner for controlling the disease described herein, including, but not limited to, cancer. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques.
  • the compounds of this disclosure may be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from cancer in a pharmaceutically acceptable manner and in an amount effective to treat cancer.
  • the compound crystalline forms of this disclosure may be used in compositions and methods for treating or protecting individuals against the diseases described herein, including but not limited to cancer, over extended periods of time.
  • the compound crystalline forms may be employed in such compositions either alone or together with other compounds of this disclosure in a manner consistent with the conventional utilization of such compounds in pharmaceutical compositions.
  • a compound crystalline form of this disclosure may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against the diseases described herein, including, but not limited to, cancer.
  • the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a described compound crystalline form may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present disclosure provides a single unit dosage form comprising a described compound crystalline form, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • Two or more agents are typically considered to be administered “in combination” when a patient or individual is simultaneously exposed to both agents.
  • two or more agents are considered to be administered “in combination” when a patient or individual simultaneously shows therapeutically relevant levels of the agents in a particular target tissue or sample (e.g.
  • compositions according to this disclosure comprise a combination of a compound crystalline form described herein and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as “agents appropriate for the disease, or condition, being treated.”
  • compositions and methods of this disclosure may also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those, which increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and/or alter rate of excretion.
  • compositions of this disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human being.
  • a subject or patient e.g., a mammal, preferably a human being.
  • Such pharmaceutical compositions are used to ameliorate, treat or prevent any of the diseases described herein including but not limited to cancer in a subject
  • compositions comprising an active therapeutic agent, i.e., and a variety of other pharmaceutically acceptable components. See Remington's Pharmaceutical Science (15th ed. , Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application.
  • the compositions can also include, depending on the formulation desired, pharmaceutically acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
  • the diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of a described compound crystalline form , formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents for use in treating the diseases described herein, including, but not limited to cancer. While it is possible for a described compound crystalline form to be administered alone, it is preferable to administer a described compound crystalline form as a pharmaceutical formulation (composition) as described herein. Described compound crystalline forms may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • compound crystalline forms described herein are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% of active ingredient in combination with a pharmaceutically acceptable carrier. In some embodiments, 0.5% to 90% of active ingredient can be used.
  • Preparations described herein may be given orally, nasally, as by, for example, a spray, parenterally, intravaginally, intraci stemally, rectally, or topically, as by powders, ointments or drops, including buccally and sublingually. They are of course given in forms suitable for the relevant administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • compound crystalline forms described herein which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • compositions of the disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of
  • the compound crystalline forms of the disclosure can be administered in combination with one or more additional therapeutic agents.
  • the phrases “combination therapy”, “combined with” and the like refer to the use of more than one medication or treatment simultaneously to increase the response.
  • the TEAD1, 2, 3, and/or 4 inhibitor of the present disclosure might for example be used in combination with other drugs or treatment in use to treat cancer.
  • the compound crystalline form is administered prior to, simultaneously with or following the administration of the chemotherapeutic agent.
  • the present disclosure is directed to the use of compound crystalline forms of Formula I, and/or a pharmaceutically acceptable salt thereof in the treatment of any cancer indication where YAP is localized in the nucleus of the tumor cells, including, but is not limited to, lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast, and skin cancer.
  • the disclosed compound crystalline forms or pharmaceutical composition thereof can disrupt YAP interactions with TEAD1, 2, 3, and/or 4. In certain embodiments, the disclosed compound crystalline forms or pharmaceutical composition thereof can prevent YAP from binding to TEAD1, 2, 3, and/or 4. In some embodiments, the disclosed compound crystalline forms or pharmaceutical composition thereof can compete with YAP for binding to TEAD1, 2, 3, and/or 4. In some embodiments, the disclosed compound crystalline forms or pharmaceutical composition thereof can bind to TEAD1, 2, 3, and/or 4. In some embodiments, the disclosed compounds or pharmaceutical composition thereof can bind to TEAD1 and 3. In some embodiments, the disclosed compounds or pharmaceutical composition thereof can selectively bind to TEAD1 and 3 over that of the other TEAD isoforms.
  • the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the carrier, diluent, or excipient or composition thereof may be administered to a subject along with a TEAD1, 2, 3, and/or 4 inhibitor of the disclosure without causing any undesirable biological effects or interacting in an undesirable manner with the TEAD1, 2, 3, and/or 4 inhibitor of the pharmaceutical composition in which it is contained.
  • Figure 1 is the XRPD pattern of crystalline form I.
  • Figure 2 is the DSC curve of crystalline form I.
  • Figure 3 is the XRPD pattern of crystalline form II prepared by acetone.
  • N,O- dimethylhydroxylamine hydrochloride 2 (1.40 kg, 14.4 mol, 1.10 eq.) was charged into the reactor at 15 to 25°C.
  • the resulting solution was stirred for 15 hours at 15 to 25°C, and HPLC showed the reaction was completed.
  • the reaction solution was filtered and the wet cake was washed with EtOAc (6.00 L, 2.00 v/w).
  • the filtrate was concentrated to 2.00 to 3.00V, and EtOAc (15. 0 L, 5.00 v/w) was added at 15 to 25°C.
  • the organic phase was washed with HC1 aqueous solution (IN, 1.50 L, 5.00 v/w) (pH value was 3-4).
  • THF (4.5 L, 3.00v/w) was charged into a reactor (50.0L) at 15 to 25°C, and the solution was cooled to -60 to -70°C.
  • n-BuLi (5.51 L, 2.50 M, 13.8 mol, 2.50 eq.) was added dropwise into the reactor at -60 to -70°C, then l-bromo-4-(trifluoromethyl)benzene (3.10 kg, 13.8 mol, 2.50 eq.) 4 in THF solution (1.50 L, 1.00 v/w) was added dropwise into the reactor at -60 to -70°C .
  • the reaction mixture was stirred at -60 to -70°C for 1 hour.
  • EtOAc (10.5 L, 7.00 v/w) was charged into the mixture.
  • the organic phase was separated, washed with NaHCCh aqueous solution (7.50 L, 5.00 v/w) followed by NaCl aqueous solution (7.50 L, 5.00 v/w).
  • the organic phase was concentrated under the reduced pressure at 40 to 50°C.
  • Heptane (10.5 L, 7.00 v/w) was charged into the reactor and the suspension was concentrated under the reduced pressure at 40 to 50°C until the volume was 2.00 to 3.00 V, then heptane (7.50 L, 5.00 v/w) was charged into the reactor again.
  • the suspension was cooled to 0 to 10°C, and stirred for 2 hours.
  • EtOH (17.5 L, 7.00 v/w) was charged into a reactor (50.0L) at 15 to 25°C, then tert-butyl (R)- 3-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) pyrrolidine-l-carboxylate 5 (2.50 kg, 7.00 mol, 1.00 eq.) was added.
  • the suspension was cooled to 0 to 10°C, and NaBH4 (79.5 g, 2.10 mol, 0.30 eq.) was added to the reactor at 0 to 10°C.
  • the resulting mixture was stirred for 1 hour at 0 to 10°C, and HPLC showed the reaction was completed.
  • HC1 aqueous solution (1.50 L, 0.60 v/w) was added dropwise to the reactor at 0 to 10°C.
  • the suspension solution was filtered and the wet cake was washed with EtOAc (5.00 L, 2.00 v/w).
  • Water (12.5 L, 5.00 v/w) was added to the above mixture and the solution was concentrated to 5.00 to 6.00 V.
  • EtOAc (17.5 L, 7.00 v/w) was added.
  • the organic phase was separated and washed with NaCl aqueous solution (12.5 L, 5.00 v/w).
  • the organic phase was concentrated under the reduced pressure at 40 to 50°C.
  • Heptane (12.5 L, 5.00 v/w) was added into the reactor.
  • 1,4-Dioxane (17.5 L, 7.00 v/w) was charged into a reactor at 15 to 25°C, then concentrated H2SO4 (4.09 kg, 41.8 mol, 6.00 eq.) was added into 1,4-dioxane at 15 to 25°C.
  • Zc/V-Butyl (37?)- 3 -(2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)pyrrolidine-l -carboxylate 6 (2.50 kg, 6.96 mol, 1.00 eq.) was added into the reactor at 15 to 25°C.
  • the resulting suspension was stirred for 2 hours at 15 to 25°C, then heated to 95 to 105°C.
  • the reaction solution continued to stir for 3 hours at 100°C, and HPLC showed the reaction was completed.
  • the solution was cooled to 15 to 25°C, and poured into water (12.5 L, 5.00 v/w) at 15 to 25°C.
  • the solution was concentrated to 5.00 to 7.00 V, and cooled to 0 to 10°C.
  • the mixture was adjusted with NaOH aqueous solution (40% w/w) to pH around 11 to 12 at 0 to 10°C.
  • the suspension was filtered and solid was washed with C ⁇ Ch/MeOH (7.50 L, 3.00 v/w, 6/1).
  • the filtrate was added C ⁇ Ch/MeOH (17.50 L, 3.00 v/w, 6/1).
  • the organic layer was separated.
  • Acetonitrile (17.5 L, 7.00 v/w) was charged into a reactor at 10 to 20°C, then (A,E)-3-(4- (trifluoromethyl)styryl)pyrrolidine 7 (2.50 kg, 10.4 mol, 1.00 eq.) and NaHCCf (0.81 kg, 10.4 mol, 1.00 eq) were added subsequently at 10 to 20°C.
  • the suspension was cooled to 0 to 10°C, and prop-2-enoyl chloride (0.94 kg, 11.2 mol, 1.08 eq.) was added dropwise into the reactor at 0 to 10°C.
  • the mixture was stirred for 3 hours at 0 to 10°C, and HPLC showed the reaction was completed.
  • the solution was filtered and the wet cake was washed with EtOAc (5.00 L, 2.00 v/w). The filtrate was concentrated to 1.00 to 2.00 V, then EtOAc (12.5 L, 5.00 v/w) was added.
  • the organic solution was washed with NaHCOs aqueous solution (7.50 L, 3.00 v/w). The organic phase was concentrated to 1.00 to 2.00 V, then MTBE (12.5 L, 5.00 v/w) was added. The solution was concentrated to 1.00 to 2.00 V, and another portion of MTBE (12.5 L, 5.00 v/w) was added. The solution was concentrated to 2.00 to 3.00 V, and cooled to -10 to 0°C.
  • the measured XRPD pattern is shown in Figure 1, and its DSC curve is shown in Figure 2.
  • the crystalline form prepared in Example 1 named Crystalline form I, which is characterized by X- ray powder diffraction peaks at 29 angles ( ⁇ 0.2°) 20.4°, 21.1°, 21.7°, 15.2°, 23.0°, 13.6°, 14.0°, 16.5° and 17.0°.
  • the start and end of melting point of the product is measured three times and shown in Table 1, and the peaks of the XRPD pattern are shown in Table 2.
  • the racemic product was further separated by SFC (Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH 3 -MeOH)-HPLC, Mobile Phase B: IPA- HPLC; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 21 min; Wave Length: 220/254 nm; RTl(min): 14.491 (first isomer); Sample Solvent: EtOH-HPLC; Injection Volume: 0.4 mL; Number Of Runs: 2) to afford one stereoisomer Compound I, assigned as R (second eluting isomer), (R, £)-l-(3-(4-(trifluoromethyl)styryl)pyrrolidin-l-yl)prop-2-en-l-one as a white solid (3.8 mg).
  • TEADl-Luc MCF7 average IC50 value ⁇ 10 nM
  • TEADl-Luc MCF7 maximum inhibition rate >75%.
  • the potency and efficacy of Compound I in inhibiting cell proliferation and viability were assessed in multiple cell lines.
  • the average IC50 value measured in NCI-226 cells was less than 100 nM, and the maximum average inhibition rate was 50%-75%.
  • the average IC50 value measured in H2052 cells was less than 100 nM, and the maximum average inhibition rate was 50%-75%.
  • the inhibition percentages of 3pm Compound I against TEAD1, TEAD2, TEAD3, and TEAD4 were 94%, 57%, 98%, and 52% respectively.
  • Crystalline form II is characterized by X-ray powder diffraction peaks at 29 angles ( ⁇ 0.2°) 17.3°, 18.3°, 20.4°, 21.1° and 21.7°. Crystalline form I and Crystalline form II had different XRPD pattern compared to the Compound I prepared in Example 2. Table 3 Characterization of the products prepared by evaporation crystallization method

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Abstract

L'invention concerne un procédé de préparation du composé (R, £')-l-(3-(4-(trifluorométhyl)styryl)pyrrolidin-l-yl)prop-2-én-1-one et des formes cristallines de celui-ci.
PCT/US2024/020722 2024-03-20 2024-03-20 Préparation d'un composé et de formes cristallines de celui-ci Pending WO2025198588A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0524846A1 (fr) * 1991-06-27 1993-01-27 Synthelabo Dérivés de 2-(pipéridin-1-y1) éthanol, leur préparation et leur application en thérapeutique
US5824690A (en) * 1993-05-06 1998-10-20 Hoechst Marion Roussel Inc. Substituted pyrrolidin-3-yl-alkyl-piperidines
US20060160788A1 (en) * 2005-01-18 2006-07-20 Synese Jolidon Substituted phenyl methanone derivatives
US20110237791A1 (en) * 2009-12-04 2011-09-29 Taisho Pharmaceutical Co., Ltd 2-pyridone compounds
WO2020081572A1 (fr) * 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
WO2022006548A1 (fr) * 2020-07-02 2022-01-06 Bridgene Biosciences, Inc. Inhibiteurs d'oncoprotéines yap/taz-tead, leur synthèse et leur utilisation
WO2024059317A1 (fr) * 2022-09-15 2024-03-21 Bridgene Biosciences, Inc. Inhibiteurs d'oncoprotéines yap/taz-tead

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0524846A1 (fr) * 1991-06-27 1993-01-27 Synthelabo Dérivés de 2-(pipéridin-1-y1) éthanol, leur préparation et leur application en thérapeutique
US5824690A (en) * 1993-05-06 1998-10-20 Hoechst Marion Roussel Inc. Substituted pyrrolidin-3-yl-alkyl-piperidines
US20060160788A1 (en) * 2005-01-18 2006-07-20 Synese Jolidon Substituted phenyl methanone derivatives
US20110237791A1 (en) * 2009-12-04 2011-09-29 Taisho Pharmaceutical Co., Ltd 2-pyridone compounds
WO2020081572A1 (fr) * 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
WO2022006548A1 (fr) * 2020-07-02 2022-01-06 Bridgene Biosciences, Inc. Inhibiteurs d'oncoprotéines yap/taz-tead, leur synthèse et leur utilisation
WO2024059317A1 (fr) * 2022-09-15 2024-03-21 Bridgene Biosciences, Inc. Inhibiteurs d'oncoprotéines yap/taz-tead

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